TY - JOUR
T1 - A dose-ranging study of ticagrelor in children aged 3-17 years with sickle cell disease
T2 - A 2-part phase 2 study
AU - on behalf of the HESTIA1 Investigators
AU - Hsu, Lewis L.
AU - Sarnaik, Sharada
AU - Williams, Suzan
AU - Amilon, Carl
AU - Wissmar, Jenny
AU - Berggren, Anders
N1 - Funding Information:
information: AstraZenecaThe authors on this article are the Study Steering Committee members for HESTIA1 and selected people from the AZ/Sponsor team. All authors recognize and appreciate the contribution made to this study by all of the investigators, staff, the patients and their families at the other participating centers who screened/randomized patients for HESTIA1 - USA: Penn State Hershey Children's Hospital, Hershey, PA; Medical University of South Carolina, Charleston, SC; Children's Hospital of Philadelphia, Philadelphia, PA; Children's Hospital of Orange County, Orange, CA; UK: University Health Board, Cardiff; Evelina London Children's Hospital, St. Thomas Hospital, London; Royal London Hospital-Barts Health NHS Trust, London; Royal Manchester Children's Hospital-Central Manchester University Hospital NHS Foundation Trust, Manchester; Kenya: Gertrude's Childrens’ Hospital, University of Nairobi, Nairobi; KEMRI - US Army - Kenya, Medical Research, Kisumu; Lebanon: Rafik Hariri University Hospital, Bir Hasan, Beirut; American University of Beirut Medical Center, Pediatrics/Adolescent Medicine Department, Hamra, Beirut; Nini Hospital, Tripoli; South Africa: Red Cross War Memorial Childrens' Hospital, Cape Town, Western Cape; Tygerberg Hospital, University of Stellenbosch, Parow Valley, Cape Town. The authors also thank Jackie Phillipson from Zoetic Science (UK), who provided medical writing support (outline, drafts, assembling tables and figures, collating author comments, grammatical editing, and referencing) funded by AstraZeneca. This study was funded by AstraZeneca. Contributed to conception and design (protocol development and/or design advice), acquisition of data, data analysis and data interpretation.: LLH, SS, SW, CA. Contributed to acquisition of data and data interpretation: JW, AB.
Funding Information:
The authors on this article are the Study Steering Committee members for HESTIA1 and selected people from the AZ/Sponsor team. All authors recognize and appreciate the contribution made to this study by all of the investigators, staff, the patients and their families at the other participating centers who screened/randomized patients for HESTIA1 - USA: Penn State Hershey Children's Hospital, Hershey, PA; Medical University of South Carolina, Charleston, SC; Children’s Hospital of Philadelphia, Philadelphia, PA; Children’s Hospital of Orange County, Orange, CA; UK: University Health Board, Cardiff; Evelina London Children's Hospital, St. Thomas Hospital, London; Royal London Hospital-Barts Health NHS Trust, London; Royal Manchester Children's Hospital-Central Manchester University Hospital NHS Foundation Trust, Manchester; Kenya: Gertrude’s Childrens’ Hospital, University of Nairobi, Nairobi; KEMRI - US Army - Kenya, Medical Research, Kisumu; Lebanon: Rafik Hariri University Hospital, Bir Hasan, Beirut; American University of Beirut Medical Center, Pediatrics/Adolescent Medicine Department, Hamra, Beirut; Nini Hospital, Tripoli; South Africa: Red Cross War Memorial Childrens' Hospital, Cape Town, Western Cape; Tygerberg Hospital, University of Stellenbosch, Parow Valley, Cape Town. The authors also thank Jackie Phil-lipson from Zoetic Science (UK), who provided medical writing support (outline, drafts, assembling tables and figures, collating author comments, grammatical editing, and referencing) funded by AstraZe-neca. This study was funded by AstraZeneca.
Publisher Copyright:
© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.
PY - 2018/12
Y1 - 2018/12
N2 - Antiplatelet treatment is a potential therapeutic approach for sickle cell disease (SCD). Ticagrelor inhibits platelet aggregation and is approved for adults with acute coronary syndrome and following myocardial infarction. HESTIA1 (NCT02214121) was a 2-part, phase 2 dose-finding study generating ticagrelor exposure, platelet inhibition, and safety data in children with SCD (3-17 years). In part A (n = 45), patients received 2 ticagrelor single doses, 0.125-2.25 mg/kg (washout ≥7 days), then 7 days of twice-daily (bid) dosing with 0.125, 0.563, or 0.75 mg/kg. In the 4-week blinded Part B extension (optional), patients received ticagrelor (0.125, 0.563, or 0.75 mg/kg bid; n = 16) or placebo (n = 7). Platelet reactivity decreased from baseline to 2 hours postdosing, and returned to near baseline after 6 hours postdosing. Dose-dependent platelet inhibition was seen with ticagrelor; mean relative P2Y12 reaction unit inhibition 2 hours after a single dose ranged from 6% (0.125 mg/kg) to 73% (2.25 mg/kg). Ticagrelor plasma exposure increased approximately dose proportionally. No patients experienced a hemorrhagic event during treatment. No differences were seen between groups in pain ratings and analgesic use during Part B. Ticagrelor was well tolerated with no safety concerns, no discontinuations due to adverse events (AEs), and reported AEs were mainly due to SCD. In conclusion, a dose-exposure-response relationship for ticagrelor was demonstrated in children with SCD for the first time. These data are important for future pediatric studies of the efficacy and safety of ticagrelor in SCD.
AB - Antiplatelet treatment is a potential therapeutic approach for sickle cell disease (SCD). Ticagrelor inhibits platelet aggregation and is approved for adults with acute coronary syndrome and following myocardial infarction. HESTIA1 (NCT02214121) was a 2-part, phase 2 dose-finding study generating ticagrelor exposure, platelet inhibition, and safety data in children with SCD (3-17 years). In part A (n = 45), patients received 2 ticagrelor single doses, 0.125-2.25 mg/kg (washout ≥7 days), then 7 days of twice-daily (bid) dosing with 0.125, 0.563, or 0.75 mg/kg. In the 4-week blinded Part B extension (optional), patients received ticagrelor (0.125, 0.563, or 0.75 mg/kg bid; n = 16) or placebo (n = 7). Platelet reactivity decreased from baseline to 2 hours postdosing, and returned to near baseline after 6 hours postdosing. Dose-dependent platelet inhibition was seen with ticagrelor; mean relative P2Y12 reaction unit inhibition 2 hours after a single dose ranged from 6% (0.125 mg/kg) to 73% (2.25 mg/kg). Ticagrelor plasma exposure increased approximately dose proportionally. No patients experienced a hemorrhagic event during treatment. No differences were seen between groups in pain ratings and analgesic use during Part B. Ticagrelor was well tolerated with no safety concerns, no discontinuations due to adverse events (AEs), and reported AEs were mainly due to SCD. In conclusion, a dose-exposure-response relationship for ticagrelor was demonstrated in children with SCD for the first time. These data are important for future pediatric studies of the efficacy and safety of ticagrelor in SCD.
UR - http://www.scopus.com/inward/record.url?scp=85054296878&partnerID=8YFLogxK
U2 - 10.1002/ajh.25273
DO - 10.1002/ajh.25273
M3 - Article
C2 - 30187935
AN - SCOPUS:85054296878
VL - 93
SP - 1493
EP - 1500
JO - American Journal of Hematology
JF - American Journal of Hematology
SN - 0361-8609
IS - 12
ER -