Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202003558059352 Date of Approval: 26/03/2020
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title A Randomised, Double Blind, Parallel Group, Multicentre, Phase III Study to Evaluate the Effect of Ticagrelor versus Placebo in Reducing the Number of Vaso-Occlusive Crises in Paediatric Patients Aged 6 Months to <18 Years with Sickle Cell Disease (HESTIA5)
Official scientific title A Randomised, Double Blind, Parallel Group, Multicentre, Phase III Study to Evaluate the Effect of Ticagrelor versus Placebo in Reducing the Number of Vaso-Occlusive Crises in Paediatric Patients Aged 6 Months to <18 Years with Sickle Cell Disease (HESTIA5)
Brief summary describing the background and objectives of the trial There is a high unmet need for treatment options in sickle cell disease (SCD) and there is a scientific rationale, supported by clinical data, that platelet inhibition has the potential to reduce the risk for acute vaso-occlusions. This study will evaluate the efficacy, safety and tolerability of ticagrelor versus placebo in children aged 6 months to <18 years with SCD during treatment for at least 12 months and up to 24 months. This is a randomised, double-blind, parallel-group, multicentre, Phase III study to evaluate the effect of ticagrelor twice daily (bd) versus placebo in reducing the number of vaso-occlusive crises (VOCs) in paediatric patients with SCD. The target population is children (males and females) aged 6 months to <18 years and body weight ≥6 kg diagnosed with homozygous sickle cell (HbSS) or sickle beta-zero-thalassaemia (HbS/β0). Prior to randomisation in this study, patients aged 6 to <24 months will undergo a 14-day Run in period in which they will receive open-label ticagrelor bd for 14 days according to weight, to ensure that the treatment is well-tolerated, and that the exposure is in line with model-based predictions following repeated bd dosing with ticagrelor in this age group. Approximately 182 patients aged 6 months to <18 years are planned to be randomised in proportions of 1:1 ticagrelor:placebo at approximately 50 centres in approximately 20 countries. Randomisation to investigational product (IP) will be done via an Interactive Voice/Web Response System (IXRS) at Visit 2 in balanced blocks to ensure balance between the 2 treatment arms (1:1). Patients are to be followed until a common study end date (CSED) is reached (defined as 12 months after the last patient is randomised) or up to a maximum of 24 months. The primary objective is to ompare the effect of ticagrelor vs placebo for the reduction of VOCs, which is the composite of painful crisis and/or ACS, in paediatric patients with SCD
Type of trial RCT
Acronym (If the trial has an acronym then please provide) Hestia 5
Disease(s) or condition(s) being studied Haematological Disorders
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/11/2020
Actual trial start date
Anticipated date of last follow up 31/05/2022
Actual Last follow-up date
Anticipated target sample size (number of participants) 8
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Central randomisation by phone/fax Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Ticagrelor The double-blind IP will be based on 5 weight bands: • 6 to ≤9 kg: ticagrelor 5 mg or matching placebo bd • >9 to ≤12 kg: ticagrelor 10 mg or matching placebo bd • >12 to ≤24 kg: ticagrelor 15 mg or matching placebo bd • >24 to ≤48 kg: ticagrelor 30 mg or matching placebo bd • >48 kg: ticagrelor 45 mg or matching placebo bd Treatment duration is at least 12 months for study participants, and patients will continue treatment until 12 months after the last patient is randomised, up to a maximum of 24 months. Ticagrelor (BRILINTA™) is an oral, direct-acting, selective, reversibly binding P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated platelet activation and aggregation. 91
Control Group Placebo The double-blind IP will be based on 5 weight bands: • 6 to ≤9 kg: ticagrelor 5 mg or matching placebo bd • >9 to ≤12 kg: ticagrelor 10 mg or matching placebo bd • >12 to ≤24 kg: ticagrelor 15 mg or matching placebo bd • >24 to ≤48 kg: ticagrelor 30 mg or matching placebo bd • >48 kg: ticagrelor 45 mg or matching placebo bd Treatment duration is at least 12 months for study participants, and patients will continue treatment until 12 months after the last patient is randomised, up to a maximum of 24 months. Treatment duration is at least 12 months for study participants, and patients will continue treatment until 12 months after the last patient is randomised, up to a maximum of 24 months. 91 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Patients are eligible to be included in the study only if all of the following inclusion criteria and none of the exclusion criteria apply: 1 Provision of signed and dated informed consent prior to any study specific procedures not part of standard medical care (local regulations and international guidelines are to be followed in determining the assent/consent requirements for children). The Informed consent form (ICF) process is described in Appendix A 3. 2 Children aged 6 months to <18 years of age and body weight ≥6 kg diagnosed with HbSS or HbS/β0 as confirmed by high-performance liquid chromatography (HPLC) or haemoglobin electrophoresis. Note: Diagnosis of SCD (if not confirmed prior to screening and records not available on the medical file) should be confirmed for HbSS or HbS/β0 by HPLC or haemoglobin electrophoresis, performed at the site’s local laboratory, in order to confirm the type of mutation. Children being judged to be severely underweight (<3rd percentile according the World Health Organisation [WHO] growth charts) cannot be included. 3 Have experienced at least 2 VOCs (painful crisis and/or ACS) as judged by the Investigator in the past 12 months prior to Visit R1 (patients aged 6 to <24 months) or Visit 1 (patients aged 2 to <18 years). These VOCs need to be documented in the patient’s medical records or in other documents that can be reconciled. 4 If aged 2 to ≤16 years, must have had a TCD within the past year prior to Visit 2 (see Yawn et al 2014). If this is not the case, a TCD examination must be done before randomisation. 5 If aged ≥10 years, must have had an ophthalmological examination within the past year prior to Visit 1 (see Yawn et al 2014). If this is not the case, the patient must be examined by an ophthalmologist before proceeding in the study. If local guidelines dictate ophthalmological examination at younger ages, those local guidelines should be followed. 6 If treated with hydroxyurea or L-glutamine, the weight-adjusted d 1 As judged by the Investigator, any evidence of unsuitability which in the Investigator’s opinion makes it undesirable for the patient to participate in the study. 2 History of transient ischaemic attack (TIA) or cerebrovascular accident (ischaemic or haemorrhagic), severe head trauma, intracranial haemorrhage, intracranial neoplasm, arteriovenous malformation, aneurysm, or proliferative retinopathy. 3 Findings on TCD: Current or previous values for time averaged mean of the maximum velocity (TAMMV) that are Conditional or Abnormal. Patients with Conditional TAMMV values or higher (≥153 cm/sec using TCD imaging technique [TCDi] which is corresponding to ≥170 cm/sec by the non-imaging technique). Both the middle cerebral artery and the internal carotid artery should be considered. Any other criteria that would locally be considered as TCD indications for chronic transfusion would also exclude the patient. 4 Pathological finding on any other imaging assay indicating increased risk for intracerebral bleeding or thromboembolism. 5 International normalised ratio (INR) >1.4 or active pathological bleeding or increased risk of bleeding complications according to Investigator. 6 Haemoglobin <6 g/dL from test performed at Visit R1 and Visit 1 (patients aged 6 to <24 months) or at Enrolment (Visit 1) (patients aged 2 to <18 years). 7 Platelets <100 × 109/L from test performed at Visit R1 and Visit 1 (patients aged 6 to <24 months) or at Enrolment (Visit 1) (patients aged 2 to <18 years). 8 Undergoing treatment with chronic red blood cell transfusion therapy. 9 Chronic use of NSAIDs defined as continuous intake >3 days per week that cannot be discontinued (see Appendix K). 10 Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be discontinued. 11 Moderate or severe hepatic impairment defined as laboratory values of alanine aminotransferase (ALT) >2×upper limit of normal (ULN), total bilirubin >2×ULN (unless judged by the Investigator to be cau Adolescent: 13 Year-18 Year,Child: 6 Year-12 Year,Infant: 0 Month(s)-12 Month(s),Infant: 13 Month(s)-24 Month(s),Preschool Child: 2 Year-5 Year 6 Month(s) 17 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 31/03/2020 National Heatlh Research Ethics committee
Ethics Committee Address
Street address City Postal code Country
Federal Ministry of Health, Federal Secretariat Complex Shehu Shagari Way, Garki, Abuja P.M.B. 083 Garki-Abuja 900001 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 31/03/2020 National Health Research Ethics Review Committee National Institute for Medical Research
Ethics Committee Address
Street address City Postal code Country
2448 Ocean Road Dar es Salaam 11101 Tanzania
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 01/06/2020 Ghana Health Service
Ethics Committee Address
Street address City Postal code Country
Private Mail Bag, Ministries, Accra. Accra 00000 Ghana
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 17/03/2020 Korle Bu Teaching Hospital Institutional Review Board
Ethics Committee Address
Street address City Postal code Country
PO Box 4236 Accra 00000 Ghana
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 02/04/2020 University of Health and Allied Sciences Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
PMB 31 Ho 00000 Ghana
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 07/04/2020 Kintampo Health Research Centre Institutional Ethics Committee
Ethics Committee Address
Street address City Postal code Country
PO Box 200 Kintampo-Brong Ahafo Kintampo 00000 Ghana
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 10/04/2020 Navrongo Health Research Center Institutional Review Board
Ethics Committee Address
Street address City Postal code Country
PO Box 114 Navrongo 00000 Ghana
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Number of VOCs 24 months.
Secondary Outcome Number of VOCs in patients aged 2 to <18 years 24 Months
Secondary Outcome Number of painful crises 24 months
Secondary Outcome Number of ACSs 24 months
Secondary Outcome Duration of painful crises 24 months
Secondary Outcome Number of VOCs requiring hospitalisation or emergency department visits 24 months
Secondary Outcome Number of days hospitalised for VOC 24 months
Secondary Outcome Number of acute SCD complications 24 months
Secondary Outcome Number of days hospitalised for acute SCD complications 24 months
Secondary Outcome Number of sickle cell-related RBC transfusions 24 months
Secondary Outcome HRQL total score and by dimension using Paediatric Quality of Life Inventory (PedsQL) SCD Module; and Fatigue total score and by dimension using the PedsQL Multidimensional Fatigue Scale (age appropriate versions: 2 to 4 years; 5 to 7 years; 8 to 12 years; 13 to 18 years); HRQL total score and by dimension using the PedsQL Infant Scale (age appropriate versions: 1 to 12 months; 13 to 24 months) 24 months
Secondary Outcome Proportion of days of absence from school or work (only if going to school or work at randomisation) 24 months
Secondary Outcome Intensity of worst pain daily during VOC • For patients aged ≤4 years, observer reported using the Face, Legs, Activity, Cry, Consolability (FLACC) scale • For patients aged 5 to <18 years, self-reported using the Faces Pain Scale - Revised (FPS-R) 24 months
Secondary Outcome Type of analgesics (opioid and non-opioid) use 24 months
Secondary Outcome • For patients aged ≤4 years taking the tablet dispersed or whole, an observer assessment of palatability and swallowability will be undertaken • For patients aged ≥5 years taking the tablet dispersed or whole, palatability will be assessed and categorised using the Facial Hedonic Scale 24 months
Secondary Outcome Adverse Events (AE)/Serious Adverse Events (SAEs) including bleeding Vital signs and laboratory safety variables 24 months
Secondary Outcome Duration of ACS 24 months
Secondary Outcome Population PK parameters such as oral clearance (CL/F) and ticagrelor exposure (AUC) 24 monhts
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Lagos University Teaching Hospital Ishaga Road, Idi-Araba, Surulere, Lagos Nigeria
Department of Paediatrics University of Calabar Teaching Hospital Cross River State Calabar Nigeria
University of Abuja Teaching Hospital Hospital Road Gwagwalada Nigeria
Nigeria Teaching Hospital Ituku-Ozalla Enugu Nigeria
NIMR Tanga Centre Bombo Hospital Road Tanga City Tanzania
National Institute for Medical Research Mbeya Medical Research Center NIMR MMRC Hospital hill road P.O.Box 2410 Mbeya Tanzania
KorleBu Teaching Hospital Child Health Guggisberg Ave, Korle-Bu Teaching Hospital, Accra, Ghana Accra Ghana
Kintampo Health Research Center Kintampo North Municipality, Brong Ahafo Region. PO Box 200 Kintampo-Brong Ahafo Kintampo Ghana
Navrongo Health Research Center Behind Navrongo War Memorial Hospital. PO Box 114 Navrongo Ghana
University of Health and Allied Sciences School of Medicine, Volta Regional Hospital. PMB 31 Ho Ghana
Joint Clinical Research Centre Plot 101, Upper lubowa Estates,PO Box 10005 Kampala 759125 Uganda
Getrudes Childrens Hospital Muthaiga Road Off Thika Super Highway Nairobi Kenya
KEMRI Siaya Clinical Research Annexe Siaya County Referral Hospital Siaya Kenya
KEMRI Centre for Respiratory Disease Research Hospital Road next to Kenyatta National Hospital Past Government Chemist Nairobi Kenya
KEMRI Kondele Centre for Clinical Research Kondele Childrens Hospital Within Jaramogi Oginga Odinga Hospital Along Kisumu Kakamega Road Kisumu Kenya
KEMRI Kombewa Kombewa Clinical Research Centre Walter Reed Project Off Kisumu Bondo Road Opposite Kombewa Sub County Hospital Kombewa Kenya
CREATES Strathmore University Medical Centre Centre for Research in Therapeutic Sciences Madaraka Estate Ole Sangale Road off Langata Road Nairobi Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
AstraZeneca AB SE-151 85 Sodertalje Sweden
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor AstraZeneca AB SE-151 85 Sodertalje Sweden Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
IQVIA 1021 Lenchen Avenue North corner of John Vorster Centurion 0157 South Africa
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator JOhns Lusingu jpalusingu@gmail.com +255787679515 Hospital Road
City Postal code Country Position/Affiliation
Tanga City Tanzania Principal Investigator
Role Name Email Phone Street address
Public Enquiries Issa Sabi isabi@nimr-mmrc.org +255252503364 Hospital hill road
City Postal code Country Position/Affiliation
Mbeya Tanzania Principal Investigator and National Coordinator
Role Name Email Phone Street address
Principal Investigator Adeseye Akinsete aakinsete@unilag.edu.ng +2348023535659 Ishaga Road, Idi-Araba, Surulere
City Postal code Country Position/Affiliation
Lagos Nigeria Principal Investigator
Role Name Email Phone Street address
Principal Investigator Martin Meremikwu mmeremiku@yahoo.co.uk +2348036742377 University of Calabar Teaching Hospital
City Postal code Country Position/Affiliation
Calabar Nigeria Principal Investigator
Role Name Email Phone Street address
Principal Investigator Obiageli Nnodu oennodu@gmail.com +2348130610603 Hospital Road
City Postal code Country Position/Affiliation
Gwagwalada Nigeria Principal Investigator
Role Name Email Phone Street address
Public Enquiries Iheanyi Okpala Iheanyi.okpala@unn.edu.ng +2348025453354 University of Nigeria Teaching Hospital Ituku-Ozalla
City Postal code Country Position/Affiliation
Enugu Nigeria Principal Investigator and National coordinator
Role Name Email Phone Street address
Scientific Enquiries Matthew Heeney matthew.heeney@childrens.harvard.edu 6179193242 300 Longwood Ave
City Postal code Country Position/Affiliation
Boston 02115 United States of America Assistant Professor of Paediatrics Harvard Medical School
Role Name Email Phone Street address
Principal Investigator Seyram Kaali kaali.seyram@kintampo-hrc.org +233546381925 PO Box 200 Kintampo-Brong Ahafo
City Postal code Country Position/Affiliation
Kintampo Ghana Physician
Role Name Email Phone Street address
Principal Investigator Patrick Ansah lonpoa2@gmail.com +233245279984 PO Box 114 Navrongo
City Postal code Country Position/Affiliation
Navrongo Ghana Physician
Role Name Email Phone Street address
Principal Investigator Kokou Amegan Aho kamegan@uhas.edu.gh +233202640443 PMB 31
City Postal code Country Position/Affiliation
Ho Ghana Physician
Role Name Email Phone Street address
Principal Investigator Catherine Segbefia csegbefia@gmail.com +233208887888 PO Box 4236
City Postal code Country Position/Affiliation
Accra Ghana Physician
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Trial Result Summaries are a short and easy to understand summary of the results of this study. These will be added to www.trialsummaries.com within 6 months of the last study participants last site visit. The participant can visit www.trialsummaries.com website anytime to sign up to be notified via email when the trial results summary of your study is available. Participants will also receive information on the treatment you received in this study. Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol within 6 months of the last study participants last site visit The participants can visit www.trialsummaries.com website anytime to sign up to be notified via email when the trial results summary of the study is available.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
www.trialsummaries.com No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information