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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease

Intervention / Treatment
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* Drug: Ticagrelor Dose 1a + Dose 2a
* Drug: Ticagrelor Dose 1b + Dose 2b


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Ticagrelor Dose 1a + Dose 2a<br>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<br>* Ticagrelor Dose 1a and ticagrelor Dose 2a single doses + 1 week ticagrelor repeated dosing followed by 4 weeks repeated dosing ticagrelor or placebo.<br>|
| Other: Ticagrelor Dose 1b + Dose 2b<br>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<br>* Ticagrelor Dose 1b and ticagrelor Dose 2b single doses + 1 week ticagrelor repeted dosing followed by 4 weeks repeated dosing ticagrelor or placebo.<br>|

What is the study measuring?
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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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle cell anemia, paediatric