| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040645 |
| E.1.2 | Term | Sickle cell disease NOS |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 compare the effect of ticagrelor vs placebo for the reduction of VOCs, which is the composite of painful crisis and/or ACS, in paediatric patients with SCD |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives are:To compare the effect of ticagrelor vs placebo for the reduction of VOCs, which is the composite of painful crisis and/or ACS, in paediatric patients with SCD aged 2 to <18 years
To compare the effect of ticagrelor vs placebo for the reduction of painful crises
To compare the effect on ticagrelor vs placebo for the reduction of ACS
To compare the effect of ticagrelor vs placebo for the reduction of duration of painful crises
To compare the effect of ticagrelor vs placebo on the number of VOCs requiring hospitalisation or emergency department visits
To compare the effect of ticagrelor vs placebo on reduction of days hospitalised for VOC
To compare the effect of ticagrelor vs placebo on the number of acute SCD complications
To compare the effect of ticagrelor vs placebo on reduction of days hospitalised for acute SCD
complications
To compare the effect of ticagrelor vs placebo on the number of sickle cell-related red blood cell (RBC) transfusions |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Provision of signed and dated informed consent prior to any study specific procedures not
part of standard medical care (local regulations and international guidelines are to be followed in determining the assent/consent requirements for children). The Informed consent form (ICF) process is described in Appendix A 3 of the protocol.
2 Children aged 6 months to <18 years of age and body weight ≥6 kg diagnosed with HbSS
or HbS/β0 as confirmed by high-performance liquid chromatography (HPLC) or haemoglobin electrophoresis.
Note: Diagnosis of SCD (if not confirmed prior to screening and records not available on the medical file) should be confirmed for HbSS or HbS/β0 by HPLC or haemoglobin electrophoresis, performed at the site’s local laboratory, in order to confirm the type of mutation. Children being judged to be severely underweight (<3rd percentile according the World Health Organisation [WHO] growth charts) cannot be included.
3 Have experienced at least 2 VOCs (painful crisis and/or ACS) as judged by the Investigator in the past 12 months prior to Visit R1 (patients aged 6 to <24 months) or Visit 1 (patients aged 2 to <18 years). These VOCs need to be documented in the patient’s medical records or in other documents that can be reconciled.
4 If aged 2 to ≤16 years, must have had a TCD within the past year prior to Visit 2 (see Yawn et al 2014). If this is not the case, a TCD examination must be done before randomisation.
5 If aged ≥10 years, must have had an ophthalmological examination within the past year prior to Visit 1 (see Yawn et al 2014). If this is not the case, the patient must be examined by an ophthalmologist before proceeding in the study. If local guidelines dictate ophthalmological examination at younger ages, those local guidelines should be followed.
6 If treated with hydroxyurea or L-glutamine, the weight-adjusted dose must be stable for 3 months before screening.
7 Suitable venous access for the study-related blood sampling.
8 Prior to dosing on day of randomisation (Visit 2), a negative urine (dipstick) pregnancy test performed at Enrolment (Visit 1) and at Visit 2 must be available for female patients of childbearing potential.
9 Females of childbearing potential (after menarche) must not become pregnant during the study. Sexually active females must use a highly effective method of contraception which results in a low failure rate (ie, less than 1% per year). If use of effective contraception cannot be secured in sexually active females, the patient cannot be included in this study. Refer to Section 5.3 of the protocol for highly effective methods of contraception. |
|
| E.4 | Principal exclusion criteria |
1 As judged by the Investigator, any evidence of unsuitability which in the Investigator’s opinion makes it undesirable for the patient to participate in the study.
2 History of transient ischaemic attack (TIA) or cerebrovascular accident (ischaemic or haemorrhagic), severe head trauma, intracranial haemorrhage, intracranial neoplasm, arteriovenous malformation, aneurysm, or proliferative retinopathy.
3 Findings on TCD: Current or previous values for time averaged mean of the maximum velocity (TAMMV) that are Conditional or Abnormal. Patients with Conditional TAMMV values or higher (≥153 cm/sec using TCD imaging technique [TCDi] which is corresponding to ≥170 cm/sec by the non-imaging technique). Both the middle cerebral artery and the internal carotid artery should be considered. Any other criteria that would locally be considered as TCD indications for chronic transfusion would also exclude the patient.
4 Pathological finding on any other imaging assay indicating increased risk for intracerebral
bleeding or thromboembolism.
5 International normalised ratio (INR) >1.4 or active pathological bleeding or increased risk of bleeding complications according to Investigator.
6 Haemoglobin <6 g/dL from test performed at Visit R1 and Visit 1 (patients aged 6 to <24 months) or at Enrolment (Visit 1) (patients aged 2 to <18 years).
7 Platelets <100 × 109/L from test performed at Visit R1 and Visit 1 (patients aged 6 to <24 months) or at Enrolment (Visit 1) (patients aged 2 to <18 years).
8 Undergoing treatment with chronic red blood cell transfusion therapy.
9 Chronic use of NSAIDs defined as continuous intake >3 days per week that cannot be discontinued (see Appendix K of the protocol).
10 Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be
discontinued.
11 Moderate or severe hepatic impairment defined as laboratory values of alanine aminotransferase (ALT) >2×upper limit of normal (ULN), total bilirubin >2×ULN (unless judged by the Investigator to be caused by haemolysis), albumin <35 g/L (3.5 g/dL) and INR >1.4, or symptoms of liver disease (eg, ascites) from test performed at Visit R1 and Visit 1 (patients aged 6 to <24 months) or at Enrolment (Visit 1) (patients aged 2 to <18 years).
12 Renal failure requiring dialysis.
13 Patient considered to be at risk of bradycardic events (eg, known sick sinus syndrome or
second- or third-degree atrioventricular block) unless already treated with a permanent pacemaker.
14 Concomitant oral or intravenous therapy with strong cytochrome P450 3A (CYP3A) inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers (see full list in Appendix K of the protocol), which cannot be stopped at least 5 half-lives before randomisation.
15 Active untreated malaria. Patients with suspected malaria at Visit R1 (patients aged 6 to <24 months) or at Enrolment (Visit 1) (patients aged 2 to <18 years) will be tested.
16 Known hypersensitivity or contraindication to ticagrelor.
17 Patients who are currently pregnant or breastfeeding or planning to become pregnant during the study or have given birth less than 3 months prior to Enrolment (Visit 1).
18 Concern for the inability of the patient or caregiver (defined as legally authorised representative) to comply with study procedures and/or follow-up.
19 Previous randomisation in the present study or participation in any previous HESTIA study.
20 Participation in another clinical study with an IP or device during the last 30 days preceding screening.
21 Involvement of member of patient’s family, or patient self, in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Number of Vaso-occlusive crisis (VOCs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to End of Study Visit (12 to 24 months) |
|
| E.5.2 | Secondary end point(s) |
1.Number of VOCs in patients aged 2 to <18 years
2.Number of painful crises
3.Number of ACSs
4.Duration of painful crises
5.Number of VOCs requiring hospitalisation or emergency department visits
6.Number of days hospitalised for VOC
7.Number of acute SCD complications
8.Number of days hospitalised for acute SCD complications
9.Number of sickle cell-related RBC transfusions
10.HRQL total score and by dimension using Paediatric Quality of Life Inventory (PedsQL) SCD Module; and Fatigue total score and by dimension using the PedsQL Multidimensional Fatigue Scale (age appropriate versions: 2 to 4 years; 5 to 7 years; 8 to 12 years; 13 to 18 years); HRQL total score and by dimension using the PedsQL Infant Scale (age appropriate versions: 1 to 12 months; 13 to 24 months)
11.Proportion of days of absence from school or work (only if going to school or work at randomisation)
12.Intensity of worst pain daily during VOC
•For patients aged ≤4 years, observer reported using the Face, Legs, Activity, Cry, Consolability (FLACC) scale
13.Type of analgesics (opioid and non-opioid) use
14. •For patients aged ≤4 years taking the tablet dispersed or whole, an observer assessment of palatability and swallowability will be undertaken
•For patients aged ≥5 years taking the tablet dispersed or whole, palatability will be assessed and categorised using the Facial Hedonic Scale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,2,3,4,5,6,7,8, 9,11, 12,13 - Secondary end points will be measured up to End of
Study Visit
10-HRQL (PedsQL) assessment will be performed at randomization visit, visits 9, 15, 21 and End of Study
14-Palatability/swallowability will be performed at randomization visit and visits 2 and 9 |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open label run-in period for age group 6-24 months |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Egypt |
| Ghana |
| India |
| Italy |
| Kenya |
| Lebanon |
| Nigeria |
| Oman |
| Tanzania, United Republic of |
| Turkey |
| Uganda |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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