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Effect of Ticagrelor vs. Placebo in the Reduction of Vaso-occlusive Crises in Pediatric Patients With Sickle Cell Disease (HESTIA3)

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ClinicalTrials.gov Identifier: NCT03615924
Recruitment Status : Recruiting
First Posted : August 6, 2018
Last Update Posted : October 22, 2019
Sponsor:
Collaborator:
Iqvia Pty Ltd
Information provided by (Responsible Party):
AstraZeneca

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

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Ticagrelor Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 182 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 18, 2018
Estimated Primary Completion Date : November 9, 2020
Estimated Study Completion Date : November 9, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Ticagrelor

Arm Intervention/treatment
Experimental: 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.
Drug: 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.

Placebo Comparator: 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.
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.




Primary Outcome Measures :
  1. Number of VOCs [ Time Frame: Up to End of Study visit (12 to 24 months) ]

    Vaso-occlusive crises (VOC) defined as the composite of a painful crisis and/or an Acute Chest Syndrome (ACS) . Each component is defined as:

    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 NSAIDs, or other analgesics prescribed by a health care provider in a medical setting (such as a hospital, clinic or emergency room visit) or at home.

    An ACS is an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray.



Secondary Outcome Measures :
  1. Number of painful crises [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  2. Number of ACSs [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  3. Duration of painful crises [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  4. Number of VOCs requiring hospitalisation or emergency department visits [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  5. Number of days hospitalised for VOC [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  6. Number of acute SCD complications [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  7. Number of days hospitalised for acute SCD complications [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  8. Number of sickle cell-related RBC transfusions [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  9. Health-related quality of life (HRQL) score [ Time Frame: up to 24 months ]
    The HRQL will be assessed using the PedsQL SCD (Paediatric Quality of Life Inventory) Model and Multidimensional Fatigue Scale. The SCD consists of 43 items and measures problems with the patients' pain (severity, impact, management/control), worry, emotions, treatment and communication. There are 4 age group questionnaires: 1st: age 13-18 (teen report), 2nd age 8-12 (child report), 3rd age 5-7 (young child report), 4th age 2-4 (parent report for toddlers). 5-point Likert scale from 0 (Never) to 4 (Almost always). Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Higher scores indicate lower problems. The SCD module measures 9 sub-scales and a total score. Items are reverse-scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL. Scale Scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data).

  10. Fatigue total score [ Time Frame: up to 24 months ]
    Fatigue total score. By dimension using the PedsQL (Paediatric Quality of Life Inventory) Multidimensional Fatigue Scale (age appropriate versions: 2-4 years; 5-7 years; 8-12 years; 13-18 years). There are 4 age group questionnaires: 1st: age 13-18 (teen report-ACUTE version), 2nd age 8-12 (child report ACUTE version), 3rd age 5-7 (young child report), 4th age 2-4 (parent report for toddlers). 5-point Likert scale from 0 (Never) to 4 (Almost always) 3-point scale: 0 (Not at all), 2 (Sometimes) and 4 (A lot) for the Child Report for Young Children (ages 5-7). Scores are transformed on a scale from 0 to 100. Higher scores indicate lower problems. The Multidimensional Fatigue Scale consists of 18 items measuring problems with general, sleep/rest and cognitive fatigue. The Multidimensional Fatigue scale measure 3 sub-scales and a total score. The scales are scored similarly to the SCD Module scales, with higher scores indicating better HRQOL (lower fatigue).

  11. Proportion of days of absence from school or work (only if going to school or work at randomisation) [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  12. Intensity of worst pain daily during VOC [ Time Frame: Up to End of Study visit (12 to 24 months) ]
    Pain during VOC assessed by NRS (Numerical Rating Scale) [for patients ≤4 years of age: the observer reported Face, Legs, Activity, Cry, Consolability Scale (FLACC) will be used; each of the 5 behaviors observed are assigned a score of 0, 1 or 2. The total FLACC score will then range between 0 and 10, with 0 representing no pain. For patient from 5 to 18 years of age, the Faces Pain Scale - Revised (FPS-R) will be administered. The scale consists of 6 faces and scoring ranges between 0 and 10 (with an increase in numeric value by 2 (i.e., 0, 2,4, 6, 8, 10), where 0 is no pain and 10 is very much pain.)

  13. Type of analgesics (opioid and non-opioid) use [ Time Frame: Up to End of Study visit (12 to 24 months) ]
  14. Palatability and swallowability [ Time Frame: randomization and 6 months post randomization ]
    Palatability and swallowability assessment [for patients ≥5 years (taking the tablet dispersed or whole), will be performed and categorized by the Facial Hedonic Scale (FHS); the FHS consists of 5 faces with descriptions ranging from 'Dislike very much' to 'Like very much'. For patients 2-4 years of age an observer's assessment of the patient's behavior (not a scale), including willingness to swallow, will be performed directly after the patient has received the IP]. An observer will have an option to choose from: swallowed without problem, some resistance but did swallow, spit out some / all of medication, vomited up medication.



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Ages Eligible for Study:   2 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03615924


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

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Locations
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United States, California
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Oakland, California, United States, 94609
United States, Colorado
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Aurora, Colorado, United States, 80045
United States, Florida
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Fort Lauderdale, Florida, United States, 33316
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Jacksonville, Florida, United States, 32207
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Miami, Florida, United States, 33155
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Tampa, Florida, United States, 33606
United States, Georgia
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Atlanta, Georgia, United States, 30342
United States, Illinois
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Chicago, Illinois, United States, 60612
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Oak Lawn, Illinois, United States, 60453
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Peoria, Illinois, United States, 61637
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Boston, Massachusetts, United States, 02115
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Detroit, Michigan, United States, 48201
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Las Vegas, Nevada, United States, 89135
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Hackensack, New Jersey, United States, 07601
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New Brunswick, New Jersey, United States, 08901
United States, New York
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Brooklyn, New York, United States, 11212
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Lake Success, New York, United States, 11042
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Greenville, North Carolina, United States, 27834
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Oklahoma City, Oklahoma, United States, 73112-4703
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Philadelphia, Pennsylvania, United States, 19104
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Charleston, South Carolina, United States, 29425
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Ghent, Belgium, 9000
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Athens, Greece, 11527
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India
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Kolkata, India, 700017
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Siaya, Kenya, 40600
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Tripoli, Lebanon, 961
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Cape Town, South Africa, 7700
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Soweto, South Africa, 2013
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Tygerberg, South Africa, 7505
Spain
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Barakaldo, Spain, 48903
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El Palmar (Murcia), Spain, 30120
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Sponsors and Collaborators
AstraZeneca
Iqvia Pty Ltd
Investigators
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Study Director: Anders Berggren, MD, PhD AstraZeneca
Principal Investigator: Matthew Heeney, MD Harvard Medical School

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03615924     History of Changes
Other Study ID Numbers: D5136C00009
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: October 22, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by AstraZeneca:
Sickle Cell Disease
Sickle Cell Anemia
SCD
Platelet aggregation
Ticagrelor
Brilinta
VOC
Vaso-Occlusive Crises
ACS
painful crisis
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Hematologic Diseases
Genetic Diseases, Inborn
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hemoglobinopathies
Ticagrelor
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs