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Project 11: Safety

project 11 team photoProject Title

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

Project Location(s)

Chikwawa District, Southern Malawi

Lead Principal Investigator

United Kingdom - David Lalloo MB BS MD FRCP FFTM RCPS, is a Professor in Clinical Tropical Medicine and head of the Clinical Research Group at the Liverpool School of Tropical Medicine (LSTM). David trained in General (Internal) Medicine, Infectious Diseases and Tropical Medicine, spending three years in Papua New Guinea. He undertook clinical and laboratory research in Oxford before moving to LSTM in 1999. Since then he has focused on clinical trials in the tropics, particularly in HIV related infections, malaria and envenoming. Previous work on malaria included a trial in Malawi examining the effect of adherence on effectiveness of chlorproguanil-dapsone in uncomplicated malaria.

Malawi -Kamija Phiri MD MSc PhD, is currently working as a Lecturer in Department of Haematology, College of Medicine and is a Clinical Epidemiologist at the Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW) in Blantyre, Malawi. His previous research work has been on aetiology and long-term outcome of severe anaemia in children in particular looking at the assessment and contribution of iron deficiency. Present research interests are the post-discharge management of malaria and anaemia in both healthy and HIV infected children.

Other Principal Investigators


Dr Dianne (Anja) Terlouw, Clinical Epidemiologist, LSTM

Prof Malcolm Molyneux, Professor Tropical Medicine, MLW

Dr Arantxa Roca-Feltrer, Epidemiologist, LSTM/MLW

Dr Miguel Sanjoaquin, Epidemiologist, LSTM/MLW

Dr Ian McKenzie, Consultant paediatric and adult audiological physician, LSTM

Dr Bertha Nhlema Simwaka, Social Scientist, REACH, Lilongwe.

Dr Sally Theobald, Social Scientist, LSTM

Dr Brian Faragher, Statistician, LSTM


Dr Doreen Ali, Director, National Malaria Control Programme

Dr Madalitso Mbewe, District Health Officer, Chikwawa

Dr Victor Mwapasa, Clinical Epidemiologist, MLW

Prof Feiko ter Kuile, Professor in Tropical Epidemiology, LSTM

Ms Pamela Fergusson, Social Scientist, LSTM

Ms Victoria Ewing, PhD student, LSTM

Ms Ireen Makwiza, Social Scientist, REACH Trust, Lilongwe

Research Aim(s)

Safety, Access, Longtitudinal Studies

Project Background and Rationale

The international drive to the rapid roll out of ACTs, has been based on the premise that this will lead to significantly fewer episodes of malaria and thus lower morbidity, and that these drugs are safe with repeated use in high-transmission settings. While there is no evidence to suggest concern, this has not been demonstrated directly in under-fives in high-transmission settings.

The majority of safety data on ACTs during the drug development process has been based on treatment trials which assessed single treatment exposures. In many parts of Africa however, young children may be (presumptively) treated 3 or more times a year with little to no monitoring of safety signals, so issues of safety are more likely to become apparent in this young age group. Also, and in contrast to Asia where ACTs have been used for a number of years, the majority  of treatments are dosed based on the patient's age instead of their body weight, with increased risk of under and overdosing, particularly in young children during the phase of rapid growth. It has been suggested that auditory brainstem response tests may be a sensitive tool to identify (or confirm the absence of) early signs of specific drug, including artemisinin, related toxicity.

Furthermore, with the availability of several highly efficacious ACTs, minor differences in effectiveness and tolerability in real-life use may have major consequences for wide-scale programmatic implementation. In high-transmission areas, ACTs with longer half-life partner drugs may result in a lower clinical malaria incidence than ACTs with a shorter prophylactic time window. Similarly, a drug that has a more complex dosing schedule or causes mild side effects that lower adherence to the full treatment course may result in more treatment failures.

In the proposed prospective cohort study we plan to measure drug effectiveness and safety in young children with repeated treatments in real-life conditions at health centre and community level.

Current Status of Project

The recruitment phase for this trial has now been completed, and follow-up is ongoing.