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

Phase 2

Completed

• Conditions: Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease
• Interventions: Drug: Ticagrelor Dose 1a + Dose 2a; Drug: Ticagrelor Dose 1b + Dose 2b

• Registration Number: NCT02214121
• Lead Sponsor: AstraZeneca

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 Timeline

• Study First Submitted: 2014-08-08
• Study First Submitted QC: 2014-08-08
• Study First Posted: 2014-08-12
• Study Start: 2014-09-11
• Primary Completion: 2017-02-27
• Study Completion: 2017-02-27
• Results First Submitted: 2018-02-05
• Results First Submitted QC: 2018-05-09
• Results First Posted: 2018-05-11
• Status Verified: 2018-11
• Last Update Submitted: 2018-11-22
• Last Update Posted: 2018-12-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ticagrelor Dose 1a + Dose 2a	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.
Ticagrelor Dose 1b + Dose 2b	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.

Primary Outcome Measures

Name	Time	Method
P2Y12 Reaction Units (PRU) - Part B	PRU measurements are taken after 4 weeks of double blind treatment at the end of Part B.
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.
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	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	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 Outcome Measures

Name	Time	Method
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).
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 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)
Percentage of Days With Pain (Age >=4) - Part B	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
Assessment of AR-C124910XX 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)	AR-C124910XX is the active metabolite of Ticagrelor
Assessment of AR-C124910XX 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.	AR-C124910XX is the active metabolite of Ticagrelor
Oral Clearance (CL/F) - 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).	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	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	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	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	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).

Trial Locations

Locations (1)

Research Site; 🇬🇧 Manchester, United Kingdom