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

AstraZeneca46 enrolled

Overview

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

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease

Interventions

Ticagrelor Dose 1a + Dose 2aDRUG

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 2bDRUG

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

Eligibility

Sex: ALLMin age: 2 YearsMax age: 17 Years

Medical Language ↔ Plain English

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.

Locations (18)

Research Site

Orange, California, United States

Research Site

Chicago, Illinois, United States

Research Site

Detroit, Michigan, United States

Outcomes

Primary Outcomes

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

The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.

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).

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.

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.

Secondary Outcomes

Assessment of Ticagrelor Concentration - Part A

Data from ClinicalTrials.gov

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Research Site

Hershey, Pennsylvania, United States

Research Site

Philadelphia, Pennsylvania, United States

Research Site

Charleston, South Carolina, United States

Research Site

Toronto, Ontario, Canada

Research Site

Kisian, Kenya

Research Site

Nairobi, Kenya

Research Site

Beirut, Lebanon

...and 8 more locations

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

AR-C124910XX is the active metabolite of Ticagrelor

Assessment of AR-C124910XX Concentration - Part B

AR-C124910XX is the active metabolite of Ticagrelor

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.

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.

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).

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.

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.

Number of Vaso-occlusive Crises - Part B