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

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

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

Study Overview

• Status: Completed
• Conditions: Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease
• Intervention / Treatment: Drug: Ticagrelor Dose 1a + Dose 2a; Drug: Ticagrelor Dose 1b + Dose 2b

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: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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.
Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
P2Y12 Reaction Units (PRU) - Part A		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		PRU measurements are taken after 4 weeks of double blind treatment at the end of Part B.
Maximum Plasma Concentration (Cmax) - Part A		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		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	The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.	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).
Area Under the Plasma Concentration Time Curve (AUC) - Part B	The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.	PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Ticagrelor Concentration - Part A		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		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	AR-C124910XX is the active metabolite of Ticagrelor	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 AR-C124910XX Concentration - Part B	AR-C124910XX is the active metabolite of Ticagrelor	PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.
Oral Clearance (CL/F) - Part A	The PK parameter presented were derived using a model based analysis and not from a non-compartmental (NCA) analysis.	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).
Oral Clearance (CL/F) - Part B	The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.	PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.
Number of Vaso-occlusive Crises - Part B		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		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		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	Pain measured using the Faces Pain Scale, range 0-10 (0, 2, 4, 6, 8, 10), where 0 is no pain	During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
Mean Intensity of Pain (Age >=4) - Part B	Pain measured using the Faces Pain Scale, range 0-10 (0, 2, 4, 6, 8, 10), where 0 is no pain	During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
Percentage of Days of Analgesic Use (Age >= 4) - Part B		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		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		During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• Hsu LL, Sarnaik S, Williams S, Amilon C, Wissmar J, Berggren A; HESTIA1 Investigators. A dose-ranging study of ticagrelor in children aged 3-17 years with sickle cell disease: A 2-part phase 2 study. Am J Hematol. 2018 Dec;93(12):1493-1500. doi: 10.1002/ajh.25273. Epub 2018 Oct 2.
• Amilon C, Niazi M, Berggren A, Astrand M, Hamren B. Population Pharmacokinetics/Pharmacodynamics of Ticagrelor in Children with Sickle Cell Disease. Clin Pharmacokinet. 2019 Oct;58(10):1295-1307. doi: 10.1007/s40262-019-00758-0.

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2014
• Primary Completion (Actual): February 27, 2017
• Study Completion (Actual): February 27, 2017

Study Registration Dates

• First Submitted: August 8, 2014
• First Submitted That Met QC Criteria: August 8, 2014
• First Posted (Estimate): August 12, 2014

Study Record Updates

• Last Update Posted (Actual): December 14, 2018
• Last Update Submitted That Met QC Criteria: November 22, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: sickle cell anemia; paediatric
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor
• Other Study ID Numbers: D5136C00007; 2014-001006-18 (EudraCT Number)