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

NCT03615924 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: D5136C00009
• Study Type: interventional
• Target: 193
• Locations: 16 countries
• Sites: 55

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

Conditions

Sickle Cell Disease

Keywords

Sickle Cell Disease; Sickle Cell Anemia; SCD; Platelet aggregation; Ticagrelor; Brilinta; VOC; Vaso-Occlusive Crises; ACS; painful crisis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (17)

• Number of Painful Crisis 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

  From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

• Duration of Painful Crises

  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

  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

  From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Study Arms (2)

Ticagrelor

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Ticagrelor 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.

Ticagrelor

Placebo 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.

Placebo

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• AstraZeneca: lead
• Iqvia Pty Ltd: collaborator

Study Sites (55)

Research Site

Fort Lauderdale, Florida, 33316, United States

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Miami, Florida, 33155, United States

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Chicago, Illinois, 60612, United States

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Oak Lawn, Illinois, 60453, United States

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Las Vegas, Nevada, 89135, United States

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Brooklyn, New York, 11212, United States

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Charleston, South Carolina, 29425, United States

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Brussels, 1200, Belgium

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Edegem, 2650, Belgium

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Porto Alegre, 90035-903, Brazil

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Rio de Janeiro, 20211-080, Brazil

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Salvador, 41253-190, Brazil

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São Paulo, 01221010, Brazil

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São Paulo, 08270-070, Brazil

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Al Sharkeya, 44519, Egypt

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Alexandria, 21131, Egypt

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Cairo, 11521, Egypt

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Cairo, 11566, Egypt

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Cairo, 12655, Egypt

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Dakahlia, 35516, Egypt

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Accra, 233, Ghana

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Ho, 0, Ghana

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Kumasi, 1934, Ghana

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Athens, 11521, Greece

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Mumbai, 400053, India

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Nagpur, 440003, India

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Nagpur, 440012, India

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Pune, 411001, India

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Pune, 411004, India

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Wardha, 442004, India

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Catania, 95123, Italy

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Naples, 80138, Italy

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Padua, 35128, Italy

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Verona, 37126, Italy

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Kisumu, 40100, Kenya

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Nairobi, 00200, Kenya

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Siaya, 40600, Kenya

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Beirut, 11-0236, Lebanon

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Tripoli, 961, Lebanon

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Cape Town, 7700, South Africa

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Soweto, 2013, South Africa

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Barakaldo, 48903, Spain

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Barcelona, 08035, Spain

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Madrid, 28007, Spain

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Madrid, 28009, Spain

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Mbeya, 2410, Tanzania

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Antalya, 7070, Turkey (Türkiye)

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Mersin, 33343, Turkey (Türkiye)

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Seyhan, 01130, Turkey (Türkiye)

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Kampala, 10005, Uganda

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Masaka, 0000, Uganda

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Cardiff, CF14 4XW, United Kingdom

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Glasgow, G51 4TF, United Kingdom

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London, E1 1BB, United Kingdom

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London, SE1 7EH, United Kingdom

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Related Publications (2)

• 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.

  PMID: 35849650 DERIVED

• 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.

  PMID: 31446143 DERIVED

Related Links

• Statistical Analysis Plan redacted
• Clinical Study Protocol redacted

MeSH Terms

Conditions

Anemia, Sickle Cell; Vaso-Occlusive Crises

Interventions

Ticagrelor

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Limitations and Caveats

AstraZeneca took the decision to terminate the study early, following a recommendation from the independent Data Monitoring Committee. This early termination was not considered to have had an impact on the robustness of the study results.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Anders Berggren, MD, PhD

  AstraZeneca

  STUDY DIRECTOR

• Matthew Heeney, MD

  Harvard Medical School (HMS and HSDM)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 22, 2018
• First Posted: August 6, 2018
• Study Start: September 26, 2018
• Primary Completion: August 13, 2020
• Study Completion: August 13, 2020
• Last Updated: April 9, 2021
• Results First Posted: April 9, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

EG (6); BE (2); LE (2); IT (4); TU (3); GH (3); US (7); KE (3); ZA (2); IN (6); TA (1); GB (4); ES (4); GR (1); BR (5); UG (2)