Insights

The field of global health is full of opportunities to enhance the health and well-being of people worldwide, but the path to success is rarely straightforward. Sometimes, researchers find themselves grappling with the question: What happens when the outcome of a study does not deliver the desired results? The CARAMAL project team was faced with this issue, demonstrating that even the most promising ideas can encounter unforeseen challenges.

The Community Access to Rectal Artesunate for Malaria (CARAMAL) project, a large-scale study that investigated the roll-out of rectal artesunate (RAS) in the Democratic Republic of the Congo, Nigeria and Uganda, was designed to be a game changer for young children suffering from severe malaria.

With the introduction of RAS as pre-referral treatment administered by health workers in remote villages, the hope was to bridge the time until the sick child was transported to a hospital where comprehensive post-referral care is available.

The results were sobering: researchers found that when used as an emergency treatment under real-world conditions, RAS did not improve the odds of survival for children with severe malaria.

“Our findings point to an inconvenient but important truth,” said Manuel Hetzel, malaria expert at Swiss TPH. “We found that the overall management of severe malaria cases is so poor in many areas with a high malaria burden, that adding a single product does not seem to make a positive difference. Our focus must be on investments in improving existing health systems instead of relying solely on individual interventions.”

The study, which was published in October 2022 in BMC Medicine, included 6,200 severely ill children under the age of 5 years in remote resource-constrained settings. “RAS was previously shown in a controlled study to have a beneficial effect when it was followed by adequate post-referral care at a hospital,” added Hetzel. “But more often than not, children do not finish the entire treatment due to lack of transportation to hospitals, cost of transport and treatment, or poor quality of care at hospitals. On its own, RAS is not sufficient to cure severe malaria.”

Current and future recommendation by the World Health Organization (WHO)

The current WHO guidance on using RAS as pre-referral treatment is based on a randomised controlled trial that took place between 2000 and 2006 in Ghana, Tanzania and Bangladesh. This trial offered limited guidance on introducing RAS at scale. “Under real-life conditions, many factors influence whether an individual is appropriately treated and cured, which is why interventions that work well in a controlled trial may not always fulfil their potential in real life.” said Phyllis Awor, CARAMAL co-investigator at the Makerere University School of Public Health in Uganda. be addressed to ensure a functioning continuum of care before pushing for a large-scale rollout of pre-referral RAS,” said Hetzel. “Without a comprehensive approach that acknowledges the complex realities faced by caregivers and health workers in remote, underserved areas, children will continue to die from malaria, and promising interventions such as RAS will fail to meet their full potential.”

About CARAMAL

Based on the results of the CARAMAL study, the WHO issued an Information Note in October 2021 recommending that countries either temporarily delay scale-up, or urgently review the conditions under which RAS is currently being used. At present, a team of WHO-appointed experts are reviewing all available evidence to develop guidance on the safe implementation of pre-referral RAS in highly malaria-endemic countries.

“The real-world evidence generated in our study identified health systems constraints that must

The CARAMAL project was an observational study that accompanied the introduction of pre-referral RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda between 2018 and 2021. It is the first study of its kind to look at the introduction of quality-assured RAS in existing community-level healthcare systems at a large scale. The project was implemented by the Clinton Health Access Initiative (CHAI), Unicef and Swiss TPH, with funding from Unitaid. Swiss TPH was responsible for the evidence generation jointly with the University of Kinshasa School of Public Health in the DRC, Akena Associates in Nigeria, the Makerere University

School of Public Health in Uganda, and Pasteur Institute of Cambodia. Medicines for Malaria Venture and WHO also supported the project. Key study findings were presented in more than ten scientific publications.

Hetzel MW, Okitawutshu J, Tshefu A, et al. Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study. BMC Medicine 2022, 20:343

DOI https://doi.org/10.1186/s12916-022-02541-8

In remote villages, where immediate injectable malaria treatment is not available, health workers may administer pre-referral RAS suppositories as emergency treatment to children with severe malaria. The treatment quickly reduces the number of malaria parasites in the blood and helps bridge the time until the child is admitted to a hospital for comprehensive post-referral care. Post-referral care for severe malaria includes an intravenous antimalarial, followed by a full oral course of artemisinin-based combination therapy, plus antibiotics and measures to manage potential complications.

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