Pharmacokinetics of Oral Hydroxyurea Solution

Study Overview
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Brief Summary
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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.

Official Title
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A Prospective Open Label, Pharmacokinetic Study of an Oral Hydroxyurea Solution in Children With Sickle Cell Anemia.

Conditions
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Sickle Cell Disease, Sickle-Cell; Hemoglobin Disease, Thalassemia, Sickle Cell-beta-thalassemia, Sickle Cell Hemoglobin C

Intervention / Treatment
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* Drug: Hydroxyurea


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged from 6 months to 17.99 years of age (i.e. to the day before 18th birthday). Diagnosis of sickle cell anemia (HbSS and HbSβº). Parent(s)/legal guardian able and willing to provide written informed consent for the child to take part in the study. Where applicable, the child should assent to undergo blood sampling for pharmacokinetic and biochemistry purposes and to allow physiological measurements to be made. Exclusion Criteria: Any clinically significant medical condition or abnormality, which, in the opinion of the investigator, might compromise the safety of the patient or which might interfere with the study. Hydroxyurea use within 6 months before enrolment. Renal insufficiency (known creatinine more than twice the upper limit of normal (ULN) for age and > 1.0 mg/dL [88.4 micromol/L]) Clinical evidence of hepatic compromise with alanine aminotransferase (ALT) more than 3 times the ULN (a temporary swing in ALT will not result in exclusion). Other significant organ system dysfunction based on the site investigator's discretion. Severe active infections: fungal, viral, or bacterial (as confirmed by culture). Examples include tuberculosis, malaria, active hepatitis, osteomyelitis, or any other illness that would preclude the use of hydroxyurea in normal clinical practice. Active chronic leg ulcers. Known allergy to oral hydroxyurea solution or any of the excipients. Positive pregnancy test for females of child-bearing potential (in post-menarcheal females) before initiation of treatment, unless patient is sexually abstinent. Note: true abstinence is considered as being in line with the preferred and usual lifestyle of the patient. Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Inadequate contraception measures in sexually active females (in post-menarcheal females) and males of child-bearing age. Currently breastfeeding. Participating in another clinical study of an investigational medicinal product (IMP). Known infection with Human Immunodeficiency Virus.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label<br>Novel oral solution formulation of hydroxyurea | Drug: Hydroxyurea<br>* Oral Hydroxyurea<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance (CL/F) | Pharmacokinetic Parameters | 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) | 
| Volume of distribution (V/F) | Pharmacokinetic Parameters | 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 to maximum concentration (Tmax) | Pharmacokinetic Parameters | 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) | 
| Maximum plasma concentration (Cmax) | Pharmacokinetic Parameters | 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) | 
| Area under plasma concentration time curve (AUC) | Pharmacokinetic Parameters | 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) | 
| Half-life (t½) | Pharmacokinetic Parameters | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Safety | Up to Week 64 | 
| Absolute neutrophil count | Safety | Up to Week 60 | 
| White Blood Cell Count and Differentials | Safety | Up to Week 60 | 
| Platelets | Safety | Up to Week 60 | 
| Mean Corpuscular Hemoglobin | Safety | Up to Week 60 | 
| Hematocrit | Safety | Up to Week 60 | 
| Bilirubin | Safety | Up to Week 60 | 
| Elevation in liver function tests (LFTs) | Safety | Up to Week 60 | 
| Hemoglobin/Anemia | Safety | Up to Week 60 | 
| Clinically significant change in hematology | Safety | Up to Week 60 | 
| Clinically significant change in biochemistry | Safety | Up to Week 60 | 
| Clinically significant change in urinalysis | Safety | Up to Week 60 | 
| Bacterial infections | Safety | Up to Week 60 | 
| Viral infections | Safety | Up to Week 60 | 
| Fungal infections | Safety | Up to Week 60 | 
| Leg ulcers | Safety | Up to Week 60 | 
| Fetal hemoglobin | Biomarker endpoints | Up to Week 60 | 
| Mean Corpuscular Volume | Biomarker endpoints | Up to Week 60 | 
| Cystatin C | Biomarker Endpoints | Up to Week 60 | 
| Incidence of acute pain crises | Clinical status endpoints | Up to Week 60 | 
| Number and frequency of blood transfusions | Clinical status endpoints | Up to Week 60 | 
| Incidence of acute chest syndrome | Clinical status endpoints | Up to Week 60 | 
| Hospitalizations | Clinical Status endpoints | Up to Week 60 | 
| Dose escalation i.e. time to maximum tolerated dose | Clinical status endpoints | Up to Week 60 | 
| Clinically parameters (symptoms) | Clinical status endpoints | Up to Week 60 | 
| 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 | Clinical status endpoints | Up to Week 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hydroxyurea, Hydroxycarbamide, Xromi