E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Investigation of platelet aggregation in paediatric patients with sickle cell disease |
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E.1.1.1 | Medical condition in easily understood language |
In children diagnosed with sickle cell disease, to study the effects of study treatment on platelets and blood vessel blockage. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040644 |
E.1.2 | Term | Sickle cell disease |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To characterise the relationship between ticagrelor dose and inhibition of platelet aggregation in paediatric patients with Sickle Cell Disease (SCD), using PK-PD modelling, to support dose selection for Phase III |
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E.2.2 | Secondary objectives of the trial |
To determine the PK properties of ticagrelor in paediatric patients with Sickle Cell Disease (SCD) and to assess impact of weight, age and other demographic on the ticagrelor pharmacokinetics
Investigation of efficacy of ticagrelor vs. placebo in paediatric patients with SCD in reducing:
Number of Vaso-occlusive crises (VOC)
Days hospitalized for VOC or other complications of SCD
Days with pain (ages ≥4 years only)
Intensity of pain (ages ≥4 years only)
Days of analgesic use (ages ≥4 years only)
Days of opioid analgesic use
Days of absence from school or work (ages ≥6 years only)
To assess safety and tolerability of single and multiple doses of ticagrelor in paediatric patients with SCD
To determine the percent of patients with haemorrhagic events requiring medical intervention. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Children aged ≥2 to <18 years of age and body weight >16 kg diagnosed with homozygous sickle cell (HbSS) or sickle beta-zero-thalassaemia (HbS/β0)
2.If treated with an anti-sickling agent such as hydroxyurea, the weight adjusted dose must be stable for 1 month before enrolment
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E.4 | Principal exclusion criteria |
1.Previous history of transient ischemic attack (TIA) or clinically overt cerebrovascular accident (CVA) (ischemic or haemorrhagic), severe head trauma, intracranial haemorrhage, intracranial neoplasm, arteriovenous malformation, aneurysm, or proliferative retinopathy
2.Findings on TCD: Current or previous values for time averaged mean of the maximum velocity (TAMMV) that are Conditional or Abnormal*.
Conditional TAMMV values are ≥153 cm/sec using imaging TCD (TCDi) technique (corresponding to ≥170 cm/sec by the non-imaging technique). Both the middle cerebral artery and the internal carotid artery should be considered. Abnormal TAMMV values are ≥180 cm/sec using TCDi (corresponding to ≥200 cm/sec by the non-imaging technique) and are an indication for chronic transfusions because of a high stroke risk. Any other criteria that would locally be considered as TCD indications for chronic transfusion would also exclude the patient.
3.Undergoing treatment with chronic RBC transfusion therapy
4.Use of non-steroidal anti-inflammatory drugs (NSAIDs) >3 days per week
5.Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be discontinued.
6.Moderate or severe hepatic impairment, defined as Child-Pugh Class B or C,or renal failure requiring dialysis
7.Active pathological bleeding or increased risk of bleeding complications according to Investigator
8.Risk of bradycardic events (known sick sinus syndrome or second or third degree atrioventricular block)
9.Concomitant oral or intravenous therapy with strong CYP3A4 inhibitors, CYP3A4 substrates with narrow therapeutic indices, or strong CYP3A4 inducers
10.Surgical procedure planned to occur during the study
11.Patients who are currently pregnant or breastfeeding, or planning to become pregnant during the study
12.Known hypersensitivity or contraindication to ticagrelor
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E.5 End points |
E.5.1 | Primary end point(s) |
P2Y12 reaction units (PRU), Maximum plasma concentration (Cmax), Area under the plasma concentration time curve (AUC) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PRU:Pre-dose, 2, 6 h post-dose at Visit 2 and 3 (after single dosing); Pre-dose, 2h post-dose at Visit 4 (after repeated dosing)
Cmax and AUC: Visits 2,3, and 4
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E.5.2 | Secondary end point(s) |
Concentrations of Ticagrelor an its active metabolite
Efficacy endpoints: number of Vaso-occlusive crises, number of Vaso-occlusive crises requiring hospitalization or emergency department visits, days hospitalized for complications of sickle cell disease, days with pain, intensity of pain, days of analgesic use, days of opioid analgesic use, days of absence from school or work
Safety endpoints: AEs/Serious Adverse Events (SAE)s, Vital signs, laboratory safety samples, Haemorrhagic events
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Ticagrelor concentration: 1, 2, 4, 6 h post-dose at Visit 2 and 3 (after single dosing); Pre-dose, 1, 2h post-dose at Visit 4 (after repeated dosing).
Efficacy endpoints: during 4 weeks of study treatment starting from randomization in Part B.
Safety endpoints: vital signs at all study visits (1-9), laboratory samples at Visits 1, 4 and 9, SAEs from enrollment until Visit 9 and AEs, haemorrhagic events from randomization (Visit 2) until Visit 9.
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Part A is open label and Part B is double blind part |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 | No |
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 |
Canada |
Egypt |
Ghana |
Italy |
Kenya |
Lebanon |
South Africa |
Turkey |
United Kingdom |
United States |
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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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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 | 8 |
E.8.9.1 | In the Member State concerned days | |
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 |