RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF ORAL ARTEMETHER FOR THE PREVENTION OF PATENT SCHISTOSOMA HAEMATOBIUM INFECTIONS ELIÉZER K. N’GORAN, JÜRG UTZINGER, HENRI N. GNAKA, AHOA YAPI, NICAISE A. N’GUESSAN, SILUÉ D. KIGBAFORI, CHRISTIAN LENGELER, JACQUES CHOLLET, XIAO SHUHUA, AND MARCEL TANNER Laboratoire de Biologie Animale, Université de Cocody, Abidjan, Côte d’Ivoire; Centre Suisse de Recherches Scientifiques, Abidjan, Côte d’Ivoire; Office of Population Research, Princeton University, Princeton, N.J.; Grandes Endémies de Tiassalé, Tiassalé, Côte d’Ivoire; Swiss Tropical Institute, Basel, Switzerland; Institute of Parasitic Diseases, Chinese Centre for Disease Control and Prevention, Shanghai, China Abstract. Artemether is an efficacious antimalarial drug that also displays antischistosomal properties. Laboratory studies have found that artemether curtails the development of adult worms of Schistosoma japonicum, S. mansoni, and S. haematobium, and thus prevents morbidity. These findings have been confirmed in clinical trials for the former two parasites; administered orally once every 2–3 weeks, artemether significantly reduced the incidence and intensity of patent infections. Here, we present the first randomized, double-blind, placebo-controlled trial of artemether against S. haematobium, done in a highly endemic area of Côte d’Ivoire. Urine specimens from 440 schoolchildren were examined over 4 consecutive days, followed by two systematic praziquantel treatments 4 weeks apart. S. haematobium-negative children were randomized to receive 6 mg/kg artemether (N  161) or placebo (N  161). Medication was administered orally for a total of six doses once every 4 weeks. Adverse events were assessed 72 hours after medication, and perceived illness episodes were monitored throughout the study period. Incidence and intensity of S. haematobium infections, and microhematuria and macrohematuria were assessed 3 weeks after the final dosing. We also monitored malaria parasit- emia and treated positive cases with sulfadoxine-pyrimethamine (SP). Oral artemether was well tolerated. The incidence of patent S. haematobium infections in artemether recipients was significantly lower than in placebo recipients (49% versus 65%, protective efficacy: 0.25, 95% CI: 0.08–0.38, P  0.007). The geometric mean infection intensity in the artemether group was less than half that of the placebo recipients (3.4 versus 7.4 eggs/10 mL urine, P < 0.001). Heavy S. haematobium infections, microhematuria and macrohematuria, and the incidence of malaria parasitemia were all significantly lower in artemether recipients. In conclusion, previous findings of efficacy of artemether against S. japoni- cum and S. mansoni were confirmed for S. haematobium, although the protective efficacy was considerably lower. These findings enlarge the scope and potential of artemether and further contribute to discussions of its role as an additional tool for integrated schistosomiasis control. INTRODUCTION Schistosomiasis is a chronic and debilitating disease that remains one of the most prevalent parasitic infections in the humid tropics, with an estimated 650 million people at risk of infection and 200 million actually infected. 1 Three species— Schistosoma haematobium, S. japonicum, and S. mansoni— cause the bulk of an estimated global burden of 4.5 million disability-adjusted life years, 85% of them concentrated in sub-Saharan Africa. 1,2 Awareness is growing that the burden of schistosomiasis is largely underestimated and requires re- vision, as it might actually rank close to that of malaria. 2,3 It is encouraging that significant progress in the control of schis- tosomiasis has been achieved over the last several years in Brazil, China, and Egypt. However, because of environmental changes linked to water resources development and rapidly increasing sizes and movements of population, the disease has spread to previously nonendemic or low endemic areas. 4,5 With the discovery of safe and efficacious antischistosomal drugs 3–4 decades ago, chemotherapy has become the cor- nerstone of schistosomiasis control. Praziquantel is the cur- rent drug of choice; single oral doses are well tolerated and show high cure and egg reduction rates against all human schistosome parasites. 2 There has been considerable discus- sion about the possibility of development and spread of schis- tosome strains that are resistant to praziquantel. However, there is no compelling evidence of this, and results are of no clinical significance. 6–8 On the other hand, praziquantel is vir- tually the only antischistosomal drug readily available for treatment. Metrifonate (which is active against S. haemato- bium) has recently been withdrawn from the market, 9 and oxamniquine (widely and effectively used against S. mansoni in Brazil) is being replaced by praziquantel. 10,11 Therefore, research and development of novel antischistosomal drugs is a pressing need, 6,12 which has recently been acknowledged by WHO/TDR. Compounds exhibiting activity against the young develop- mental stages of the schistosome parasites also are relevant, as praziquantel is largely ineffective in this period. 13,14 Arte- mether, a derivative of the antimalarial artemisinin, 15 has been identified with exactly these characteristics. Detailed laboratory studies have revealed that schistosomula of S. japonicum, S. mansoni, and S. haematobium are significantly more susceptible to artemether than adult worms. 16–18 These laboratory findings have been confirmed for S. japonicum and S. mansoni in eight randomized controlled clinical trials with > 5,000 study participants (for review, see Utzinger et al. 19 ). Administered orally once every 2–3 weeks for up to 20 weeks at a dose of 6 mg/kg, artemether was safe, prevented acute cases of schistosomiasis japonica, and showed significant ef- fects on the incidence and intensity of patent infections. 20,21 The efficacy of artemether for prevention of patent S. hae- matobium infections in a human population has not been investigated. Our detailed laboratory investigations—dem- onstrating in vitro and in vivo activity of artemether against this schistosome species 18,22–24 —formed a sound basis for car- rying out the first randomized, double-blind, placebo- controlled trial. Our study was done in an area highly endemic Am. J. Trop. Med. Hyg., 68(1), 2003, pp. 24–32 Copyright © 2003 by The American Society of Tropical Medicine and Hygiene 24