Clinical trial NCT02214121: A Pharmacokinetic (PK) and Pharmacodynamic (PD) Dose-ranging Phase II Study of Ticagrelor in Paediatric Patients With Sickle Cell Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease
Keywords: sickle cell anemia
paediatric
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-08-12
Enrollment: 46
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: P2Y12 Reaction Units (PRU) - Part A
timeFrame: 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.
measure: P2Y12 Reaction Units (PRU) - Part B
timeFrame: PRU measurements are taken after 4 weeks of double blind treatment at the end of Part B.
measure: Maximum Plasma Concentration (Cmax) - Part A
timeFrame: 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).
measure: Maximum Plasma Concentration (Cmax) - Part B
timeFrame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.
measure: Area Under the Plasma Concentration Time Curve (AUC) - Part A
timeFrame: 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).
measure: Area Under the Plasma Concentration Time Curve (AUC) - Part B
timeFrame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.
Secondary outcomes:
measure: Assessment of Ticagrelor Concentration - Part A
timeFrame: 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)
measure: Assessment of Ticagrelor Concentration - Part B
timeFrame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.
measure: Assessment of AR-C124910XX Concentration - Part A
timeFrame: 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)
measure: Assessment of AR-C124910XX Concentration - Part B
timeFrame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.
measure: Oral Clearance (CL/F) - Part A
timeFrame: 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).
measure: Oral Clearance (CL/F) - Part B
timeFrame: PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.
measure: Number of Vaso-occlusive Crises - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
measure: Number of Vaso-occlusive Crises Requiring Hospitalization or Emergency Department Visits - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
measure: Percentage of Days Hospitalized for Vaso-occlusice Crisis or Other Complications of Sickle Cell Disease - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
measure: Percentage of Days With Pain (Age >=4) - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
measure: Mean Intensity of Pain (Age >=4) - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
measure: Percentage of Days of Analgesic Use (Age >= 4) - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
measure: Percentage of Days of Opioid Analgesic Use (Age >=4) - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
measure: Percentage of Days of Absence From School or Work (Age >=6) - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
Other outcomes:
measure: Haemorrhagic Events - Part A
timeFrame: From randomisation to Part A (week 0) through Visit 4 (week 2)
measure: Haemorrhagic Events - Part B
timeFrame: During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
Locations:
city: Orange
country: United States
facility: Research Site
state: California
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Hershey
country: United States
facility: Research Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Charleston
country: United States
facility: Research Site
state: South Carolina
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Kisian
country: Kenya
facility: Research Site
city: Nairobi
country: Kenya
facility: Research Site
city: Beirut
country: Lebanon
facility: Research Site
city: Beirut
country: Lebanon
facility: Research Site
city: Tripoli
country: Lebanon
facility: Research Site
city: Parow
country: South Africa
facility: Research Site
city: Rondebosch
country: South Africa
facility: Research Site
city: Cardiff
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
Study officials:
References:
citation: 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.
citation: 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.