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

Phase 3

Conditions: Sickle cell disease
Circulatory System

Registration Number: ISRCTN15724013

Lead Sponsor: Imperial College London

Brief Summary: 2020 Other publications in https://pubmed.ncbi.nlm.nih.gov/32802962/ baseline characteristics (added 21/08/2020)

Detailed Description: Not available

Recruitment & Eligibility

Status: Ongoing

Sex: All

Target Recruitment: 1800

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

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

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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:<br>Group 1: Mortality<br>Group 2: Malaria-associated hospitalisations (diagnosed by rapid diagnostic test (RDT) and confirmed by microscopy and/or PCR)<br>Group 3: Hospitalisations for any reason

Secondary Outcome Measures

Name	Time	Method
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:<br>1. Mortality (for both randomisations in which mortality is not the primary outcome - G2 and G3)<br>2. Malaria-associated hospitalisations (where not the primary outcome - G1 and G3)<br>3. All-cause hospitalisations (where not the primary outcome - G1 and G2)<br>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.