Pharmacokinetics of Oral Hydroxyurea Solution

Phase 1

Completed

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

Interventions: Drug: Oral Hydroxyurea (100 mg/mL) Solution

Registration Number: NCT03763656

Lead Sponsor: Nova Laboratories Limited

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 33

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 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]).
Clinical evidence of hepatic compromise with alanine aminotransferase (ALT) >3 times the ULN (a temporary swing in ALT did not result in exclusion).
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open Label	Oral Hydroxyurea (100 mg/mL) Solution	Novel oral solution formulation of hydroxyurea

Primary Outcome Measures

Name	Time	Method
Clearance (CL/F)	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)	Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).
Volume of Distribution (V/F)	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)	Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).
Time to Maximum Concentration (Tmax)	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)	Mean Tmax (h) pharmacokinetic parameter derived using the final population PK model.
Maximum Plasma Concentration Cmax (ug/mL)	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)	Mean Cmax (ug/mL) pharmacokinetic parameter derived using the final population PK model.
Area Under Plasma Concentration Time Curve (AUC 0-Inf)	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)	Mean AUC 0-Infinity (hr\*ug/mL) pharmacokinetic parameters derived using the final population PK model.
Terminal Half-life (Hours)	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)	Mean Terminal Half-life (hours) pharmacokinetic parameter derived using the final population PK model.

Secondary Outcome Measures

Name	Time	Method
Platelets	Baseline to Week 60 (or Final Visit), max 15 months on treatment	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Mean Corpuscular Hemoglobin (MCH)	Baseline to Week 60 (or Final Visit), max 15 months on treatment	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Hematocrit	Up to Week 60	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Bilirubin	Up to Week 60	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Elevation in Liver Function Tests (LFTs)	Up to Week 60	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)
Hemoglobin	Baseline to Week 60 (or Final Visit); max 15 months on treatment	Safety and efficacy of hydroxyurea therapy
Bacterial Infections	Up to Week 60	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Leg Ulcers	Up to Week 60	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Fetal Hemoglobin	Baseline to Week 60 (or Final Visit); max 15 months on treatment	Biomarker endpoints of Hydroxyurea efficacy
Viral Infections	Up to Week 60	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Fungal Infections	Up to Week 60	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Mean Corpuscular Volume (MCV)	Baseline to Week 60 (or Final Visit); max 15 months on treatment	Biomarker endpoints of Hydroxyurea efficacy
Cystatin C	PK1 (day 1), week 20-32 (6 months) and Week 60 (Final Visit)	Biomarker Endpoints
Incidence of Acute Vaso-Occlusive Pain Crises (VOC)	12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP	Hospitalization Incidence for 12 Months Prior to and After First Dose of IMP (Safety Population) for vaso-occlusive crisis (Mean \[SD\])
Number and Frequency of Blood Transfusions	Up to Week 60	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)
Acute Chest Syndrome (ACS)	12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP	Hospitalization Incidence for 12 Months Prior to and After First Dose of IMP (Safety Population) for Acute Chest Syndrome (Mean \[SD\])
Adverse Events	Screening Up to Week 64	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.
Absolute Neutrophil Count (ANC)	Baseline and Week 60 (or final visit); max 15 months on treatment	Safety review for haematological toxicity (mild myelosuppression target: 1-3x10\^9/L)
White Blood Cell Count (Leukocytes)	Baseline to Week 60 or Final Visit; max 15 months on treatment	Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Hospitalizations	12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP	Clinical Status endpoints, all hospitalisations (not ER/Accident without hospitalization) (Mean \[SD\])
Dose Escalation i.e. Maximum Tolerated Dose (MTD)	Screening Up to Final Visit (Week 60 or Withdrawal), maximum 15 months on IMP	Summary of maximum tolerated dose achieved in mg/kg (Mean \[SD\])
Other SCA-related Hospitalizations	12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP	Clinical parameters (symptoms), secondary clinical status endpoints (not including ACS, VOC, Other Non-SCA related) (mean \[SD\])
Parent/Caregiver Palatability and Acceptability Questionnaire	Taken once at any point after 8 weeks on study medication (or at early Withdrawal)	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.
Vitamin D	From Screening Up to Final Visit (Week 60 or WD)	Biochemistry
Other Non-SCA-related Hospitalizations	12 months prior to treatment and 12 months post-treatment; maximum 15 months on IMP	Clinical parameters (symptoms), secondary clinical status endpoints (not including ACS, VOC, Other SCA-related)

Trial Locations

Locations (6): Dr Angela E Rankine- Mullings
🇯🇲
Kingston, Jamaica
Evelina London Children's Hospital
🇬🇧
London, United Kingdom
King's College Hospital NHS Foundation Trust
🇬🇧
London, United Kingdom
Birmingham Women's and Children's NHS Foundation Trust
🇬🇧
Birmingham, United Kingdom
Alder Hey Children's NHS Foundation Trust
🇬🇧
Liverpool, United Kingdom
The Royal London Children's Hospital, Barts Health NHS Trust
🇬🇧
London, United Kingdom