Condition category
Circulatory System
Date applied
13/02/2020
Date assigned
25/02/2020
Last edited
24/02/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

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 a number of 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 25 +/-5mg/kg/day, with clinically based monitoring only, versus placebo control. The second and third randomisations will be to 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?
1. Mbale Clinical Research Institute (Uganda)
2. Soroti Regional Hospital (Uganda)
3. Atutur District Hospital (Uganda)
4. Ngora District Hospital (Uganda)

When is the study starting and how long is it expected to run for?
January 2021 to December 2025

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

Trial website

Contact information

Type

Public

Primary contact

Mr Dennis Amorut

ORCID ID

http://orcid.org/0000-0003-4456-2382

Contact details

Mbale Clinical Research Institute
Pallisa Road Zone
PO Box 921
Mbale
-
Uganda
+256 774 573 991
damoruts@gmail.com

Type

Scientific

Additional contact

Prof Thomas Williams

ORCID ID

http://orcid.org/0000-0003-4456-2382

Contact details

KEMRI-Wellcome Trust Research Programme
PO Box 230
Kilifi
-
Kenya
+254 417 522063
twilliams@kemri-wellcome.org

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

V2.0

Study information

Scientific title

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

Acronym

H-PRIME

Study 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

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. Approval pending, 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

Study design

2x2x2 factorial multi-centre randomised partially placebo-controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Prevention

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Sickle cell disease

Intervention

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

Phase

Phase III

Drug names

Hydroxyurea (Siklos, addmedica)
Dihydroartemisinin-piperoquine
Cotrimoxazole

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 trial start date

22/07/2017

Overall trial end date

31/12/2025

Reason abandoned (if study stopped)

Eligibility

Participant 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

Participant type

Other

Age group

Child

Gender

Both

Target number of participants

1,800

Participant 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

Recruitment start date

01/01/2021

Recruitment end date

01/01/2025

Locations

Countries of recruitment

Uganda

Trial participating centre

Mbale Clinical Research Institute
Mbale Regional Referral & Teaching Hospital Complex Pallisa Road Plot 29-33
Mbale
PO Box 921
Uganda

Trial participating centre

Soroti Regional Hospital
Soroti Regional Referral Hospital
Soroti
P.O Box 289
Uganda

Trial participating centre

Atutur District Hospital
Kumi District
Atutur
PO Box 22
Uganda

Trial participating centre

Ngora District Hospital
Ngora
-
Uganda

Sponsor information

Organisation

Imperial College London

Sponsor details

Joint Research Office
Room 221
Medical School Building
St Mary’s Campus
Norfolk Place
London
W2 1PG
United Kingdom
+44 (0)20 7594 1188
jrco@ic.ac.uk

Sponsor type

Research council

Website

https://www.imperial.ac.uk

Funders

Funder type

Government

Funder name

The Joint Global Health Trials Scheme of the Department for International Development, UK (DFID), the Wellcome Trust and the Medical Research Council (MRC UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Department for International Development, UK Government

Alternative name(s)

Department for International Development, UK, DFID

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Funder name

Wellcome Trust

Alternative name(s)

Wellcome

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

United Kingdom

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

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 statement:
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.

Intention to publish date

31/12/2025

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

24/02/2020: Trial’s existence confirmed by the Medical Research Council.