Clinical trial NCT03763656: Pharmacokinetics of Oral Hydroxyurea Solution
Official title: A Prospective Open Label, Pharmacokinetic Study of an Oral Hydroxyurea Solution in Children With Sickle Cell Anemia.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Sickle Cell Disease
Sickle-Cell; Hemoglobin Disease, Thalassemia
Sickle Cell-beta-thalassemia
Sickle Cell Hemoglobin C
Keywords: Hydroxyurea
Hydroxycarbamide
Xromi
Lead sponsor: Nova Laboratories Limited
Sponsor class: INDUSTRY
First posted: 2018-12-04
Enrollment: 33
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label, observational, pharmacokinetic study of oral hydroxyurea solution administered to children from 6 months-17.99 years over a 12-15-month period
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Clearance (CL/F)
timeFrame: 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)
measure: Volume of Distribution (V/F)
timeFrame: 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)
measure: Time to Maximum Concentration (Tmax)
timeFrame: 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)
measure: Maximum Plasma Concentration Cmax (ug/mL)
timeFrame: 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)
measure: Area Under Plasma Concentration Time Curve (AUC 0-Inf)
timeFrame: 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)
measure: Terminal Half-life (Hours)
timeFrame: 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:
measure: Adverse Events
timeFrame: Screening Up to Week 64
measure: Absolute Neutrophil Count (ANC)
timeFrame: Baseline and Week 60 (or final visit); max 15 months on treatment
measure: White Blood Cell Count (Leukocytes)
timeFrame: Baseline to Week 60 or Final Visit; max 15 months on treatment
measure: Platelets
timeFrame: Baseline to Week 60 (or Final Visit), max 15 months on treatment
measure: Mean Corpuscular Hemoglobin (MCH)
timeFrame: Baseline to Week 60 (or Final Visit), max 15 months on treatment
measure: Hematocrit
timeFrame: Up to Week 60
measure: Bilirubin
timeFrame: Up to Week 60
measure: Elevation in Liver Function Tests (LFTs)
timeFrame: Up to Week 60
measure: Hemoglobin
timeFrame: Baseline to Week 60 (or Final Visit); max 15 months on treatment
measure: Bacterial Infections
timeFrame: Up to Week 60
measure: Viral Infections
timeFrame: Up to Week 60
measure: Fungal Infections
timeFrame: Up to Week 60
measure: Leg Ulcers
timeFrame: Up to Week 60
measure: Fetal Hemoglobin
timeFrame: Baseline to Week 60 (or Final Visit); max 15 months on treatment
measure: Mean Corpuscular Volume (MCV)
timeFrame: Baseline to Week 60 (or Final Visit); max 15 months on treatment
measure: Cystatin C
timeFrame: PK1 (day 1), week 20-32 (6 months) and Week 60 (Final Visit)
measure: Incidence of Acute Vaso-Occlusive Pain Crises (VOC)
timeFrame: 12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP
measure: Number and Frequency of Blood Transfusions
timeFrame: Up to Week 60
measure: Acute Chest Syndrome (ACS)
timeFrame: 12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP
measure: Hospitalizations
timeFrame: 12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP
measure: Dose Escalation i.e. Maximum Tolerated Dose (MTD)
timeFrame: Screening Up to Final Visit (Week 60 or Withdrawal), maximum 15 months on IMP
measure: Other SCA-related Hospitalizations
timeFrame: 12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP
measure: Parent/Caregiver Palatability and Acceptability Questionnaire
timeFrame: Taken once at any point after 8 weeks on study medication (or at early Withdrawal)
measure: Vitamin D
timeFrame: From Screening Up to Final Visit (Week 60 or WD)
measure: Other Non-SCA-related Hospitalizations
timeFrame: 12 months prior to treatment and 12 months post-treatment; maximum 15 months on IMP
Other outcomes:
measure: Transcranial Doppler Velocity
timeFrame: Baseline to Week 40-56 (Follow up scan).
Locations:
city: Kingston
country: Jamaica
facility: Dr Angela E Rankine- Mullings
city: Birmingham
country: United Kingdom
facility: Birmingham Women's and Children's NHS Foundation Trust
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's NHS Foundation Trust
city: London
country: United Kingdom
facility: Evelina London Children's Hospital
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: The Royal London Children's Hospital, Barts Health NHS Trust
Study officials:
affiliation: University of the West Indies, Mona, Kingston, Jamaica
name: Angela E Rankine- Mullings, MD
role: PRINCIPAL_INVESTIGATOR
References: