Study site and participants
This study was conducted in primary schools located in the Lwanda Kotieno region in Rarieda sub-County, Siaya County, western Kenya. In the study area, more than 96% of the residents belong to the Luo ethnic group, and the majority of the adults are fishermen or small-scale subsistence farmers. Similarly, S. mansoni was the most prevalent schistosome species in school children, with a mean school prevalence of 16% (range 0–80%) .
School children were included if they were aged 6–15 years, appeared healthy at enrolment (as assessed by the study clinician), able to provide sufficient volume of a stool sample, had S mansoni infection (eggs excreted in stool), and could take oral treatment. We excluded children who weighed more than 50 kg, were pregnant or lactating (assessed by self-report), had co-infection with P falciparum, had severe illness (such as epilepsy), or had signs of severe malnutrition (MUAC < 11.5 cm). We also excluded children with a history of hypersensitivity to artesunate, sulfonamides or praziquantel, and those who had ingested another antimalarial or antischistosomal drug in 72hours before the study.
Study Design, Randomization, And Blinding
We conducted an exploratory open-label, randomized, controlled trial to evaluate the efficacy and safety of a single oral dose of artesunate plus sulfalene/pyrimethamine compared with a single oral dose of praziquantel in the treatment of children with S. mansoni in western Kenya. The randomization sequence was computer-generated by the study statistician. Eligible children were randomly assigned (1:1) to receive either artesunate plus sulfalene/pyrimethamine or praziquantel. The study nurse administered all the study medications after confirming the treatment allocation from the randomization sequence. The study nurse and study participants were aware of treatment assignment, but the laboratory technicians assessing study outcomes were masked to treatment assignment throughout the study.
For screening, every child provided a fresh stool sample (about 5 g), which was used to detect the presence of S. mansoni, hookworms, Ascaris lumbricoides, and Trichuris trichiura. Children whose stools tested positive for S. mansoni eggs and who met all eligibility criteria were invited to participate in the study.
At enrolment, the study clinician took a standard baseline medical history and performed a clinical examination. Eligible children were sequentially assigned the next lowest study number, corresponding to the randomization list. Children who were assigned praziquantel (Biltricide, Bayer Healthcare, Leverkusen, Germany) received one dose of 40 mg/kg per day to the nearest half tablet (tablets of 600 mg). Children who were assigned artesunate plus sulfalene/pyrimethamine (Co-Arinate Junior FDC [fixed-dose combination], Dafra Pharma, Turnhout, Belgium) received a single oral dose of 12 mg/kg per day to the nearest half tablet. Artesunate plus sulfalene/pyrimethamine is a fixed-dose combination of 100 mg artesunate with 250 mg sulfalene plus 12·5 mg pyrimethamine, packaged as three tablets per packet. All children received slices of bread and a glass of orange juice to improve bioavailability before drug ingestion. Children were observed for 1 h after taking the drug to ensure retention and to check for any immediate adverse events. If vomiting occurred within 1 h of drug ingestion, a second full dose was given. Children with repeated vomiting were withdrawn from the study. Adverse events were assessed on day 0 and day 1. If any children developed adverse events, they were followed up until the event resolved. Children with geo-helminthic infections were treated with 400 mg albendazole.
All the children were followed up for 28 days after treatment. At the follow-up visit on day 28 (range 26–30), children provided an early morning stool sample, and the study clinician took a medical history and performed a clinical examination. Participants who did not return for the scheduled follow-up visit were visited at home. Children who were not cured at the end of the study were treated using praziquantel.
Duplicate slides were prepared from stool samples using the Kato-Katz faecal thick-smear technique with a template containing about 41·7 mg of faeces when filled. The S. mansoni eggs were examined under a microscope independently counted by two experienced laboratory technicians. The mean number of S. mansoni eggs counted was multiplied by 24 to compute the eggs per gram (epg) of faeces. The intensity of infection was categorized based on the WHO classification as light (1–99 epg), moderate (100–399 epg), or heavy (≥ 400 epg) . As a quality control measure to minimise interobserver variability, a third technician reread a random sample of 10% of slides and all slides for which the readings varied by more than 20% between the two technicians.
This exploratory study was designed to evaluate the feasibility of a novel treatment. WHO recommends the following formula for computing sample size in studies assessing the efficacy of anthelminthic drugs: N = 50/(0.8 X prevalence) . Using a prevalence of 86% from our study at the same site , we calculated that we needed 73 children for this exploratory study. Data collected from participants were recorded on paper-based case report forms, entered into computers by use of Epi Info (version 3.2.2), and analyzed with SPSS for Windows (version 21.0).
The primary outcome was the proportion of participants cured between enrolment and day 28. The cure was defined as the proportion of children infected with S. mansoni at enrolment who were not excreting eggs on day 28 after treatment. Cure rates were compared between treatment groups by use of the Pearson χ² test for contingency tables and were summarised as risk difference (RD) with 95% CIs. In all comparisons, the praziquantel arm served as the control group. Secondary outcomes included the proportion of participants excreting S. mansoni eggs (egg reduction rate), the egg load (infection intensity), and the incidence of adverse events in each treatment group. The egg reduction rate (ERR) was defined as the proportionate reduction of the geometric mean [GM] egg count among S. mansoni positive children after treatment, computed as:
Changes in continuous variables between day 0 and day 28 were examined with student’s t-test. Safety outcomes (adverse events) were analyzed for all participants who received at least one dose of the study drug regardless of whether they completed the study or not. Two-sided p values of less than 0·05 were regarded as statistically signiﬁcant.