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The ACTia trial: Safety of repeated drug use in children from ACT Consortium on Vimeo.

Scientific title: Programmatic implementation of ACTs in Malawi: Safety and effectiveness of combination therapies with repeated treatments for uncomplicated P. falciparum malariaover a three-year period

What did we know before this research?
International efforts to increase the use of artemisinin-based combination therapy (ACT) over the past decade have been based on the argument that this will lead to fewer malaria deaths. It has also been assumed that these drugs are safe even if used repeatedly. While there is no evidence to suggest concern, this has not been demonstrated directly in children under five years of age living in those areas.

When producing ACT drugs, most data around their safety has been based on trials where treatment was given only once or twice. However, in many parts of Africa young children are likely to receive treatment three or more times a year. Since safety signals are hardly monitored, this age group is more vulnerable to safety risks.

Also, most treatments in Africa are dosed according to the patient's age rather than their body weight; this is not the case in Asia (where these drugs have been used for many years). This increases the risk of under and overdosing, particularly in young children during the phase of rapid growth.

Because there are several highly effective ACTs available, spotting differences in the way individuals react to them could have major consequences for a wide roll-out. In areas with high transmission rates, ACTs of which partner drugs have a longer duration of action (known as half-life) may result in fewer cases of malaria than drugs with a shorter, preventive period of time (known as prophylaxis).

Similarly, more treatments could fail if a drug has a more complex dosing schedule or causes side effects that reduce adherence to the full treatment.

What does this study add?
We are comparing the effectiveness and safety of the use of ACT drugs in children under five years in different health centres and communities. We measured this by using auditory brainstem response tests, a widely used hearing screening test in children, which can also identify signs of drug-related adverse effects on the nervous system of the brain that is involved in hearing.

The research team
Principal Investigators

Prof David Lalloo, Liverpool School of Tropical Medicine

Dr Anja Terlouw, Liverpool School of Tropical Medicine

Dr Kamija Phiri, University of Malawi

Other Investigators

Prof Malcolm Molyneux, Professor Tropical Medicine, MLW
Dr Arantxa Roca-Feltrer, Epidemiologist, Liverpool School of Tropical Medicine /MLW
Dr Ian McKenzie, Consultant paediatric and adult audiological physician, Liverpool School of Tropical Medicine
Dr Sally Theobald, Social Scientist, Liverpool School of Tropical Medicine
Dr Brian Faragher, Statistician, Liverpool School of Tropical Medicine
Dr Doreen Ali, Director, National Malaria Control Programme
District Health Officer, Chikwawa
Ms Victoria Ewing, PhD student, Liverpool School of Tropical Medicine

Latest on this research
The trial follow-up phase was completed in April 2013. A total of 838 children were recruited and followed over time for episodes of fever as per standard care, and were repeatedly treated with the same ACT (artemether-lumefantrine or dihydroartemisinin-piperaquine according to their treatment arm). During the follow-up we measured the safety and effectiveness of both drugs over time.

This trial included a number of nested study components within the trial participants and their home villages, in order to conduct more in-depth assessments related to drug safety and effectiveness.

For example, we conducted visits to households to identify possible challenges to the patients’ compliance to treatment, as well as adverse effects at community level. Such challenges may affect the perception of these drugs by caretakers, their behaviour in seeking treatment, their adherence to future treatment and the reputation of a drug in the community. At community level, a continuous malaria indicator survey (MIS) was used to monitor variations of the disease burden in space and time within the area, as well as any changes in malaria control efforts.

At present the trial data is being prepared for data analysis.