Effect of Ticagrelor vs. Placebo in the Reduction of Vaso-occlusive Crises in Pediatric Patients With Sickle Cell Disease

Study Overview
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Brief Summary
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The purpose of the study is to Evaluate the Effect of Ticagrelor versus Placebo in Reducing the Rate of Vaso-Occlusive Crises in Paediatric Patients with Sickle Cell Disease

Detailed Description
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Hestia3 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. The target population are children aged ≥2 to <18 years of age and body weight of ≥12 kg diagnosed with HbSS or HbS/β0 confirmed by high-performance liquid chromatography or hemoglobin electrophoresis. 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. 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 enroll only children aged 2 years or above, since VOCs become more frequent with age. 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 immunizations according to local guidelines and health care programmers. Study drug will be given on the background of standard treatments for SCD. Study participants are not withheld from any other treatments that may be used in SCD (eg., hydroxyurea) during the trial, which is important considering the use of a placebo control group. However, restrictions apply to some medications and interventions that may be necessary for the patient's health and well-being during the study. Patients are to be followed up to 24 months or until a common study end date is reached defined as 12 months after the last patient is randomised. The expected average follow-up is 18 months. Considering inclusion of patients with at least 2 VOC events in the past year, this treatment duration is considered long enough to evaluate effects on VOC events as well as to capture safety and tolerability data supporting a potential future long term use of ticagrelor. 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. 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). Patients will be treated with 15, 30 and 45 mg bd or matching placebo, depending on body weight.

Official Title
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A Randomised, Double-Blind, Parallel-Group, Multicentre, Phase III Study to Evaluate the Effect of Ticagrelor Versus Placebo in Reducing the Rate of Vaso-Occlusive Crises in Paediatric Patients With Sickle Cell Disease (HESTIA3)

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Ticagrelor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Male or female paediatric patients aged ≥2 to <18 years and body weight of ≥12 kg (at Visit 1), diagnosed with HbSS or HbS/β0 as confirmed by high-performance liquid chromatography or haemoglobin electrophoresis. Note: Diagnosis of SCD (if not confirmed prior to screening and records available on the medical file) should be confirmed for HbSS or HbS/β0 by high-performance liquid chromatography or haemoglobin electrophoresis, performed at the site's local lab, in order to confirm the type of mutation. Have experienced at least 2 VOCs (painful crisis and/or ACS) as judged by the Investigator in the past 12 months prior to Visit 1. These VOCs need to be documented in the patient's medical records or in other documents that can be reconciled. If ≤16 years old, must have had transcranial Doppler (TCD) within the past year prior to Visit 1. If this is not the case, a TCD examination must be done before proceeding in the study. If ≥10 years old, must have had an ophthalmological examination within the past year prior to Visit 1. 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. If treated with hydroxyurea, the weight-adjusted dose must be stable for 3 months before screening. Suitable venous access for the study-related blood sampling Prior to dosing on day of randomisation (Visit 2), a negative urine (dipstick) pregnancy test performed at Screening (Visit 1) and at Visit 2 must be available for female patients of childbearing potential. Females of childbearing potential (after menarche) must not become pregnant during 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. Exclusion Criteria: 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. 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. Active pathological bleeding or increased risk of bleeding complications according to Investigator Haemoglobin <6 g/dL from test performed at Screening (Visit 1) Platelets <100 x 10^9/L from test performed at Screening (Visit 1) Undergoing treatment with chronic red blood cell transfusion therapy. Undergoing treatment with chronic red blood cell transfusion therapy. Chronic use of NSAIDs defined as continuous intake >3 days per week that cannot be discontinued Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be discontinued Moderate or severe hepatic impairment defined as laboratory values of alanine aminotransferase (ALT) >2 × upper limits 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 International normalised ratio (INR) >1.4, or symptoms of liver disease (eg, ascites) from test performed at Screening (Visit 1). Renal failure requiring dialysis 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. Concomitant oral or intravenous therapy with strong or moderate cytochrome P450 3A (CYP3A) inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers, which cannot be stopped at least 5 half-lives before randomisation. Active untreated malaria. Patients with suspected malaria at Screening (Visit 1) will be tested. Known hypersensitivity or contraindication to ticagrelor 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 Screening (Visit 1) Any condition which, in the opinion of the Investigator, would make it unsafe or unsuitable for the patient to participate in this study Concern for the inability of the patient or caregiver (defined as legally authorized representative) to comply with study procedures and/or follow-up Previous randomisation in the present study. Participation in another clinical study with an IP or device during the last 30 days preceding screening. 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).

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor<br>The double-blinded study drug dose will be weight dependent: ≥12 to ≤24kg: Ticagrelor 15 mg, twice a day >24 to ≤48 kg: Ticagrelor 30 mg, twice a day >48 kg: Ticagrelor 45 mg, twice a day. | Drug: Ticagrelor<br>* The double-blinded study drug dose will be weight dependent: ≥12 to ≤24kg: Ticagrelor 15 mg, twice a day >24 to ≤48 kg: Ticagrelor 30 mg, twice a day >48 kg: Ticagrelor 45 mg, twice a day.<br>|
| Placebo Comparator: Placebo<br>The double-blinded study drug dose will be weight dependent: ≥12 to ≤24kg: Placebo to match ticagrelor 15 mg, twice a day >24 to ≤48 kg: Placebo to match ticagrelor 30 mg, twice a day >48 kg: Placebo to match ticagrelor 45 mg, twice a day. | Drug: Placebo<br>* The double-blinded study drug dose will be weight dependent: ≥12 to ≤24kg: Placebo to match ticagrelor 15 mg, twice a day >24 to ≤48 kg: Placebo to match ticagrelor 30 mg, twice a day >48 kg: Placebo to match ticagrelor 45 mg, twice a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Vaso-Occlusive Crisis Events | A VOC is the composite of a painful crisis and/or an acute chest syndrome (ACS) event. The number of VOC events is defined as the count of VOC events experienced by a participant throughout the treatment period. | From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Painful Crisis Events | A painful crisis is an onset or worsening of pain that lasts at least 2 hours, for which there is no explanation other than vaso-occlusion and which requires therapy with oral or parenteral opioids, parenteral non-steroidal anti-inflammatory drugs, or other analgesics prescribed by a healthcare provider in a medical setting (such as a hospital, clinic or emergency room visit) or at home. Events with an onset date <=7 days of the previous event onset date are not counted as new events. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Number of Acute Chest Syndrome Events | The ACS is an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray. Events with an onset date <=7 days of the previous event onset date are not counted as new events. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Duration of Painful Crises | The duration of painful crises is defined as the sum of the duration of painful crises experienced by a participant over the defined treatment period. If two or more events have overlapping durations, the overlapping days were counted only once. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits | The number of VOC events requiring hospitalization or emergency department visits is defined as the count of VOC events experienced by a participant over the treatment period, for which the primary setting for VOC treatment was in-patient hospitalization or emergency department. Events with an onset date <=7 days of the previous event onset date are not counted as new events. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Number of Days Hospitalized for Vaso-Occlusive Crisis Events | The number of days hospitalized for all individual VOC events experienced by a participant during the treatment period is defined as the sum of the duration of all individual hospitalizations (taking into account potential overlapping hospitalization days of VOC components) during VOC events experienced by a participant over the treatment period for which the primary setting for VOC treatment was in-patient hospitalization. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Number of Acute Sickle Cell Disease Complications | The number of acute SCD complications is defined as the count of all individual acute SCD complications experienced by a participant over the treatment period. Acute SCD complications are defined as any one or more of the following individual complications: Transient ischaemic attack/ischaemic stroke, hepatic sequestration, splenic sequestration, priapism, and dactylitis. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Number of Days Hospitalized for Acute Sickle Cell Disease Complications | The number of days hospitalized for acute SCD complications is defined as the sum of the duration of all individual hospitalizations (taking into account potential overlapping hospitalization days) due to acute SCD complications experienced by a participant over the treatment period, for which hospitalization was reported. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions | The number of participants with at least one sickle cell-related RBC transfusion reported. Adverse events resulting in the need for RBC transfusions were captured prior to database lock to determine if the transfusion was sickle cell-related or not. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module | The PedsQL SCD module instrument developed using a 5-point Likert scale (where 0= never and 4= almost always) for the participant self-report forms for ages ≥5 to <8 years, ≥8 to <13 years, and ≥13 to ≤18 years and the caregiver proxy-report form specific for ≥2 to <5 years was used. The PedsQL SCD module measures problems in the following categories: Pain: 3 sub-scales Worry: 2 sub-scales Emotions: 1 sub-scale Treatment: 1 sub-scale Communication: 2 sub-scales Total score PedsQL SCD module items were reverse-scored and linearly transformed to a 0 to 100 scale (0= 100, 1= 75, 2= 50, 3= 25, 4= 0) so that higher scores indicate better quality of life. To create the PedsQL SCD module total score (43/42/40 items - depending on version completed) the arithmetic mean of the transformed scores was computed as the sum of the items transformed scores divided by the number of items answered. Baseline values are the closest observation prior to and including the randomization visit. | For ages ≥2 to <5 years and ≥5 to <8 years: Baseline (observation prior to and including the randomization visit) and Months 6, and 12; For ages ≥8 to <13 years and ≥13 to ≤18 years: Baseline and Months 6, 12, and 18 | 
| Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale | The PedsQL multidimensional fatigue scale instrument developed using a 5-point Likert scale (where 0= never and 4= almost always) for the participant self-report forms for ages ≥5 to <8 years, ≥8 to <13 years, and ≥13 to ≤18 years and the caregiver proxy-report form specific for ≥2 to <5 years was used. The PedsQL multidimensional fatigue scale measures problems in the following categories: General (6 items) Sleep/rest (6 items) Cognitive fatigue (6 items) Total score (18 items) PedsQL multidimensional fatigue scale items were reverse-scored and linearly transformed to a 0 to 100 scale (0= 100, 1= 75, 2= 50, 3= 25, 4= 0) so that higher scores indicate better quality of life. To create the PedsQL multidimensional fatigue scale total score (18 items), the arithmetic mean of the transformed scores was computed as the sum of the items transformed scores divided by the number of items answered. Baseline values are closest observation prior to and including randomization visit. | For ages ≥2 to <5 years and ≥5 to <8 years: Baseline (observation prior to and including the randomization visit) and Months 6, and 12; For ages ≥8 to <13 years and ≥13 to ≤18 years: Baseline and Months 6, 12, and 18 | 
| Percentage of Days of Absence From School or Work Due to Sickle Cell Disease | For participants attending school/work at randomization, absence from school/work due to SCD was recorded weekly by the participant in the eDevice with the help of the caregiver if needed. The percentage of days absent from school/work due to SCD in the defined treatment period was calculated as follows: Percentage of absent days = (total number of days reported)/(total number of questionnaires answered ×7). | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 Years of Age | The Face, Legs, Activity, Cry, Consolability (FLACC) scale is caregiver-reported and used to assess pain daily during the VOC event for those participants <5 years of age as determined at randomization. Each of the 5 behaviours observed are assigned a score of 0, 1 or 2. The total FLACC score ranges between 0 and 10, with 0 representing no pain and 10 representing very much pain. Lower score indicate better outcome. Worst pain ratings were collected once daily throughout the duration of the VOC event using an eDevice. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 Years of Age | The Faces Pain Scale-revised (FPS-R) was administered to assess pain daily during the VOC event by those participants aged ≥5 years as determined at randomization. The FPS-R consists of 6 faces and scoring ranges between 0 and 10 (with an increase in numeric value by 2), where 0 is no pain and 10 is very much pain. Lower score indicate better outcome. Worst pain ratings were collected once daily throughout the duration of the VOC event using an eDevice. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events | Analgesics use (opioid and non-opioid) during VOC events. | From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months | 
| Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age | Response to palatability was assessed through the SMPA question Was any behaviour observed when the study medication was given to this participant that would be indicative of a negative response to the palatability of the study medication?. This was presented as a binary outcome (that is, where No is no negative response and Yes is negative response). No negative response was considered as a positive outcome. | Baseline (randomization visit) and Month 6 | 
| Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age | An observer's assessment of the participant's behaviour using the SMPA was performed for all participants taking the study treatment who are 2 to 4 years of age. Willingness to swallow was assessed and categorized as follows: Swallowed without a problem Some resistance but did swallow Spit out some/all of the medication Vomited up the medication. The category swallowed without a problem was considered as positive outcome. | Baseline (randomization visit) and Month 6 | 
| Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age | The FHS method was used for all participants taking the study treatment who are ≥5 years of age. The FHS consists of 5 faces with descriptions ranging from Dislike very much to Like very much. The face with description Like very much was considered as positive outcome. The way in which the study treatment was taken, that is, whether the tablet is whole or dispersed, was captured. | Baseline (randomization visit) and Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle Cell Disease, Sickle Cell Anemia, SCD, Platelet aggregation, Ticagrelor, Brilinta, VOC, Vaso-Occlusive Crises, ACS, painful crisis