CSP Amendment 1: The purpose of this amendment was to address changes in the CSP related to the FDA’s identified potential hold issues and non-hold comments for IND 120,366, dated 11 April 2014. An additional haematology and chemistry assessment was included at Visit 4. The stopping rules in Section 3.11 of the CSP were revised. Patients will be discontinued from study drug if any major bleeding should occur, not at the discretion of the PI. The time of the study follow-up visit (Visit 9) was changed to 30-35 days after last dose. Severity of AEs will be collected by maximum intensity. The intensity ratings are mild, moderate and severe. The Faces Pain Scale - Revised will be administered to patients aged ≥4 years instead of all patients. Inclusion criterion 2 was amended to read: “Experienced at least 2 vaso-occlusive crises requiring medical intervention during the past 12 months”. The study was amended to a double-blind design. In addition clarifications on exclusion criterion 1, order of study procedures during study visits and recording of study drug intake in dosing diary have been made. First dose after each visit in the repeated dosing phase will be administered in the evening to simplify for the patients. Exclusion criterion 12; Males were deleted and 1 variable collected for AE was deleted due to error in writing. The time of the study enrolment visit (Visit 1) was changed, and is ≤30 days before Visit 2. TCD exams and ophthalmological exams were added as study procedures, for any patients who had not had the exams within the specified time periods, the new maximum time between Visit 1 and 2 allowed for these exams to be scheduled if needed.

CSP Amendment 3: Analysis of the first 12 randomised patients showed that the exposure to ticagrelor was lower than predicted and the platelet inhibitory effect was also lower than intended. Protocol was therefore amended to increase to better characterise the PK-PD relationship for ticagrelor. The following is a description of changes: Initial doses of 0.125 mg/kg, followed 7 days later by 0.375 mg/kg or 0.563 mg/kg were amended to initial doses of 0.75 mg/kg, followed 7 days later by 1.125 mg/kg or 2.25 mg/kg. Inclusion criterion 2 concerning the history of VOC in the prior 12 months was removed. Inclusion criterion 4: The requirement for stable hydroxyurea dosing was changed from 3 months to 1 month. The amended protocol allowed for patients to opt out of participation in Part B to reduce study burden on patients/families. Since Part B was now optional, the PK-PD determinations previously scheduled for Visit 8 were moved to Visit 4 in order to assure that steady state PK-PD was obtained in all study patients. The pregnancy urine testing was moved from Visit 3 to Visit 2 to ensure that all patients were tested prior to first dose. A pregnancy test was added to Visit 4 for the patients only completing Part A to insure that all patients were tested following repeated dosing. If most of the remaining patients declined participation in Part B, the patients in the EAS were prone to selection bias. Results of statistical tests conducted under such circumstances were not generalisable and hence only descriptive statistics were used. The minimum number of days between Visit 1 and Visit 2 was increased from 7 days to 14 days to ensure that 30 days elapsed between Visit 1 and Visit 4. This ensured that the volume of blood to be drawn within 30 days was not higher than 3% of blood volume. The visit window between the treatment visits was shortened to better fit the visit schedule and to avoid requiring patients to take home large volumes of study drug.

CSP Amendment 2: AstraZeneca Study Team initiated the amendment to clarify wording, decrease patient burden, and to incorporate requests from the PDCO of the European Medicines Agency and the MHRA. The following is a description of notable changes: Updated the secondary objective to include the PK properties of the active metabolite of ticagrelor. Re-worded some inclusion/exclusion criteria for clarification and consistency with other parts of the CSP. Stated that randomisation would take place 7 to 30 days after enrolment. Changed collection of haematology and clinical chemistry sample at Visit 4 to 2 hours post-dose. Shortened the PK and PRU sampling time for Visit 2 and Visit 3 as last measurement occurred at 6 hours post-dose and corrected the volume of blood collection for patients with a weight of 16 to 21 kg. Confirmed that Visit 5 and Visit 7 could optionally be performed as telephone contacts rather than centre visits if the PI deemed this acceptable. Updated the criteria for interruption or discontinuation of study drug. Stated that laboratory testing performed prior to enrolment as part of usual clinical care did not need to be repeated as long as the values were obtained no more than 30 days prior to Visit 2. Added a new section specify ECG parameters collected for the study. Stated that NSAIDs could not be administered more frequently than 3 days per week during the study. Added a new section to clarify that any blood transfusion during the study will be recorded in the eCRF. Stated the maximum dose of ticagrelor in this study was 45 mg, regardless of the weight of a patient . Added pain assessment for SCD pain for children aged 2 to <4 years. FLACC form and instructions for completion of the form were added. This was studied as exploratory objectives. Added description of how PD (VerifyNow P2Y12) samples were collected and handled. Clarified that definition of VOC included medical intervention at short-stay unit.