Pharmacokinetics of Oral Hydroxyurea Solution (HUPK)

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

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Sickle Cell Hemoglobin C; Sickle Cell-beta-thalassemia; Sickle-Cell; Hemoglobin Disease, Thalassemia
• Intervention / Treatment: Drug: Hydroxyurea

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• Jamaica
  • Kingston, Jamaica
    • Dr Angela E Rankine- Mullings
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Women's and Children's NHS Foundation Trust
  • Liverpool, United Kingdom
    • Alder Hey Children's NHS Foundation Trust
  • London, United Kingdom
    • King's College Hospital NHS Foundation Trust
  • London, United Kingdom
    • Evelina London Children's Hospital
  • London, United Kingdom
    • The Royal London Children's Hospital, Barts Health NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female aged from 6 months to 17.99 years of age (i.e. to the day before 18th birthday).
2. Diagnosis of sickle cell anemia (HbSS and HbSβº).
3. Parent(s)/legal guardian able and willing to provide written informed consent for the child to take part in the study.
4. 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:

1. 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.
2. Hydroxyurea use within 6 months before enrolment.
3. Renal insufficiency (known creatinine more than twice the upper limit of normal (ULN) for age and > 1.0 mg/dL [88.4 micromol/L])
4. 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).
5. Other significant organ system dysfunction based on the site investigator's discretion.
6. 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.
7. Active chronic leg ulcers.
8. Known allergy to oral hydroxyurea solution or any of the excipients.
9. 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.
10. Inadequate contraception measures in sexually active females (in post-menarcheal females) and males of child-bearing age.
11. Currently breastfeeding.
12. Participating in another clinical study of an investigational medicinal product (IMP).
13. Known infection with Human Immunodeficiency Virus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open Label; Novel oral solution formulation of hydroxyurea	Drug: Hydroxyurea; Oral Hydroxyurea

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transcranial Doppler velocity	Exploratory	Up to Week 56
Urine parameters (albumin, creatinine, for urinary ACR ratio)	Exploratory	Up to Week 60

Collaborators and Investigators

• Sponsor: Nova Laboratories Limited
• Investigators: Principal Investigator: Angela E Rankine- Mullings, MD, University of the West Indies, Mona, Kingston, Jamaica

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2018
• Primary Completion (Actual): May 19, 2021
• Study Completion (Actual): December 29, 2021

Study Registration Dates

• First Submitted: December 3, 2018
• First Submitted That Met QC Criteria: December 3, 2018
• First Posted (Actual): December 4, 2018

Study Record Updates

• Last Update Posted (Actual): February 11, 2022
• Last Update Submitted That Met QC Criteria: February 10, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Hydroxyurea; Hydroxycarbamide; Xromi
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Thalassemia; beta-Thalassemia; Hemoglobin SC Disease; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antisickling Agents; Hydroxyurea
• Other Study ID Numbers: INV543; 2017-004568-37 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No