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.: PACTR202401802272880 Date of Approval: 09/01/2024
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Hydroxyurea – Pragmatic Reduction in Mortality and Economic burden: A multi-centre Phase III trial to investigate the efficacy of hydroxyurea for children with sickle cell anaemia when administered in a pragmatic fashion.
Official scientific title H-PRIME: Hydroxyurea - Pragmatic Reduction In Mortality and Economic burden
Brief summary describing the background and objectives of the trial Sickle cell disease is an inherited condition of red blood cells that affects approximately 1% of all children born in much of sub-Saharan Africa. Without early diagnosis and appropriate treatment, under-5 mortality in those affected totals 50 to 90%. H-PRIME will be a randomized, open label, pragmatic clinical trial aimed at investigating THREE different types of treatment that might realistically improve outcomes for children born in Africa with this condition. Through H-PRIME, we will address three key questions in a single clinical trial. A 2x2x2 factorial randomised open-label trial, conducted in four centres in Eastern Uganda involving 1800 children aged 1 to 10 years inclusive with a laboratory confirmed diagnosis of sickle cell disease (SCD). The trial has 3 intervention strategies aimed at reducing mortality and morbidity in children with SCD Randomisation (R)1: high-dose (daily dosing) versus low-dose (thrice weekly dosing) of oral hydroxyurea based on standard weight-bands and and given with clinically driven (based on clinical signs/symptoms) rather than routine, scheduled laboratory monitoring. R2: enhanced antimalarial prophylaxis with weekly dihydroartemisinin-piperaquine (DHA-PQP) vs standard of care (SOC) (monthly sulphadoxine-pyrimethamine, SP) (open-label) and R3: antimicrobial prophylaxis with daily co-trimoxazole (CTX) throughout childhood/adolescence vs SOC (twice-daily penicillin V until the age of 5 years) (open-label). Participants will be randomised over 2 years, and will be followed until the common end of follow-up date 48 months after the first randomisation. All endpoints will be included from enrolment to the common trial follow-up end-date 48 months after the first randomisation.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) HPRIME
Disease(s) or condition(s) being studied Haematological Disorders,Infections and Infestations,Paediatrics
Sub-Disease(s) or condition(s) being studied Bacterial infection,Malaria
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/09/2023
Actual trial start date 16/01/2024
Anticipated date of last follow up 31/01/2028
Actual Last follow-up date
Anticipated target sample size (number of participants) 1800
Actual target sample size (number of participants)
Recruitment status 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
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously Randomised Permuted block randomization 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 Hydroxyurea 25mg/kg/day given daily 48 months Scored 1000mg tablet of hydroxyurea given at a fixed high dose equivalent to 25 (15-30) mg/kg/day using a fixed weight-band dosage chart 900
Control Group Hydroxyurea 25 mg/kg/dose given 3 days a week 48 months Scored 1000mg tablet of hydroxyurea given at a fixed low dose three days a week (Monday Wednesday and Friday) equivalent to 10 (6-13) mg/kg/day using fixed weight-band based doses 900 Dose Comparison
Experimental Group DHAPQP WHO-recommended weight-band based doses (if 5-<8kg 20/160mg; 8-<11kg 30/240mg; 11-<17 kg 40/320 and ≥17 kg 60/480) given once weekly 48 months One-third of the monthly dose of dihydroartemisinine-piperaquine (DHA-PQP) given once a week 900
Control Group Sulphadoxine Pyrimthamine WHO-recommended age-based dosing (1-5 years ½ tab (250/12.5mg); 5-10 years 1 tab (500/25mg); 10-15 years 2 tabs (1000/50mg) monthly 48 months Oral tablets as per WHO recommended dosage for malaria prophylaxis 900 Active-Treatment of Control Group
Experimental Group Cotrimoxazole WHO weight-band based recommendations for infection prophylaxis: if 3-<6kg 100/20mg; 6-<14kg 200/40mg; 14–<25kg 400/80mg; 25+kg 900/160mg once daily 48 months Any formulation including suspension 200/40mg per 5mls, 100/20mg dispersible tablets or 400/80mg or 800/160mg tablets or parts thereof. The dispersible tablets may be taken with water or mixed with feeds. 900
Control Group Penicillin Oral penicilin given according to age group: if <3 years 125mg; 3-5 years 250mg as a twice daily medication 48 months Given as a tablet twice a day 900 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
 Aged 1-10 years inclusive  Confirmed SCD (either by HPLC or IEF at a qualified laboratory)  Have received conjugate pneumococcal vaccination against Hib and S. pneumoniae (otherwise eligible but unvaccinated children will be vaccinated through the study as above)  Carer willing/able to provide consent and to bring the child for follow-up visits, as demonstrated by either regular attendance at SCD clinics to date, or attending two visits (one of which may be the screening visit) before randomisation  Weighing <8kg – temporary exclusion pending the achievement of 8kg or more  Already meet criteria for starting hydroxyurea in national guidelines (frequent crises (>5/year), known abnormal transcranial Doppler ultrasound velocities, stroke or acute chest syndrome)  Already receiving hydroxyurea  Taking concomitant medications that are contraindicated with any of the trial medications (hydroxyurea, SP, DHA-PQP, penicillin V, cotrimoxazole) (including, but not limited to, nefazodone, verapamil, rifampicin, isoniazid, ethambutol)  A positive pregnancy test at screening or enrolment visits  Known cancer  A clinical history of previous or existing liver or renal diseases unrelated to sickle cell disease  Known cardiac ventricular dysfunction or failure or a previous history of cardiac arrhythmias  Known HIV (these children should receive cotrimoxazole prophylaxis and many will be receiving antiretrovirals that are contraindicated with one or more trial medications (zidovudine, amprenavir, atazanavir, indinavir, nelfinavir, ritonavir))  Current participation in any other clinical trial of an investigational medicinal product  Presence of acute infection on the day of screening (e.g. symptomatic P. falciparum malaria, pneumonia, septicaemia, meningitis, newly identified tuberculosis) – such children may be enrolled after recovery from an acute infection if they do not meet other exclusion criteria Child: 6 Year-12 Year,Infant: 1 Month-23 Month,Preschool Child: 2 Year-5 Year 12 Month(s) 10 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
Yes 24/04/2023 Mbale Regional Referral Hospital Research and Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Palissa Road Mbale POBox 921 Uganda
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome  R1: mortality (all-cause)  R2: malaria-associated hospitalisations (diagnosed by rapid diagnostic test (RDT) and confirmed by microscopy and/or PCR)  R3: hospitalisation for any reason All endpoints will be included from enrolment to the common trial follow-up end-date 48 months after the first randomisation.
Secondary Outcome  Mortality (where mortality is not the primary outcome for that randomisation)  Malaria-associated hospitalisations (where not the primary outcome)  All-cause hospitalisations (where not the primary outcome)  Any of the following SCD-specific complications requiring medical intervention (Grade 2 or above): painful crisis, hand-foot syndrome, splenic sequestration, acute chest syndrome or stroke  Number of blood transfusions and volume of blood transfused  Haemoglobin (Hb) and fetal haemoglobin (HbF) concentrations  The frequencies of abnormal renal or liver function test result  Febrile events treated with intravenous antibiotics  Specific bacterial bloodstream infections confirmed by blood culture or molecular typing  Serious adverse events (SAEs) All endpoints will be included from enrolment to the common trial follow-up end-date 48 months after the first randomisation.
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Mbale Regional Referral Hospital Palissa Road Mbale PO Box 92 Uganda
Soroti Regional Referral Hospital Mohamadan Road Soroti POBox 289 Uganda
Atutur District Hospital Mbale Soroti Road Apokin Uganda
Ngora District Hospital Mukura Road Ngora Uganda
FUNDING SOURCES
Name of source Street address City Postal code Country
Joint Global Health Trials Scheme Caxton House, Tothill Street London SW1H 9NA United Kingdom
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Imperial College Exhibition Road London SW7 2AZ United Kingdom University
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Thomas N Williams twilliams@kemri-wellcome.org +254742105040 KEMRI Wellcome Trust Research Programme, Hospital Road
City Postal code Country Position/Affiliation
Kilifi POBox 230 Kenya Professor of Haemoglobinopathy Research Imperial College London
Role Name Email Phone Street address
Public Enquiries Denis Aromut damoruts@gmail.com +2567744573911 Pallisa Road Zone
City Postal code Country Position/Affiliation
Mbale Uganda Trial Manager
Role Name Email Phone Street address
Scientific Enquiries Thomas N Williams twilliams@kemri-wellcome.org +254742105040 KWTRP Hospital Road
City Postal code Country Position/Affiliation
Kilifi POBox 230 Kenya Trial Chief Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes We have a data sharing plan for investigator and external requests. De-identified individual trial participant data H-Prime trial will be shared according to a controlled access approach in accordance to the funders policy based on the following principles: No data should be released that would compromise an on-going trial or study. There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose. Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers. There sources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore, adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources. Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries. Informed Consent Form,Statistical Analysis Plan,Study Protocol IPD will be shared following a period of exclusivity as outlined above. The minimum period of exclusivity will be 2 years following the publication of the trial results. The study protocol, statistical analysis plan and ICF will be published after all ethics and regulatory approvals in an open access journal. On completion of the trial, local researchers will have unrestricted access rights to data sets collected through this collaborative research project. We will follow the funder’s regulations with regard to Intellectual Property (IP). As this relates to a legal issue, IP issues will be laid out in the contract between partners. Standard data request form should be completed and access granted by Trial Steering Committee (custodians of the trial data) where the resources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources. The H-PRIME dataset will be held electronically for at least 20 years after the end of the trial in accordance with MRC policy. As above, proposals to use H-PRIME data and samples will be welcomed and supported widely where this does not conflict with existing plans within the trial team (e.g. as described in the primary and secondary objectives of the trial above).
URL Results Available Results Summary Result Posting Date First Journal Publication Date
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