Tolerance and efficacy of praziquantel in phase IIA and IIB therapeutic trials in Zambian patients

Initial studies of the tolerance and efficacy of 2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4 -one (praziquantel, EMBAY 8440, Biltricide®) in the treatment of human infections due to Schistosoma haematobium were conducted at the WHO Tropical Diseases Research Centre, Ndola (Zambia). The phase II A trial was a double-blind assessment against placebo of the tolerance and efficacy of oral doses of 1 x 20, 2 x 20, or 3 x 20 mg/kg in 79 patients with a minimum schistosome egg excretion of 50 per random 10 ml sample of urine. Later a single-blind trial was carried out on the efficacy of three oral doses, each of 20 mg/kg, given at 4-h intervals, or of a single oral dose of 50 mg/kg. Tolerance to the drug was very good, only minor post-treatment symptoms being noted, all of a short duration. No changes of clinical relevance were detected in the results of a battery of haematological and biochemical tests and serial electrocardiography. At six months after treatment of 73 patients followed up, only 1 case of parasitological failure was detected. At one year, 66 (83.5%) of 79 patients with S. haematobium infection were followed up and 2 (2.5%) parasitological failures were detected. At 2 years, 45 (57%) showed negative urines, 7 (9%) had positive hatching tests and 27 (34%) were absent. The phase II B trial was a single-blind study of the tolerance and efficacy of three different doses against S. haematobium in Zambian schoolchildren. Pretreatment quantitative urinary examinations were used to classify trial entrants into three strata based on geometric mean egg excretions of 50-250 per 10 random ml urine, 251-500 and over 500/10 ml. From within these strata, patients were randomised to dose regimens of 1 x 30 mg/kg body weight (n = 53), 1 x 40 mg/kg (n = 45) and 2 x 20 mg/kg (n = 53). Side effects were absent in 71%-83% of the three treatment groups. The commonest adverse reactions encountered after treatment were abdominal pain and headache (12% and 10% overall). Many children had an abnormal haemoglobin genotype or G6PD deficiency. Pre and post treatment estimations of many clinicochemical and haematological variables revealed no changes of biological or clinical significance. Parasitological follow-up was at 1, 3, 7, 12 and 24 months after treatment. Although a simple statistical analysis suggested little difference between failure rates at different doses or between different strata, regression analysis indicated clearly that success rates were maximal after a single oral dose of 40 mg/kg and that cure rates did in fact vary inversely with strata. At 12 and 24 months 70% and 58% patients given 1 x 40 remained urine negative in an area where re-exposure was constant and where no other control method was employed.