FACT

The challenge

Malaria remains a major public health challenge, particularly in the Global South, causing around 600,000 deaths each year. Most deaths occur in children in sub-Saharan countries.

Severe malaria is a medical emergency requiring immediate treatment. However, the fever of malaria overlaps with symptoms of other serious conditions, including invasive bacterial infections. About one-third of patients treated for severe malaria are misdiagnosed, and invasive bacterial (co-) infections are the most common missed underlying cause. Even a positive rapid diagnostic test result for malaria may not be conclusive. Malaria is highly prevalent among healthy individuals in endemic regions, and even when Plasmodium parasites are present, they may not be the primary cause of illness. 

For these reasons, the WHO recommends that children with suspected severe malaria are treated with the injectable antimalarial artesunate, accompanied by broad-spectrum antibiotics. In practice, many children do not receive both treatments. Also, artesunate alone increases the risk of parasites escaping treatment, with particular concern for mutations associated with partial resistance to artemisinins. Many African countries also face a growing challenge from antibiotic resistance, highlighting the use of antibiotics with different modes of action.

The project

The FACT project is evaluating a new treatment approach that simultaneously covers severe malaria and common bacterial pathogens affecting children in sub-Saharan Africa. It reduces the risk of antimalarial resistance and shortens treatment duration.

The treatment is a novel antibiotic-based combination therapy that combines two licensed drugs and one in late-stage development:

• Artesunate: standard antimalarial for severe malaria.
• Fosmidomycin: a drug in late-stage development with activity against Plasmodium parasites and Gram-positive bacteria.
• Clindamycin: a licensed drug with activity against Plasmodium parasites and Gram-negative bacteria.

This triple combination enhances the spectrum of antimalarial activity and introduces antimicrobial properties. All drugs are individually safe and effective and work in oral combination in adults and children. Importantly, the three drugs have different mechanisms of action while maintaining compatible pharmacokinetic properties, including short half-lives. This combination protects individual partners from developing drug resistance. The full treatment regimen will be delivered by injection in the hospital, further reducing the risk of resistance by ensuring full treatment courses are completed. The combination will also shorten in-hospital treatment from up to 6 to 4 days. 

The FACT consortium is conducting a randomised controlled phase II trial in Gabon to determine an optimal dosing for parenteral treatment. At the outset of the development program, different treatment regimens will be evaluated in children with uncomplicated malaria, using an age-step-down algorithm. 

Once the optimal dose of fosmidomycin has been determined, a randomised controlled multi-country phase III trial will be conducted in the Republic of Congo, Ethiopia, Gabon and Ghana. Children with severe malaria will be randomised to receive either the triple combination or the usual standard of care. 

The project team is also conducting susceptibility testing to determine the sensitivity patterns of Plasmodium parasites to antimalarial drugs. It will also genotype isolates for genes known to be associated with partial artemisinin resistance. Parasites causing breakthrough infections will be fully sequenced to identify potentially new resistance genes. Similarly, any bacterial pathogens identified will undergo antibiotic susceptibility testing. 

Additional studies will examine the cost-effectiveness of the new approach, and its acceptability to key stakeholders, including community members, will be explored.

Impact

The FACT project will advance a new treatment strategy for severe malaria with several potential advantages. It will:

• Assess if FACT novel triple therapy is as effective as current monotherapy with artesunate for severe malaria.
• Provide an efficacious artemisinin-based treatment option for severe malaria in line with WHO recommendations.
• Reveal whether triple therapy leads to improved outcomes due to additional effects on bacterial bloodstream infections.
• Help to protect individual drugs from selection for parasite resistance.
• Reduce the time spent in hospital by up to two days, financially benefiting both households and health systems.

The FACT project could improve the treatment of severely ill children at significant risk of death by targeting a wide range of pathogens in one combination treatment, protecting the long-term potency of artesunate on the African continent, ensuring the availability of a treatment option against severe malaria beyond the spread of artemisinin partial-resistance, and benefiting households and health systems by reducing the duration of hospital stays.