Clinical trial NCT03615924: Effect of Ticagrelor vs. Placebo in the Reduction of Vaso-occlusive Crises in Pediatric Patients With Sickle Cell Disease
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease
Sickle Cell Anemia
SCD
Platelet aggregation
Ticagrelor
Brilinta
VOC
Vaso-Occlusive Crises
ACS
painful crisis
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Iqvia Pty Ltd
First posted: 2018-08-06
Enrollment: 193
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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).
2. 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.
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 1. These VOCs need to be documented in the patient's medical records or in other documents that can be reconciled.
4. 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.
5. 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.
6. If treated with hydroxyurea, 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 Screening (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 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:

1. 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.
2. 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.
3. Active pathological bleeding or increased risk of bleeding complications according to Investigator
4. Haemoglobin \<6 g/dL from test performed at Screening (Visit 1)
5. Platelets \<100 x 10\^9/L from test performed at Screening (Visit 1) Undergoing treatment with chronic red blood cell transfusion therapy.
6. Undergoing treatment with chronic red blood cell transfusion therapy.
7. Chronic use of NSAIDs defined as continuous intake \>3 days per week that cannot be discontinued
8. Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be discontinued
9. 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).
10. Renal failure requiring dialysis
11. 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.
12. 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.
13. Active untreated malaria. Patients with suspected malaria at Screening (Visit 1) will be tested.
14. Known hypersensitivity or contraindication to ticagrelor
15. 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)
16. Any condition which, in the opinion of the Investigator, would make it unsafe or unsuitable for the patient to participate in this study
17. Concern for the inability of the patient or caregiver (defined as legally authorized representative) to comply with study procedures and/or follow-up
18. Previous randomisation in the present study.
19. Participation in another clinical study with an IP or device during the last 30 days preceding screening.
20. 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).

Primary outcomes:
measure: Number of Vaso-Occlusive Crisis Events
timeFrame: From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months
Secondary outcomes:
measure: Number of Painful Crisis Events
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Number of Acute Chest Syndrome Events
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Duration of Painful Crises
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Number of Days Hospitalized for Vaso-Occlusive Crisis Events
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Number of Acute Sickle Cell Disease Complications
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Number of Days Hospitalized for Acute Sickle Cell Disease Complications
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module
timeFrame: 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
measure: Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale
timeFrame: 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
measure: Percentage of Days of Absence From School or Work Due to Sickle Cell Disease
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 Years of Age
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 Years of Age
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events
timeFrame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
measure: Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age
timeFrame: Baseline (randomization visit) and Month 6
measure: Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age
timeFrame: Baseline (randomization visit) and Month 6
measure: Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age
timeFrame: Baseline (randomization visit) and Month 6
Other outcomes:
Locations:
city: Fort Lauderdale
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Oak Lawn
country: United States
facility: Research Site
state: Illinois
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Brooklyn
country: United States
facility: Research Site
state: New York
city: Charleston
country: United States
facility: Research Site
state: South Carolina
city: Brussel
country: Belgium
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Rio de Janeiro
country: Brazil
facility: Research Site
city: Salvador
country: Brazil
facility: Research Site
city: São Paulo
country: Brazil
facility: Research Site
city: São Paulo
country: Brazil
facility: Research Site
city: Al Sharkeya
country: Egypt
facility: Research Site
city: Alexandria
country: Egypt
facility: Research Site
city: Cairo
country: Egypt
facility: Research Site
city: Cairo
country: Egypt
facility: Research Site
city: Cairo
country: Egypt
facility: Research Site
city: Dakahlia
country: Egypt
facility: Research Site
city: Accra
country: Ghana
facility: Research Site
city: Ho
country: Ghana
facility: Research Site
city: Kumasi
country: Ghana
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Mumbai
country: India
facility: Research Site
city: Nagpur
country: India
facility: Research Site
city: Nagpur
country: India
facility: Research Site
city: Pune
country: India
facility: Research Site
city: Pune
country: India
facility: Research Site
city: Wardha
country: India
facility: Research Site
city: Catania
country: Italy
facility: Research Site
city: Naples
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Verona
country: Italy
facility: Research Site
city: Kisumu
country: Kenya
facility: Research Site
city: Nairobi
country: Kenya
facility: Research Site
city: Siaya
country: Kenya
facility: Research Site
city: Beirut
country: Lebanon
facility: Research Site
city: Tripoli
country: Lebanon
facility: Research Site
city: Cape Town
country: South Africa
facility: Research Site
city: Soweto
country: South Africa
facility: Research Site
city: Barakaldo
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Mbeya
country: Tanzania
facility: Research Site
city: Antalya
country: Turkey
facility: Research Site
city: Mersin
country: Turkey
facility: Research Site
city: Seyhan
country: Turkey
facility: Research Site
city: Kampala
country: Uganda
facility: Research Site
city: Masaka
country: Uganda
facility: Research Site
city: Cardiff
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Anders Berggren, MD, PhD
role: STUDY_DIRECTOR
affiliation: Harvard Medical School (HMS and HSDM)
name: Matthew Heeney, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Heeney MM, Abboud MR, Githanga J, Inusa BPD, Kanter J, Michelson AD, Nduba V, Musiime V, Apte M, Inati A, Taksande AM, Andersson M, Astrand M, Maklad N, Niazi M, Himmelmann A, Berggren AR. Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study. Blood. 2022 Sep 29;140(13):1470-1481. doi: 10.1182/blood.2021014095.
citation: Heeney MM, Abboud MR, Amilon C, Andersson M, Githanga J, Inusa B, Kanter J, Leonsson-Zachrisson M, Michelson AD, Berggren AR; HESTIA3 study investigators. Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: Rationale and design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3). Contemp Clin Trials. 2019 Oct;85:105835. doi: 10.1016/j.cct.2019.105835. Epub 2019 Aug 22.