MICA: Hydroxyurea - Pragmatic Reduction In Mortality and Economic burden (H-PRIME)

Sickle cell anaemia (SCA) is a common inherited condition that affects around 1% of all children born in much of sub-Saharan Africa. Without early diagnosis and appropriate treatment under-5 mortality in those affected is between 50 and 90%. As a result, through much of the continent SCA is responsible for between 5 and 16% of total under-5 mortality. These high levels of mortality could be reduced dramatically with simple treatments that include educating parents to recognise danger signs and seek emergency care, and by measures that protect against acute bacterial and malarial infections using vaccines and prophylactic antibiotic and anti-malarial drugs. Nevertheless, without specific treatments that modify the course of the disease, many of those affected will live lives that are characterized by frequent and recurrent bouts of severe illness that include acute and chronic pain and progressive multi-organ deterioration.

Unlike diseases like HIV, malaria and tuberculosis, SCA does not enjoy a high profile in the eyes of the international community and remains widely neglected by ministries of health through much of sub-Saharan Africa. Through H-PRIME, we will address three key questions in the management of children with SCA in Africa today through a single large, efficient and pragmatic clinical trial.

First, we will determine whether hydroxyurea, a common and effective treatment for SCA in resource-rich regions, could be a useful option in parts of Africa with limited access to medical care. In most countries hydroxyurea is administered and monitored in a way that will not be achievable in most of Africa and our primary question, therefore, will be whether the drug can be used safely and effectively to reduce mortality and improve the quality of life in survivors when administered pragmatically following a weight-band-based dosing strategy with minimal clinical and laboratory monitoring.

Second, we will investigate whether better protection from bacterial infections in children with SCA can reduce all cause hospital admission and further reduce mortality. The current approach to the prevention of bacterial infections is through the use of oral penicillin. However, this is only effective against a narrow range of bacterial organisms and we will therefore investigate whether the addition of a second agent, co-trimoxazole, could bring further benefits in the absence of harm.

Finally, the current approach to the prevention of malaria infections relies on drugs that are associated with high levels of resistance. We will therefore investigate whether malaria prevention with a more modern and highly effective drug - dihidroartemisinin-piperaquine - could be used as an alternative, and that this will not cause harm in terms of side effects and the development of further drug resistance.

H-PRIME will be a phase III 2x2x2 factorial randomised partially placebo-controlled trial. We aim to conduct a policy changing trial to address three key interventions that could make a substantial difference to the lives of children born with sickle cell anaemia (SCA) in low-income regions in sub-Saharan Africa. H-PRIME will answer all three questions efficiently in a single clinical trial.

We will recruit 1800 children with confirmed SCA at three sites in Eastern Uganda who will be randomised to: (1) daily oral hydroxyurea vs placebo; (2) enhanced antimalarial prophylaxis with monthly dihydroartemisinin-piperaquine (DHA-PQP) vs standard of care (SOC) (monthly sulphadoxine-pyrimethamine, SP) (open-label) and (3) enhanced antimicrobial prophylaxis with daily co-trimoxazole (CTX) AND twice-daily penicillin V throughout childhood vs SOC (twice-daily penicillin V until the age of 5 years; open-label). A 3-month pre-treatment screening and observation period will allow diagnostic confirmation of SCA status and the collection of baseline data on clinical event rates, laboratory variables and potential confounders.

The primary outcome the hydroxyurea randomization will be death from any cause. The primary outcome for the anti-malarial randomisation will be malaria-associated hospitalisation while for the antibiotic randomisation it will be hospital admission (all-cause, due to the challenges in diagnosing bacterial infections as above).

Assuming recruitment over 2 years, a maximum 4 years of follow-up, 10% loss to follow-up at 4 years and mortality in the control arm of 2.6/100CY (i.e. 10% cumulative mortality at 4 years, H-PRIME will provide 90% power to detect a 50% relative reduction for hydroxyurea vs placebo. The study will provide 86% power to detect a 36% relative reduction from 4.7 to 3.0 malaria-associated hospitalisations/100CY respectively and 87% power to detect a 20% relative reduction from 20 to16 all-cause hospitalisations/100CY respectively.

The first strategic approach for achieving impact has already started: ensuring the trial addresses priority issues for the target audiences and will provide results that are applicable. The questions that H-PRIME aims to address have been identified in published reviews and recognised as important evidence gaps by a range of international agencies. The trial will be pragmatic, to ensure the results are applicable to poorly resourced health services in Africa. The health economics component is also vital to ensuring that we provide evidence not just on effectiveness but also on cost-effectiveness, to allow policymakers to make decisions on how best to allocate scarce resources.

We will strengthen our engagement with key audiences before, during and after the trial. This will allow us to seek their advice on how best to communicate the results and their views on the conduct and implications of the trial. At the international level we will engage with relevant committees at the WHO and with other organisations already active in this area such as UNICEF, Medecins Sans Frontiers and Save the Children, to advocate for appropriate policy and guideline changes at national and international levels if the results of the trial indicate this is necessary. We will set up an electronic newsletter to keep these constituencies informed of the progress of the trial. We will also develop a website for H-PRIME that will be kept up-to-date with the latest news on the trial and resources that are developed by the trial team.

Another key element of our pathway to impact is ensuring the results are available in formats that are accessible and appropriate to our key audiences. We will publish the trial protocol, when approved, in an open access journal such as Wellcome Open Research and we will publish the results of the main trial and sub-studies in open access peer-reviewed journals and present them at relevant international conferences. This will reach our academic audience and will also provide the quality assurance needed by guideline developers such as WHO. We will also present results in other formats such as briefs aimed at national policymakers (including Ministries of Health and child health departments), and provide clear interpretation of the results that can feed into training programmes or work aids for child health practitioners. We will produce video and radio programmes / podcasts that can be used for communicating the results to communities and health professionals.

We will seek to have an impact through increasing the capacity of health researchers involved in the trial. We will provide opportunities for scientific exchange visits across sites and with UK partners.

Following analysis of the results of the trial, we will engage with training programmes in Africa to ensure they have access to the information and tools they need to update their training programmes for care of children with sickle cell anaemia, based on our findings. Communication and engagement activities will be undertaken in large part by our collaborators in Africa who will take the lead on activities to engage with national stakeholders in their countries and will making important contributions to regional and international communication activities. Our collaborators already have experience of this work from previous trials and the PIs are all influential experts in their field.