<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03020615</url>
  </required_header>
  <id_info>
    <org_study_id>HUGKISS</org_study_id>
    <secondary_id>R34HL127162</secondary_id>
    <nct_id>NCT03020615</nct_id>
  </id_info>
  <brief_title>Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies</brief_title>
  <official_title>Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Jude Children's Research Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>St. Jude Children's Research Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a pilot study, single-blind, randomized, multicenter, therapeutic clinical trial&#xD;
      designed to evaluate the feasibility of enrolling infants and toddlers (9 months to 36&#xD;
      months) with sickle cell anemia (SCA; HbSS or HbSβ^0thalassemia), regardless of disease&#xD;
      severity, to a therapeutic trial. A prior clinical trial at St. Jude Children's Research&#xD;
      Hospital (SJCRH) (BABYHUG, NCT01783990) demonstrated that a fixed dose (20 mg/kg/day) of&#xD;
      hydroxyurea was safe and effective in decreasing SCA-related complications in very young&#xD;
      children (9-18 months), and largely due to these findings, hydroxyurea is recommended to be&#xD;
      offered to all children (≥9 months old) with SCA, independent of disease severity.&#xD;
      Nevertheless, children in the treatment arm of BABYHUG continued to experience vaso-occlusive&#xD;
      symptoms and to incur organ damage. In clinical trials of older children with SCA,&#xD;
      intensification of hydroxyurea to a maximum tolerated dosage (MTD), defined by mild to&#xD;
      moderate myelosuppression, may be associated with improved laboratory parameters compared to&#xD;
      fixed lower-dosing, but the clinical benefits gained from dose intensification have not been&#xD;
      described. Therefore, in this trial, children in the standard treatment arm will receive a&#xD;
      fixed dose of hydroxyurea (20 mg/kg/day), and participants in the experimental arm will&#xD;
      receive hydroxyurea intensified to MTD, defined by a goal absolute neutrophil count (ANC) of&#xD;
      1500-3000 cells/µL. This trial aims to establish a multicenter infrastructure that will&#xD;
      identify, enroll and randomize very young children (9-36 months) to receive fixed dose versus&#xD;
      intensified-dose hydroxyurea in a single blinded manner, and to obtain prospective pilot data&#xD;
      comparing the clinical and laboratory outcomes between the treatment arms to facilitate&#xD;
      design of a definitive phase III trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All participants will initially receive hydroxyurea at a dose of ~20 mg/kg/day in an open&#xD;
      label fashion for eight weeks (± 2 weeks) prior to randomization. Participants will receive&#xD;
      monthly medical evaluations (every 4 ± 2 weeks) where they will have height and weight&#xD;
      measurements, medical history, physical examination, and medication adherence assessments.&#xD;
      During these monthly visits complete blood counts with absolute reticulocyte count will be&#xD;
      monitored. Hemoglobin electrophoresis, complete serum chemistries, urinalysis, lactate&#xD;
      dehydrogenase and quality of life measurements will be obtained every 20 (±2) weeks.&#xD;
      Transcranial Doppler (TCD) ultrasound velocities will be obtained at study entry (in&#xD;
      participants ≥2 years of age) and study exit. Participants randomized to receive hydroxyurea&#xD;
      at MTD will have their dose increased by 5 mg/kg/day every 8 weeks, in the absence of&#xD;
      toxicity, until a goal ANC of 1500-3000 cells/µL is achieved, up to a maximum of 35&#xD;
      mg/kg/day.&#xD;
&#xD;
      Both groups will receive their assigned treatment for 48 weeks (± 3 weeks). Participants will&#xD;
      be in the study for a total of 56 weeks (± 3 weeks) and have 14 clinic visits to the St. Jude&#xD;
      outpatient Hematology Clinic during that time. After the 56 weeks, participants will be&#xD;
      followed for an additional 30 days for side effects and will then be taken off study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 12, 2017</start_date>
  <completion_date type="Actual">June 8, 2020</completion_date>
  <primary_completion_date type="Actual">June 8, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Patients Enrolled.</measure>
    <time_frame>at baseline</time_frame>
    <description>A count of the number of patients enrolled will be provided.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Patients Randomized</measure>
    <time_frame>Eight weeks (± 2 weeks) after study enrollment</time_frame>
    <description>A count of the number of patients randomized will be provided.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Randomized Patients With ≥80% Chronic Medication Compliance</measure>
    <time_frame>At completion of therapy, up to 56 weeks after study enrollment</time_frame>
    <description>Chronic medication compliance is defined based on medication possession ratio (MPR), a measure of the percentage of time that a patient has access to medication. Each participant's MPR is calculated as [(days medication in family's possession/days prescribed medication) * 100].</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit</measure>
    <time_frame>At baseline and at completion of the protocol, up to 56 weeks after study enrollment</time_frame>
    <description>The number of patients who have successfully provided %HbF at baseline and study exit will be provided.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Frequency by Reason Given for Refusal for Study Participation</measure>
    <time_frame>Once, at enrollment</time_frame>
    <description>Descriptive statistics of count and frequency will be provided for participants who were approached but refused to be enrolled on the study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With Hospitalizations by Arm</measure>
    <time_frame>From baseline through completion of therapy, up to 56 weeks</time_frame>
    <description>The number of patients with hospitalizations will be provided by arm. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative Number of Hospitalizations by Arms</measure>
    <time_frame>From baseline through completion of therapy, up to 56 weeks</time_frame>
    <description>The total number of hospitalization events will be provided by arms. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Hemoglobin (g/dL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in Hemoglobin (g/dL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Fetal Hemoglobin (%)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in Fetal Hemoglobin (%)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Mean Corpuscular Volume (fL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in Mean Corpuscular Volume (fL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Platelet Count (*10^3 Platelets/µL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in Platelet Count (*10^3 Platelets/µL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Bilirubin (mg/dL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in Bilirubin (mg/dL)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Lactate Dehydrogenase (Units/L)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in Lactate Dehydrogenase (Units/L)</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Normal TCD velocities will be defined as TCD velocities &lt;170 cm/s.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Who Undergo Surgery</measure>
    <time_frame>From start of therapy through completion of therapy, up to 56 weeks</time_frame>
    <description>Any operative procedure will be included.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Who Undergo Transfusion</measure>
    <time_frame>From start of therapy through completion of therapy, up to 56 weeks</time_frame>
    <description>Transfusion will be defined as the provision of red blood cells to correct anemia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With Toxicities Related to Hydroxyurea Dosing</measure>
    <time_frame>From start of therapy through completion of therapy, up to 56 weeks</time_frame>
    <description>Number of patients with toxicities to include: neutropenia (ANC &lt;1000*/µL), reticulocytopenia (ARC &lt;80*10^3/µL and concomitant anemia (hemoglobin &lt;6 g/dL), and thrombocytopenia (platelets &lt;100*10^3/µL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Toxicities Related to Hydroxyurea Dosing</measure>
    <time_frame>From start of therapy through completion of therapy, up to 56 weeks</time_frame>
    <description>Number of toxicities will be reported to include: neutropenia (ANC &lt;1000*/µL), reticulocytopenia (ARC &lt;80*10^3/µL and concomitant anemia (hemoglobin &lt;6 g/dL), and thrombocytopenia (platelets &lt;100*10^3/µL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Pain and Hurt Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Pain Impact Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Pain Management Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Worry I Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Worry II Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Emotions Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Treatment Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Communication I Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Communication II Score</measure>
    <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
    <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">58</enrollment>
  <condition>Sickle Cell Anemia</condition>
  <arm_group>
    <arm_group_label>Stable Dosing</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intensive Dosing</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxyurea</intervention_name>
    <description>Given orally once daily.</description>
    <arm_group_label>Intensive Dosing</arm_group_label>
    <arm_group_label>Stable Dosing</arm_group_label>
    <other_name>HU</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children with HbSS or sickle hemoglobin (HbS)/β^0thalassemia&#xD;
&#xD;
          -  ≥9 to ≤ 36 months of age at study initiation&#xD;
&#xD;
          -  Enrollment will occur irrespective of clinical severity&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Permanent:&#xD;
&#xD;
          -  Receiving chronic red blood cell transfusion therapy.&#xD;
&#xD;
          -  Condition or chronic illness, which in the opinion of the PI makes participation&#xD;
             unsafe.&#xD;
&#xD;
        Transient (participants may be re-evaluated after ≥14 days):&#xD;
&#xD;
          -  Recent (&lt;30 days) participation in another clinical intervention trial utilizing an&#xD;
             investigational new drug/investigational device exemption (IND/IDE) agent.&#xD;
&#xD;
          -  Erythrocyte transfusion in the past 2 months.&#xD;
&#xD;
          -  Laboratory Assessments:&#xD;
&#xD;
               -  Hemoglobin &lt;6.0 g/dL&#xD;
&#xD;
               -  Absolute reticulocyte count &lt;80 * 10^3/µL if hemoglobin &lt;9.0 mg/dL&#xD;
&#xD;
               -  Absolute neutrophil count &lt;1.5 * 10^3/µL&#xD;
&#xD;
               -  Platelet count &lt;100 * 10^3/µL&#xD;
&#xD;
               -  Serum creatinine &gt; twice the upper limit of normal for age&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) &gt; twice the upper limit of normal&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>9 Months</minimum_age>
    <maximum_age>36 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jeremie Estepp, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Jude Children's Research Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Emory University/Children's Health Care of Atlanta</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Mississippi Medical Center</name>
      <address>
        <city>Jackson</city>
        <state>Mississippi</state>
        <zip>39216</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Jude Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center at Dallas</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390-9063</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.stjude.org</url>
    <description>St. Jude Children's Research Hospital</description>
  </link>
  <link>
    <url>http://www.stjude.org/protocols</url>
    <description>Clinical Trials Open at St. Jude</description>
  </link>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>January 11, 2017</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 13, 2017</study_first_posted>
  <results_first_submitted>May 6, 2021</results_first_submitted>
  <results_first_submitted_qc>June 3, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">June 25, 2021</results_first_posted>
  <last_update_submitted>June 3, 2021</last_update_submitted>
  <last_update_submitted_qc>June 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 25, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Sickle cell</keyword>
  <keyword>Hydroxyurea</keyword>
  <keyword>Infants</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxyurea</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 9, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/15/NCT03020615/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study planned to enroll up to 65 children with sickle cell anemia (SCA) to get 50 randomized in a 27-month period. All eligible participants who consented were enrolled on the study. The duration of the study is based on sample size of 50 patients randomized and/or 27-month period, whichever comes first. Actual recruitment occurred 5/3/2017 to 6/3/2019 and 58 subjects were enrolled to yield 51 randomized at 4 clinical centers.</recruitment_details>
      <pre_assignment_details>Participants without toxicity or with toxicity which requires discontinuation of hydroxyurea (HU) but resolved and participant continuing HU during those eight weeks (±2 weeks), were randomized to receive standard or intensive therapy based on a block randomization (block size of 4 used in each stratum) stratified by clinical center and by baseline age of the participant (9 to &lt;24 months and 24 to 36 months) because of the natural physiologic decline of HbF with increasing age.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Stable Dosing</title>
          <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
        </group>
        <group group_id="P2">
          <title>Intensive Dosing</title>
          <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
        </group>
        <group group_id="P3">
          <title>Non-Randomized</title>
          <description>Participants who came off study prior to randomization</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
                <participants group_id="P2" count="25"/>
                <participants group_id="P3" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="23"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="7"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Parent/guardian/patient choice</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Screen failure</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Stable Dosing</title>
          <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.&#xD;
Hydroxyurea: Given orally once daily.</description>
        </group>
        <group group_id="B2">
          <title>Intensive Dosing</title>
          <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.&#xD;
Hydroxyurea: Given orally once daily.</description>
        </group>
        <group group_id="B3">
          <title>Non-Randomized Patients</title>
          <description>Patients who came off study prior to randomization</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="26"/>
            <count group_id="B2" value="25"/>
            <count group_id="B3" value="7"/>
            <count group_id="B4" value="58"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9" lower_limit="9" upper_limit="36"/>
                    <measurement group_id="B2" value="10" lower_limit="9" upper_limit="32"/>
                    <measurement group_id="B3" value="18" lower_limit="10" upper_limit="23"/>
                    <measurement group_id="B4" value="10" lower_limit="9" upper_limit="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>months</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12.9" spread="7.9"/>
                    <measurement group_id="B2" value="12.8" spread="6.2"/>
                    <measurement group_id="B3" value="18.1" spread="4.7"/>
                    <measurement group_id="B4" value="13.5" spread="7.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Black</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Spanish speaking Non Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Spanish speaking Non Hispanic (Unknown)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <title>St. Jude Children's Research Hospital</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="33"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Children's Healthcare of Atlanta</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>University of Mississippi Medical Center</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>University of Texas Southwestern Medical Center</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Patients Enrolled.</title>
        <description>A count of the number of patients enrolled will be provided.</description>
        <time_frame>at baseline</time_frame>
        <population>58 subjects enrolled on study. Of those, n=7 came off study prior to randomization (N=2 came off study due to PI discretion, n=4 came off study due to Parent/guardian/patient choice, and n=1 was a screen failure (HBG)). The remaining n=51 were randomized.</population>
        <group_list>
          <group group_id="O1">
            <title>All Participants</title>
            <description>All Participants enrolled on study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Enrolled.</title>
          <description>A count of the number of patients enrolled will be provided.</description>
          <population>58 subjects enrolled on study. Of those, n=7 came off study prior to randomization (N=2 came off study due to PI discretion, n=4 came off study due to Parent/guardian/patient choice, and n=1 was a screen failure (HBG)). The remaining n=51 were randomized.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="58"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Patients Randomized</title>
        <description>A count of the number of patients randomized will be provided.</description>
        <time_frame>Eight weeks (± 2 weeks) after study enrollment</time_frame>
        <population>Fifty-one were randomized out of the 58 enrolled.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Randomized</title>
          <description>A count of the number of patients randomized will be provided.</description>
          <population>Fifty-one were randomized out of the 58 enrolled.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26"/>
                    <measurement group_id="O2" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Randomized Patients With ≥80% Chronic Medication Compliance</title>
        <description>Chronic medication compliance is defined based on medication possession ratio (MPR), a measure of the percentage of time that a patient has access to medication. Each participant's MPR is calculated as [(days medication in family's possession/days prescribed medication) * 100].</description>
        <time_frame>At completion of therapy, up to 56 weeks after study enrollment</time_frame>
        <population>There were 51 subjects randomized to treatment of which 42 completed the protocol therapy. MPR was calculated on the full study period. The n=9 patients that were withdrawn were counted as &lt;80% chronic medical compliance. Of the n=42 patients that completed protocol treatment, n=41 had ≥80% chronic medication compliance.</population>
        <group_list>
          <group group_id="O1">
            <title>Randomized Participants</title>
            <description>Number of participants randomized.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Randomized Patients With ≥80% Chronic Medication Compliance</title>
          <description>Chronic medication compliance is defined based on medication possession ratio (MPR), a measure of the percentage of time that a patient has access to medication. Each participant's MPR is calculated as [(days medication in family's possession/days prescribed medication) * 100].</description>
          <population>There were 51 subjects randomized to treatment of which 42 completed the protocol therapy. MPR was calculated on the full study period. The n=9 patients that were withdrawn were counted as &lt;80% chronic medical compliance. Of the n=42 patients that completed protocol treatment, n=41 had ≥80% chronic medication compliance.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit</title>
        <description>The number of patients who have successfully provided %HbF at baseline and study exit will be provided.</description>
        <time_frame>At baseline and at completion of the protocol, up to 56 weeks after study enrollment</time_frame>
        <population>N=42 patients completed the protocol therapy and had labs collected at exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit</title>
          <description>The number of patients who have successfully provided %HbF at baseline and study exit will be provided.</description>
          <population>N=42 patients completed the protocol therapy and had labs collected at exit visit.</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Frequency by Reason Given for Refusal for Study Participation</title>
        <description>Descriptive statistics of count and frequency will be provided for participants who were approached but refused to be enrolled on the study.</description>
        <time_frame>Once, at enrollment</time_frame>
        <population>n=154 subjects declined to participate in HUGKISS and provided the following reasons for declining to participate.</population>
        <group_list>
          <group group_id="O1">
            <title>Subjects Approached Who Declined Participation</title>
            <description>Subjects who declined to participate in HUGKISS and provided reasons for declining</description>
          </group>
        </group_list>
        <measure>
          <title>Frequency by Reason Given for Refusal for Study Participation</title>
          <description>Descriptive statistics of count and frequency will be provided for participants who were approached but refused to be enrolled on the study.</description>
          <population>n=154 subjects declined to participate in HUGKISS and provided the following reasons for declining to participate.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="154"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Does not meet eligibility criteria</title>
                  <measurement_list>
                    <measurement group_id="O1" value="33"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Family wants more time to consider participation</title>
                  <measurement_list>
                    <measurement group_id="O1" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Child on hydroxyurea (HU)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown reason</title>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not interested in HU</title>
                  <measurement_list>
                    <measurement group_id="O1" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Poor clinic visit compliance</title>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not interested in research</title>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Logistics - travel distance to site, frequency of appointments</title>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With Hospitalizations by Arm</title>
        <description>The number of patients with hospitalizations will be provided by arm. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.</description>
        <time_frame>From baseline through completion of therapy, up to 56 weeks</time_frame>
        <population>The n=51 subjects that were randomized to treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Hospitalizations by Arm</title>
          <description>The number of patients with hospitalizations will be provided by arm. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.</description>
          <population>The n=51 subjects that were randomized to treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cumulative Number of Hospitalizations by Arms</title>
        <description>The total number of hospitalization events will be provided by arms. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.</description>
        <time_frame>From baseline through completion of therapy, up to 56 weeks</time_frame>
        <population>The n=51 subjects that were randomized to treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Cumulative Number of Hospitalizations by Arms</title>
          <description>The total number of hospitalization events will be provided by arms. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.</description>
          <population>The n=51 subjects that were randomized to treatment.</population>
          <units>hospitalizations</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Hemoglobin (g/dL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard arm.) N=42 subjects completed protocol therapy (n=23 to the intensive arm and n=19 to the standard arm.) All n=42 that completed the study had HGB measurements at both baseline and at exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Hemoglobin (g/dL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard arm.) N=42 subjects completed protocol therapy (n=23 to the intensive arm and n=19 to the standard arm.) All n=42 that completed the study had HGB measurements at both baseline and at exit visit.</population>
          <units>g/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.42" spread="0.84"/>
                    <measurement group_id="O2" value="1.15" spread="1.21"/>
                    <measurement group_id="O3" value="0.82" spread="1.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.033</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Hemoglobin (g/dL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard arm.) N=42 subjects completed protocol therapy (n=23 to the intensive arm and n=19 to the standard arm.) All n=42 that completed the study had hemoglobin (HGB) measurements at both baseline and at exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Hemoglobin (g/dL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard arm.) N=42 subjects completed protocol therapy (n=23 to the intensive arm and n=19 to the standard arm.) All n=42 that completed the study had hemoglobin (HGB) measurements at both baseline and at exit visit.</population>
          <units>g/dL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.40" lower_limit="-1.30" upper_limit="1.50"/>
                    <measurement group_id="O2" value="1.20" lower_limit="-1.90" upper_limit="3.35"/>
                    <measurement group_id="O3" value="1.05" lower_limit="-1.90" upper_limit="3.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Fetal Hemoglobin (%)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had Hemoglobin F (HbF) measurements at both baseline and at exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Fetal Hemoglobin (%)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had Hemoglobin F (HbF) measurements at both baseline and at exit visit.</population>
          <units>percentage of Hemoglobin F</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.97" spread="18.97"/>
                    <measurement group_id="O2" value="7.67" spread="12.09"/>
                    <measurement group_id="O3" value="1.05" spread="17.06"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Fetal Hemoglobin (%)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had Hemoglobin F (Hbf) measurements at both baseline and at exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Fetal Hemoglobin (%)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had Hemoglobin F (Hbf) measurements at both baseline and at exit visit.</population>
          <units>percentage of Hemoglobin F</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.20" lower_limit="-60.70" upper_limit="4.80"/>
                    <measurement group_id="O2" value="8.00" lower_limit="-23.50" upper_limit="24.70"/>
                    <measurement group_id="O3" value="1.70" lower_limit="-60.70" upper_limit="24.70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0005</p_value>
            <method>Exact Wilcoxon (Mann-Whitley), two-sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Mean Corpuscular Volume (fL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had mean corpuscular volume (MCV) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Mean Corpuscular Volume (fL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had mean corpuscular volume (MCV) measurements at both baseline and exit visits.</population>
          <units>fL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.87" spread="6.17"/>
                    <measurement group_id="O2" value="11.36" spread="4.84"/>
                    <measurement group_id="O3" value="8.88" spread="6.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Mean Corpuscular Volume (fL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had mean corpuscular volume (MCV) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Mean Corpuscular Volume (fL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had mean corpuscular volume (MCV) measurements at both baseline and exit visits.</population>
          <units>fL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.00" lower_limit="-7.10" upper_limit="16.00"/>
                    <measurement group_id="O2" value="9.60" lower_limit="5.40" upper_limit="20.10"/>
                    <measurement group_id="O3" value="8.70" lower_limit="-7.10" upper_limit="20.10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.011</p_value>
            <method>Exact Wilcoxon (Mann-Whitney), two-sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the n=42 subjects that completed the study had absolute reticulocyte count (ARC) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the n=42 subjects that completed the study had absolute reticulocyte count (ARC) measurements at both baseline and exit visits.</population>
          <units>*10^3 reticulocytes/µL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="22"/>
                <count group_id="O3" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-83.69" spread="65.65"/>
                    <measurement group_id="O2" value="-145.43" spread="107.10"/>
                    <measurement group_id="O3" value="-116.82" spread="94.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.030</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the n=42 subjects that completed the study had absolute reticulocyte count (ARC) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the n=42 subjects that completed the study had absolute reticulocyte count (ARC) measurements at both baseline and exit visits.</population>
          <units>*10^3 reticulocytes/µL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="22"/>
                <count group_id="O3" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-91.6" lower_limit="-202.3" upper_limit="55.1"/>
                    <measurement group_id="O2" value="-175.9" lower_limit="-300" upper_limit="109.1"/>
                    <measurement group_id="O3" value="-120.5" lower_limit="-300" upper_limit="109.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had white blood cell (WBC) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had white blood cell (WBC) measurements at both baseline and exit visits.</population>
          <units>*10^3 white blood cells/µL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.32" spread="4.78"/>
                    <measurement group_id="O2" value="-5.64" spread="5.56"/>
                    <measurement group_id="O3" value="-3.23" spread="5.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had white blood cell (WBC) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had white blood cell (WBC) measurements at both baseline and exit visits.</population>
          <units>*10^3 white blood cells/µL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.77" lower_limit="-8.07" upper_limit="12.46"/>
                    <measurement group_id="O2" value="-4.50" lower_limit="-20.35" upper_limit="4.23"/>
                    <measurement group_id="O3" value="-3.14" lower_limit="-20.35" upper_limit="12.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0009</p_value>
            <method>Exact Wilcoxon (Mann-Whitney), two-sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the 42 that completed the study had absolute neutrophil count (ANC) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the 42 that completed the study had absolute neutrophil count (ANC) measurements at both baseline and exit visits.</population>
          <units>*10^3 neutrophils/µL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.74" spread="2.53"/>
                    <measurement group_id="O2" value="-1.69" spread="2.09"/>
                    <measurement group_id="O3" value="-0.62" spread="2.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the 42 that completed the study had absolute neutrophil count (ANC) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the 42 that completed the study had absolute neutrophil count (ANC) measurements at both baseline and exit visits.</population>
          <units>*10^3 neutrophils/µL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.35" lower_limit="-2.13" upper_limit="9.30"/>
                    <measurement group_id="O2" value="-1.43" lower_limit="-8.10" upper_limit="1.49"/>
                    <measurement group_id="O3" value="-0.52" lower_limit="-8.10" upper_limit="9.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0004</p_value>
            <method>Exact Wilcoxon (Mann-Whitney), two-sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Platelet Count (*10^3 Platelets/µL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had platelet (PLT) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Platelet Count (*10^3 Platelets/µL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had platelet (PLT) measurements at both baseline and exit visits.</population>
          <units>*10^3 platelets/µL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-10.92" spread="161.90"/>
                    <measurement group_id="O2" value="-11.20" spread="145.78"/>
                    <measurement group_id="O3" value="-11.07" spread="151.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Platelet Count (*10^3 Platelets/µL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had platelet (PLT) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Platelet Count (*10^3 Platelets/µL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had platelet (PLT) measurements at both baseline and exit visits.</population>
          <units>*10^3 platelets/µL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-48" lower_limit="-241" upper_limit="407"/>
                    <measurement group_id="O2" value="-18" lower_limit="-324" upper_limit="484"/>
                    <measurement group_id="O3" value="-22" lower_limit="-324" upper_limit="484"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.75</p_value>
            <method>Exact Wilcoxon (Mann-Whitney), two-sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Bilirubin (mg/dL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=40 had bilirubin measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Bilirubin (mg/dL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=40 had bilirubin measurements at both baseline and exit visits.</population>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.24" spread="0.56"/>
                    <measurement group_id="O2" value="-0.54" spread="1.05"/>
                    <measurement group_id="O3" value="-0.21" spread="0.95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Bilirubin (mg/dL)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=40 had bilirubin measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Bilirubin (mg/dL)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=40 had bilirubin measurements at both baseline and exit visits.</population>
          <units>mg/dL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.30" lower_limit="-0.80" upper_limit="1.30"/>
                    <measurement group_id="O2" value="-0.30" lower_limit="-4.60" upper_limit="1.00"/>
                    <measurement group_id="O3" value="-0.07" lower_limit="-4.60" upper_limit="1.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0013</p_value>
            <method>Exact Wilcoxon (Mann-Whitney), two-sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Lactate Dehydrogenase (Units/L)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=41 had lactate dehydrogenase (LDH) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Lactate Dehydrogenase (Units/L)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=41 had lactate dehydrogenase (LDH) measurements at both baseline and exit visits.</population>
          <units>units/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-11.94" spread="101.99"/>
                    <measurement group_id="O2" value="-129.17" spread="181.47"/>
                    <measurement group_id="O3" value="-77.71" spread="161.25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.013</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Lactate Dehydrogenase (Units/L)</title>
        <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=41 had lactate dehydrogenase (LDH) measurements at both baseline and exit visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
          <group group_id="O3">
            <title>Overall</title>
            <description>All subjects who completed protocol therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Lactate Dehydrogenase (Units/L)</title>
          <description>Descriptive statistics of the change between baseline and completion of the study will be provided.</description>
          <population>Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=41 had lactate dehydrogenase (LDH) measurements at both baseline and exit visits.</population>
          <units>units/L</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.5" lower_limit="-189.0" upper_limit="219.0"/>
                    <measurement group_id="O2" value="-94.0" lower_limit="-477.0" upper_limit="248.0"/>
                    <measurement group_id="O3" value="-54.0" lower_limit="-477.0" upper_limit="248.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities</title>
        <description>Normal TCD velocities will be defined as TCD velocities &lt;170 cm/s.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Subjects that complete protocol therapy and have TCD ultrasound at exit visit. N=42 subjects completed protocol therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities</title>
          <description>Normal TCD velocities will be defined as TCD velocities &lt;170 cm/s.</description>
          <population>Subjects that complete protocol therapy and have TCD ultrasound at exit visit. N=42 subjects completed protocol therapy.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Who Undergo Surgery</title>
        <description>Any operative procedure will be included.</description>
        <time_frame>From start of therapy through completion of therapy, up to 56 weeks</time_frame>
        <population>Includes all randomized patients, n=51.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who Undergo Surgery</title>
          <description>Any operative procedure will be included.</description>
          <population>Includes all randomized patients, n=51.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Who Undergo Transfusion</title>
        <description>Transfusion will be defined as the provision of red blood cells to correct anemia.</description>
        <time_frame>From start of therapy through completion of therapy, up to 56 weeks</time_frame>
        <population>Includes all randomized patients, n=51.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who Undergo Transfusion</title>
          <description>Transfusion will be defined as the provision of red blood cells to correct anemia.</description>
          <population>Includes all randomized patients, n=51.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With Toxicities Related to Hydroxyurea Dosing</title>
        <description>Number of patients with toxicities to include: neutropenia (ANC &lt;1000*/µL), reticulocytopenia (ARC &lt;80*10^3/µL and concomitant anemia (hemoglobin &lt;6 g/dL), and thrombocytopenia (platelets &lt;100*10^3/µL).</description>
        <time_frame>From start of therapy through completion of therapy, up to 56 weeks</time_frame>
        <population>N=51 randomized patients (n=25 intensive arm and n=26 standard arm).</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Toxicities Related to Hydroxyurea Dosing</title>
          <description>Number of patients with toxicities to include: neutropenia (ANC &lt;1000*/µL), reticulocytopenia (ARC &lt;80*10^3/µL and concomitant anemia (hemoglobin &lt;6 g/dL), and thrombocytopenia (platelets &lt;100*10^3/µL).</description>
          <population>N=51 randomized patients (n=25 intensive arm and n=26 standard arm).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Neutropenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Reticulocytopenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Thrombocytopenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Toxicities Related to Hydroxyurea Dosing</title>
        <description>Number of toxicities will be reported to include: neutropenia (ANC &lt;1000*/µL), reticulocytopenia (ARC &lt;80*10^3/µL and concomitant anemia (hemoglobin &lt;6 g/dL), and thrombocytopenia (platelets &lt;100*10^3/µL).</description>
        <time_frame>From start of therapy through completion of therapy, up to 56 weeks</time_frame>
        <population>N=51 randomized patients (n=25 intensive arm and n=26 standard arm).</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Toxicities Related to Hydroxyurea Dosing</title>
          <description>Number of toxicities will be reported to include: neutropenia (ANC &lt;1000*/µL), reticulocytopenia (ARC &lt;80*10^3/µL and concomitant anemia (hemoglobin &lt;6 g/dL), and thrombocytopenia (platelets &lt;100*10^3/µL).</description>
          <population>N=51 randomized patients (n=25 intensive arm and n=26 standard arm).</population>
          <units>Toxicities</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Neutropenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Reticulocytopenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Thrombocytopenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Pain and Hurt Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Pain and Hurt Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.1" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Pain Impact Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Pain Impact Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Pain Management Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Pain Management Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-25" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Worry I Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Worry I Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Worry II Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Worry II Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Emotions Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Emotions Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Treatment Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Treatment Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.5" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Communication I Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Communication I Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Communication II Score</title>
        <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
        <time_frame>From baseline at study entry to completion of therapy, up to 56 weeks</time_frame>
        <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Stable Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
          </group>
          <group group_id="O2">
            <title>Intensive Dosing</title>
            <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Communication II Score</title>
          <description>Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.</description>
          <population>Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.3" spread="NA">Only 1 patient had data at both baseline and exit visit.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Subjects in both treatment arms will be followed for a maximum of 56 weeks regardless of the actual number of study visits. Upon completion of the 56 weeks, patients will be followed for an additional 30 days for toxicities and will then be taken off study.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Stable Dosing - Post Randomization</title>
          <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.</description>
        </group>
        <group group_id="E2">
          <title>Intensive Dosing - Post Randomization</title>
          <description>In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.</description>
        </group>
        <group group_id="E3">
          <title>All Participants - Pre Randomization</title>
          <description>All participants enrolled</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Immune system disorders,- Other specify</sub_title>
                <description>Fever in pediatric patient</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <description>Norovirus/rotovirus diarrhea</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Other (Specify_)</sub_title>
                <description>&quot;breath holding spell&quot;</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Surgical and medical procedures - Other specify</sub_title>
                <description>Removal of foreign object</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Jeremie Estepp, MD</name_or_title>
      <organization>St. Jude Children's Research Hospital</organization>
      <phone>(901) 595-5703</phone>
      <email>jeremie.estepp@stjude.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03020615
org study id: HUGKISS
secondary id: R34HL127162
nct id: NCT03020615
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a pilot study, single-blind, randomized, multicenter, therapeutic clinical trial
      designed to evaluate the feasibility of enrolling infants and toddlers (9 months to 36
      months) with sickle cell anemia (SCA; HbSS or HbSβ^0thalassemia), regardless of disease
      severity, to a therapeutic trial. A prior clinical trial at St. Jude Children's Research
      Hospital (SJCRH) (BABYHUG, NCT01783990) demonstrated that a fixed dose (20 mg/kg/day) of
      hydroxyurea was safe and effective in decreasing SCA-related complications in very young
      children (9-18 months), and largely due to these findings, hydroxyurea is recommended to be
      offered to all children (≥9 months old) with SCA, independent of disease severity.
      Nevertheless, children in the treatment arm of BABYHUG continued to experience vaso-occlusive
      symptoms and to incur organ damage. In clinical trials of older children with SCA,
      intensification of hydroxyurea to a maximum tolerated dosage (MTD), defined by mild to
      moderate myelosuppression, may be associated with improved laboratory parameters compared to
      fixed lower-dosing, but the clinical benefits gained from dose intensification have not been
      described. Therefore, in this trial, children in the standard treatment arm will receive a
      fixed dose of hydroxyurea (20 mg/kg/day), and participants in the experimental arm will
      receive hydroxyurea intensified to MTD, defined by a goal absolute neutrophil count (ANC) of
      1500-3000 cells/µL. This trial aims to establish a multicenter infrastructure that will
      identify, enroll and randomize very young children (9-36 months) to receive fixed dose versus
      intensified-dose hydroxyurea in a single blinded manner, and to obtain prospective pilot data
      comparing the clinical and laboratory outcomes between the treatment arms to facilitate
      design of a definitive phase III trial.
All participants will initially receive hydroxyurea at a dose of ~20 mg/kg/day in an open
      label fashion for eight weeks (± 2 weeks) prior to randomization. Participants will receive
      monthly medical evaluations (every 4 ± 2 weeks) where they will have height and weight
      measurements, medical history, physical examination, and medication adherence assessments.
      During these monthly visits complete blood counts with absolute reticulocyte count will be
      monitored. Hemoglobin electrophoresis, complete serum chemistries, urinalysis, lactate
      dehydrogenase and quality of life measurements will be obtained every 20 (±2) weeks.
      Transcranial Doppler (TCD) ultrasound velocities will be obtained at study entry (in
      participants ≥2 years of age) and study exit. Participants randomized to receive hydroxyurea
      at MTD will have their dose increased by 5 mg/kg/day every 8 weeks, in the absence of
      toxicity, until a goal ANC of 1500-3000 cells/µL is achieved, up to a maximum of 35
      mg/kg/day.

      Both groups will receive their assigned treatment for 48 weeks (± 3 weeks). Participants will
      be in the study for a total of 56 weeks (± 3 weeks) and have 14 clinic visits to the St. Jude
      outpatient Hematology Clinic during that time. After the 56 weeks, participants will be
      followed for an additional 30 days for side effects and will then be taken off study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Investigator)
measure: Number of Patients Enrolled.
time frame: at baseline
description: A count of the number of patients enrolled will be provided.
measure: Number of Patients Randomized
time frame: Eight weeks (± 2 weeks) after study enrollment
description: A count of the number of patients randomized will be provided.
measure: Number of Randomized Patients With ≥80% Chronic Medication Compliance
time frame: At completion of therapy, up to 56 weeks after study enrollment
description: Chronic medication compliance is defined based on medication possession ratio (MPR), a measure of the percentage of time that a patient has access to medication. Each participant's MPR is calculated as [(days medication in family's possession/days prescribed medication) * 100].
measure: Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit
time frame: At baseline and at completion of the protocol, up to 56 weeks after study enrollment
description: The number of patients who have successfully provided %HbF at baseline and study exit will be provided.
measure: Frequency by Reason Given for Refusal for Study Participation
time frame: Once, at enrollment
description: Descriptive statistics of count and frequency will be provided for participants who were approached but refused to be enrolled on the study.
measure: Number of Patients With Hospitalizations by Arm
time frame: From baseline through completion of therapy, up to 56 weeks
description: The number of patients with hospitalizations will be provided by arm. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.
measure: Cumulative Number of Hospitalizations by Arms
time frame: From baseline through completion of therapy, up to 56 weeks
description: The total number of hospitalization events will be provided by arms. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.
measure: Mean Change in Hemoglobin (g/dL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Median Change in Hemoglobin (g/dL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Mean Change in Fetal Hemoglobin (%)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Median Change in Fetal Hemoglobin (%)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Mean Change in Mean Corpuscular Volume (fL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Median Change in Mean Corpuscular Volume (fL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Mean Change in Platelet Count (*10^3 Platelets/µL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Median Change in Platelet Count (*10^3 Platelets/µL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Mean Change in Bilirubin (mg/dL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Median Change in Bilirubin (mg/dL)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Mean Change in Lactate Dehydrogenase (Units/L)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
measure: Median Change in Lactate Dehydrogenase (Units/L)
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Descriptive statistics of the change between baseline and completion of the study will be provided.
measure: Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Normal TCD velocities will be defined as TCD velocities <170 cm/s.
measure: Number of Participants Who Undergo Surgery
time frame: From start of therapy through completion of therapy, up to 56 weeks
description: Any operative procedure will be included.
measure: Number of Participants Who Undergo Transfusion
time frame: From start of therapy through completion of therapy, up to 56 weeks
description: Transfusion will be defined as the provision of red blood cells to correct anemia.
measure: Number of Patients With Toxicities Related to Hydroxyurea Dosing
time frame: From start of therapy through completion of therapy, up to 56 weeks
description: Number of patients with toxicities to include: neutropenia (ANC <1000*/µL), reticulocytopenia (ARC <80*10^3/µL and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^3/µL).
measure: Number of Toxicities Related to Hydroxyurea Dosing
time frame: From start of therapy through completion of therapy, up to 56 weeks
description: Number of toxicities will be reported to include: neutropenia (ANC <1000*/µL), reticulocytopenia (ARC <80*10^3/µL and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^3/µL).
measure: Change in Pain and Hurt Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
measure: Change in Pain Impact Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
measure: Change in Pain Management Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
measure: Change in Worry I Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
measure: Change in Worry II Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
measure: Change in Emotions Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
measure: Change in Treatment Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
measure: Change in Communication I Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
measure: Change in Communication II Score
time frame: From baseline at study entry to completion of therapy, up to 56 weeks
description: Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
arm group label: Stable Dosing
arm group type: Active Comparator
description: In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.
arm group label: Intensive Dosing
arm group type: Experimental
description: In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
intervention type: Drug
intervention name: Hydroxyurea
description: Given orally once daily.
arm group label: Intensive Dosing
arm group label: Stable Dosing
other name: HU
criteria: 
gender: All
minimum age: 9 Months
maximum age: 36 Months
healthy volunteers: No
last name: Jeremie Estepp, MD
role: Principal Investigator
affiliation: St. Jude Children's Research Hospital
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://www.stjude.org
description: St. Jude Children's Research Hospital
url: http://www.stjude.org/protocols
description: Clinical Trials Open at St. Jude
responsible party type: Sponsor
mesh term: Anemia, Sickle Cell
mesh term: Hydroxyurea
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 