638 Am. J. Trop. Med. Hyg., 58(5), 1998, pp. 638–644 Copyright  1998 by The American Society of Tropical Medicine and Hygiene A RANDOMIZED CONTROLLED TRIAL OF ARTEMETHER/BENFLUMETOL, A NEW ANTIMALARIAL AND PYRIMETHAMINE/SULFADOXINE IN THE TREATMENT OF UNCOMPLICATED FALCIPARUM MALARIA IN AFRICAN CHILDREN LORENZ VON SEIDLEIN, KALIFA BOJANG, PETER JONES, SHABBAR JAFFAR, MARGARET PINDER, STEVENOBARO, TOM DOHERTY, MICHELLE HAYWOOD, GEORGES SNOUNOU, BEATRICE GEMPERLI, INSA GATHMANN, CATHERINE ROYCE, KEITH McADAM, AND BRIAN GREENWOOD Medical Research Council Laboratories, Fajara, Banjul, The Gambia; Department of Epidemiology and Population Sciences, and Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, London, United Kingdom; Department of Infection and Tropical Medicine (Lister Unit), Imperial College School of Medicine Northwick Park Hospital, Harrow, Middlesex, United Kingdom; International Clinical Research, Novartis Pharma AG, Basel, Switzerland Abstract. We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1–5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P  0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P  0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697. Malaria is estimated to kill between 1.5 and 2.7 million people every year. An additional 300–500 million people suffer annually from malaria attacks but survive. 1 Nine of 10 cases occur in sub-Saharan Africa, where malaria is re- sponsible for more disability adjusted life years than any other disease. 2 The main burden of malaria falls on children less than five years of age. The most commonly used treat- ments, chloroquine and pyrimethamine/sulfadoxine (P/S), have become less effective in the regions where they have been used the longest and are most widely available, such as Southeast Asia. Chloroquine remains useful in selected areas of sub-Saharan Africa, but Malawi, Kenya, and Zam- bia have been forced to replace chloroquine with P/S as a first-line treatment. However, the efficacy of P/S is already compromised in some parts of Africa. High level resistance of Plasmodium falciparum to P/S has been reported in Tan- zania and lower levels of resistance have been recorded in other parts of Africa. 3, 4 Thus, alternative antimalarial drugs are needed urgently. Atovaquone in combination with pro- guanil is effective, but like halofantrine and mefloquine, it is too expensive to be used widely in resource poor areas of the world although a donation program is being planned. 5 Pyronaridine is highly effective, but has yet to be registered outside China. 6 Therefore, great hope is placed on artemi- sinin derivatives, natural products found in the leafy portions of Artemisia annua (qinghao), a plant used by Chinese herb- alists since 168 BC. 7 However, the use of short courses of artemisinin derivatives has been limited by their relatively short half-life, which is associated with recurrence of para- sitemia following the clearance of P. falciparum. Thus, ar- temether, the methyl ether of dihydroartemisinin, has been combined with benflumetol, a novel aryl amino alcohol (class II schizontocide) with a relatively slow onset but a half-life of 4–6 days, in an oral formulation known as CGP56697. This drug is undergoing randomized controlled trials in Hainan China, in Bangkok, Thailand, along the Thailand-Myanmar border, in India, and in Ifakara, Tanzania. Following a successful safety trial of CGP56697 in The Gambia, 8 we conducted a randomized controlled trial that compared CGP56697 with P/S. During the safety study of CGP56697, it had been ob- served that up to one-third of the children returned during the four-week follow-up period with new infections of P. falciparum. A strategy was therefore needed to treat repeated infections, which were unlikely to be resistant to CGP56697. To investigate the efficacy of CGP56697 in repeated malaria episodes, we treated children who returned with falciparum malaria with open label (i.e., the investigator and parent or guardian were aware which drug the child received) CGP56697 and followed their response. METHODS The trial design was a randomized, double-blind, con- trolled efficacy trial that compared CGP56697 with P/S as a treatment for uncomplicated falciparum malaria. The trial was conducted in The Gambia at two centers, one in a semi- urban coastal area and the other in a rural region. Children between one and five years of age were eligible for enroll- ment if they had a parasitemia of more than 5,000 P. falcip- arum parasites/l, a history of fever, lived within 20 km of either trial center, and if a parent or guardian gave informed consent. Children who required parenteral treatment, had been treated within two weeks with P/S, or had a hematocrit