H-PRIME: A clinical trial with three separate randomisations aimed at investigating the benefits of hydroxyurea, used pragmatically with only clinically-based monitoring, antimalarial prophylaxis with dihydroartemisinin-piperaquine and antibacterial prophylaxis with cotrimoxazole as potential improvements in the standard care of children living in Africa with sickle cell disease
| ISRCTN | ISRCTN15724013 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15724013 |
| Secondary identifying numbers | V2.0 |
- Submission date
- 13/02/2020
- Registration date
- 25/02/2020
- Last edited
- 23/06/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Circulatory System
Plain English summary of protocol
Background and study aims
Sickle cell disease is a common but neglected genetic disease that has its greatest burden in sub-Saharan Africa. Without early diagnosis and appropriate treatment, aimed primarily at preventing the common causes of ill-health and death (which include bacterial diseases and malaria) the disease is associated with high mortality during childhood. Although implementation of early life screening and the prevention of infections with vaccines, penicillin and drugs for malaria, can lead to greatly improved survival, other complications of sickle cell disease can still lead to a reduced quality of life. The overarching aim of this study will be to investigate whether several alternative treatments, delivered pragmatically by non-specialist staff in, could improve survival and quality of life for children with sickle cell disease living in resource-poor environments within sub-Saharan Africa.
Who can participate?
Children aged 1-10 years inclusive with confirmed Sickle Cell Disease (SCD).
What does the study involve?
Participants will be randomly allocated to receive one of three different treatments and will be followed up over a maximum of 48 months. The first randomisation will be to hydroxyurea, prescribed pragmatically through a weight-band-based dosing strategy aimed at delivering either a higher dose (25 +/-5mg/kg/day), with clinically based monitoring only, versus a lower dose (10 mg/kg +/-4 mg/kg/day). The second and third randomisations will be to the standard of care prophylaxis for malaria using suphadoxine-pyramethamine given monthly or alternative prophylaxis with dihydroartemisinin-piperoquine given weekly and standard of care prophylaxis for bacterial infections with penicillin V given twice daily until the age of 5years or alternative prophylaxis with cotrimoxazole given once daily throughout childhood.
What are the possible benefits and risks of participating?
BENEFITS
Extra clinical personnel, regular clinical assessment of participants and basic equipment for patient monitoring will be available during the trial so that if SCD complications were to arise they will be detected and treated more often. Pre-trial training will include sign recognition for these complications and training on treatment. Both these will be covered in detail in the trial Manual of Operations (MOP).
The direct benefits to the participating centres will include:
• Support, capacity development and training in the management of SCD in childhood and the use of hydroxyurea therapy.
• Establishing or further developing SCD clinics
Benefits For the health personnel involved
The direct benefits to health personnel are mainly professional development of the members of the trial teams and clinical teams for the purposes of running the trial – including training in clinical trials, good clinical and laboratory practice and research ethics. However, as above, they will also receive standardised training in the identification and treatment of SCD and relevant adverse events
BENEFITS TO WIDER SOCIETY
Wider society will benefit from all of the above factors and the study will also act as a focal point for a greater appreciation and understanding of sickle cell disease within the region.
RISKS OF PARTICIPATING
It is anticipated that all study participants will be at lower risk of morbid and mortal events than they would be if not recruited to the study and that one or more of the interventions will improve their lives even further. We assess the risk benefit ratio to be extremely favourable
Where is the study run from?
Mbale Clinical Research Institute (Uganda) and KEMRI-Wellcome Trust Research Programme (Kenya)
When is the study starting and how long is it expected to run for?
January 2021 to December 2032
Who is funding the study?
The Joint Global Health Trials Scheme of the Department for International Development, UK (DFID), the Wellcome Trust and the Medical Research Council (MRC UK)
Who is the main contact?
Dennis Amorut (public), damoruts@gmail.com
Prof. Thomas Williams (scientific), twilliams@kemri-wellcome.org
Contact information
Public
Mbale Clinical Research Institute
Pallisa Road Zone
PO Box 921
Mbale
-
Uganda
 ORCID ID |
0000-0003-4456-2382 |
|---|---|
| Phone | +256 774 573 991 |
| damoruts@gmail.com |
Scientific
KEMRI-Wellcome Trust Research Programme
PO Box 230
Kilifi
-
Kenya
| ORCID ID |
0000-0003-4456-2382 |
|---|---|
| Phone | +254 417 522063 |
| twilliams@kemri-wellcome.org |
Study information
| Study design | 2x2x2 factorial randomized open-label trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Factorial design |
| Study setting(s) | Hospital |
| Study type | Prevention |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | H-PRIME: Hydroxyurea – Pragmatic Reduction in Mortality and Economic burden: A multi-centre Phase III trial to investigate the efficacy of hydroxyurea in children with sickle cell anaemia when administered in a pragmatic fashion. |
| Study acronym | H-PRIME |
| Study objectives | Current hypothesis as of 07/08/2023: 1. Oral high-dose (daily) hydroxyurea with clinically driven rather than routine laboratory monitoring will reduce all-cause mortality compared with oral low-dose (thrice-weekly) hydroxyurea 2. Enhanced antimalarial prophylaxis with a highly-effective antimalarial drug - dihydroartemisinin-piperaquine given weekly - will reduce malaria-associated hospitalisations in comparison to normal Ugandan standard of care - sulphadoxine-pyrimethamine given monthly 3. Antimicrobial prophylaxis with co-trimoxazole given daily throughout childhood will reduce all-cause hospitalisations in comparison to standard of care prophylaxis with penicillin V, given twice daily until the age of 5 years _____ Previous hypothesis: 1. Daily oral dosing with hydroxyurea, with clinically-driven rather than routine laboratory monitoring will reduce all-cause mortality compared with placebo 2. Enhanced antimalarial prophylaxis with a highly-effective antimalarial drug - dihydroartemisinin-piperaquine given weekly - will reduce malaria-associated hospitalisations in comparison to normal Ugandan standard of care- sulphadoxine-pyrimethamine given monthly 3. Antimicrobial prophylaxis with co-trimoxazole given daily throughout childhood will reduce all-cause hospitalisations in comparison to standard of care prophylaxis with penicillin V, given twice daily until the age of 5 years |
| Ethics approval(s) | 1. Approved 17/09/2019, Imperial College Research Ethics Committee (Imperial College Research Ethics Committee, Imperial College London, Room 221 Medical School Building, St Marys Campus, London, W2 1PG, UK; +44 (0)207 594 1872; researchethicscommittee@imperial.ac.uk), ref: 19IC5453 2. Approved 24/04/2023, Mbale Regional Referral Hospital Research Ethics Committee (accredited by the Uganda National Council for Science and Technology, P.O Box 921, Mbale, Uganda; +256 (0)39 3289584; mrrhrec@gmail.com), ref: UG-REC-011 |
| Health condition(s) or problem(s) studied | Sickle cell disease |
| Intervention | Current interventions as of 27/02/2024: H-PRIME will recruit children between the ages of 1-10 years and follow them over a maximum period of 48 months. Children in different randomisations will be followed for the same period. Group 1: High-dose (daily) versus low-dose (thrice weekly) oral hydroxyurea (Novartis) with clinically-driven, as opposed to routine laboratory, monitoring Group 2: Enhanced antimalarial prophylaxis with dihydroartemisinin-piperoquine (DHA-PQP), given weekly versus Uganda standard of care (sulphadoxine-pyrimethamine given monthly) Group 3: Antimicrobial prophylaxis with cotrimoxazole (given once daily throughout childhood) versus standard of care (penicillin V given twice daily until the age of 5 years) Randomisation in each part of the factorial will be stratified by centre, hydroxyurea initial dose (to ensure balance across the specific doses proposed) and the other randomisations in the factorial. Randomisation will be done by the Mbale data centre using an online randomisation server. Other sites will telephone Mbale to perform randomisation. Randomisation lists will be prepared by the Trial Statistician at the MRC CTU using random permuted blocks, stratified by trial centre and initial hydroxyurea weight-band and incorporated securely into the online randomisation server, ensuring allocation concealment. If there are connectivity issues, randomisation will be delayed, since this is not an emergency situation. Previous interventions: H-PRIME will recruit children between the ages of 1-10 years and follow them over a maximum period of 48 months. Children in different randomisations will be followed for the same period. Group 1: Daily oral hydroxyurea (Siklos, addmedica) with clinically-driven, as opposed to routine laboratory, monitoring versus placebo Group 2: Enhanced antimalarial prophylaxis with dihydroartemisinin-piperoquine (DHA-PQP), given weekly versus Uganda standard of care (sulphadoxine-pyrimethamine given monthly) Group 3: Antimicrobial prophylaxis with cotrimoxazole (given once daily throughout childhood) versus standard of care (penicillin V given twice daily until the age of 5 years) Randomisation in each part of the factorial will be stratified by centre, hydroxyurea/placebo initial dose (since this will determine drug supply) and the other randomisations in the factorial. Randomisation lists will be prepared by the Trial Statistician at the MRC CTU using random permuted blocks, stratified by trial centre and initial hydroxyurea weight-band. Randomisation cards will be prepared at the KEMRI-Wellcome Trust Research Programme (KWTRP) Clinical Trial Facility (CTF) before the trial starts by staff who will not be involved in its conduct, and placed in sealed packs together with case record forms labelled with the associated trial number. A separate set of consecutively-numbered envelopes will be generated, each linked to a trial number/randomised allocation. At enrolment, the next consecutively-numbered envelope will be opened which will direct the clinician to a pack number which will always be in the next 16 packs but will not necessarily be the next one. Only when the pack is opened will the randomised allocation to interventions R1, R2 and R3 be visible on the randomisation card. The link between pack number and trial number (and hence randomised allocation) will also be randomised within blocks. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Dose response |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Hydroxyurea (Novartis), dihydroartemisinin-piperaquine, sulphadoxine-pyrimethamine, co-trimoxazole, penicillin V |
| Primary outcome measure | Determined either at the time they occur, via direct communication from participants to the study team, or at each of the 3 monthly followup appointments: Group 1: Mortality Group 2: Malaria-associated hospitalisations (diagnosed by rapid diagnostic test (RDT) and confirmed by microscopy and/or PCR) Group 3: Hospitalisations for any reason |
| Secondary outcome measures | Determined either at the time they occur, via direct communication from participants to the study team, or at each of the 3 monthly followup appointments: 1. Mortality (for both randomisations in which mortality is not the primary outcome - G2 and G3) 2. Malaria-associated hospitalisations (where not the primary outcome - G1 and G3) 3. All-cause hospitalisations (where not the primary outcome - G1 and G2) 4. Any of the following specific SCD-specific complications requiring medical intervention (Grade 2 or above): painful crisis, hand-foot syndrome, splenic sequestration, acute chest syndrome or stroke. |
| Overall study start date | 22/07/2017 |
| Completion date | 15/01/2028 |
Eligibility
| Participant type(s) | Other |
|---|---|
| Age group | Child |
| Lower age limit | 1 Year |
| Upper age limit | 10 Years |
| Sex | Both |
| Target number of participants | 1,800 |
| Key inclusion criteria | 1. Aged 1-10 years inclusive 2. Confirmed Sickle Cell Disease (SCD) (diagnosed either by HPLC or IEF at a qualified laboratory) 3. Have received conjugate pneumococcal vaccination against Hib and S. pneumoniae (otherwise eligible but unvaccinated children will be vaccinated through the study) 4. 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 |
| Key exclusion criteria | 1. Already meet criteria for starting hydroxyurea under Uganda National Guidelines 2026 (frequent crises (>5/year), abnormal transcranial Doppler ultrasound velocities, stroke or acute chest syndrome) 2. Already receiving hydroxyurea 3. 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) 4. Known cancer 5. A clinical history of previous or existing liver or renal diseases unrelated to sickle cell disease 6. Known cardiac ventricular dysfunction or failure or a previous history of cardiac arrhythmias 7. 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)) 8. Current participation in any other clinical trial of an investigational medicinal product 9. 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 |
| Date of first enrolment | 16/01/2024 |
| Date of final enrolment | 15/06/2025 |
Locations
Countries of recruitment
- Uganda
Study participating centres
Pallisa Road Plot 29-33
Mbale
PO Box 921
Uganda
Soroti
P.O Box 289
Uganda
Atutur
PO Box 22
Uganda
-
Uganda
Sponsor information
University/education
Joint Research Office
Room 221
Medical School Building
St Mary’s Campus
Norfolk Place
London
W2 1PG
England
United Kingdom
| Phone | +44 (0)20 7594 1188 |
|---|---|
| jrco@ic.ac.uk | |
| Website | https://www.imperial.ac.uk |
"ROR" |
https://ror.org/041kmwe10 |
Funders
Funder type
Government
No information available
Government organisation / National government
- Alternative name(s)
- Department for International Development, UK, DFID
- Location
- United Kingdom
Private sector organisation / International organizations
- Location
- United Kingdom
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2033 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. All publications and presentations relating to the trial will be authorised by the Trial Management Group. Named authors of the first publication of the trial results will include at least the trial’s Chief Investigator, Centre Principal Investigators, Statistician and Trial Coordinator. Members of the TMG and the Data Monitoring Committee will be listed, and contributors will be cited by name if published in a journal where this does not conflict with the journal’s policy. Authorship of parallel studies initiated outside of the Trial Management Group will be according to the individuals involved in the project but must acknowledge the contribution of the Trial Management Group and the Trial Coordination Centre. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. The collaborating research partners have met and have agree on the following data access and use rights before commencement of the study. First, that the ownership of the H-PRIME dataset will lie with the H-PRIME Trial Steering Committee, who will approve all requests for use of trial data before and after the trial ends, based on a controlled access approach (requests before the end of the trial also to be approved by the H-PRIME Data Monitoring Committee). No data will be shared that compromises the confidentiality of research participants or their communities. No collaborating research partner will transfer data to any third parties without the written consent of the other partners. On completion of the trial, local researchers will have unrestricted access rights to data sets collected through this collaborative research project. 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). The controlled access approach is based on the following principles: - No data should be released that would compromise an ongoing trial. - 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. - 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. - Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries. Researchers wishing to access data should contact the Trial Management Group in the first instance. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Other publications | baseline characteristics | 07/07/2020 | 21/08/2020 | Yes | No |
| Protocol file | version 4.0.1 | 18/09/2023 | 16/05/2024 | No | No |
| Statistical Analysis Plan | version 1.0 | 16/05/2024 | 21/05/2024 | No | No |
| Protocol (preprint) | 16/05/2025 | 23/06/2025 | No | No | |
| Protocol file | version 5.0 | 18/12/2024 | 23/06/2025 | No | No |
| Statistical Analysis Plan | version 2.0 | 16/06/2025 | 23/06/2025 | No | No |
Additional files
Editorial Notes
23/06/2025: The following changes were made:
1. The recruitment start date was changed from 01/12/2023 to 16/01/2024.
2. The recruitment end date was changed from 31/12/2028 to 15/06/2025.
3. The overall study end date was changed from 31/12/2032 to 15/01/2028.
4. Protocol version 5.0 and SAP version 2.0 uploaded.
5. Publication reference added.
21/05/2024: Statistical analysis plan uploaded.
16/05/2024: Protocol uploaded.
17/04/2024: Due to the COVID-19 effects, the study approval process was delayed and the following changes have been made:
1. The recruitment start date was changed from 01/09/2021 to 01/12/2023.
2. The recruitment end date was changed from 01/01/2025 to 31/12/2028.
3. The overall study end date was changed from 31/12/2028 to 31/12/2032.
4. The intention to publish date was changed from 31/12/2028 to 31/12/2033.
27/02/2024: The following changes were made:
1. The plain English summary was updated to reflect the below change in protocol.
2. The study design was changed from "2x2x2 factorial multi-centre randomized partially placebo-controlled trial" to "2x2x2 factorial randomized open-label trial".
3. The secondary study design was changed from randomised controlled trial to factorial design.
4. The interventions were changed.
07/08/2023: The following changes have been made:
1. The scientific title has been changed from "H-PRIME: a 2x2x2 factorial randomised partially placebo-controlled mortality trial, conducted in four centres in Eastern Uganda investigating the use of hydroxyurea, antibiotics and antimalarials in children with sickle cell disease recruited at the ages of 1 to 10 years" to "H-PRIME: Hydroxyurea – Pragmatic Reduction in Mortality and Economic burden: A multi-centre Phase III trial to investigate the efficacy of hydroxyurea in children with sickle cell anaemia when administered in a pragmatic fashion.".
2. The study hypothesis has been changed.
3. The ethics approval has been updated to include the approval date for Mbale Regional Referral Hospital Research Ethics Committee.
4. The overall study end date has been changed from 31/12/2025 to 31/12/2028 and the plain English summary updated accordingly.
5. The drug names have been updated.
6. The intention to publish date has been changed from 31/12/2025 to 31/12/2028.
21/09/2021: Internal review.
20/01/2021: The recruitment start date was changed from 01/01/2021 to 01/09/2021.
21/08/2020: Publication reference added.
24/02/2020: Trial’s existence confirmed by the Medical Research Council.
