Recruitment will begin this month for a Phase II clinical trial in Gabon and Malawi that will assess the efficacy of two intravenous artesunate dosing regimens in eliminating Plasmodium falciparum parasites from children with severe malaria.

The 5.3 million euros study is being funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) and sponsored by Medicines for Malaria Venture (MMV). Other partners in the initiative are the Severe Malaria in African Children network, which is supplying the trial investigators; the US Walter Reed Army Institute of Research, which is donating the intravenous artesunate; and, in a supervisory capacity, Eberhard Karls Universität Tübingen in Germany.

The Phase II randomised, double-blind trial, which has been approved by the relevant ethics committees and national regulatory authorities in Malawi and Gabon, will be conducted at the Albert Schweitzer Hospital in Lambaréné, Gabon, the Université de Médecine et Science de Santé, Gabon, and the Queen Elizabeth Central Hospital in Blantyre, Malawi. It will look at the efficacy, safety, tolerability and pharmacokinetics of intravenous artesunate in African children with severe malaria.

The two main objectives are:

- to expand the body of evidence for use of intravenous artesunate in children living in high-transmission areas for malaria as well as showing that the use of potentially more toxic intravenous quinine can be avoided;

- to simplify the dosing regimen for intravenous artesunate from five to three injections.

Antimalarial chemotherapy is the mainstay of treatment for severe malaria, which kills more than one million African children each year, the EDCTP points out. Intravenous quinine is currently used in children with severe malaria in Africa but it is poorly tolerated, with a number of side-effects. While large studies in Asia and Africa have found artemether to be safer and easier to use than quinine, it may not be the most suitable artemisinin derivative due to erratic and slow absorption from intramuscular injection sites, the Partnership notes.

By contrast, artesunate (a water-soluble artemisinin derivative) has proved to be less neurotoxic than the lipid-soluble artemether in preclinical studies. Unlike artemether, it can also be given intravenously, making it one of the most rapidly acting antiparasitics and “an excellent candidate to challenge quinine’s position as the current therapy of choice for severe malaria”, the EDCTP says. This promise has been further corroborated by a recent study in Asia, in which artesunate was shown to be superior to quinine for adults with severe malaria, it adds.

Major policy change

The World Health Organization now recommends intravenous artesunate for the treatment of severe adult malaria in low-transmission areas, the Partnership notes. However, there is little information available on the regimen’s efficacy in children living in high-transmission regions, such as Africa.

“If we can show superior efficacy and/or safety and tolerability of the new artesunate regimen in African children, we are likely to see a major policy change in the treatment of severe malaria in African children,” predicted Dr J Carl Craft, MMV’s chief scientific officer.

Funded under the European Commission’s Sixth Framework Programme for research and technological development, the EDCTP is a partnership between European and sub-Saharan countries that aims to reduce poverty by developing new clinical interventions to fight HIV/AIDS, malaria and tuberculosis. The focus is on Phase II and III clinical trials in sub-Saharan Africa. Partners include 14 European Union member states, Norway, Switzerland and 47 sub-Saharan African countries.

Medicines for Malaria Venture is a non-profit organisation dedicated to reducing the burden of disease in malaria-endemic countries by discovering, developing and delivering safe, effective and affordable antimalarial drugs through public-private partnerships. It currently has more than 25 projects at various stages of research and development, with three new artemisinin combination therapies (ACTs) awaiting registration.