Major Clinical Trial Prompts Call for Change of Treatment Guidelines for Severe Malaria Worldwide

Results of the largest ever clinical trial in patients hospitalized with severe malaria and published today online in the Journal The Lancet, has concluded that the drug artesunate should now be the preferred treatment for the disease in both children and adults worldwide.

The study, funded by the Wellcome Trust, involved an international consortium of researchers, led by Professor Nick White of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme in Bangkok, Thailand. They compared treatment with artesunate, which is used in Asia to treat severe malaria, against quinine, which has been in use worldwide for over three hundred years. The trial- known as the African Quinine v. Artesunate Malaria Trial (AQUAMAT)- was carried out over a five year period in hospitals across nine African countries, including Kenya and studied 5,425 children with severe malaria.

Severe malaria kills nearly a million people each year, mainly young children and pregnant women. It is caused by parasites which are injected into the bloodstream by infected mosquitoes. Severe malaria is often the main reason why children are admitted to hospital in Sub-Saharan Africa, and one in ten of these children die.

For over three centuries, doctors have relied upon the bark of a South American tree to treat tropical fevers. This bark gives quinine, a bitter medicine used to flavour tonic water, prevent night cramps, and cure malaria. Quinine is a reliably effective drug, but it is difficult to give by injection and has unpleasant side effects, some of which are potentially dangerous.

The AQUAMAT study compared quinine against the more recent drug artesunate both given either intravenously or by intramuscular injection. The results showed that treatment with artesunate reduced the number of deaths from severe malaria by 22.5%. With artesunate treatment, 8.5% of the patients died, compared to 10.9% with quinine. The results were very similar in all the study sites.

Children treated with artesunate were also less likey to slip into a deeper coma or have seizures after the treatment was started. Severe hypoglycaemia- dangerously low blood sugar- was also less common in children treated with artesunate. In addition, artesunate was easy to administer, well tolerated, and proved very safe.

Artesunate is derived from a Chinese herb called qinghao (artemisia annua). Nearly forty years ago, Chinese scientists reported that an extract of this herb was an effective anti-malarial. These reports were treated initially with suspicion but the compounds derived from it (such artemisinin) have steadily gained acceptance throughout the world. In uncomplicated malaria, artemisinin compounds such as artesunate are now part of the arteminisin combination treatments  (ACTs) recommended everywhere in the world.

Five years ago, the then largest ever trial in patients hospitalized with severe malaria showed that artesunate, given by injection, reduced the death rate compared with quinine. However, this trial was conducted in Asia and most of the patients studied were adults, so there was uncertainty over whether artesunate injection should replace quinine as a treatment of severe malaria in children in Africa, where most of the deaths occur. Today nearly all the children admitted to hospital with severe malaria in Africa still receive quinine.

Dr Arjen Dondorp, Professor White and colleagues from Mahidol University and the University of Oxford, who conducted the original study in Asia, also led the AQUAMAT study. AQUAMAT was carried out in eleven hospitals across Mozambique, Tanzani, Kenya, Uganda, Rwanda, The Democratic Republic of Congo, Nigeria, Ghana, and The Gambia and involved over 200 collaborators. The trial was funded entirely by the Wellcome Trust, a global charitable foundation, and received no funding from the pharmaceutical industry.

Professor White comments: '' For over a century, quinine administered by injection has been the best treatment available for treating severe malaria, but thanks to the development of the artemisinin compounds, we now have a safer and much more effective treatment.''

Professor Kathryn Maitland, who was the Principal Investigator for the AQUAMAT study at the KEMRI-Wellcome Trust Research Programme in Kenya, had this to say: '' This study has shown a clear result. We now recommend that artesunate should now replace quinine in the treatment of severe malaria in both children and adults all over the world.''

''Our institution is very proud to have participated in this trial. The results are significant and confirm our commitment to delivering world class scientific output, in collaboration with the rest of the world,'' says Dr Solomon Mpoke, the Director of KEMRI.

Dr Norbert Peshu, the Director of the Centre for Geographic Medicine Research- Coast (CGMR-C), which hosts the KEMRI-Wellcome Trust Research Programme said: '' We're very excited about the results of this study. I now urge policy makers all over the world to use this evidence and change the treatment guidelines accordingly.''

Dr Olugbenga Mokuolu from the University of Ilorin in Nigeria, one of the trial collaborating centres, adds: '' Severe malaria is a terrible burden on the African continent and across the developing world and we need the best treatments available to combat it. If half of the estimated eight million children annually who suffer from the disease could be treated with injectable artesunate, we could potentially save 100,000 young lives each year. For those of us who treat malaria in Africa, this trial is a turning point. Finally we have a better treatment to offer to our malaria patients.''

The Ministry of Public Health and Sanitation (MOPHS) through the Head of the Division of Malaria Control, Dr Elizabeth Juma, said; '' The Division of Malaria Control is happy about the results of the trial comparing artesunate with quinine for severe malaria in children. The current malaria treatment guidelines recommend the use of IV artesunate for the treatment of severe malaria in adults and from 2009, the Division has provided IV artesunate, job aids and guidelines on its use, but on a limited scale due to the current relative high cost of the product. Severe malaria is life threatening and clinicians should be reminded that supportive treatment is as critical as the malaria medicine in ensuring a good outcome for all patients with severe malaria.''

A major factor limiting the use of artesunate has been the lack of availability of a product satisfying international good manufacturing standards. The most widely used product, evaluated in this study, does not yet have this certification but still proved to be superior to quinine.

The results have been welcomed by Professor Kevin Marsh, Director of the KEMRI-Wellcome Trust Research Programme in Kenya: '' We at the Programme are happy to have participated in this major clincial trial which potentially could save the lives of hundreds of thousands of children who die of severe malaria in Africa.''

ENDS

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Author contacts for commentary

Professor Kathryn Maitland: kmaitlandkilifi [dot] kemri-wellcome [dot] org (Tel: +254 (0) 41-7525603

Professor Kevin Marsh: kmarshkilifi [dot] kemri-wellcome [dot] org (Tel:+254 (0) 41-7525603

Professor Charles Newton: cnewtonkilifi [dot] kemri-wellcome [dot] org (Tel: +254 (0) 41-7525603

Notes for Editors

Maitland, K., Kivaya, E. (2010) "AQUAMAT: an open randomised comparison of artesunate versus quinine in the treatment of severe falciparum malaria in African children. '' The Lancet: e-pub 6 Nov 2010

Dondorp, A. et al. AQUAMAT: an open randomised comparison of artesunate versus quinine in the treatment of severe falciparum malaria in African children. Lancet: e-pub 6 Nov 2010.

The Wellcome Trust is a global charitable foundation dedicated to achieving extra-ordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk

The Kenya Medical Research Institute (KEMRI) is a Kenya government parastatal with the responsiblity for health research to improve the health of Kenyans. It is one of the most well developed national research institutes in Africa with a network of centres of across Kenya such as the Centre for Geographic Medicine Research- Coast (CGMR-C), which is home to the KEMRI-Wellcome Trust Research Programme. The Programme was formally established in 1989 and is a partnership between KEMRI, Oxford University and the Wellcome Trust. It conducts basic, epidemiological and clinical research in parallel, with results feeding directly into local and international health policy, and aims to expand the country's capacity to conduct multidisciplinary research that is strong, sustainable and internationally competitive. www.kemri-wellcome.org