There is a high-unmet need for treatment options in children with sickle cell disease (SCD) and there is a scientific rationale, supported by clinical data, that preventing platelet clamping has the potential to reduce the risk for acute clogging of small blood vessels. A programme is currently ongoing to assess the potential treatment benefits of ticagrelor in reduction of the occurrence of blood vessel blockage in children with SCD. Before the first study in children, laboratory study to investigate the potency of ticagrelor, showed similar ticagrelor potency in blood from children aged 0 to 2 years old, as compared to older children and adults.

Sickle cell disease (SCD) is a genetic, autosomal, recessive blood disorder resulting an altered haemoglobin β-chain (HbS). When the altered haemoglobin is deoxygenated it aggregates into large polymers, distorting the shape of the red cells to sickle-shaped. A vaso-occlusive crisis (VOC) is a severe, acute painful episode that occurs when sickle-shaped red blood cells obstruct the microcirculation and restrict blood flow to an organ or tissue, resulting in ischaemia, necrosis and organ damage. There is a high unmet need for treatment options in SCD and there is a scientific rationale, supported by clinical data, that platelet inhibition has the potential to reduce the risk for acute vaso-occlusions.

This is an international, multicentre, double-blind, randomised, parallel-group, placebo controlled Phase III study to evaluate the effect of ticagrelor versus placebo in reducing the rate of Vaso-Occlusive Crises (VOCs) in paediatric patients with Sickle Cell Disease (SCD). During the treatment period, patients will be monitored for occurrence of VOCs and other acute SCD complications. Study participants should receive standard of care for SCD, adjusted to the individual patient at the discretion of the investigator, including routine health care screening examinations and immunisations according to local guidelines and health care programmes. Study drug will be given on the background of standard treatments for SCD. However, restrictions apply to some medications and interventions that may be necessary for the patient's health and well-being during the study. Temporary hold of study drug dosing could therefore be needed in case of short-term treatment with a medication not to be combined with study drug or in case of surgical interventions. Patients are to be followed until a common study end date (CSED) is reached defined as 12 months after the last patient is randomised. The target population are children aged ≥2 to <18 years of age and body weight of ≥12 kg diagnosed with homozygous sickle cell anaemia (HbSS) or sickle beta-zero-thalassaemia (HbS/β0 ). At least 50 evaluable patients should be recruited in each of the age groups, ≥2 years to <12 years and ≥12 years to <18 years. Dosages: Ticagrelor tablets of 15 mg and its matching placebo (approximately 6 mm in diameter) will be packed in high density polyethylene bottles containing 100 tablets. Subsequent intervals between dispensing visits must not be more than 100 days. Randomization: Randomisation to twice daily double-blind treatment with ticagrelor or placebo will occur at Visit 2 via the IXRS. Eligible patients will be randomly assigned to 1 of 2 treatment regimens, based on body weight at Visit 2:≥12 to ≤24 kg body weight: 15 mg - 1 tablet of ticagrelor 15mg or 1 tablet of placebo to match ticagrelor 15 mg twice daily • >24 to ≤48 kg body weight: 30 mg - 2 tablets of ticagrelor 15mg or 2 tablets of placebo to match ticagrelor 15mg twice daily • >48 kg body weight: 45 mg - 3 tablets of ticagrelor 15mg or 3 tablets of placebo to match ticagrelor 15mg twice daily At Visit 2, the first dose of IP will be administered at the clinic by site staff as soon as possible after randomisation and after all baseline assessments have been completed. Subsequent doses should be taken morning and evening, at approximately 12 hour intervals. Missed doses of ticagrelor or placebo blinded IP should not be compensated (ie, if a dose is missed the next regularly scheduled dose should be taken and should not be doubled). The study drug will be administered orally either swallowed whole or dispersed in water, other suitable liquids or vehicles based on age and/or ability to swallow study drugs. Refer to handling instructions for further details Methods for assigning treatment groups: The randomisation codes will be computer generated by AstraZeneca R&D and loaded into the IXRS database. Randomisation codes will be generated in blocks to ensure approximate balance (1:1) between the 2 treatment arms (ticagrelor or placebo bd). Stratification for baseline hydroxyurea use by country will be applied. For each patient randomised the IXRS will provide the Investigator with a unique kit ID number matching the treatment arm assigned to the patient. Following randomisation, the first dose of study drug will be administered to the patient as soon as possible. At randomisation and subsequent dispensing visits the patient should always be provided medication with the kit ID(s) allocated by the IXRS. If a patient receives the incorrect randomised treatment at any time during the study, this must be corrected as soon as discovered after discussing with the study physician. Methods for ensuring blinding: This is a double-blind study. Ticagrelor and matching ticagrelor placebo tablets will be identical in appearance and packaging. The bottles with IPs will be labelled with unique ID numbers allocated from the IXRS, but it will not indicate treatment allocation. No member of the study team at AstraZeneca or representative, personnel at study centres or any contract research organisation (CRO) handling data will have access to the randomisation scheme during the conduct of the study, with the exception of the AstraZeneca personnel generating the randomisation scheme and the bioanalysis personnel analysing the pharmacokinetic (PK) samples as well as AstraZeneca Supply Chain, the Patient safety data entry site and the CRO companies providing the IXRS and carrying out the packaging and labelling of IPs. This documentation will be kept in a secure location until the end of the study. There will be an independent, unblinded statistical team that will support the DMC with data during the study. Personnel involved in the clinical study at AstraZeneca or representative will remain blinded to these analyses and will have no knowledge of the results presented to the DMC. Dose increase during study For any patient having a weight gain during the study period clearly exceeding the upper weight limit of the band (≥27 kg and ≥54 kg, respectively), the dose will need to be increased according to the next weight band. In case of a dose increase: IXRS will generate correct dose based on body weight range entered Stop date for the old dose and start date for the new dose should be recorded in the eCRF. The patient should return all unused IP and empty bottles and new IP bottles should be dispensed PK and PD samples should be taken at the following visit after the adjusted dose has been dispensed, see Sections 5.4 and 5.5 of Protocol. Justification of Phase Assessment of the safety and efficacy of ticagrelor for the treatment of paediatric and young adult patients with sickle cell disease is ongoing in the HESTIA clinical development. The HESTIA 1 and HESTIA 2 Phase II studies have not indicated increased bleeding risk or raised other safety concerns. This phase III study will evaluate the efficacy, safety and tolerability of ticagrelor versus placebo in children with SCD during treatment for at least 12 months and up to approximately 24 months. Justification for Choice of design: Patients diagnosed with homozygous sickle cell (HbSS) or sickle beta zero thalassemia (HbS/β0) will be eligible. Patients with clinically milder variants (eg, sickle cell haemoglobin C [HbSC]) will not be eligible, since they usually have a lower frequency of painful. The different pattern of SCD manifestations in patients with HbSC could introduce heterogeneity into the study population. In addition, there are data to suggest that platelet activation in HbSS is elevated compared with HbSC, thus, patients with HbSC may be less likely to benefit from P2Y12 inhibition. To be eligible for the study, patients must have experienced at least 2 VOCs (defined as painful crisis and/or ACS) events in the past 12 months prior to Visit 1, indicating that the severity of the patient’s disease justifies preventive chronic long-term treatment. The intent is to enrol only children aged 2 years or above, since VOCs become more frequent with age. Above 2 years of age, children may have experienced more than 1 VOC, and established a pattern of frequency such that an intervention to reduce the rate of VOCs can be justified and meaningfully evaluated. Thus, the unmet need to prevent VOCs is most evident in children from 2 years of age and above. Due to ticagrelor mechanism of action and the potential to reduce symptoms caused by ischemia during a vaso-occlusion, a composite endpoint with painful crises and/or ACS has been selected for the primary endpoint. Painful crisis is the most common reason for emergency department visits for patients with SCD with a significant impact on young patients’ lives, affecting them physically and emotionally. ACS is a potentially life threatening condition involving vaso-occlusion, eg, when caused by pulmonary infarction or indirectly because of fat embolism secondary to bone marrow infarction, and/or a pulmonary infection. Both painful crises and/or ACS are identified by patients/parents as the acute SCD-related complications having the most impact on their lives, and these endpoints are commonly used for evaluation of clinical outcome in trials in SCD. Secondary endpoints are included to broaden the understanding of effects in patients with SCD and to also assess potential benefits on symptomatic disease burden and health-related quality of life (HRQL). Justification for Use of placebo There are no other drugs approved for reduction of VOCs in children with SCD with a similar mechanism of action as ticagrelor. Hydroxyurea is approved for use in children with SCD in some markets and more recently, L-glutamine was approved by the US FDA. Evaluation of ticagrelor when given in addition to standard of care including these medications, where available and when considered medically appropriate, is considered acceptable for studying the efficacy and safety of ticagrelor in this patient group as compared with placebo. Justification of Dosages The ticagrelor PK/PD modelling and simulation work based on the results from HESTIA1 and HESTIA2 studies identifies 15, 30 and 45 mg bd, depending on body weight, as relevant doses in the HESTIA3 study. These doses are predicted to result in a platelet activity measured as P2Y12 reaction units ([PRU] as measured by VerifyNow®) of less than 180, corresponding to >35% platelet inhibition in terms of reduction in PRU assuming a baseline PRU of 280 (which was the baseline PRU observed in HESTIA1, and similar to prasugrel Phase III DOVE study [Heeney et al 2016]). The predicted platelet inhibition in HESTIA3 is similar to what was observed in the 45 mg bd dose group in the HESTIA2 study in young adults, where after 1 week of treatment the mean percentage decrease from baseline PRU was 48% before morning dose and 81% at 2 hrs after dose. The 45 mg bd dose group was well tolerated and events of bleeding were of the same number and similar compared to the placebo and the 10 mg bd dose groups. Given the reversible mechanism of action for ticagrelor, the level of P2Y12 inhibition during ticagrelor treatment is expected to vary within a dosing interval and peak around 2 hours after dosing. When developing the dosing strategy for this study, the target for platelet inhibition was guided by the results from the recent prasugrel Phase III study in paediatric patients with SCD aged 2 to 17 years, showing insufficient efficacy with a mean PRU of 207 (ie, approximately 20% reduction from baseline) (Jakubowski et al 2017). The lack of therapeutic benefit with prasugrel may have been related to a too low platelet inhibition (Heeney et al 2016), and consequently, doses for HESTIA3 were selected to achieve a greater level of platelet inhibition. Moreover, a study with ticlopidine in adolescents and adult patients with SCD showing significant reductions in VOC (Cabannes et al 1984) used doses that generally provide <60% inhibition of platelet aggregation, which provides further support for the platelet inhibition target and the selected doses for the HESTIA3 study. Justification for Randomisation Randomization will be used to minimize bias in the assignment of subjects to treatment arms, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment arms, and to enhance the validity of statistical comparisons across treatment arms. Justification for Blinding Blinding will be used to reduce potential bias during data collection and evaluation of clinical endpoints.