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: Oral Hydroxyurea (100 mg/mL) Solution

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 1

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

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 have compromised the safety of the patient or which might have interfered 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 μmol/L]).
4. Clinical evidence of hepatic compromise with alanine aminotransferase (ALT) >3 times the ULN (a temporary swing in ALT did not result in exclusion).
5. Other significant organ system dysfunction based on the site Investigators discretion.
6. Severe active infections: fungal, viral or bacterial (as confirmed by culture), examples included tuberculosis, malaria, active hepatitis, osteomyelitis or any other illness that would have precluded the use of HU in normal clinical practice.
7. Active chronic leg ulcers.
8. Known allergy to oral HU 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 participant was sexually abstinent. Note: True abstinence was considered as being in line with the preferred and usual lifestyle of the participant. 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 (post-menarcheal females) and males of child-bearing age (see Section 9.5.1.10.4).
11. Breastfeeding at study initiation.
12. Participation in another clinical trial of an IMP.
13. Known infection with HIV.

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: Oral Hydroxyurea (100 mg/mL) Solution; Participants received Oral Hydroxyurea 15 mg/kg once daily. Escalated by 5 mg/kg/day every 8-12 weeks until maximum tolerated dose achieved, up to a maximum 35 mg/kg/day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clearance (CL/F)	Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).	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)	Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).	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)	Mean Tmax (h) pharmacokinetic parameter derived using the final population PK model.	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 (ug/mL)	Mean Cmax (ug/mL) pharmacokinetic parameter derived using the final population PK model.	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 0-Inf)	Mean AUC 0-Infinity (hr*ug/mL) pharmacokinetic parameters derived using the final population PK model.	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)
Terminal Half-life (Hours)	Mean Terminal Half-life (hours) pharmacokinetic parameter derived using the final population PK model.	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
Adverse Events	Incidence of Adverse events during the course of the trial from screening to final follow up phone call at Week 64. Relatedness refers to 'at least possibly related to the IMP', with severity/toxicity assessed using the CTCAE Toxicity Grade and seriousness based on the standard definition for SAE in accordance with GCP. With the exception of SCA related events, requiring >7day hospitalisation, or extension of hospitalisation before being reported as an SAE due to their frequency within the disease population. All other non-SCA related SAEs were reportable.	Screening Up to Week 64
Absolute Neutrophil Count (ANC)	Safety review for haematological toxicity (mild myelosuppression target: 1-3x10^9/L)	Baseline and Week 60 (or final visit); max 15 months on treatment
White Blood Cell Count (Leukocytes)	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Baseline to Week 60 or Final Visit; max 15 months on treatment
Platelets	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Baseline to Week 60 (or Final Visit), max 15 months on treatment
Mean Corpuscular Hemoglobin (MCH)	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Baseline to Week 60 (or Final Visit), max 15 months on treatment
Hematocrit	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Up to Week 60
Bilirubin	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Up to Week 60
Elevation in Liver Function Tests (LFTs)	Impact of Hydroxyurea on Safety, Hematology and Biochemistry, including Liver Function Tests (LFTs): Alkaline Phosphatase (ALP), Gamma Glutamyl Transferase (GGT), Aspartate Amino Transferase (AST), Alanine Aminotransferase (ALT)	Up to Week 60
Hemoglobin	Safety and efficacy of hydroxyurea therapy	Baseline to Week 60 (or Final Visit); max 15 months on treatment
Bacterial Infections	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Up to Week 60
Viral Infections	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Up to Week 60
Fungal Infections	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Up to Week 60
Leg Ulcers	Impact of Hydroxyurea on Safety, Hematology and Biochemistry	Up to Week 60
Fetal Hemoglobin	Biomarker endpoints of Hydroxyurea efficacy	Baseline to Week 60 (or Final Visit); max 15 months on treatment
Mean Corpuscular Volume (MCV)	Biomarker endpoints of Hydroxyurea efficacy	Baseline to Week 60 (or Final Visit); max 15 months on treatment
Cystatin C	Biomarker Endpoints	PK1 (day 1), week 20-32 (6 months) and Week 60 (Final Visit)
Incidence of Acute Vaso-Occlusive Pain Crises (VOC)	Hospitalization Incidence for 12 Months Prior to and After First Dose of IMP (Safety Population) for vaso-occlusive crisis (Mean [SD])	12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP
Number and Frequency of Blood Transfusions	Clinical status endpoints, related to blood transfusions for treatment of SCA, this may be hospitalization, A&E, or in-clinic treatment from safety population (n=32)	Up to Week 60
Acute Chest Syndrome (ACS)	Hospitalization Incidence for 12 Months Prior to and After First Dose of IMP (Safety Population) for Acute Chest Syndrome (Mean [SD])	12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP
Hospitalizations	Clinical Status endpoints, all hospitalisations (not ER/Accident without hospitalization) (Mean [SD])	12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP
Dose Escalation i.e. Maximum Tolerated Dose (MTD)	Summary of maximum tolerated dose achieved in mg/kg (Mean [SD])	Screening Up to Final Visit (Week 60 or Withdrawal), maximum 15 months on IMP
Other SCA-related Hospitalizations	Clinical parameters (symptoms), secondary clinical status endpoints (not including ACS, VOC, Other Non-SCA related) (mean [SD])	12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP
Parent/Caregiver Palatability and Acceptability Questionnaire	Clinical status endpoints. Visual Analogue scale used to determine, taste, smell, aftertaste, acceptability and ease of dosing (1-100mm scale) with 1 being worst possible and 100 being best possible. Assessed for <6 years of age by parents/guardians. Assessed for >6 years of age, combination of parent/guardian and participant responses.	Taken once at any point after 8 weeks on study medication (or at early Withdrawal)
Vitamin D	Biochemistry	From Screening Up to Final Visit (Week 60 or WD)
Other Non-SCA-related Hospitalizations	Clinical parameters (symptoms), secondary clinical status endpoints (not including ACS, VOC, Other SCA-related)	12 months prior to treatment and 12 months post-treatment; maximum 15 months on IMP

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transcranial Doppler Velocity	Exploratory Endpoint; clinical output of hydroxyurea treatment	Baseline to Week 40-56 (Follow up scan).

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): January 3, 2019
• 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): October 28, 2024
• Last Update Submitted That Met QC Criteria: August 12, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Hydroxyurea; Hydroxycarbamide; Xromi
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Anemia, Sickle Cell; Thalassemia; beta-Thalassemia; Hemoglobin SC Disease; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; 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