Pharmacokinetics of Oral Hydroxyurea Solution

NCT03763656 | Completed Phase 1 Results DMC

• 2 other identifiers: INV5432017-004568-37
• Study Type: interventional
• Target: 33
• Locations: 2 countries
• Sites: 6

Brief Summary

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.

Conditions

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

Keywords

Hydroxyurea; Hydroxycarbamide; Xromi

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (25)

• Adverse Events

  Screening Up to Week 64

• Absolute Neutrophil Count (ANC)

  Baseline and Week 60 (or final visit); max 15 months on treatment

• White Blood Cell Count (Leukocytes)

  Baseline to Week 60 or Final Visit; max 15 months on treatment

• Platelets

  Baseline to Week 60 (or Final Visit), max 15 months on treatment

• Mean Corpuscular Hemoglobin (MCH)

  Baseline to Week 60 (or Final Visit), max 15 months on treatment

Other Outcomes (1)

• Transcranial Doppler Velocity

  Baseline to Week 40-56 (Follow up scan).

Study Arms (1)

Open Label

EXPERIMENTAL

Novel oral solution formulation of hydroxyurea

Drug: Oral Hydroxyurea (100 mg/mL) Solution

Interventions

Oral Hydroxyurea (100 mg/mL) Solution DRUG

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.

Open Label

Eligibility Criteria

• Age: 6 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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 \[88.4 μmol/L\]).
• Other significant organ system dysfunction based on the site Investigators discretion.
• 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.
• Active chronic leg ulcers.
• Known allergy to oral HU solution or any of the excipients.
• 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.
• Inadequate contraception measures in sexually active females (post-menarcheal females) and males of child-bearing age (see Section 9.5.1.10.4).
• Breastfeeding at study initiation.
• Participation in another clinical trial of an IMP.
• Known infection with HIV.

Sponsors & Collaborators

• Nova Laboratories Limited: lead

Study Sites (6)

Dr Angela E Rankine- Mullings

Kingston, Jamaica

Location

Birmingham Women's and Children's NHS Foundation Trust

Birmingham, United Kingdom

Location

Alder Hey Children's NHS Foundation Trust

Liverpool, United Kingdom

Location

Evelina London Children's Hospital

London, United Kingdom

Location

King's College Hospital NHS Foundation Trust

London, United Kingdom

Location

The Royal London Children's Hospital, Barts Health NHS Trust

London, United Kingdom

Location

MeSH Terms

Conditions

Anemia, Sickle Cell; Hemoglobinopathies; Thalassemia; Hemoglobin SC Disease

Interventions

Hydroxyurea; Solutions

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals; Pharmaceutical Preparations

Results Point of Contact

• Title: Dr Hussain Mulla, Head of Clinical Development
• Organization: Nova Laboratories Ltd

hussain.mulla@novalabs.co.uk

0116 223 0101

Study Officials

• Angela E Rankine- Mullings, MD

  University of the West Indies, Mona, Kingston, Jamaica

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open label, observational, pharmacokinetic study of oral hydroxyurea solution administered to children from 6 months-17.99 years over a 12-15-month period

Study Record Dates

• First Submitted: December 3, 2018
• First Posted: December 4, 2018
• Study Start: January 3, 2019
• Primary Completion: May 19, 2021
• Study Completion: December 29, 2021
• Last Updated: October 28, 2024
• Results First Posted: October 28, 2024

Record last verified: 2024-08

Locations

GB (5); JA (1)