A Randomized Trial of Azithromycin + Artesunate v Artemether-lumefantrine in Uncomplicated Malaria in Tanzanian Children.

Trial drugs. Artemether-lumefantrine (AL) has been selected to be the drug used to treat uncomplicated malaria in Tanzania. There is extensive efficacy, effectiveness and safety data on this combination from Tanzania. Artesunate is a key component of most ACTs. It should not be used as monotherapy, but is highly effective as an antimalarial when used in combination with another drug with antimalarial properties. There are now many years of experience of artesunate combinations on Africa and it appears safe in children. Azithromycin is licensed for use in childhood infections and trachoma. It is well tolerated and appears very safe in children; for example it does not have the effects of occasional bone-marrow toxicity seen with chroramphenicol, or the skin reactions sometimes seen with sulpha-drugs. It is active against the majority of childhood bacterial infections. There is extensive safety data on azithromycin, including data on azithromycin safety and tolerability in African children. Azithromycin has been shown to have significant antimalarial activity in vitro. There is good in vitro data on artemisinin + azithromycin combinations against malaria including tests for interactions . As a prophylactic drug against malaria azithromycin is effective in both West and East Africa. Azithromycin-artesunate has been used as an antimalarial drug combination in Asia. There is experience from small trials of combinations of artemisinin drugs and azithromycin to treat P. falciparum in Southeast Asia which were less effective than artesunate-mefloquine and artemether-doxycycline but several factors, especially the low doses of azithromycin used in two of these studies and patterns of antibiotic use locally may well have contributed to this; the combination appears safe . This contrasts with the evidence in East Africa that azithromycin is an effective antimalarial when used for prophylaxis, and there are several reasons why it may well be more effective in East Africa than in SE Asia.

Objectives. The overall study objectives will therefore be to compare the efficacy of azithromycin-artesunate and artemether-lumefantrine in the treatment of non-severe falciparum malaria in children in an area of high antimalarial drug resistance.

Specific objectives are i) to compare the effects of the drugs on parasitological failure rates at 28 days in each arm, both unadjusted and adjusting for reinfection judged by genotyping ii) to compare the drugs for clinical failure rate at 28 days. iii) to compare the drugs for clinical and parasitological failure at day 42. iv) to compare the drug combinations for adverse events and side effects v) to undertake a cost-effectiveness analysis of the two drug combinations.

Study design.

A randomised controlled trial of azithromycin-artesunate and artemether-lumefantrine for the treatment of non-severe falciparum malaria in children between 6 months and 5 years old.