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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)

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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

Tracking Information
First Submitted Date  ICMJE August 8, 2014
First Posted Date  ICMJE August 12, 2014
Results First Submitted Date  ICMJE February 5, 2018
Results First Posted Date  ICMJE May 11, 2018
Last Update Posted Date December 14, 2018
Actual Study Start Date  ICMJE September 11, 2014
Actual Primary Completion Date February 27, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 9, 2018)
  • 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. ]
  • 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. ]
  • 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). ]
  • 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. ]
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 8, 2014)
  • P2Y12 reaction units (PRU) [ Time Frame: PRU: Baseline, Day 7, Day 14, Day 42 ]
  • Maximum plasma concentration (Cmax) [ Time Frame: Visits 2 (Day 0) ,3 (Day 7), and 8 (Day 42) ]
  • Assessment of Area under the plasma concentration time curve (AUC) [ Time Frame: AUC: Visits 2 (Day 0) ,3 (Day 7), and 8 (Day 42) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2018)
  • 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) ]
  • 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. ]
  • 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
  • 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
  • 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.
  • 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.
  • 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). ]
  • 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). ]
  • 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). ]
  • 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
  • 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
  • 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). ]
  • 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). ]
  • 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). ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 8, 2014)
  • Assessment of Ticagrelor concentration [ Time Frame: Baseline, Day 7, Day 14, Day 42 ]
  • Number of Vaso-occlusive crises [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  • Number of Vaso-occlusive crises requiring hospitalization or emergency department visits [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  • Days hospitalized for complications of sickle cell disease [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  • Days with pain [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  • Intensity of pain [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  • Days of analgesic use [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  • Days of opioid analgesic use [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
  • Days of absence from school or work [ Time Frame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6). ]
Current Other Pre-specified Outcome Measures
 (submitted: May 9, 2018)
  • Haemorrhagic Events - Part A [ Time Frame: From randomisation to Part A (week 0) through Visit 4 (week 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). ]
Original Other Pre-specified Outcome Measures
 (submitted: August 8, 2014)
Safety endpoints: AEs/Serious Adverse Events (SAE)s, Vital signs, laboratory safety samples, Haemorrhagic events [ Time Frame: Vital signs at all study visits (1-9), laboratory samples at Visits 1, Visit 4 (week 2) and Visit 9 (week 10), SAEs from enrollment until Visit 9 (week 10) and AEs, haemorrhagic events from randomization (Visit 2)(week 0) until Visit 9 ( week 10). ]
 
Descriptive Information
Brief Title  ICMJE A Pharmacokinetic (PK) and Pharmacodynamic (PD) Dose-ranging Phase II Study of Ticagrelor in Paediatric Patients With Sickle Cell Disease
Official Title  ICMJE 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
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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Ticagrelor Dose 1a + Dose 2a
  • 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.
    Intervention: Drug: Ticagrelor Dose 1b + Dose 2b
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 9, 2018)
46
Original Estimated Enrollment  ICMJE
 (submitted: August 8, 2014)
49
Actual Study Completion Date  ICMJE February 27, 2017
Actual Primary Completion Date February 27, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Kenya,   Lebanon,   South Africa,   United Kingdom,   United States
Removed Location Countries Egypt,   Ghana,   Italy,   Turkey
 
Administrative Information
NCT Number  ICMJE NCT02214121
Other Study ID Numbers  ICMJE D5136C00007
2014-001006-18 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP