<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/NCT02225132</url>
  </required_header>
  <id_info>
    <org_study_id>140172</org_study_id>
    <secondary_id>14-H-0172</secondary_id>
    <nct_id>NCT02225132</nct_id>
  </id_info>
  <brief_title>Assessment of Algorithm-Based Hydroxyurea Dosing on Fetal Hemoglobin Response, Acute Complications, and Organ Function in People With Sickle Cell Disease</brief_title>
  <official_title>Assessment of Computerized Algorithm-Based Hydroxyurea Dosing on Fetal Hemoglobin Response, Acute Complications, and Organ Function in Subjects With Sickle Cell Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Sickle cell disease (SCD) is a blood disease. The drug hydroxyurea (HU) is approved to&#xD;
      prevent pain crises in people with SCD. Researchers want to see how higher doses of HU affect&#xD;
      the blood. This will help them learn about the right dosage of HU to give to people with SCD.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To improve hydroxyurea dosing in people with SCD.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - People age 15 or older with homozygous SCD (HbSS).&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with medical history, physical exam, medication review,&#xD;
           and blood and urine tests.&#xD;
&#xD;
        -  Participants will be in the study for about 15 months.&#xD;
&#xD;
        -  First 3 months: monthly study visits with blood and urine tests.&#xD;
&#xD;
        -  After 3 months: participants will take HU as a capsule by mouth. If you are already&#xD;
           taking HU, your dose will be increased.&#xD;
&#xD;
        -  Within a month of starting or increasing HU: participants will keep a daily pain diary&#xD;
           for 2 weeks. They will have an echocardiogram (ultrasound) of the heart, a 6-minute walk&#xD;
           test. They will complete a quality-of-life questionnaire.&#xD;
&#xD;
        -  Participants will visit every month until they reach their highest tolerated dose of HU.&#xD;
           They may need to come as often as every week sometimes to closely monitor their blood&#xD;
           counts. Then they will alternate a phone call one month and a visit the next. At the&#xD;
           visits, participants will bring their pill bottle, answer questions about side effects,&#xD;
           and have blood tests.&#xD;
&#xD;
        -  Every 2 months, participants will have a medical history, physical exam, and blood&#xD;
           tests.&#xD;
&#xD;
        -  Every 4 months, participants will have blood and urine tests. They will also complete&#xD;
           another 2-week pain diary and quality-of-life questionnaire.&#xD;
&#xD;
        -  About 12 months after starting or increasing HU, participants will have blood tests, an&#xD;
           echocardiogram, and a 6-minute walk test.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sickle cell disease (SCD) is associated with significant morbidity and early mortality.&#xD;
      Despite the discovery of the disease more than 100 years ago, only one drug, hydroxyurea&#xD;
      (HU), has been FDA-approved. Hydroxyurea exerts its beneficial effects largely by inducing&#xD;
      fetal hemoglobin (HbF) and thereby inhibiting red blood cell sickling. Hydroxyurea has been&#xD;
      shown to decrease the frequency of acute complications such as painful crises and acute chest&#xD;
      syndrome. However, previous studies are conflicting regarding whether HU improves survival; 2&#xD;
      long-term studies where HU was titrated to the maximum tolerated dose show that HU improves&#xD;
      survival. However, multiple studies performed in the era post-FDA approval of HU show no&#xD;
      change in median survival. We and others have found that patients with SCD who die&#xD;
      prematurely have more evidence of renal, hepatic, and cardiopulmonary damage. Our work also&#xD;
      suggests that HU treatment per se is not sufficient to improve survival and decrease organ&#xD;
      damage in patients with homozygous SCD (HbSS). Instead, patients treated with the highest HU&#xD;
      doses and who had the highest HbF levels appeared more likely to survive and had less&#xD;
      evidence of organ damage over time. Hydroxyurea management can be intimidating; therefore,&#xD;
      many adults with HbSS are either not treated with HU or are treated with doses below that&#xD;
      which are FDA-approved. A HU dosing algorithm may simplify dosing such that not only are more&#xD;
      patients treated with HU, but more may be titrated to the maximal tolerated dose which may be&#xD;
      necessary to prevent organ damage and prolong survival. Further, myelosuppression beyond what&#xD;
      has traditionally been recommended may further maximize HbF response. This protocol is a&#xD;
      prospective pilot study which follows a 2 month run-in period. Hydroxyurea dosing will be&#xD;
      based on a written algorithm which will be derived manually, and by a computer program which&#xD;
      was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic&#xD;
      parameters will be monitored at baseline and after treatment to further study the effect of&#xD;
      maximum HbF response on acute complications associated with HbSS and organ function.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 23, 2014</start_date>
  <completion_date type="Actual">May 24, 2018</completion_date>
  <primary_completion_date type="Actual">May 24, 2018</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Fetal Hemoglobin Level</measure>
    <time_frame>Baseline</time_frame>
    <description>Mean fetal hemoglobin calculated to indicate effectiveness of hydroxyurea dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Fetal Hemoglobin Level</measure>
    <time_frame>12 months</time_frame>
    <description>Mean fetal hemoglobin calculated to indicate effectiveness of hydroxyurea dose</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a one arm, open-label, non- randomized pilot study to evaluate the effect of algorithm- based HU dosing on the HbF response, the ability to titrate each patient to the MTD of HU, acute complications, and organ function in patients with HbSS.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxyurea</intervention_name>
    <description>The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.&#xD;
The mechanisms by which DROXIA produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.</description>
    <arm_group_label>1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
               1. Age greater than or equal to 15 years&#xD;
&#xD;
               2. Homozygous sickle cell disease (HbSS)&#xD;
&#xD;
               3. Patients with recent transfusion must have HbA &lt;15% prior to enrollment&#xD;
&#xD;
               4. ANC greater than or equal to 2,000/microL, platelets greater than or equal&#xD;
                  to150,000/microL, Hb &gt; 5.4g/dL, and ARC greater than or equal to100,000/microL&#xD;
                  (unless the Hb is &gt; 8g/dL) at baseline&#xD;
&#xD;
               5. Patients on angiotensin-converting enzyme inhibitors and angiotensin receptor&#xD;
                  blockers should be on a stable dose for 2 weeks prior to initiating or adjusting&#xD;
                  HU&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Pregnant or lactating women or patients planning to get pregnant during the study&#xD;
             period&#xD;
&#xD;
          2. Patients unwilling to use two forms of contraception throughout the period of HU&#xD;
             administration&#xD;
&#xD;
          3. Patients receiving chronic transfusion therapy&#xD;
&#xD;
          4. Patients receiving a HU dose of greater than or equal to 20 mg/kg/day&#xD;
&#xD;
          5. Patients with history of allergy or intolerance to HU judged by the investigator to be&#xD;
             prohibitive against restarting HU&#xD;
&#xD;
        6 Patients with end stage renal disease defined as GFR &lt;10mL/min/1.73m(2)&#xD;
&#xD;
        7. Patients being treated with antiretroviral agents (such as didanosine and stavudine)&#xD;
        because of a higher risk for potentially fatal pancreatitis, hepatic failure, hepatitis,&#xD;
        and severe peripheral neuropathy when co-administered with hydroxyurea.&#xD;
&#xD;
        8. Participation on any other chronic investigative treatment studies&#xD;
&#xD;
        9. Unable to understand the investigational nature of the study or give informed consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Courtney D Fitzhugh, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Heart, Lung, and Blood Institute (NHLBI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-H-0172.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>April 25, 2019</verification_date>
  <study_first_submitted>August 23, 2014</study_first_submitted>
  <study_first_submitted_qc>August 23, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 26, 2014</study_first_posted>
  <results_first_submitted>July 15, 2019</results_first_submitted>
  <results_first_submitted_qc>July 15, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">August 6, 2019</results_first_posted>
  <last_update_submitted>July 15, 2019</last_update_submitted>
  <last_update_submitted_qc>July 15, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 6, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Hydroxyurea</keyword>
  <keyword>Sickle Cell Disease</keyword>
  <keyword>Fetal Hemoglobin Induction</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>August 23, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/32/NCT02225132/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Hydroxyurea</title>
          <description>Hydroxyurea is given to the patients as per a dosing algorithm.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Hydroxyurea</title>
          <description>Hydroxyurea is given to the patients as per a dosing algorithm.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="10"/>
          </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="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="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Fetal Hemoglobin Level</title>
        <description>Mean fetal hemoglobin calculated to indicate effectiveness of hydroxyurea dose</description>
        <time_frame>Baseline</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hydroxyurea</title>
            <description>Hydroxyurea is given to the patients as per a dosing algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Fetal Hemoglobin Level</title>
          <description>Mean fetal hemoglobin calculated to indicate effectiveness of hydroxyurea dose</description>
          <units>Percentage</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.3" spread="5.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Fetal Hemoglobin Level</title>
        <description>Mean fetal hemoglobin calculated to indicate effectiveness of hydroxyurea dose</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hydroxyurea</title>
            <description>Hydroxyurea is given to the patients as per a dosing algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Fetal Hemoglobin Level</title>
          <description>Mean fetal hemoglobin calculated to indicate effectiveness of hydroxyurea dose</description>
          <units>Percentage</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.1" spread="6.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Hydroxyurea</title>
          <description>Hydroxyurea is given to the patients as per a dosing algorithm.</description>
        </group>
      </group_list>
      <serious_events>
        <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="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Acute chest syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Sickle cell anaemia with crisis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Knee arthroplasty</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <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="10" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Blood disorder</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lymph node pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vitreous floaters</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nervous system disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Chromaturia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis bullous</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nail discolouration</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Embolism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Thrombophlebitis superficial</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </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>Fitzhugh, Courtney</name_or_title>
      <organization>National Heart Lung and Blood Institute</organization>
      <phone>+1 301 402 6496</phone>
      <email>courtney.fitzhugh@nih.gov</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/NCT02225132
org study id: 140172
secondary id: 14-H-0172
nct id: NCT02225132
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - Sickle cell disease (SCD) is a blood disease. The drug hydroxyurea (HU) is approved to
      prevent pain crises in people with SCD. Researchers want to see how higher doses of HU affect
      the blood. This will help them learn about the right dosage of HU to give to people with SCD.

      Objective:

      - To improve hydroxyurea dosing in people with SCD.

      Eligibility:

      - People age 15 or older with homozygous SCD (HbSS).

      Design:

        -  Participants will be screened with medical history, physical exam, medication review,
           and blood and urine tests.

        -  Participants will be in the study for about 15 months.

        -  First 3 months: monthly study visits with blood and urine tests.

        -  After 3 months: participants will take HU as a capsule by mouth. If you are already
           taking HU, your dose will be increased.

        -  Within a month of starting or increasing HU: participants will keep a daily pain diary
           for 2 weeks. They will have an echocardiogram (ultrasound) of the heart, a 6-minute walk
           test. They will complete a quality-of-life questionnaire.

        -  Participants will visit every month until they reach their highest tolerated dose of HU.
           They may need to come as often as every week sometimes to closely monitor their blood
           counts. Then they will alternate a phone call one month and a visit the next. At the
           visits, participants will bring their pill bottle, answer questions about side effects,
           and have blood tests.

        -  Every 2 months, participants will have a medical history, physical exam, and blood
           tests.

        -  Every 4 months, participants will have blood and urine tests. They will also complete
           another 2-week pain diary and quality-of-life questionnaire.

        -  About 12 months after starting or increasing HU, participants will have blood tests, an
           echocardiogram, and a 6-minute walk test.
Sickle cell disease (SCD) is associated with significant morbidity and early mortality.
      Despite the discovery of the disease more than 100 years ago, only one drug, hydroxyurea
      (HU), has been FDA-approved. Hydroxyurea exerts its beneficial effects largely by inducing
      fetal hemoglobin (HbF) and thereby inhibiting red blood cell sickling. Hydroxyurea has been
      shown to decrease the frequency of acute complications such as painful crises and acute chest
      syndrome. However, previous studies are conflicting regarding whether HU improves survival; 2
      long-term studies where HU was titrated to the maximum tolerated dose show that HU improves
      survival. However, multiple studies performed in the era post-FDA approval of HU show no
      change in median survival. We and others have found that patients with SCD who die
      prematurely have more evidence of renal, hepatic, and cardiopulmonary damage. Our work also
      suggests that HU treatment per se is not sufficient to improve survival and decrease organ
      damage in patients with homozygous SCD (HbSS). Instead, patients treated with the highest HU
      doses and who had the highest HbF levels appeared more likely to survive and had less
      evidence of organ damage over time. Hydroxyurea management can be intimidating; therefore,
      many adults with HbSS are either not treated with HU or are treated with doses below that
      which are FDA-approved. A HU dosing algorithm may simplify dosing such that not only are more
      patients treated with HU, but more may be titrated to the maximal tolerated dose which may be
      necessary to prevent organ damage and prolong survival. Further, myelosuppression beyond what
      has traditionally been recommended may further maximize HbF response. This protocol is a
      prospective pilot study which follows a 2 month run-in period. Hydroxyurea dosing will be
      based on a written algorithm which will be derived manually, and by a computer program which
      was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic
      parameters will be monitored at baseline and after treatment to further study the effect of
      maximum HbF response on acute complications associated with HbSS and organ function.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Fetal Hemoglobin Level
time frame: Baseline
description: Mean fetal hemoglobin calculated to indicate effectiveness of hydroxyurea dose
measure: Fetal Hemoglobin Level
time frame: 12 months
description: Mean fetal hemoglobin calculated to indicate effectiveness of hydroxyurea dose
arm group label: 1
arm group type: Experimental
description: This is a one arm, open-label, non- randomized pilot study to evaluate the effect of algorithm- based HU dosing on the HbF response, the ability to titrate each patient to the MTD of HU, acute complications, and organ function in patients with HbSS.
intervention type: Drug
intervention name: Hydroxyurea
description: The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.
The mechanisms by which DROXIA produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.
arm group label: 1
criteria: 
gender: All
minimum age: 15 Years
maximum age: 99 Years
healthy volunteers: No
last name: Courtney D Fitzhugh, M.D.
role: Principal Investigator
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-H-0172.html
description: NIH Clinical Center Detailed Web Page
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: 