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A Pharmacokinetic (PK) and Pharmacodynamic (PD) Dose-ranging Phase II Study of Ticagrelor in Paediatric Patients With Sickle Cell Disease (HESTIA 1)

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: NCT02214121
Recruitment Status : Completed
First Posted : August 12, 2014
Results First Posted : May 11, 2018
Last Update Posted : December 14, 2018
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Description
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Brief Summary:
The purpose of this Phase II dose-ranging study is to investigate pharmacokinetic (PK) and pharmacodynamic (PD) properties of various doses of ticagrelor followed by 4 weeks of twice-daily treatment in paediatric patients with sickle cell disease

Condition or disease Intervention/treatment Phase
Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease Drug: Ticagrelor Dose 1a + Dose 2a Drug: Ticagrelor Dose 1b + Dose 2b Phase 2

Detailed Description:

This is a multicenter, open-label, dose-ranging study of ticagrelor followed by a double blind, placebo-controlled extension phase in paediatric patients with sickle cell disease (SCD).

Part A: Patients will be randomised 1:1 to receive one of two dosing schedules consisting of two single weight-adjusted doses of ticagrelor. Pharmacokinetic (PK) parameters and pharmacodynamic (PD) measurements will be determined following each dose. Platelet aggregation will be measured using the VerifyNow™ P2Y12 assay.

Following these 2 single doses, all patients will receive open-label one-week treatment with ticagrelor twice daily to determine tolerability prior to randomisation into Part B.

Part B: In this part patients will be randomised (2:1 ratio) to ticagrelor twice daily or placebo for a 4-week treatment phase.

During the study, patients will be followed for the occurrence of vaso-occlusive crisis (VOC) and for other disease manifestations such as daily pain, analgesic use and complications of SCD.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Multicenter, Open-label, Randomised, Pharmacokinetic (PK) and Pharmacodynamic (PD) Dose-ranging Phase II Study of Ticagrelor Followed by a Double-blind, Randomised, Parallel-group, Placebo-controlled 4 Weeks Extension Phase in Paediatric Patients With Sickle Cell Disease
Actual Study Start Date : September 11, 2014
Actual Primary Completion Date : February 27, 2017
Actual Study Completion Date : February 27, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Ticagrelor

Arms and Interventions
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Arm Intervention/treatment
Ticagrelor Dose 1a + Dose 2a
Part A: Ticagrelor Dose 1a and ticagrelor Dose 2a single doses + 1 week repeated dosing Part B: Ticagrelor or placebo 4 weeks repeated dosing.
 Drug: Ticagrelor Dose 1a + Dose 2a
Ticagrelor Dose 1a and ticagrelor Dose 2a single doses + 1 week ticagrelor repeated dosing followed by 4 weeks repeated dosing ticagrelor or placebo.
Ticagrelor Dose 1b + Dose 2b
Part A: Ticagrelor Dose 1b and ticagrelor Dose 2b single doses + 1 week repeated dosing. Part B: Ticagrelor or placebo 4 weeks repeated dosing.
 Drug: Ticagrelor Dose 1b + Dose 2b
Ticagrelor Dose 1b and ticagrelor Dose 2b single doses + 1 week ticagrelor repeted dosing followed by 4 weeks repeated dosing ticagrelor or placebo.


Outcome Measures
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Primary Outcome Measures :
  1. P2Y12 Reaction Units (PRU) - Part A [ Time Frame: PRU measurements are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14). Up to 8 hours post-dose (6 hours following protocol amendment) Visit 2 and 3, and up to 2 hours Visit 4. ]
  2. P2Y12 Reaction Units (PRU) - Part B [ Time Frame: PRU measurements are taken after 4 weeks of double blind treatment at the end of Part B. ]
  3. Maximum Plasma Concentration (Cmax) - Part A [ Time Frame: PK measurements (up to 8 hours post-dose) are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14). ]
  4. Maximum Plasma Concentration (Cmax) - Part B [ Time Frame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B. ]
  5. Area Under the Plasma Concentration Time Curve (AUC) - Part A [ Time Frame: PK measurements (up to 8 hours post-dose) are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14). ]
    The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.

  6. Area Under the Plasma Concentration Time Curve (AUC) - Part B [ Time Frame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B. ]
    The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.


Secondary Outcome Measures :
  1. Assessment of Ticagrelor Concentration - Part A [ Time Frame: In conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7), after repeated dosing at Visit 4 (Day 14). Up to 8h post-dose (6h following protocol amendment, no pre-dose) Visit 2 and 3, up to 2h Visit 4 (pre-dose, 1h added following amendment) ]
  2. Assessment of Ticagrelor Concentration - Part B [ Time Frame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B. ]
  3. Assessment of AR-C124910XX Concentration - Part A [ Time Frame: In conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7), after repeated dosing at Visit 4 (Day 14). Up to 8h post-dose (6h following protocol amendment, no pre-dose) Visit 2 and 3, up to 2h Visit 4 (pre-dose, 1h added following amendment) ]
    AR-C124910XX is the active metabolite of Ticagrelor

  4. Assessment of AR-C124910XX Concentration - Part B [ Time Frame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B. ]
    AR-C124910XX is the active metabolite of Ticagrelor

  5. Oral Clearance (CL/F) - Part A [ Time Frame: PK measurements (up to 8 hours post-dose) are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14). ]
    The PK parameter presented were derived using a model based analysis and not from a non-compartmental (NCA) analysis.

  6. Oral Clearance (CL/F) - Part B [ Time Frame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B. ]
    The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.

  7. Number of Vaso-occlusive Crises - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  8. Number of Vaso-occlusive Crises Requiring Hospitalization or Emergency Department Visits - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  9. Percentage of Days Hospitalized for Vaso-occlusice Crisis or Other Complications of Sickle Cell Disease - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  10. Percentage of Days With Pain (Age >=4) - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
    Pain measured using the Faces Pain Scale, range 0-10 (0, 2, 4, 6, 8, 10), where 0 is no pain

  11. Mean Intensity of Pain (Age >=4) - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
    Pain measured using the Faces Pain Scale, range 0-10 (0, 2, 4, 6, 8, 10), where 0 is no pain

  12. Percentage of Days of Analgesic Use (Age >= 4) - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  13. Percentage of Days of Opioid Analgesic Use (Age >=4) - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  14. Percentage of Days of Absence From School or Work (Age >=6) - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]

Other Outcome Measures:
  1. Haemorrhagic Events - Part A [ Time Frame: From randomisation to Part A (week 0) through Visit 4 (week 2) ]
  2. Haemorrhagic Events - Part B [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]

Eligibility Criteria
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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

  • Children aged ≥2 to <18 years of age
  • Diagnosed with homozygous sickle cell (HbSS) or sickle beta-zero-thalassaemia (HbS/β0)

Exclusion criteria

  • At risk for haemorrhagic or bradycardic events
  • Significant hepatic impairment
  • Renal failure requiring dialysis
  • Concomitant oral or intravenous therapy with strong CYP3A4 (cytochrome) inhibitors, CYP3A4 substrates with narrow therapeutic indices, or strong CYP3A4 inducers.
  • Surgical procedure planned to occur during the study.
  • Patients who are currently pregnant or breastfeeding or planning to become pregnant during the study.
  • Patients who have known hypersensitivity or contraindication to ticagrelor.
Contacts and Locations
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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): NCT02214121


Locations
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United States, California
Research Site
Orange, California, United States, 92868
United States, Illinois
Research Site
Chicago, Illinois, United States, 60612
United States, Michigan
Research Site
Detroit, Michigan, United States, 48201
United States, Pennsylvania
Research Site
Hershey, Pennsylvania, United States, 17022
Research Site
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Research Site
Charleston, South Carolina, United States, 29425
Canada, Ontario
Research Site
Toronto, Ontario, Canada, M5G 1X8
Kenya
Research Site
Kisian, Kenya, 100
Research Site
Nairobi, Kenya
Lebanon
Research Site
Beirut, Lebanon, 1107 2020
Research Site
Beirut, Lebanon, 113-6044
Research Site
Tripoli, Lebanon, 1434
South Africa
Research Site
Parow, South Africa, 7500
Research Site
Rondebosch, South Africa, 7700
United Kingdom
Research Site
Cardiff, United Kingdom, CF4 4XN
Research Site
London, United Kingdom, E1 1BB
Research Site
London, United Kingdom, SE1 7EH
Research Site
Manchester, United Kingdom, M13 9PT
Sponsors and Collaborators
AstraZeneca
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Statistical Analysis Plan  [PDF] March 13, 2017
Study Protocol  [PDF] December 22, 2015

More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02214121    
Other Study ID Numbers: D5136C00007
2014-001006-18 ( EudraCT Number )
First Posted: August 12, 2014    Key Record Dates
Results First Posted: May 11, 2018
Last Update Posted: December 14, 2018
Last Verified: November 2018
Keywords provided by AstraZeneca:
sickle cell anemia
paediatric
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