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NCT Number: NCT02214121

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

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

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Key information

Conditions

Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease Anemia Anemia, Hemolytic Anemia, Hemolytic, Congenital Anemia, Sickle Cell Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemoglobinopathies

Age range

2 year–17 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Research Site, Toronto, Ontario, Canada

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Ticagrelor Dose 1a + Dose 2a

Drug

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

Drug

Ticagrelor Dose 1b and ticagrelor Dose 2b single doses + 1 week ticagrelor repeted dosing followed by 4 weeks repeated dosing ticagrelor or placebo.

Primary outcomes

  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 outcomes

  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 outcomes

  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).

Sponsors and collaborators

Lead sponsor

AstraZeneca

Industry

Registry information

Official study 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

Acronym: HESTIA 1

Important dates

Study start
2014
Primary completion
2017
Study completion
2017
First posted
Aug 12, 2014
Registry last updated
Dec 14, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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