<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/NCT03763656</url>
  </required_header>
  <id_info>
    <org_study_id>INV543</org_study_id>
    <secondary_id>2017-004568-37</secondary_id>
    <nct_id>NCT03763656</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics of Oral Hydroxyurea Solution</brief_title>
  <acronym>HUPK</acronym>
  <official_title>A Prospective Open Label, Pharmacokinetic Study of an Oral Hydroxyurea Solution in Children With Sickle Cell Anemia.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nova Laboratories Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Nova Laboratories Limited</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      An open label, safety and pharmacokinetic study of oral hydroxyurea solution administered to&#xD;
      children from 6 months to 17.99 years (i.e. to the day before 18th birthday), with a 12 to 15&#xD;
      month treatment period for each participant. The study treatment duration will be for 6&#xD;
      months at the maximum tolerated dose [MTD], which is usually reached by 6 months after&#xD;
      initiation of treatment. For patients in whom time to MTD is longer than 6 months or not&#xD;
      achieved at all, the maximum duration of study treatment will be 15 months.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 20, 2018</start_date>
  <completion_date type="Actual">December 29, 2021</completion_date>
  <primary_completion_date type="Actual">May 19, 2021</primary_completion_date>
  <phase>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>Clearance (CL/F)</measure>
    <time_frame>0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)</time_frame>
    <description>Pharmacokinetic Parameters</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Volume of distribution (V/F)</measure>
    <time_frame>0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)</time_frame>
    <description>Pharmacokinetic Parameters</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to maximum concentration (Tmax)</measure>
    <time_frame>0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)</time_frame>
    <description>Pharmacokinetic Parameters</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum plasma concentration (Cmax)</measure>
    <time_frame>0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)</time_frame>
    <description>Pharmacokinetic Parameters</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under plasma concentration time curve (AUC)</measure>
    <time_frame>0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)</time_frame>
    <description>Pharmacokinetic Parameters</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Half-life (t½)</measure>
    <time_frame>0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)</time_frame>
    <description>Pharmacokinetic Parameters</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to Week 64</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute neutrophil count</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>White Blood Cell Count and Differentials</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Platelets</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Corpuscular Hemoglobin</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hematocrit</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bilirubin</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Elevation in liver function tests (LFTs)</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hemoglobin/Anemia</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinically significant change in hematology</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinically significant change in biochemistry</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinically significant change in urinalysis</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bacterial infections</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Viral infections</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fungal infections</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Leg ulcers</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Safety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fetal hemoglobin</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Biomarker endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Corpuscular Volume</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Biomarker endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cystatin C</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Biomarker Endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute pain crises</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Clinical status endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number and frequency of blood transfusions</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Clinical status endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute chest syndrome</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Clinical status endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospitalizations</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Clinical Status endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dose escalation i.e. time to maximum tolerated dose</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Clinical status endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinically parameters (symptoms)</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Clinical status endpoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parent/caregiver palatability and acceptability: To evaluate the taste and acceptability of the new oral liquid formulation of hydroxyurea by use of a simple opinion questionnaire and visual analogue hedonic scale</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Clinical status endpoints</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Transcranial Doppler velocity</measure>
    <time_frame>Up to Week 56</time_frame>
    <description>Exploratory</description>
  </other_outcome>
  <other_outcome>
    <measure>Urine parameters (albumin, creatinine, for urinary ACR ratio)</measure>
    <time_frame>Up to Week 60</time_frame>
    <description>Exploratory</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Sickle Cell Disease</condition>
  <condition>Sickle-Cell; Hemoglobin Disease, Thalassemia</condition>
  <condition>Sickle Cell-beta-thalassemia</condition>
  <condition>Sickle Cell Hemoglobin C</condition>
  <arm_group>
    <arm_group_label>Open Label</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Novel oral solution formulation of hydroxyurea</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxyurea</intervention_name>
    <description>Oral Hydroxyurea</description>
    <arm_group_label>Open Label</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female aged from 6 months to 17.99 years of age (i.e. to the day before 18th&#xD;
             birthday).&#xD;
&#xD;
          2. Diagnosis of sickle cell anemia (HbSS and HbSβº).&#xD;
&#xD;
          3. Parent(s)/legal guardian able and willing to provide written informed consent for the&#xD;
             child to take part in the study.&#xD;
&#xD;
          4. Where applicable, the child should assent to undergo blood sampling for&#xD;
             pharmacokinetic and biochemistry purposes and to allow physiological measurements to&#xD;
             be made.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any clinically significant medical condition or abnormality, which, in the opinion of&#xD;
             the investigator, might compromise the safety of the patient or which might interfere&#xD;
             with the study.&#xD;
&#xD;
          2. Hydroxyurea use within 6 months before enrolment.&#xD;
&#xD;
          3. Renal insufficiency (known creatinine more than twice the upper limit of normal (ULN)&#xD;
             for age and &gt; 1.0 mg/dL [88.4 micromol/L])&#xD;
&#xD;
          4. Clinical evidence of hepatic compromise with alanine aminotransferase (ALT) more than&#xD;
             3 times the ULN (a temporary swing in ALT will not result in exclusion).&#xD;
&#xD;
          5. Other significant organ system dysfunction based on the site investigator's&#xD;
             discretion.&#xD;
&#xD;
          6. Severe active infections: fungal, viral, or bacterial (as confirmed by culture).&#xD;
             Examples include tuberculosis, malaria, active hepatitis, osteomyelitis, or any other&#xD;
             illness that would preclude the use of hydroxyurea in normal clinical practice.&#xD;
&#xD;
          7. Active chronic leg ulcers.&#xD;
&#xD;
          8. Known allergy to oral hydroxyurea solution or any of the excipients.&#xD;
&#xD;
          9. Positive pregnancy test for females of child-bearing potential (in post-menarcheal&#xD;
             females) before initiation of treatment, unless patient is sexually abstinent. Note:&#xD;
             true abstinence is considered as being in line with the preferred and usual lifestyle&#xD;
             of the patient. Periodic abstinence (such as calendar, ovulation, symptothermal,&#xD;
             post-ovulation methods) and withdrawal are not acceptable methods of contraception.&#xD;
&#xD;
         10. Inadequate contraception measures in sexually active females (in post-menarcheal&#xD;
             females) and males of child-bearing age.&#xD;
&#xD;
         11. Currently breastfeeding.&#xD;
&#xD;
         12. Participating in another clinical study of an investigational medicinal product (IMP).&#xD;
&#xD;
         13. Known infection with Human Immunodeficiency Virus.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Angela E Rankine- Mullings, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of the West Indies, Mona, Kingston, Jamaica</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dr Angela E Rankine- Mullings</name>
      <address>
        <city>Kingston</city>
        <country>Jamaica</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Birmingham Women's and Children's NHS Foundation Trust</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alder Hey Children's NHS Foundation Trust</name>
      <address>
        <city>Liverpool</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Evelina London Children's Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King's College Hospital NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal London Children's Hospital, Barts Health NHS Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Jamaica</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 3, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 4, 2018</study_first_posted>
  <last_update_submitted>February 10, 2022</last_update_submitted>
  <last_update_submitted_qc>February 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 11, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Hydroxyurea</keyword>
  <keyword>Hydroxycarbamide</keyword>
  <keyword>Xromi</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
    <mesh_term>Thalassemia</mesh_term>
    <mesh_term>beta-Thalassemia</mesh_term>
    <mesh_term>Hemoglobin SC Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxyurea</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>December 21, 2022</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03763656
org study id: INV543
secondary id: 2017-004568-37
nct id: NCT03763656
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
An open label, safety and pharmacokinetic study of oral hydroxyurea solution administered to
      children from 6 months to 17.99 years (i.e. to the day before 18th birthday), with a 12 to 15
      month treatment period for each participant. The study treatment duration will be for 6
      months at the maximum tolerated dose [MTD], which is usually reached by 6 months after
      initiation of treatment. For patients in whom time to MTD is longer than 6 months or not
      achieved at all, the maximum duration of study treatment will be 15 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Clearance (CL/F)
time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)
description: Pharmacokinetic Parameters
measure: Volume of distribution (V/F)
time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)
description: Pharmacokinetic Parameters
measure: Time to maximum concentration (Tmax)
time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)
description: Pharmacokinetic Parameters
measure: Maximum plasma concentration (Cmax)
time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)
description: Pharmacokinetic Parameters
measure: Area under plasma concentration time curve (AUC)
time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)
description: Pharmacokinetic Parameters
measure: Half-life (t½)
time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose.on Day 1 and Day 2 (Week 20-36)
description: Pharmacokinetic Parameters
measure: Incidence of adverse events
time frame: Up to Week 64
description: Safety
measure: Absolute neutrophil count
time frame: Up to Week 60
description: Safety
measure: White Blood Cell Count and Differentials
time frame: Up to Week 60
description: Safety
measure: Platelets
time frame: Up to Week 60
description: Safety
measure: Mean Corpuscular Hemoglobin
time frame: Up to Week 60
description: Safety
measure: Hematocrit
time frame: Up to Week 60
description: Safety
measure: Bilirubin
time frame: Up to Week 60
description: Safety
measure: Elevation in liver function tests (LFTs)
time frame: Up to Week 60
description: Safety
measure: Hemoglobin/Anemia
time frame: Up to Week 60
description: Safety
measure: Clinically significant change in hematology
time frame: Up to Week 60
description: Safety
measure: Clinically significant change in biochemistry
time frame: Up to Week 60
description: Safety
measure: Clinically significant change in urinalysis
time frame: Up to Week 60
description: Safety
measure: Bacterial infections
time frame: Up to Week 60
description: Safety
measure: Viral infections
time frame: Up to Week 60
description: Safety
measure: Fungal infections
time frame: Up to Week 60
description: Safety
measure: Leg ulcers
time frame: Up to Week 60
description: Safety
measure: Fetal hemoglobin
time frame: Up to Week 60
description: Biomarker endpoints
measure: Mean Corpuscular Volume
time frame: Up to Week 60
description: Biomarker endpoints
measure: Cystatin C
time frame: Up to Week 60
description: Biomarker Endpoints
measure: Incidence of acute pain crises
time frame: Up to Week 60
description: Clinical status endpoints
measure: Number and frequency of blood transfusions
time frame: Up to Week 60
description: Clinical status endpoints
measure: Incidence of acute chest syndrome
time frame: Up to Week 60
description: Clinical status endpoints
measure: Hospitalizations
time frame: Up to Week 60
description: Clinical Status endpoints
measure: Dose escalation i.e. time to maximum tolerated dose
time frame: Up to Week 60
description: Clinical status endpoints
measure: Clinically parameters (symptoms)
time frame: Up to Week 60
description: Clinical status endpoints
measure: Parent/caregiver palatability and acceptability: To evaluate the taste and acceptability of the new oral liquid formulation of hydroxyurea by use of a simple opinion questionnaire and visual analogue hedonic scale
time frame: Up to Week 60
description: Clinical status endpoints
measure: Transcranial Doppler velocity
time frame: Up to Week 56
description: Exploratory
measure: Urine parameters (albumin, creatinine, for urinary ACR ratio)
time frame: Up to Week 60
description: Exploratory
arm group label: Open Label
arm group type: Experimental
description: Novel oral solution formulation of hydroxyurea
intervention type: Drug
intervention name: Hydroxyurea
description: Oral Hydroxyurea
arm group label: Open Label
criteria: 
gender: All
minimum age: 6 Months
maximum age: 17 Years
healthy volunteers: No
last name: Angela E Rankine- Mullings, MD
role: Principal Investigator
affiliation: University of the West Indies, Mona, Kingston, Jamaica
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Jamaica
country: United Kingdom
responsible party type: Sponsor
mesh term: Anemia, Sickle Cell
mesh term: Thalassemia
mesh term: beta-Thalassemia
mesh term: Hemoglobin SC Disease
mesh term: Hydroxyurea
submitted: December 21, 2022