Introduction

Sickle cell disease is an inherited blood disorder resulting from a genetic mutation of the beta

hemoglobin chain (HbSS), with high prevalence in Sub-Saharan Africa. Due to a complex interplay of adhesive events, these altered erythrocytes can obstruct the vasculature, producing episodes of pain, organ ischemia and infarction and early mortality.  Activated platelets promote the adherence of sickle cells to endothelial cells and thus participate in the vaso-occlusive process.  Inhibition of platelet activation has therefore been proposed as a potential therapeutic option in the treatment of children and adults with SCD.

Ticagrelor is an orally active, reversibly binding cyclopentyl-triazolo-pyrimidine P2Y₁₂ receptor antagonist that produces dose‑related inhibition of adenosine diphosphate (ADP) induced platelet aggregation. Ticagrelor is indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). The ticagrelor development program to date has focused on adult patients since there is no paediatric correlate for the adult condition of ACS. This study will therefore seek to characterise the relationship between ticagrelor dose and inhibition of platelet aggregation in paediatric patients with SCD to support a Phase III study.

Primary Objective:

To characterise the relationship between ticagrelor dose and inhibition of platelet aggregation in paediatric patients with SCD, using PK-PD modelling, to support dose selection for Phase III

Secondary Objective:

1.       To determine the PK properties of ticagrelor and its active metabolite in paediatric patients with SCD and to assess impact of weight, age and other demographic on the ticagrelor pharmacokinetics.

2.       Investigation of efficacy of ticagrelor vs. placebo in paediatric patients with SCD in reducing the number and severity of VOCs

3.       To assess safety and tolerability of single and multiple doses of ticagrelor in paediatric patients with SCD

4.       To determine the percent of patients with haemorrhagic events requiring medical intervention.

5.       Investigation of efficacy of ticagrelor vs. placebo in paediatric patients with SCD in reducing frequency and intensity of pain*

* These do not apply to the study arm in Kenya

Study site(s) and number of subjects planned

This study is currently conducted in 5 countries (United States, United Kingdom, South Africa, Canada and Lebanon) and approximately 8 to 20 sites, with a minimum of 36 patients and a maximum of 50 patients to be randomised in the study, depending on how many patients are required in order to have 36 evaluable patients.

Study design

This is a multicenter, open-label, dose-ranging study of ticagrelor followed by a double blind, placebo-controlled extension phase in paediatric patients with sickle cell disease (SCD). 

Part A: Patients will be randomised in a 1:1 ratio to receive one of the two dosing schedules. All patients will receive 0.75 mg/kg as their initial single dose, followed 7 days later by 1.125 mg/kg or 2.25 mg/kg with determination of pharmacokinetic (PK) parameters and pharmacodynamic (PD) platelet inhibition following each single dose. The PK and platelet aggregation data are intended to support modelling-based selection of a weight-based dose for Phase III. Platelet aggregation will be measured using the VerifyNow™ P2Y₁₂ assay and reported as P2Y₁₂ reaction units (PRU).

Following the 2 single doses, all patients will receive open-label one-week treatment with ticagrelor 0.75 mg/kg twice daily to determine tolerability prior to randomisation into Part B.

Part B: Part B will be optional for patients. The investigator should present Part B to each patient and the decision to participate in Part B should be made by the patient (or parents/legal guardian). In this part patients will be randomised (2:1 ratio) to ticagrelor 0.75 mg/kg twice daily or placebo for a 4-week treatment phase. In some countries (Lebanon, Ghana, and Kenya), Part B will not be performed.

Kenya centres: In Kenya patients will not be randomised to Part B. The patients will finish study treatment after 1 week open-label treatment and will visit site 30 days after treatment is stopped for follow-up. 

During the study, patients will be followed for the occurrence of vaso-occlusive crisis (VOC) and for other disease manifestations such as daily pain, analgesic use and complications of SCD.

For safety reasons the dosing schedule will be modified for individual patients as follows: If PRU at 2 hr following dosing of 0.75 mg/kg is <95, the subsequent maximum dose for this patient will be 0.563 mg/kg throughout the study. If PRU <95 following dosing of 0.563 mg/kg, the patient will be discontinued from further study drug.

Since Part A of the study is open‑label, the PK and PD results will be monitored as the study proceeds and the doses may be further adjusted in both Part A and B based on emerging PK and PD results. Doses may be adjusted following assessment by AstraZeneca and the Steering Committee of open-label Part A results in the first 6 to 12 patients randomised under this amendment. Dose adjustment decisions will be based upon a review of PK, PD and adverse events.

 Target subject population

Patients eligible for this study include all children aged ≥2 to <18 years of age (age from birth to Visit 1) who are diagnosed with SCD (homozygous sickle cell [HbSS] or sickle beta‑zero‑thalassemia [HbS/β⁰]). 

Duration of treatment

In Part A the treatment period consists of 2 single doses (separated by at least 7 days) followed by 7 days open-label ticagrelor treatment twice daily. In Part B patients will be randomised to 4 weeks twice-daily treatment. There is no washout period between Part A and Part B. The total expected study duration for an individual patient participating in both Part A and Part B is approximately 3 months (including 30 days follow-up after last dose) and approximately 2 months for an individual patients participating in only Part A (including 30 days follow-up after last dose). For Kenya centres, Part B will not be conducted).

Investigational product, dosage and mode of administration

Part A:

Ticagrelor 0.563 mg/kg, 0.75 mg/kg, 1.125 mg/kg or 2.25 mg/kg given as oral single doses.

Ticagrelor 0.563 mg/kg or 0.75 mg/kg twice daily given orally.

These doses may be adjusted based upon evaluation of PK/PD data as described in Appendix E of full protocol attached.

Part B:

Ticagrelor 0.563 mg/kg or 0.75 mg/kg twice daily given orally and matching placebo.

These doses may be adjusted based upon evaluation of PK/PD data as described in Appendix E.