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

NCT ID: NCT03615924

Last Updated: 2021-04-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 193 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-26
• Study Completion Date: 2020-08-13

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.

Conditions

Sickle Cell Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Ticagrelor

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.

Group Type: EXPERIMENTAL

Ticagrelor

Intervention Type: DRUG

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.

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

Ticagrelor

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.

Intervention Type: DRUG

Placebo

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.

Intervention Type: DRUG

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).

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Iqvia Pty Ltd

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anders Berggren, MD, PhD

Role: STUDY_DIRECTOR

AstraZeneca

Matthew Heeney, MD

Role: PRINCIPAL_INVESTIGATOR

Harvard Medical School (HMS and HSDM)

Locations

Research Site

Fort Lauderdale, Florida, United States

Research Site

Miami, Florida, United States

Research Site

Chicago, Illinois, United States

Research Site

Oak Lawn, Illinois, United States

Research Site

Las Vegas, Nevada, United States

Research Site

Brooklyn, New York, United States

Research Site

Charleston, South Carolina, United States

Research Site

Brussels, , Belgium

Research Site

Edegem, , Belgium

Research Site

Porto Alegre, , Brazil

Research Site

Rio de Janeiro, , Brazil

Research Site

Salvador, , Brazil

Research Site

São Paulo, , Brazil

Research Site

São Paulo, , Brazil

Research Site

Al Sharkeya, , Egypt

Research Site

Alexandria, , Egypt

Research Site

Cairo, , Egypt

Research Site

Cairo, , Egypt

Research Site

Cairo, , Egypt

Research Site

Dakahlia, , Egypt

Research Site

Accra, , Ghana

Research Site

Ho, , Ghana

Research Site

Kumasi, , Ghana

Research Site

Athens, , Greece

Research Site

Mumbai, , India

Research Site

Nagpur, , India

Research Site

Nagpur, , India

Research Site

Pune, , India

Research Site

Pune, , India

Research Site

Wardha, , India

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Catania, , Italy

Research Site

Naples, , Italy

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Padua, , Italy

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Verona, , Italy

Research Site

Kisumu, , Kenya

Research Site

Nairobi, , Kenya

Research Site

Siaya, , Kenya

Research Site

Beirut, , Lebanon

Research Site

Tripoli, , Lebanon

Research Site

Cape Town, , South Africa

Research Site

Soweto, , South Africa

Research Site

Barakaldo, , Spain

Research Site

Barcelona, , Spain

Research Site

Madrid, , Spain

Research Site

Madrid, , Spain

Research Site

Mbeya, , Tanzania

Research Site

Antalya, , Turkey (Türkiye)

Research Site

Mersin, , Turkey (Türkiye)

Research Site

Seyhan, , Turkey (Türkiye)

Research Site

Kampala, , Uganda

Research Site

Masaka, , Uganda

Research Site

Cardiff, , United Kingdom

Research Site

Glasgow, , United Kingdom

Research Site

London, , United Kingdom

Research Site

London, , United Kingdom

Countries

United States; Belgium; Brazil; Egypt; Ghana; Greece; India; Italy; Kenya; Lebanon; South Africa; Spain; Tanzania; Turkey (Türkiye); Uganda; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 35849650 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31446143 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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Statistical Analysis Plan redacted

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Clinical Study Protocol redacted

Other Identifiers

D5136C00009

Identifier Type: -

Identifier Source: org_study_id