E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040641 |
E.1.2 | Term | Sickle cell anaemia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040641 |
E.1.2 | Term | Sickle cell anaemia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the absorption of oral hydroxyurea solution into the body. |
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E.2.2 | Secondary objectives of the trial |
To ssesss the safety of oral hydroxycarbamide solution To assess effects on laboratory parameters To assess effects on pain, transfusions, hospitalisations and acute chest syndrome To assess the acceptability and palatability (taste and smell) of oral hydroxycarbamide solution To investigate the effects of oral hydroxycarbamide solution dose escalation on laboratory and clinical parameters |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 HbS0). 3. 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. |
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E.4 | Principal exclusion criteria |
1. Any clinically significant medical condition or abnormality, which, in the opinion of the investigator, might compromise the safety of the patient or which might interfere with the study. 2. Hydroxycarbamide use within 6 months before enrolment. 3. Renal insufficiency (either microalbuminuria, from spot urine or albumin/creatinine ratio [ACR value of > 0.03] and/or Proteinuria, from albumin specific dipstick) (for Proteinuria UTI will be excluded by culture/MSU). 4. Clinical evidence of hepatic compromise with ALT more than 3 times the upper limit of normal (a temporary swing in ALT will not result in exclusion). 5. Other significant organ system dysfunction based on the site investigator’s discretion. 6. Active infections: bacterial (as confirmed by culture), viral or fungal (tuberculosis, malaria, active hepatitis, osteomyelitis); 7. Active chronic leg ulcers. 8. Known allergy to oral hydroxycarbamide solution or any of the excipients. 9. Positive pregnancy test for females of child-bearing potential before initiation of treatment, unless participant is sexually abstinent. Note: true abstinence is considered as being in line with the preferred and usual lifestyle of the subject. 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 and males of child-bearing age (see section 5.12). 11. Currently breastfeeding. 12. Participating in another clinical trial of an IMP. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoints: Pharmacokinetic parameters • Clearance (CL/F) • Volume of distribution (V/F) • Time to maximum concentration (Tmax) • Maximum plasma concentration (Cmax) • Area under plasma concentration time curve (AUC) • Half-life (t1/2) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetics Pharmacokinetics of oral hydroxyurea solution will be evaluated at 2 study visits: Month 1: Day 1 Month 6: Day 1 On the day of sampling, hydroxyurea will be administered in the clinic. A peripheral venous catheter will be used for sampling and blood will be sampled post-dose at the following time points: Time point (h) Pre-dose 0.25 0.5 1 1.5 2 3 4 5 6 *The pre-dose sample is mandatory. At least 3 further samples (at least 2 further samples in children less than 2 years) will be collected over 0.25 to 6 hours. A single sample for pharmacokinetic analysis will also be taken at other visits, whenever feasible. If possible this sample will be taken at 12 hours post dose (i.e. doses may be adjusted to be taken in the evening to enable this sample time) |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints: Safety: • Incidence of adverse events • Absolute neutrophil count • White cell count • Platelets • Liver function tests (LFTs) • Hemoglobin/Anemia • Additional safety laboratory parameters • Bacterial infections • Viral infections • Fungal infections • Leg ulcers Biomarkers • Fetal hemoglobin • Hemoglobin • Mean Corpuscular Volume Clinical Status • Incidence of acute pain crises* • Number and frequency of blood transfusions • Incidence of acute chest syndrome • Dose escalation i.e. time to maximum tolerated dose • Clinical parameters (symptoms) • Parent/caregiver acceptability/usability by questionnaire Palatability and Acceptability: Evaluate the taste acceptability of the new oral liquid formulation of hydroxyurea. Exploratory Endpoints: • Transcranial Doppler (TCD) velocity • Urine parameters (albumin, creatinine for ACR ratio) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be assessed at each study visit as appropriate |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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For administrative and safety reporting purposes the end of the study will be defined as one month after the last child completes treatment (i.e. at the end of the follow up period for the last child). This provides for a single and conservative definition. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 21 |