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

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

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

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.

Part A: Ticagrelor Dose 1a and ticagrelor Dose 2a single doses + 1 week repeated dosing Part B: Ticagrelor or placebo 4 weeks repeated dosing.

Part A: Ticagrelor Dose 1b and ticagrelor Dose 2b single doses + 1 week repeated dosing. Part B: Ticagrelor or placebo 4 weeks repeated dosing.

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

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.

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).

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.

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.

PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.

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)

PK measurements (up to 4 hours post-dose) are taken after 4 weeks of double blind treatment at the end of Part B.

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)

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 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).

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.

During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).

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).

During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).

During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).

During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).

During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).

During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).

During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).

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.

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.