In this study, the overarching questions that we wish to address is whether the long-term survival and quality of life among children living with SCD in sub-Saharan Africa could be improved through the pragmatic delivery of simple and affordable interventions? SCD is a major cause of mortality and morbidity during childhood throughout much of sub-Saharan Africa. The main triggers relate to the pathophysiological consequences of the disease itself and to bacterial and malarial infections.

A large pragmatic mortality-endpoint trial in SCD is needed now for several compelling reasons. Previous trials investigating hydroxyurea have not been designed and powered to investigate the survival of children with SCD living in malaria-endemic regions of sub-Saharan Africa.^17,18 Moreover, strategies for delivery based on uniform weight-band based dosing were not investigated in the two most definitive trials conducted in Africa to date^17,18 which, further, did not involve clinically driven, pragmatic, laboratory monitoring approaches that could be generalisable across sub-Saharan Africa where, in the main, there is a lack of specialist laboratory services. Existing trials, therefore, have not provided the evidence that is needed to influence policy regarding the safety and efficacy of wider drug uptake in regions where quality-controlled routine and frequent laboratory monitoring is not available. However, failing to tackle SCD survival because of infrastructure constraints could mean that many countries within the region will miss their Sustainable Development Goals (SDGs) both in terms of deaths averted and their promise that “no one must be left behind”.⁵⁰ Second, with demographic transition⁵¹ an increasing number of children with SCD will inevitably survive to require medical attention, and to become chronically unwell, develop long term complications including strokes, and place a disproportionate burden on medical and blood transfusion services.⁷ Finally, SCD is at last being recognised as a key health challenge by international agencies^52,53 and by African governments, including Uganda.¹⁶ This is manifest by the recent introduction of selective early life screening in Uganda during recent years¹⁶ and their plans for universal screening in the near future. Without trials like H-PRIME, it will be impossible to develop regionally appropriate policies that could genuinely impact on morbidity and mortality. Specifically, while hydroxyurea is now increasingly being used, it is not known whether it will be either well-tolerated or effective in the informal way in which it is most commonly being taken.

The most important outstanding questions are therefore:

• Would hydroxyurea therapy, commenced early in life for all children diagnosed with SCD, be both well-tolerated and effective in reducing mortality and morbidity in sub-Saharan Africa if used at fixed weight-band based doses with minimal clinically driven (rather than regular and pre-planned routine) laboratory monitoring?
• Can further reductions in mortality and/or morbidity be achieved through better approaches to preventing malaria and bacterial infections?

The trial will have 3 intervention strategies aimed at reducing mortality and morbidity in children with SCD

• R1: daily oral hydroxyurea vs placebo, dosing 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)
• 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)