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 Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
33
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.
Dr Angela E Rankine- Mullings
Kingston, Jamaica
Birmingham Women's and Children's NHS Foundation Trust
Birmingham, United Kingdom
Alder Hey Children's NHS Foundation Trust
Liverpool, United Kingdom
Evelina London Children's Hospital
London, United Kingdom
King's College Hospital NHS Foundation Trust
London, United Kingdom
The Royal London Children's Hospital, Barts Health NHS Trust
London, United Kingdom
Clearance (CL/F)
Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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)
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.
Time frame: Screening Up to Week 64
Absolute Neutrophil Count (ANC)
Safety review for haematological toxicity (mild myelosuppression target: 1-3x10\^9/L)
Time frame: 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
Time frame: Baseline to Week 60 or Final Visit; max 15 months on treatment
Platelets
Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Time frame: Baseline to Week 60 (or Final Visit), max 15 months on treatment
Mean Corpuscular Hemoglobin (MCH)
Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Time frame: Baseline to Week 60 (or Final Visit), max 15 months on treatment
Hematocrit
Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Time frame: Up to Week 60
Bilirubin
Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Time frame: 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)
Time frame: Up to Week 60
Hemoglobin
Safety and efficacy of hydroxyurea therapy
Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment
Bacterial Infections
Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Time frame: Up to Week 60
Viral Infections
Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Time frame: Up to Week 60
Fungal Infections
Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Time frame: Up to Week 60
Leg Ulcers
Impact of Hydroxyurea on Safety, Hematology and Biochemistry
Time frame: Up to Week 60
Fetal Hemoglobin
Biomarker endpoints of Hydroxyurea efficacy
Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment
Mean Corpuscular Volume (MCV)
Biomarker endpoints of Hydroxyurea efficacy
Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment
Cystatin C
Biomarker Endpoints
Time frame: 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 \[SD\])
Time frame: 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)
Time frame: 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 \[SD\])
Time frame: 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 \[SD\])
Time frame: 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 \[SD\])
Time frame: 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 \[SD\])
Time frame: 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.
Time frame: Taken once at any point after 8 weeks on study medication (or at early Withdrawal)
Vitamin D
Biochemistry
Time frame: 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)
Time frame: 12 months prior to treatment and 12 months post-treatment; maximum 15 months on IMP
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