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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03615924
Recruitment Status : Terminated (Recommendation from an independent data monitoring committee (DMC) and accepted by AstraZeneca.)
First Posted : August 6, 2018
Results First Posted : April 9, 2021
Last Update Posted : April 9, 2021
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)
Actual Enrollment : 193 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 26, 2018
Actual Primary Completion Date : August 13, 2020
Actual Study Completion Date : August 13, 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 Vaso-Occlusive Crisis Events [ Time Frame: From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months ]
    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.


Secondary Outcome Measures :
  1. Number of Painful Crisis Events [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  2. Number of Acute Chest Syndrome Events [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  3. Duration of Painful Crises [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  4. Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  5. Number of Days Hospitalized for Vaso-Occlusive Crisis Events [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  6. Number of Acute Sickle Cell Disease Complications [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  7. Number of Days Hospitalized for Acute Sickle Cell Disease Complications [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  8. Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  9. Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module [ Time Frame: 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 ]

    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.

  10. Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale [ Time Frame: 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 ]

    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.

  11. Percentage of Days of Absence From School or Work Due to Sickle Cell Disease [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]

    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).


  12. Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 Years of Age [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  13. Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 Years of Age [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    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.

  14. Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events [ Time Frame: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months ]
    Analgesics use (opioid and non-opioid) during VOC events.

  15. Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age [ Time Frame: Baseline (randomization visit) and Month 6 ]
    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.

  16. Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age [ Time Frame: Baseline (randomization visit) and Month 6 ]

    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.

  17. Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age [ Time Frame: Baseline (randomization visit) and Month 6 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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


Locations
Show Show 55 study locations
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
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol  [PDF] April 20, 2020
Statistical Analysis Plan  [PDF] June 26, 2020

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03615924    
Other Study ID Numbers: D5136C00009
First Posted: August 6, 2018    Key Record Dates
Results First Posted: April 9, 2021
Last Update Posted: April 9, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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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
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
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