Efficacy and safety of ascending doses of praziquantel against Schistosoma haematobium infection in preschool-aged and school-aged children: a single-blind randomised controlled trial

Efficacy and safety of ascending doses of praziquantel against Schistosoma haematobium infection... Background: Despite decades of experience with praziquantel treatment in school-aged children (SAC) and adults, we still face considerable knowledge gaps relevant to the successful treatment of preschool-aged children (PSAC). This study aimed to assess the efficacy and safety of escalating praziquantel dosages in PSAC infected with Schistosoma haematobium. Methods: We conducted a randomised, dose-finding trial in PSAC (2–5 years) and as comparator a cohort of SAC (6–15 years) infected with S. haematobium in Côte d’Ivoire. A total of 186 PSAC and 195 SAC were randomly assigned to 20, 40 or 60 mg/kg praziquantel or placebo. The nature of the dose-response relationship in terms of cure rate (CR) was the primary objective. Egg reduction rate (ERR) and tolerability were secondary outcomes. CRs and ERRs were assessed using triplicate urine filtration over 3 consecutive days. Available-case analysis was performed including all participants with primary endpoint data. Results: A total of 170 PSAC and 174 SAC received treatment. Almost 90% of PSAC and three quarters of SAC were lightly infected with S. haematobium. Follow-up data were available for 157 PSAC and 166 SAC. In PSAC, CRs of praziquantel were 85.7% (30/35), 78.0% (32/41) and 68.3% (28/41) at 20, 40 and 60 mg/kg and 47.5% (19/40) for placebo. In SAC, CRs were 10.8% for placebo (4/37), 55.6% for 20 mg/kg (25/45), 68.3% for 40 mg/kg (28/41) and 60.5% for 60 mg/ kg (26/43). ERRs based on geometric means ranged between 96.5% (60 mg/kg) and 98.3% (20 mg/kg) in PSAC and between 97.6% (20 mg/kg and 60 mg/kg) and 98.6% (40 mg/kg) in SAC. Adverse events were mild and transient. Conclusions: Praziquantel revealed dose-independent efficacy against light infections of S. haematobium.Overthe dose range tested, praziquantel displayed a ceiling effect with the highest response for 20 mg/kg in PSAC. In SAC maximum efficacy was obtained with 40 mg/kg praziquantel. Further investigations are required in children with moderate to heavy infections. Trial registration: This trial is registered with International Standard Randomised Controlled Trial Number ISRCTN15280205. Keywords: Efficacy, Praziquantel, Preschool-aged children, Schistosoma haematobium, School-aged children * Correspondence: jennifer.keiser@swisstph.ch Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, CH-4002, Basel, Switzerland University of Basel, Basel, Switzerland Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Coulibaly et al. BMC Medicine (2018) 16:81 Page 2 of 10 Background process, resulting in successful control of schistosome Schistosomiasis is a major public health problem with an infection and disease. estimated 779 million people at risk of infection [1]. The disease is caused by trematode worms of the genus Schis- Methods tosoma, where infection with Schistosoma japonicum and Study design and participants S. mansoni causes mostly intestinal schistosomiasis, while We conducted a randomised, parallel-group, single-blind, S. haematobium is responsible for genitourinary schisto- placebo-controlled, dose-ranging trial between November somiasis [2–6]. Cumulative schistosome infections over 2015 and February 2016. PSAC (aged 2–5years)and SAC years, due to rapid reinfection, result in morbid sequelae, (6–15 years) were surveyed in five villages of the health including haematuria, nutritional deficiencies, anaemia, district of Adzopé, southern Côte d’Ivoire. In total, 740 hepatic peri-portal fibrosis and consequent portal hyper- PSAC and 444 SAC were registered during the census and tension and delayed physical and cognitive development were invited to participate in the study. [7–9]. Moreover, genitourinary schistosomiasis can lead to obstruction and carcinomas of urogenital organs and im- Randomisation and masking pairment to female reproductive health [6, 10]. To control Eligibility of children was based on the presence of schistosomiasis morbidity, health authorities rely on mass S. haematobium eggs in their urine. In addition, a clinical administration (preventive chemotherapy) of praziquantel examination and an oral medical history by active ques- in school-aged children (SAC), the population most af- tioning were implemented in order to exclude children fected [11–13]. In 2010, the World Health Organization with abnormal medical conditions (i.e. clinical malaria or (WHO) endorsed the inclusion of preschool-aged children hepato-splenic schistosomiasis) or those who received an (PSAC) in preventative chemotherapy programmes, since antimalarial or anthelmintic drug in the past 4 weeks. there is increasing evidence that they are also affected by S. haematobium egg-positive PSAC and SAC, eligible schistosomiasis and could suffer from morbidity [14–17]. for the study, were stratified according to baseline infec- In the absence of an appropriate paediatric formulation, tion intensity into light (< 50 eggs/10 mL of urine) or broken or crushed praziquantel tablets are commonly heavy (≥ 50 eggs/10 mL of urine) infection intensities used in PSAC using the standard 40 mg/kg dose [18]. A [25]. Children were then randomly assigned to placebo range of studies showed that this dose was well tolerated or 20, 40 or 60 mg/kg praziquantel treatment arms using and efficacious [15, 19, 20]. However, the heterogeneity of computer-generated stratified block randomisation codes methodology and reporting on praziquantel efficacy and provided by an independent statistician based on the safety assessment make decision-making difficult [21]. aforementioned infection intensity (block size of 8). Only In the paediatric population, growth and maturation of the investigator dealing with drug administration was organs are dynamic. Changes in body proportion and me- aware of the treatment assignments. The physician and tabolism occur throughout infancy and childhood that laboratory technicians were blinded to the treatment. affect how drugs are metabolised [22, 23]. Well-designed SAC might have recognised the treatment dose due to paediatric drug trials are therefore warranted in order to the number of tablets administered; however, the crush- guide the proper usage of drug treatments to avoid under- ing of tablets for PSAC was prepared in advance. Mask- dosing, overdosing, ineffectiveness and safety problems. ing was maintained throughout the trial. Randomisation We recently conducted a randomised, controlled codes were released after the database was unlocked. dose-finding study assessing the safety and efficacy of praziquantel in PSAC and SAC infected with S. mansoni. Field and laboratory procedures Considerable differences were observed between these During the baseline survey, three urine samples over 3 two age groups with regard to efficacy. For example, consecutive days and a single stool sample from the first while treatment of SAC with 40 or 60 mg/kg met the collection day were collected between 10:00 and WHO standards of clinical efficacy of ≥ 90% egg reduc- 14:00 am from each participating child. Urine and stool tion rate (ERR) based on arithmetic mean (AM), none of samples were transferred to a nearby laboratory in the doses administered could reach this threshold in Azaguié town and examined on the day of collection. PSAC [24]. S. haematobium was detected using the urine filtra- This study was designed to support the ongoing efforts tion method (syringe filtration of 10 mL of urine followed to successfully control schistosome infections in PSAC by microscopic examination of the filter) [26]. A subse- by assessing the efficacy and safety of escalating prazi- quent independent quality control of sample results (ap- quantel dosages in PSAC compared to SAC infected proximately 10%) was conducted. If a difference in with S. haematobium. The clinical evidence for prazi- presence/absence of S. haematobium eggs was observed quantel obtained for both S. haematobium and S. man- or egg counts exceeded +/−10 eggs for light infections or soni in PSAC will facilitate the clinical decision-making +/−20 eggs for heavy infections, all the slides were read Coulibaly et al. BMC Medicine (2018) 16:81 Page 3 of 10 once again by the senior technician. S. mansoni infection implemented including all treated participants (regard- was assessed through duplicate Kato-Katz thick smears less of whether they could swallow the drug or not or (standard template of 41.7 mg) [27]. Eggs of were wrongly dosed) who had at least one urine sample soil-transmitted helminths, i.e. Ascaris lumbricoides, examined with the urine filtration method at follow-up hookworm and Trichuris trichiura, were also assessed and and were not excluded due to a medical condition. recorded for each parasite species separately. Moreover, In order to calculate ERR, the AM and geometric finger prick blood samples were taken to assess Plasmo- mean (GM) of eggs per 10 mL of urine before and after dium infections and haemoglobin amount using, respect- treatment were assessed. Geometric mean egg counts 1/n ∑ log(x + 1) ively, thick and thin blood smears [24] and a calibrated were calculated as follows: e -1, and the HemoCue device (HemoCue 301 system, HemoCue, corresponding ERR ([1 – geometric mean egg output Ängelholm, Sweden). after treatment/geometric mean egg output at To assess treatment efficacy, another three urine samples baseline] × 100) was assessed. A bootstrap resampling and a single stool sample were collected between 21 and method with 5000 replicates was used to estimate 95% 25 days post-treatment and subjected to the same diagnos- CIs for ERRs. tic approaches applied at baseline. At the end of the study, E models using the DoseFinding package (version max all children enrolled in the study were offered albendazole 0∙9–14) of the statistical software environment R (v3.3.0) (400 mg) and praziquantel (40 mg/kg) for the treatment of were implemented to predict the dose-response curves helminth infections according to local guidelines. in terms of CRs and ERRs. Logistic regression was used to predict CR by infection intensity at baseline. Treatment Results Prior to treatment, each child received breakfast. In both Study flow and baseline characteristics study groups (SAC and PSAC), treatment was done Overall, 1184 children were invited to participate in the based on the child’s body weight (graduated increments study (Fig. 1). At baseline, 628 PSAC and 356 SAC were of 0.1 kg). Praziquantel (600 mg Cesol®) (used in screened for S. haematobium infection. Of these, 186 quarter-tablet increments) and placebo were obtained (29.6%) PSAC and 195 (45.7%) SAC had a detectable from Merck KGaA, Darmstadt, Germany and Fagron, S. haematobium infection and were randomised for Barsbüttel, Germany, respectively. For PSAC, tablets treatment. On the treatment day, 16 PSAC and 21 SAC were crushed using a mortar and pestle and dissolved in were absent. PSAC received 20 mg/kg (n =40), 40 mg/kg a small volume of syrup-flavoured water to mask the (n = 44) or 60 mg/kg (n = 44) praziquantel or placebo taste. SAC and the mothers/guardians of PSAC were (n = 42). SAC were likewise allocated to 20 mg/kg (n = interviewed 3, 24, 48 and 72 h after treatment for ad- 46), 40 mg/kg (n = 46) or 60 mg/kg praziquantel (n =44) verse events and the intensities graded by the study or placebo (n = 38). Two PSAC and one SAC were not physician as mild, moderate, severe or intolerable [24]. able to swallow the drug. One PSAC and one SAC were wrongly dosed (62.5 mg/kg instead of 40 mg/kg and Outcomes and sample size determination 75 mg/kg instead of 40 mg/kg, respectively). The cure rate (CR) (primary outcome) was expressed as At follow-up, data were available for 157 PSAC and the proportion of children positive for S. haematobium 166 SAC. One PSAC and 12 SAC provided only two eggs at baseline survey who became negative at urine samples, while one SAC provided only one urine follow-up. The secondary outcomes were ERR and the sample. safety of different doses of praziquantel. The median age, weight, height and sex of PSAC Simulations showed that with 40 children enrolled per and SAC were balanced among the treatment groups treatment arm (0, 20, 40 and 60 mg/kg), the dose-response (Table 1). Three quarters of PSAC and SAC were prediction model should have a median precision—defined lightly infected with S. haematobium.Noinfection as one half length of the 95% confidence interval (CI)—of with A. lumbricoides, T. trichiura or hookworm was 10% points, assuming associated cure rates of 2.5%, 50%, recorded. Co-infections among S. haematobium-infected 75% [28] and 90%. children with S. mansoni and P. falciparum were very low (less than 9%) in PSAC and SAC. Median haemoglobin Statistical analysis values ranged between 10.5 and 11.0 g/dL in PSAC and All data were first double entered into an Excel spread- between 11.0 and 11.7 g/dL in SAC. sheet, then transferred into Epi Info version 3.5.2 (Centers for Disease Control and Prevention, Atlanta, Efficacy of praziquantel GA, USA) and cross-checked. R version 3.4.0 was used The nature of the dose response based on CRs is depicted for all statistical analyses. Available-case analysis was in Fig. 2. Praziquantel revealed dose-independent efficacy Coulibaly et al. BMC Medicine (2018) 16:81 Page 4 of 10 Fig. 1 Trial profile with the highest cure rates observed at 20 and 40 mg/ 97.6%, 98.6% and 97.6% were observed with increasing kg in PSAC and SAC, respectively. The E model dosages. ERRs based on AMs had similar profiles to max based on actual doses on the per protocol population is those based on GMs and are presented in Table 2. presented in Additional file 1:FigureS1and showsa Table 2 also presents an exploratory subgroup analysis similar trend. Additional file 1: Figure S2 presents the on CRs according to S. haematobium infection inten- predicted probability of being cured by baseline infec- sity. The CR in PSAC ranged from 73.0% (60 mg/kg) tion intensity. For all treatments, including placebo, to 87.9% (20 mg/kg) in light infections and from there was a high probability of being cured at low infec- 25.0% (60 mg/kg) to 66.7% (40 mg/kg) in heavy infec- tion intensities. tions. In SAC, CRs were 70.6% (20 mg/kg) to 78.8% CRs in PSAC for 20 mg/kg, 40 mg/kg and 60 mg/kg (40 mg/kg) for light S. haematobium infections and were 85.7 (95% CI 69.7–95.2), 78.0% (95% CI 62.4–89.4) between 9.1% (20 mg/kg) and 27.3% (60 mg/kg) for and 68.3% (95% CI 51.9–81.9), respectively, whereas in heavy infections. SAC the respective CRs were 55.6% (95% CI 40.0–70.4), 68.3% (95% CI 51.9–81.9) and 60.5% (95% CI 44.4–75.0). Safety of praziquantel In the placebo groups, S. haematobium eggs were not Adverse events data were available for 168 PSAC and detected in the urine samples of 47.5% (19/40) and 173 SAC (Table 3). In both groups, more children re- 10.8% (4/37) in PSAC and SAC, respectively (Table 2). ported signs and symptoms at pre-treatment compared Imputation of missing data with treatment failure or to 3 and 24 h post-treatment. No serious adverse events success in the intention-to-treat analysis did not change were reported. Overall, adverse events were mild with the observed outcomes (Additional file 1: Table S1). fewer adverse events observed at 3 h post-treatment ERRs are summarized in Table 2 and depicted in compared to pre-treatment in PSAC (52 episodes versus Fig. 3. ERRs in PSAC were 98.3% for 20 mg/kg, 97.6% 88 episodes) and in SAC (88 episodes versus 92 epi- for 40 mg/kg and 96.5% for 60 mg/kg. In SAC ERRs of sodes), respectively. Mild events mainly included fever, Coulibaly et al. BMC Medicine (2018) 16:81 Page 5 of 10 Table 1 Baseline characteristics Preschool-aged children (PSAC) School-aged children (SAC) Treatment arm Treatment arm Characteristics Placebo 20 mg/kg 40 mg/kg 60 mg/kg Placebo 20 mg/kg 40 mg/kg 60 mg/kg 42 40 44 44 38 46 46 44 Female N (%) 23 (54.8) 21 (52.5) 20 (45.5) 27 (61.4) 23 (60.5) 25 (54.3) 25 (54.3) 25 (56.8) Age, years; median 4 4449 889 [IQR] [2–5] [2–5] [2–5] [2–5] [6–13] [6–13] [6–14] [6–13] Weight, kg; median 15 15 15 15 22 22 24 22 [IQR] [10–21] [11–19] [11–19] [11–18] [18–35] [18–33] [18–38] [18–40] Height, cm; median 97 98 101 100 125 125 125 124 [IQR] [80–117] [83–115] [84–116] [83–114] [109–141] [114–139] [113–149] [112–150] Haemoglobin (g/dL); median 10.5 11.0 10.9 10.9 11.4 11.2 11.7 11.6 [IQR] [9.1–13.2] [9.1–12.8] [8.8–12.5] [8.5–12.9] [9.7–13.7] [9.9–12.4] [9.7–12.8] [10.1–13.5] Infection intensity N (%) Light 36 (85.7) 38 (95.0) 38 (86.4) 40 (90.9) 27 (71.1) 35 (76.1) 36 (78.3) 33 (75.0) Heavy 6 (14.3) 2 (5.0) 6 (13.6) 4 (9.1) 11 (28.9) 11 (23.9) 10 (21.7) 11 (25.0) Co-infections N (%) S. mansoni 0 (0.0) 0 (0.0) 1 (2.3) 1 (2.3) 0 (0.0) 1 (2.2) 1 (2.2) 0 (0.0) Plasmodium falciparum 1 (2.4) 0 (0.0) 1 (2.3) 0 (0.0) 1 (2.6) 4 (8.7) 2 (4.3) 3 (6.8) (based on thin/thick smear) IQR interquartile range headache, nausea, diarrhoea, vomiting, dizziness and with fewer adverse events observed in the stomach ache. Few moderate cases were reported at placebo-treated groups. The most common adverse 3 h after treatment in PSAC (only one with moderate events in PSAC and SAC 24 h post-treatment were diarrhoea) and in SAC (n = 12). At 24 h diarrhoea (4.8 and 3.5%), stomach ache (3.6 and 9.8%), post-treatment, 25 (14.9%) and 47 (27.2%) adverse fever (6.0 and 13.3%), headache (3.0 and 15.6%) and events were recorded in PSAC and SAC, respectively. nausea (2.4 and 6.9%). For both age groups the number of adverse events was similar among the three praziquantel treatment arms, Discussion Over the past decade, preventive chemotherapy pro- grammes for the control of schistosomiasis targeting SAC have scaled up across many countries in tropical and subtropical areas. Great progress has been made in decreasing the burden of this disease [29–31]. However, recent modelling and health economic studies found that expanded community-wide preventive chemother- apy that includes adolescents, adults and PSAC would better reduce the overall disease burden, rates of trans- mission and reinfection [32]. It was recommended in 2010 that PSAC should be in- cluded in preventive chemotherapy programmes [33] using an adequate dose, though this age group is still lack- ing a suitable formulation. A paediatric formulation of praziquantel (small, orally dispersible tablets) is under de- Fig. 2 Cure rates in PSAC (blue lines) and SAC (red lines). Circles show velopment (https://www.pediatricpraziquantelconsortium observed cure rates with 95% CIs (vertical lines). Numbers in the circles show geometric mean infection intensities at baseline (BL). Dashed .org/node/28), but it will take several more years until the lines represent the estimated dose-response curve and corresponding drug is marketed and available to all PSAC. To be able to 95% CIs predicted by the E models. Geometric mean of infection max treat preschoolers safely and effectively, we studied as- intensity was the mean of eggs filtered from 10 mL of urine cending doses of praziquantel in PSAC and SAC infected Coulibaly et al. BMC Medicine (2018) 16:81 Page 6 of 10 Table 2 Available-case analysis of cure and egg reduction rates of 20, 40 and 60 mg/kg praziquantel versus placebo against urogenital schistosomiasis in PSAC and SAC based on the urine filtration method Preschool-aged children (PSAC) School-aged children (SAC) Placebo 20 mg/kg 40 mg/kg 60 mg/kg Placebo 20 mg/kg 40 mg/kg 60 mg/kg Infected children before treatment (N) 40 354141 37 4541 43 a b Actual dose administered (range; mg/kg) – 13.6–25 34.6–62.5 50–70 – 16.7–23.7 36.4–75 56.3–65.6 Cured children after treatment N (%) 19 (47.5) 30 (85.7) 32 (78.0) 28 (68.3) 4 (10.8) 25 (55.6) 28 (68.3) 26 (60.5) 95% CI 32.5–63.9 69.7–95.2 62.4–89.4 51.9–81.9 3.0–25.4 40.0–70.4 51.9–81.9 44.4–75.0 Cured children according to sex Male 6 (31.6) 14 (46.7) 19 (59.4) 10 (35.7) 1 (25.0) 9 (36.0) 13 (46.4) 9 (34.6) 95% CI 12.5–56.6 28.3–65.7 40.6–76.3 18.6–55.9 0.6–80.6 18.0–57.5 27.5–66.1 17.2–55.7 Female 13 (68.4) 16 (53.3) 13 (40.6) 18 (64.3) 3 (75.0) 16 (64.0) 15 (53.6) 17 (65.4) 95% CI 43.4–87.4 34.3–71.7 23.7–59.4 44.1–81.4 19.4–99.4 42.5–82.0 33.9–72.5 44.3–82.8 Cured children with light infection 19/40 (47.5) 29/33 (87.9) 28/35 (80.0) 27/37 (73.0) 4/26 (15.4) 24/34 (70.6) 26/33 (78.8) 23/32 (71.9) Cured children with heavy infections (%) 0/6 (0) 1/2 (50.0) 4/6 (66.7) 1/4 (25.0) 0/11 (0.0) 1/11 (9.1) 2/8 (25.0) 3/11 (27.3) Geometric mean eggs/10 mL of urine Before treatment 7.8 7.5 8.4 8.3 31.5 21.6 16.6 17.2 After treatment 2.4 0.1 0.2 0.3 13.1 0.5 0.2 0.4 Egg reduction rate 68.9 98.3 97.6 96.5 58.5 97.6 98.6 97.6 (95% CI) 46.6–83.6 95.4–99.8 94.9–99.2 93.1–98.7 38.7–71.4 96.4–98.6 97.7–99.3 95.3–98.9 Arithmetic mean eggs/10 mL of urine Before treatment 22.7 14.3 21.7 16.9 94.4 89.5 31.0 34.4 After treatment 11.5 0.3 0.4 0.9 49.0 1.2 0.4 1.0 Egg reduction rate 49.5 97.8 98.2 94.5 46.9 98.7 98.8 97.0 (95% CI) 0.2–77.3 93.6–99.9 96.1–99.5 85.7–99.1 36.4–77.6 96.7–99.3 97.7–99.5 92.9–99.2 Range 34.6–44.1 excluding the wrongly dosed child Range 36.4–42.9 excluding the wrongly dosed child with S. haematobium. Our results build on an earlier dose-finding study in S. mansoni-infected children [24]. Several findings of our study are worth highlighting. First, the highest overall CRs among PSAC (85.7%) and SAC (68.3%) were obtained with 20 mg/kg and 40 mg/ kg praziquantel, respectively and not with the highest dose administered, 60 mg/kg. For both age groups, CRs revealed even a slight inverse dose-rate effect. Similarly, ERRs increased very fast up to 98% and did not increase further regardless of the praziquantel dose administered. Interestingly, 60 mg/kg praziquantel also showed lower CRs in PSAC with moderate/high S. haematobium infec- tion intensities compared to the two lower doses. For ex- ample, the CR in PSAC characterised by heavy infection intensities treated with 60 mg/kg praziquantel was as low as 25%. However, only a handful of PSAC suffered from moderate and high infection intensities; hence, no clear picture can be drawn for this age group. In SAC similar CRs were observed in children harbouring heavy Fig. 3 Egg reduction rates in PSAC (blue lines) and SAC (red lines). infection intensities treated with 40 and 60 mg/kg. In Diamonds show observed cure rates with 95% CIs (vertical lines). summary, a high dose of praziquantel seems to have no Dashed lines represent the estimated dose-response curve and additional benefit in the treatment of S. haematobium corresponding 95% CI predicted by the E model max infections. This result is in contrast with our recent Coulibaly et al. BMC Medicine (2018) 16:81 Page 7 of 10 Table 3 Main type of clinical symptoms (number and percentage) before treatment and adverse events 3 and 24 h after praziquantel administration in Schistosoma haematobium-infected preschool-aged children (n = 168) and school-aged children (n = 173) a b Preschool-aged children (PSAC) School-aged children (SAC) Symptoms Placebo 20 mg/kg 40 mg/kg 60 mg/kg Overall Placebo 20 mg/kg 40 mg/kg 60 mg/kg Overall (n = 41) (n = 40) (n = 44) (n = 43) (n = 168) (n = 38) (n = 45) (n = 46) (n = 44) (n = 173) Before treatment Moderate 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Mild 24 (58.5) 19 (47.5) 26 (59.1) 19 (44.2) 88 (52.4) 20 (52.6) 26 (57.8) 25 (54.3) 21 (47.7) 92 (53.2) None 17 (41.5) 21 (52.5) 18 (40.9) 24 (55.8) 80 (47.6) 18 (47.4) 19 (42.2) 21 (45.7) 23 (52.3) 81 (46.8) Fever 6 (14.1) 3 (7.5) 7 (15.9) 5 (11.6) 21 (12.5) 5 (13.2) 7 (15.6) 5 (10.9) 6 (13.6) 23 (13.3) Headache 8 (19.5) 6 (15.0) 13 (29.5) 10 (23.3) 37 (22.0) 3 (7.9) 7 (15.6) 10 (21.7) 7 (15.9) 27 (15.6) Nausea 3 (7.3) 4 (10.0) 3 (6.8) 1 (2.3) 11 (6.5) 2 (5.3) 1 (2.2) 4 (8.7) 5 (11.4) 12 (6.9) Vomiting 1 (2.4) 1 (2.5) 1 (2.3) 2 (4.7) 5 (3.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) 1 (0.6) Diarrhoea 4 (9.6) 4 (10.0) 4 (9.1) 5 (11.6) 17 (10.1) 0 (0.0) 1 (2.2) 3 (6.5) 2 (4.5) 6 (3.5) Dizziness 2 (4.9) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Stomach ache 2 (4.9) 5 (12.5) 8 (18.2) 4 (9.3) 19 (11.3) 1 (2.6) 6 (13.3) 6 (13.0) 4 (9.1) 17 (9.8) 3 h post-treatment Moderate 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.3) 1 (0.6) 1 (2.6) 2 (4.4) 4 (8.7) 5 (11.4) 12 (6.9) Mild 6 (14.6) 8 (20.0) 15 (34.1) 23 (53.5) 52 (31.0) 18 (47.4) 23 (51.1) 21 (45.7) 26 (59.1) 88 (50.9) None 35 (85.4) 32 (80.0) 29 (65.9) 19 (44.2) 115 (68.5) 19 (50.0) 20 (44.4) 21 (45.7) 13 (29.5) 73 (42.2) Fever 3 (7.3) 3 (7.5) 2 (4.5) 4 (9.3) 12 (7.1) 6 (15.8) 4 (8.9) 8 (17.4) 12 (27.3) 30 (17.3) Headache 1 (2.4) 2 (5.0) 1 (2.3) 7 (16.3) 11 (6.5) 8 (21.1) 10 (22.2) 6 (13.0) 6 (13.6) 30 (17.3) Nausea 1 (2.4) 1 (2.5) 4 (9.1) 5 (11.6) 11 (6.5) 4 (10.5) 3 (6.7) 9 (19.6) 14 (31.8) 30 (17.3) Vomiting 0 (0.0) 1 (2.5) 3 (6.8) 9 (20.9) 13 (7.7) 1 (2.6) 3 (6.7) 8 (17.4) 10 (22.7) 22 (12.7) Diarrhoea 0 (0.0) 1 (2.5) 1 (2.3) 3 (7.0) 5 (3.0) 3 (7.9) 3 (6.7) 2 (4.3) 0 (0.0) 8 (4.6) Dizziness 1 (2.4) 1 (2.5) 2 (4.5) 4 (9.3) 8 (4.8) 5 (13.2) 4 (8.9) 8 (17.4) 5 (11.4) 22 (12.7) Stomach ache 3 (7.3) 4 (10.0) 4 (9.1) 2 (4.7) 13 (7.7) 5 (13.2) 11 (24.4) 9 (19.6) 12 (27.3) 37 (21.4) 24 h post-treatment Moderate 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Mild 4 (9.6) 7 (17.5) 8 (18.2) 6 (14.0) 25 (14.9) 12 (31.6) 12 (26.7) 12 (26.1) 11 (25.0) 47 (27.2) None 37 (90.2) 33 (82.5) 36 (81.8) 37 (86.0) 143 (85.1) 26 (68.4) 33 (73.3) 34 (73.9) 33 (75.0) 126 (72.8) Fever 2 (4.9) 4 (10.0) 2 (4.5) 2 (4.7) 10 (6.0) 5 (13.2) 7 (15.6) 5 (10.9) 6 (13.6) 23 (13.3) Headache 1 (2.4) 1 (2.5) 1 (2.3) 2 (4.7) 5 (3.0) 3 (7.9) 7 (15.6) 10 (21.7) 7 (15.9) 27 (15.6) Nausea 1 (2.4) 0 (0.0) 0 (0.0) 3 (7.0) 4 (2.4) 2 (5.3) 1 (2.2) 4 (8.7) 5 (11.4) 12 (6.9) Vomiting 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.0) 3 (1.8) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) 1 (0.6) Diarrhoea 1 (2.4) 2 (5.0) 5 (11.4) 0 (0.0) 8 (4.8) 0 (0.0) 1 (2.2) 3 (6.5) 2 (4.5) 6 (3.5) Dizziness 1 (2.4) 0 (0.0) 0 (0.0) 1 (2.3) 1 (0.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Stomach ache 2 (4.9) 0 (0.0) 2 (4.5) 2 (4.7) 6 (3.6) 1 (2.6) 6 (13.3) 6 (13.0) 4 (9.1) 17 (9.8) 2 children were absent (placebo (n = 1) and 60 mg/kg (n = 1)) following treatment and were not assessed for adverse events 1 child was absent (20 mg/kg treatment arm) following treatment and was not assessed for adverse events study, where we reported that in SAC infected with S. PSAC compared to 71.4% of SAC [34]. Nonetheless, our mansoni, CRs increased with higher doses of praziquan- finding can most likely be explained with the lower in- tel [24], while only moderate CRs were observed in fection intensities present in PSAC, as CRs in children PSAC at all doses administered. characterised by heavy infection intensities were low. Overall higher CRs were observed in PSAC (68–86%) Hence, our results confirm the relationship between CRs when compared to SAC (56–68%), which mirrors a re- and infection intensity observed in previous studies [35, cent meta-analysis by Zwang et al., where 40 mg/kg 36]. Overall, the results emphasise the need for rigorous praziquantel cured 87.3% of S. haematobium-infected treatment programmes in settings with heavy infection Coulibaly et al. BMC Medicine (2018) 16:81 Page 8 of 10 of S. haematobium, since reductions in egg output sig- With regard to safety outcomes, the main adverse nificantly correlated with decreased morbidity [37, 38]. events observed in both PSAC and SAC are in line with No dose-response relationship was observed for ERRs the adverse events reported in previous studies [16, 24, in both age groups above 20 mg/kg. This finding is in 34]. We observed an increase of adverse events severity line with an earlier meta-analysis by Zwang et al. [34] that was proportional to praziquantel dose in SAC, while which found no significant relationship for dose and only one child showed moderate diarrhoea at the ERR for any of the Schistosoma species. However, our 60 mg/kg treatment dose in PSAC. However, as men- dose-finding study in S. mansoni-infected children tioned earlier, the accuracy of the adverse event severity showed that higher ERRs (based on GMs) were observed assessment in PSAC is questionable, in particular for in children treated with 40 and 60 mg/kg compared to the less visible mild adverse events, since the reporting 20 mg/kg [24]. Recent WHO Standard Operating Proce- is done by the children’smothers. dures have set a threshold of a 90% ERR based on AM for clinical efficacy and recommend that control pro- Conclusions grammes should investigate drug performance in popu- Praziquantel showed a high response rate in PSAC and lations where the ERR is lower [39]. Regardless of age SAC infected with S. haematobium, with high efficacy group and whether GM or AM was used to determine observed already at 20 mg/kg, particularly in light infec- ERRs, we found that all praziquantel doses used against tions. No benefit was observed using higher praziquantel S. haematobium, in contrast to preschoolers infected doses in the current study. However, to be able to pro- with S. mansoni [24], yielded ERRs above 90%. Despite vide ultimate dosing recommendations of praziquantel the excellent efficacy of 20 mg/kg of praziquantel against for PSAC, additional studies might be required to sup- light S. haematobium infections in this study, the use of port our conclusions, including pharmacokinetic studies two different doses, namely 20 mg/kg for S. haemato- and studies in PSAC suffering from moderate and heavy bium and 40 mg/kg for S. mansoni in settings where S. haematobium infections. Schistosoma species are overlapping, would raise logis- tical and operational challenges since control pro- Additional file grammes are acting at large-scale levels such as district or country levels. Therefore, rigorous cost-effectiveness Additional file 1: Table S1. Imputation on cure rates of individuals lost after treatment in 20, 40 and 60 mg/kg praziquantel and placebo treatment studies need to be implemented before a change of treat- arms among Schistosoma haematobium-infected preschool-aged children ment guidelines could be considered. However, at a and school-aged children (intention-to-treat). Figure S1. E model max point-of-care level, using a test-and-treat approach, predicting cure rates (CRs) based on actual doses in preschool-aged children (blue symbols) and school-aged children (red symbols). Figure 20 mg/kg and 40 mg/kg could be recommended to treat S2. Predicted probability of being cured by baseline infection intensity in PSAC for S. haematobium and S. mansoni infections, preschool children (blue lines) and school-aged children (red lines). respectively. (DOCX 231 kb) In PSAC we observed a high CR in the placebo arm similar to what was observed in our S. mansoni study [24]. Abbreviations AM: Arithmetic mean; CR: Cure rate; ERR: Egg reduction rate; GM: The probability of being cured for placebo-treated Geometric mean; PSAC: Preschool-aged children; SAC: School-aged children was particularly high in children with low egg children; WHO: World Health Organization loads despite using a relatively strong diagnostic ap- Acknowledgements proach at baseline and follow-up by collecting per child We are grateful to all participating children and their parents. We thank the three consecutive urine samples for each time point mothers of the PSAC from the study of all five villages and the teachers from (baseline and follow-up). On the other hand, no cured Mopé and Nyan for their support. Moreover, we are thankful to our staff of doctors, nurses, technicians, volunteers and drivers, whose expertise and individual was observed in placebo-treated children dedication were indispensable. We are grateful to the European Research with heavy infection intensity at baseline. The high CR Council for financial support. This work was supported by the donation of observed in the placebo treatment arm among PSAC Cesol® tablets provided by Merck KGaA, Darmstadt, Germany. was thus likely reflective of the low sensitivity of the Funding urine filtration method for light infections [40, 41]. Our This work was supported by the European Research Council (grant number findings underscore the value of adding a placebo ERC-2013-CoG 614739-A_HERO). group in Schistosoma drug efficacy trials—the overesti- Availability of data and materials mation of CRs due to potential false negatives in light The datasets supporting the conclusions of this article are included within infections is visible. More importantly, our observations the article. emphasise the need for Schistosoma species-related Authors’ contributions standard operating procedures including reliable diag- JTC, JH and JK designed the study; JTC, GP, RBY, YKN, BB, JK and JKo conducted nostic tools, suitable for drug efficacy assessment for the study; JTC, JH and JK analysed and interpreted the data; JTC and JK wrote low infection intensities [40–42]. the first draft of the manuscript; GP, RBY, BB, YKN and JH revised the manuscript. Coulibaly et al. BMC Medicine (2018) 16:81 Page 9 of 10 All authors read and approved the final version of the manuscript. Merck KGaA, 11. World Health Organization. Preventive chemotherapy in human Darmstadt, Germany reviewed the manuscript for medical accuracy only before helminthiasis: coordinated use of anthelminthic drugs in control journal submission. The authors are fully responsible for the content of this interventions: a manual for health professionals and programme managers. manuscript, and the views and opinions described in the publication reflect solely Geneva: WHO; 2006. those of the authors. 12. Lelo AE, Mburu DN, Magoma GN, Mungai BN, Kihara JH, Mwangi IN, Maina GM, Kinuthia JM, Mutuku MW, Loker ES, et al. No apparent reduction in Ethics approval and consent to participate schistosome burden or genetic diversity following four years of school- Approval was obtained by the Comité d’Ethique et de la Recherche of the based mass drug administration in Mwea, Central Kenya, a heavy Ministry of Health in Côte d’Ivoire (CNER, reference no. 037/MSLS/CNER-dkn) transmission area. PLoS Negl Trop Dis. 2014;8:e3221. and the Ethical Committee of Northwestern and Central Switzerland (EKNZ, 13. Leenstra T, Coutinho HM, Acosta LP, Langdon GC, Su L, Olveda RM, reference no. 162/2014). McGarvey ST, Kurtis JD, Friedman JF. Schistosoma japonicum reinfection Information provided to communities and written informed consent and assent after praziquantel treatment causes anemia associated with inflammation. procedures were conducted as described elsewhere [24]. Infect Immun. 2006;74:6398–407. 14. Stothard JR, Gabrielli AF. Schistosomiasis in African infants and preschool Consent for publication children: to treat or not to treat? Trends Parasitol. 2007;23:83–6. Consent to publish from the participant (or legal parent or guardian for children) 15. Stothard JR, Sousa-Figueiredo JC, Betson M, Bustinduy A, Reinhard-Rupp J. to report individual patient data was obtained. Schistosomiasis in African infants and preschool children: let them now be treated! Trends Parasitol. 2013;29:197–205. Competing interests 16. Coulibaly JT, N'Gbesso YK, Knopp S, Keiser J, N'Goran EK, Utzinger J. 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Efficacy and safety of ascending doses of praziquantel against Schistosoma haematobium infection in preschool-aged and school-aged children: a single-blind randomised controlled trial

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Copyright © 2018 by The Author(s).
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Medicine & Public Health; Medicine/Public Health, general; Biomedicine, general
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10.1186/s12916-018-1066-y
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Abstract

Background: Despite decades of experience with praziquantel treatment in school-aged children (SAC) and adults, we still face considerable knowledge gaps relevant to the successful treatment of preschool-aged children (PSAC). This study aimed to assess the efficacy and safety of escalating praziquantel dosages in PSAC infected with Schistosoma haematobium. Methods: We conducted a randomised, dose-finding trial in PSAC (2–5 years) and as comparator a cohort of SAC (6–15 years) infected with S. haematobium in Côte d’Ivoire. A total of 186 PSAC and 195 SAC were randomly assigned to 20, 40 or 60 mg/kg praziquantel or placebo. The nature of the dose-response relationship in terms of cure rate (CR) was the primary objective. Egg reduction rate (ERR) and tolerability were secondary outcomes. CRs and ERRs were assessed using triplicate urine filtration over 3 consecutive days. Available-case analysis was performed including all participants with primary endpoint data. Results: A total of 170 PSAC and 174 SAC received treatment. Almost 90% of PSAC and three quarters of SAC were lightly infected with S. haematobium. Follow-up data were available for 157 PSAC and 166 SAC. In PSAC, CRs of praziquantel were 85.7% (30/35), 78.0% (32/41) and 68.3% (28/41) at 20, 40 and 60 mg/kg and 47.5% (19/40) for placebo. In SAC, CRs were 10.8% for placebo (4/37), 55.6% for 20 mg/kg (25/45), 68.3% for 40 mg/kg (28/41) and 60.5% for 60 mg/ kg (26/43). ERRs based on geometric means ranged between 96.5% (60 mg/kg) and 98.3% (20 mg/kg) in PSAC and between 97.6% (20 mg/kg and 60 mg/kg) and 98.6% (40 mg/kg) in SAC. Adverse events were mild and transient. Conclusions: Praziquantel revealed dose-independent efficacy against light infections of S. haematobium.Overthe dose range tested, praziquantel displayed a ceiling effect with the highest response for 20 mg/kg in PSAC. In SAC maximum efficacy was obtained with 40 mg/kg praziquantel. Further investigations are required in children with moderate to heavy infections. Trial registration: This trial is registered with International Standard Randomised Controlled Trial Number ISRCTN15280205. Keywords: Efficacy, Praziquantel, Preschool-aged children, Schistosoma haematobium, School-aged children * Correspondence: jennifer.keiser@swisstph.ch Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, CH-4002, Basel, Switzerland University of Basel, Basel, Switzerland Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Coulibaly et al. BMC Medicine (2018) 16:81 Page 2 of 10 Background process, resulting in successful control of schistosome Schistosomiasis is a major public health problem with an infection and disease. estimated 779 million people at risk of infection [1]. The disease is caused by trematode worms of the genus Schis- Methods tosoma, where infection with Schistosoma japonicum and Study design and participants S. mansoni causes mostly intestinal schistosomiasis, while We conducted a randomised, parallel-group, single-blind, S. haematobium is responsible for genitourinary schisto- placebo-controlled, dose-ranging trial between November somiasis [2–6]. Cumulative schistosome infections over 2015 and February 2016. PSAC (aged 2–5years)and SAC years, due to rapid reinfection, result in morbid sequelae, (6–15 years) were surveyed in five villages of the health including haematuria, nutritional deficiencies, anaemia, district of Adzopé, southern Côte d’Ivoire. In total, 740 hepatic peri-portal fibrosis and consequent portal hyper- PSAC and 444 SAC were registered during the census and tension and delayed physical and cognitive development were invited to participate in the study. [7–9]. Moreover, genitourinary schistosomiasis can lead to obstruction and carcinomas of urogenital organs and im- Randomisation and masking pairment to female reproductive health [6, 10]. To control Eligibility of children was based on the presence of schistosomiasis morbidity, health authorities rely on mass S. haematobium eggs in their urine. In addition, a clinical administration (preventive chemotherapy) of praziquantel examination and an oral medical history by active ques- in school-aged children (SAC), the population most af- tioning were implemented in order to exclude children fected [11–13]. In 2010, the World Health Organization with abnormal medical conditions (i.e. clinical malaria or (WHO) endorsed the inclusion of preschool-aged children hepato-splenic schistosomiasis) or those who received an (PSAC) in preventative chemotherapy programmes, since antimalarial or anthelmintic drug in the past 4 weeks. there is increasing evidence that they are also affected by S. haematobium egg-positive PSAC and SAC, eligible schistosomiasis and could suffer from morbidity [14–17]. for the study, were stratified according to baseline infec- In the absence of an appropriate paediatric formulation, tion intensity into light (< 50 eggs/10 mL of urine) or broken or crushed praziquantel tablets are commonly heavy (≥ 50 eggs/10 mL of urine) infection intensities used in PSAC using the standard 40 mg/kg dose [18]. A [25]. Children were then randomly assigned to placebo range of studies showed that this dose was well tolerated or 20, 40 or 60 mg/kg praziquantel treatment arms using and efficacious [15, 19, 20]. However, the heterogeneity of computer-generated stratified block randomisation codes methodology and reporting on praziquantel efficacy and provided by an independent statistician based on the safety assessment make decision-making difficult [21]. aforementioned infection intensity (block size of 8). Only In the paediatric population, growth and maturation of the investigator dealing with drug administration was organs are dynamic. Changes in body proportion and me- aware of the treatment assignments. The physician and tabolism occur throughout infancy and childhood that laboratory technicians were blinded to the treatment. affect how drugs are metabolised [22, 23]. Well-designed SAC might have recognised the treatment dose due to paediatric drug trials are therefore warranted in order to the number of tablets administered; however, the crush- guide the proper usage of drug treatments to avoid under- ing of tablets for PSAC was prepared in advance. Mask- dosing, overdosing, ineffectiveness and safety problems. ing was maintained throughout the trial. Randomisation We recently conducted a randomised, controlled codes were released after the database was unlocked. dose-finding study assessing the safety and efficacy of praziquantel in PSAC and SAC infected with S. mansoni. Field and laboratory procedures Considerable differences were observed between these During the baseline survey, three urine samples over 3 two age groups with regard to efficacy. For example, consecutive days and a single stool sample from the first while treatment of SAC with 40 or 60 mg/kg met the collection day were collected between 10:00 and WHO standards of clinical efficacy of ≥ 90% egg reduc- 14:00 am from each participating child. Urine and stool tion rate (ERR) based on arithmetic mean (AM), none of samples were transferred to a nearby laboratory in the doses administered could reach this threshold in Azaguié town and examined on the day of collection. PSAC [24]. S. haematobium was detected using the urine filtra- This study was designed to support the ongoing efforts tion method (syringe filtration of 10 mL of urine followed to successfully control schistosome infections in PSAC by microscopic examination of the filter) [26]. A subse- by assessing the efficacy and safety of escalating prazi- quent independent quality control of sample results (ap- quantel dosages in PSAC compared to SAC infected proximately 10%) was conducted. If a difference in with S. haematobium. The clinical evidence for prazi- presence/absence of S. haematobium eggs was observed quantel obtained for both S. haematobium and S. man- or egg counts exceeded +/−10 eggs for light infections or soni in PSAC will facilitate the clinical decision-making +/−20 eggs for heavy infections, all the slides were read Coulibaly et al. BMC Medicine (2018) 16:81 Page 3 of 10 once again by the senior technician. S. mansoni infection implemented including all treated participants (regard- was assessed through duplicate Kato-Katz thick smears less of whether they could swallow the drug or not or (standard template of 41.7 mg) [27]. Eggs of were wrongly dosed) who had at least one urine sample soil-transmitted helminths, i.e. Ascaris lumbricoides, examined with the urine filtration method at follow-up hookworm and Trichuris trichiura, were also assessed and and were not excluded due to a medical condition. recorded for each parasite species separately. Moreover, In order to calculate ERR, the AM and geometric finger prick blood samples were taken to assess Plasmo- mean (GM) of eggs per 10 mL of urine before and after dium infections and haemoglobin amount using, respect- treatment were assessed. Geometric mean egg counts 1/n ∑ log(x + 1) ively, thick and thin blood smears [24] and a calibrated were calculated as follows: e -1, and the HemoCue device (HemoCue 301 system, HemoCue, corresponding ERR ([1 – geometric mean egg output Ängelholm, Sweden). after treatment/geometric mean egg output at To assess treatment efficacy, another three urine samples baseline] × 100) was assessed. A bootstrap resampling and a single stool sample were collected between 21 and method with 5000 replicates was used to estimate 95% 25 days post-treatment and subjected to the same diagnos- CIs for ERRs. tic approaches applied at baseline. At the end of the study, E models using the DoseFinding package (version max all children enrolled in the study were offered albendazole 0∙9–14) of the statistical software environment R (v3.3.0) (400 mg) and praziquantel (40 mg/kg) for the treatment of were implemented to predict the dose-response curves helminth infections according to local guidelines. in terms of CRs and ERRs. Logistic regression was used to predict CR by infection intensity at baseline. Treatment Results Prior to treatment, each child received breakfast. In both Study flow and baseline characteristics study groups (SAC and PSAC), treatment was done Overall, 1184 children were invited to participate in the based on the child’s body weight (graduated increments study (Fig. 1). At baseline, 628 PSAC and 356 SAC were of 0.1 kg). Praziquantel (600 mg Cesol®) (used in screened for S. haematobium infection. Of these, 186 quarter-tablet increments) and placebo were obtained (29.6%) PSAC and 195 (45.7%) SAC had a detectable from Merck KGaA, Darmstadt, Germany and Fagron, S. haematobium infection and were randomised for Barsbüttel, Germany, respectively. For PSAC, tablets treatment. On the treatment day, 16 PSAC and 21 SAC were crushed using a mortar and pestle and dissolved in were absent. PSAC received 20 mg/kg (n =40), 40 mg/kg a small volume of syrup-flavoured water to mask the (n = 44) or 60 mg/kg (n = 44) praziquantel or placebo taste. SAC and the mothers/guardians of PSAC were (n = 42). SAC were likewise allocated to 20 mg/kg (n = interviewed 3, 24, 48 and 72 h after treatment for ad- 46), 40 mg/kg (n = 46) or 60 mg/kg praziquantel (n =44) verse events and the intensities graded by the study or placebo (n = 38). Two PSAC and one SAC were not physician as mild, moderate, severe or intolerable [24]. able to swallow the drug. One PSAC and one SAC were wrongly dosed (62.5 mg/kg instead of 40 mg/kg and Outcomes and sample size determination 75 mg/kg instead of 40 mg/kg, respectively). The cure rate (CR) (primary outcome) was expressed as At follow-up, data were available for 157 PSAC and the proportion of children positive for S. haematobium 166 SAC. One PSAC and 12 SAC provided only two eggs at baseline survey who became negative at urine samples, while one SAC provided only one urine follow-up. The secondary outcomes were ERR and the sample. safety of different doses of praziquantel. The median age, weight, height and sex of PSAC Simulations showed that with 40 children enrolled per and SAC were balanced among the treatment groups treatment arm (0, 20, 40 and 60 mg/kg), the dose-response (Table 1). Three quarters of PSAC and SAC were prediction model should have a median precision—defined lightly infected with S. haematobium.Noinfection as one half length of the 95% confidence interval (CI)—of with A. lumbricoides, T. trichiura or hookworm was 10% points, assuming associated cure rates of 2.5%, 50%, recorded. Co-infections among S. haematobium-infected 75% [28] and 90%. children with S. mansoni and P. falciparum were very low (less than 9%) in PSAC and SAC. Median haemoglobin Statistical analysis values ranged between 10.5 and 11.0 g/dL in PSAC and All data were first double entered into an Excel spread- between 11.0 and 11.7 g/dL in SAC. sheet, then transferred into Epi Info version 3.5.2 (Centers for Disease Control and Prevention, Atlanta, Efficacy of praziquantel GA, USA) and cross-checked. R version 3.4.0 was used The nature of the dose response based on CRs is depicted for all statistical analyses. Available-case analysis was in Fig. 2. Praziquantel revealed dose-independent efficacy Coulibaly et al. BMC Medicine (2018) 16:81 Page 4 of 10 Fig. 1 Trial profile with the highest cure rates observed at 20 and 40 mg/ 97.6%, 98.6% and 97.6% were observed with increasing kg in PSAC and SAC, respectively. The E model dosages. ERRs based on AMs had similar profiles to max based on actual doses on the per protocol population is those based on GMs and are presented in Table 2. presented in Additional file 1:FigureS1and showsa Table 2 also presents an exploratory subgroup analysis similar trend. Additional file 1: Figure S2 presents the on CRs according to S. haematobium infection inten- predicted probability of being cured by baseline infec- sity. The CR in PSAC ranged from 73.0% (60 mg/kg) tion intensity. For all treatments, including placebo, to 87.9% (20 mg/kg) in light infections and from there was a high probability of being cured at low infec- 25.0% (60 mg/kg) to 66.7% (40 mg/kg) in heavy infec- tion intensities. tions. In SAC, CRs were 70.6% (20 mg/kg) to 78.8% CRs in PSAC for 20 mg/kg, 40 mg/kg and 60 mg/kg (40 mg/kg) for light S. haematobium infections and were 85.7 (95% CI 69.7–95.2), 78.0% (95% CI 62.4–89.4) between 9.1% (20 mg/kg) and 27.3% (60 mg/kg) for and 68.3% (95% CI 51.9–81.9), respectively, whereas in heavy infections. SAC the respective CRs were 55.6% (95% CI 40.0–70.4), 68.3% (95% CI 51.9–81.9) and 60.5% (95% CI 44.4–75.0). Safety of praziquantel In the placebo groups, S. haematobium eggs were not Adverse events data were available for 168 PSAC and detected in the urine samples of 47.5% (19/40) and 173 SAC (Table 3). In both groups, more children re- 10.8% (4/37) in PSAC and SAC, respectively (Table 2). ported signs and symptoms at pre-treatment compared Imputation of missing data with treatment failure or to 3 and 24 h post-treatment. No serious adverse events success in the intention-to-treat analysis did not change were reported. Overall, adverse events were mild with the observed outcomes (Additional file 1: Table S1). fewer adverse events observed at 3 h post-treatment ERRs are summarized in Table 2 and depicted in compared to pre-treatment in PSAC (52 episodes versus Fig. 3. ERRs in PSAC were 98.3% for 20 mg/kg, 97.6% 88 episodes) and in SAC (88 episodes versus 92 epi- for 40 mg/kg and 96.5% for 60 mg/kg. In SAC ERRs of sodes), respectively. Mild events mainly included fever, Coulibaly et al. BMC Medicine (2018) 16:81 Page 5 of 10 Table 1 Baseline characteristics Preschool-aged children (PSAC) School-aged children (SAC) Treatment arm Treatment arm Characteristics Placebo 20 mg/kg 40 mg/kg 60 mg/kg Placebo 20 mg/kg 40 mg/kg 60 mg/kg 42 40 44 44 38 46 46 44 Female N (%) 23 (54.8) 21 (52.5) 20 (45.5) 27 (61.4) 23 (60.5) 25 (54.3) 25 (54.3) 25 (56.8) Age, years; median 4 4449 889 [IQR] [2–5] [2–5] [2–5] [2–5] [6–13] [6–13] [6–14] [6–13] Weight, kg; median 15 15 15 15 22 22 24 22 [IQR] [10–21] [11–19] [11–19] [11–18] [18–35] [18–33] [18–38] [18–40] Height, cm; median 97 98 101 100 125 125 125 124 [IQR] [80–117] [83–115] [84–116] [83–114] [109–141] [114–139] [113–149] [112–150] Haemoglobin (g/dL); median 10.5 11.0 10.9 10.9 11.4 11.2 11.7 11.6 [IQR] [9.1–13.2] [9.1–12.8] [8.8–12.5] [8.5–12.9] [9.7–13.7] [9.9–12.4] [9.7–12.8] [10.1–13.5] Infection intensity N (%) Light 36 (85.7) 38 (95.0) 38 (86.4) 40 (90.9) 27 (71.1) 35 (76.1) 36 (78.3) 33 (75.0) Heavy 6 (14.3) 2 (5.0) 6 (13.6) 4 (9.1) 11 (28.9) 11 (23.9) 10 (21.7) 11 (25.0) Co-infections N (%) S. mansoni 0 (0.0) 0 (0.0) 1 (2.3) 1 (2.3) 0 (0.0) 1 (2.2) 1 (2.2) 0 (0.0) Plasmodium falciparum 1 (2.4) 0 (0.0) 1 (2.3) 0 (0.0) 1 (2.6) 4 (8.7) 2 (4.3) 3 (6.8) (based on thin/thick smear) IQR interquartile range headache, nausea, diarrhoea, vomiting, dizziness and with fewer adverse events observed in the stomach ache. Few moderate cases were reported at placebo-treated groups. The most common adverse 3 h after treatment in PSAC (only one with moderate events in PSAC and SAC 24 h post-treatment were diarrhoea) and in SAC (n = 12). At 24 h diarrhoea (4.8 and 3.5%), stomach ache (3.6 and 9.8%), post-treatment, 25 (14.9%) and 47 (27.2%) adverse fever (6.0 and 13.3%), headache (3.0 and 15.6%) and events were recorded in PSAC and SAC, respectively. nausea (2.4 and 6.9%). For both age groups the number of adverse events was similar among the three praziquantel treatment arms, Discussion Over the past decade, preventive chemotherapy pro- grammes for the control of schistosomiasis targeting SAC have scaled up across many countries in tropical and subtropical areas. Great progress has been made in decreasing the burden of this disease [29–31]. However, recent modelling and health economic studies found that expanded community-wide preventive chemother- apy that includes adolescents, adults and PSAC would better reduce the overall disease burden, rates of trans- mission and reinfection [32]. It was recommended in 2010 that PSAC should be in- cluded in preventive chemotherapy programmes [33] using an adequate dose, though this age group is still lack- ing a suitable formulation. A paediatric formulation of praziquantel (small, orally dispersible tablets) is under de- Fig. 2 Cure rates in PSAC (blue lines) and SAC (red lines). Circles show velopment (https://www.pediatricpraziquantelconsortium observed cure rates with 95% CIs (vertical lines). Numbers in the circles show geometric mean infection intensities at baseline (BL). Dashed .org/node/28), but it will take several more years until the lines represent the estimated dose-response curve and corresponding drug is marketed and available to all PSAC. To be able to 95% CIs predicted by the E models. Geometric mean of infection max treat preschoolers safely and effectively, we studied as- intensity was the mean of eggs filtered from 10 mL of urine cending doses of praziquantel in PSAC and SAC infected Coulibaly et al. BMC Medicine (2018) 16:81 Page 6 of 10 Table 2 Available-case analysis of cure and egg reduction rates of 20, 40 and 60 mg/kg praziquantel versus placebo against urogenital schistosomiasis in PSAC and SAC based on the urine filtration method Preschool-aged children (PSAC) School-aged children (SAC) Placebo 20 mg/kg 40 mg/kg 60 mg/kg Placebo 20 mg/kg 40 mg/kg 60 mg/kg Infected children before treatment (N) 40 354141 37 4541 43 a b Actual dose administered (range; mg/kg) – 13.6–25 34.6–62.5 50–70 – 16.7–23.7 36.4–75 56.3–65.6 Cured children after treatment N (%) 19 (47.5) 30 (85.7) 32 (78.0) 28 (68.3) 4 (10.8) 25 (55.6) 28 (68.3) 26 (60.5) 95% CI 32.5–63.9 69.7–95.2 62.4–89.4 51.9–81.9 3.0–25.4 40.0–70.4 51.9–81.9 44.4–75.0 Cured children according to sex Male 6 (31.6) 14 (46.7) 19 (59.4) 10 (35.7) 1 (25.0) 9 (36.0) 13 (46.4) 9 (34.6) 95% CI 12.5–56.6 28.3–65.7 40.6–76.3 18.6–55.9 0.6–80.6 18.0–57.5 27.5–66.1 17.2–55.7 Female 13 (68.4) 16 (53.3) 13 (40.6) 18 (64.3) 3 (75.0) 16 (64.0) 15 (53.6) 17 (65.4) 95% CI 43.4–87.4 34.3–71.7 23.7–59.4 44.1–81.4 19.4–99.4 42.5–82.0 33.9–72.5 44.3–82.8 Cured children with light infection 19/40 (47.5) 29/33 (87.9) 28/35 (80.0) 27/37 (73.0) 4/26 (15.4) 24/34 (70.6) 26/33 (78.8) 23/32 (71.9) Cured children with heavy infections (%) 0/6 (0) 1/2 (50.0) 4/6 (66.7) 1/4 (25.0) 0/11 (0.0) 1/11 (9.1) 2/8 (25.0) 3/11 (27.3) Geometric mean eggs/10 mL of urine Before treatment 7.8 7.5 8.4 8.3 31.5 21.6 16.6 17.2 After treatment 2.4 0.1 0.2 0.3 13.1 0.5 0.2 0.4 Egg reduction rate 68.9 98.3 97.6 96.5 58.5 97.6 98.6 97.6 (95% CI) 46.6–83.6 95.4–99.8 94.9–99.2 93.1–98.7 38.7–71.4 96.4–98.6 97.7–99.3 95.3–98.9 Arithmetic mean eggs/10 mL of urine Before treatment 22.7 14.3 21.7 16.9 94.4 89.5 31.0 34.4 After treatment 11.5 0.3 0.4 0.9 49.0 1.2 0.4 1.0 Egg reduction rate 49.5 97.8 98.2 94.5 46.9 98.7 98.8 97.0 (95% CI) 0.2–77.3 93.6–99.9 96.1–99.5 85.7–99.1 36.4–77.6 96.7–99.3 97.7–99.5 92.9–99.2 Range 34.6–44.1 excluding the wrongly dosed child Range 36.4–42.9 excluding the wrongly dosed child with S. haematobium. Our results build on an earlier dose-finding study in S. mansoni-infected children [24]. Several findings of our study are worth highlighting. First, the highest overall CRs among PSAC (85.7%) and SAC (68.3%) were obtained with 20 mg/kg and 40 mg/ kg praziquantel, respectively and not with the highest dose administered, 60 mg/kg. For both age groups, CRs revealed even a slight inverse dose-rate effect. Similarly, ERRs increased very fast up to 98% and did not increase further regardless of the praziquantel dose administered. Interestingly, 60 mg/kg praziquantel also showed lower CRs in PSAC with moderate/high S. haematobium infec- tion intensities compared to the two lower doses. For ex- ample, the CR in PSAC characterised by heavy infection intensities treated with 60 mg/kg praziquantel was as low as 25%. However, only a handful of PSAC suffered from moderate and high infection intensities; hence, no clear picture can be drawn for this age group. In SAC similar CRs were observed in children harbouring heavy Fig. 3 Egg reduction rates in PSAC (blue lines) and SAC (red lines). infection intensities treated with 40 and 60 mg/kg. In Diamonds show observed cure rates with 95% CIs (vertical lines). summary, a high dose of praziquantel seems to have no Dashed lines represent the estimated dose-response curve and additional benefit in the treatment of S. haematobium corresponding 95% CI predicted by the E model max infections. This result is in contrast with our recent Coulibaly et al. BMC Medicine (2018) 16:81 Page 7 of 10 Table 3 Main type of clinical symptoms (number and percentage) before treatment and adverse events 3 and 24 h after praziquantel administration in Schistosoma haematobium-infected preschool-aged children (n = 168) and school-aged children (n = 173) a b Preschool-aged children (PSAC) School-aged children (SAC) Symptoms Placebo 20 mg/kg 40 mg/kg 60 mg/kg Overall Placebo 20 mg/kg 40 mg/kg 60 mg/kg Overall (n = 41) (n = 40) (n = 44) (n = 43) (n = 168) (n = 38) (n = 45) (n = 46) (n = 44) (n = 173) Before treatment Moderate 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Mild 24 (58.5) 19 (47.5) 26 (59.1) 19 (44.2) 88 (52.4) 20 (52.6) 26 (57.8) 25 (54.3) 21 (47.7) 92 (53.2) None 17 (41.5) 21 (52.5) 18 (40.9) 24 (55.8) 80 (47.6) 18 (47.4) 19 (42.2) 21 (45.7) 23 (52.3) 81 (46.8) Fever 6 (14.1) 3 (7.5) 7 (15.9) 5 (11.6) 21 (12.5) 5 (13.2) 7 (15.6) 5 (10.9) 6 (13.6) 23 (13.3) Headache 8 (19.5) 6 (15.0) 13 (29.5) 10 (23.3) 37 (22.0) 3 (7.9) 7 (15.6) 10 (21.7) 7 (15.9) 27 (15.6) Nausea 3 (7.3) 4 (10.0) 3 (6.8) 1 (2.3) 11 (6.5) 2 (5.3) 1 (2.2) 4 (8.7) 5 (11.4) 12 (6.9) Vomiting 1 (2.4) 1 (2.5) 1 (2.3) 2 (4.7) 5 (3.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) 1 (0.6) Diarrhoea 4 (9.6) 4 (10.0) 4 (9.1) 5 (11.6) 17 (10.1) 0 (0.0) 1 (2.2) 3 (6.5) 2 (4.5) 6 (3.5) Dizziness 2 (4.9) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Stomach ache 2 (4.9) 5 (12.5) 8 (18.2) 4 (9.3) 19 (11.3) 1 (2.6) 6 (13.3) 6 (13.0) 4 (9.1) 17 (9.8) 3 h post-treatment Moderate 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.3) 1 (0.6) 1 (2.6) 2 (4.4) 4 (8.7) 5 (11.4) 12 (6.9) Mild 6 (14.6) 8 (20.0) 15 (34.1) 23 (53.5) 52 (31.0) 18 (47.4) 23 (51.1) 21 (45.7) 26 (59.1) 88 (50.9) None 35 (85.4) 32 (80.0) 29 (65.9) 19 (44.2) 115 (68.5) 19 (50.0) 20 (44.4) 21 (45.7) 13 (29.5) 73 (42.2) Fever 3 (7.3) 3 (7.5) 2 (4.5) 4 (9.3) 12 (7.1) 6 (15.8) 4 (8.9) 8 (17.4) 12 (27.3) 30 (17.3) Headache 1 (2.4) 2 (5.0) 1 (2.3) 7 (16.3) 11 (6.5) 8 (21.1) 10 (22.2) 6 (13.0) 6 (13.6) 30 (17.3) Nausea 1 (2.4) 1 (2.5) 4 (9.1) 5 (11.6) 11 (6.5) 4 (10.5) 3 (6.7) 9 (19.6) 14 (31.8) 30 (17.3) Vomiting 0 (0.0) 1 (2.5) 3 (6.8) 9 (20.9) 13 (7.7) 1 (2.6) 3 (6.7) 8 (17.4) 10 (22.7) 22 (12.7) Diarrhoea 0 (0.0) 1 (2.5) 1 (2.3) 3 (7.0) 5 (3.0) 3 (7.9) 3 (6.7) 2 (4.3) 0 (0.0) 8 (4.6) Dizziness 1 (2.4) 1 (2.5) 2 (4.5) 4 (9.3) 8 (4.8) 5 (13.2) 4 (8.9) 8 (17.4) 5 (11.4) 22 (12.7) Stomach ache 3 (7.3) 4 (10.0) 4 (9.1) 2 (4.7) 13 (7.7) 5 (13.2) 11 (24.4) 9 (19.6) 12 (27.3) 37 (21.4) 24 h post-treatment Moderate 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Mild 4 (9.6) 7 (17.5) 8 (18.2) 6 (14.0) 25 (14.9) 12 (31.6) 12 (26.7) 12 (26.1) 11 (25.0) 47 (27.2) None 37 (90.2) 33 (82.5) 36 (81.8) 37 (86.0) 143 (85.1) 26 (68.4) 33 (73.3) 34 (73.9) 33 (75.0) 126 (72.8) Fever 2 (4.9) 4 (10.0) 2 (4.5) 2 (4.7) 10 (6.0) 5 (13.2) 7 (15.6) 5 (10.9) 6 (13.6) 23 (13.3) Headache 1 (2.4) 1 (2.5) 1 (2.3) 2 (4.7) 5 (3.0) 3 (7.9) 7 (15.6) 10 (21.7) 7 (15.9) 27 (15.6) Nausea 1 (2.4) 0 (0.0) 0 (0.0) 3 (7.0) 4 (2.4) 2 (5.3) 1 (2.2) 4 (8.7) 5 (11.4) 12 (6.9) Vomiting 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.0) 3 (1.8) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) 1 (0.6) Diarrhoea 1 (2.4) 2 (5.0) 5 (11.4) 0 (0.0) 8 (4.8) 0 (0.0) 1 (2.2) 3 (6.5) 2 (4.5) 6 (3.5) Dizziness 1 (2.4) 0 (0.0) 0 (0.0) 1 (2.3) 1 (0.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Stomach ache 2 (4.9) 0 (0.0) 2 (4.5) 2 (4.7) 6 (3.6) 1 (2.6) 6 (13.3) 6 (13.0) 4 (9.1) 17 (9.8) 2 children were absent (placebo (n = 1) and 60 mg/kg (n = 1)) following treatment and were not assessed for adverse events 1 child was absent (20 mg/kg treatment arm) following treatment and was not assessed for adverse events study, where we reported that in SAC infected with S. PSAC compared to 71.4% of SAC [34]. Nonetheless, our mansoni, CRs increased with higher doses of praziquan- finding can most likely be explained with the lower in- tel [24], while only moderate CRs were observed in fection intensities present in PSAC, as CRs in children PSAC at all doses administered. characterised by heavy infection intensities were low. Overall higher CRs were observed in PSAC (68–86%) Hence, our results confirm the relationship between CRs when compared to SAC (56–68%), which mirrors a re- and infection intensity observed in previous studies [35, cent meta-analysis by Zwang et al., where 40 mg/kg 36]. Overall, the results emphasise the need for rigorous praziquantel cured 87.3% of S. haematobium-infected treatment programmes in settings with heavy infection Coulibaly et al. BMC Medicine (2018) 16:81 Page 8 of 10 of S. haematobium, since reductions in egg output sig- With regard to safety outcomes, the main adverse nificantly correlated with decreased morbidity [37, 38]. events observed in both PSAC and SAC are in line with No dose-response relationship was observed for ERRs the adverse events reported in previous studies [16, 24, in both age groups above 20 mg/kg. This finding is in 34]. We observed an increase of adverse events severity line with an earlier meta-analysis by Zwang et al. [34] that was proportional to praziquantel dose in SAC, while which found no significant relationship for dose and only one child showed moderate diarrhoea at the ERR for any of the Schistosoma species. However, our 60 mg/kg treatment dose in PSAC. However, as men- dose-finding study in S. mansoni-infected children tioned earlier, the accuracy of the adverse event severity showed that higher ERRs (based on GMs) were observed assessment in PSAC is questionable, in particular for in children treated with 40 and 60 mg/kg compared to the less visible mild adverse events, since the reporting 20 mg/kg [24]. Recent WHO Standard Operating Proce- is done by the children’smothers. dures have set a threshold of a 90% ERR based on AM for clinical efficacy and recommend that control pro- Conclusions grammes should investigate drug performance in popu- Praziquantel showed a high response rate in PSAC and lations where the ERR is lower [39]. Regardless of age SAC infected with S. haematobium, with high efficacy group and whether GM or AM was used to determine observed already at 20 mg/kg, particularly in light infec- ERRs, we found that all praziquantel doses used against tions. No benefit was observed using higher praziquantel S. haematobium, in contrast to preschoolers infected doses in the current study. However, to be able to pro- with S. mansoni [24], yielded ERRs above 90%. Despite vide ultimate dosing recommendations of praziquantel the excellent efficacy of 20 mg/kg of praziquantel against for PSAC, additional studies might be required to sup- light S. haematobium infections in this study, the use of port our conclusions, including pharmacokinetic studies two different doses, namely 20 mg/kg for S. haemato- and studies in PSAC suffering from moderate and heavy bium and 40 mg/kg for S. mansoni in settings where S. haematobium infections. Schistosoma species are overlapping, would raise logis- tical and operational challenges since control pro- Additional file grammes are acting at large-scale levels such as district or country levels. Therefore, rigorous cost-effectiveness Additional file 1: Table S1. Imputation on cure rates of individuals lost after treatment in 20, 40 and 60 mg/kg praziquantel and placebo treatment studies need to be implemented before a change of treat- arms among Schistosoma haematobium-infected preschool-aged children ment guidelines could be considered. However, at a and school-aged children (intention-to-treat). Figure S1. E model max point-of-care level, using a test-and-treat approach, predicting cure rates (CRs) based on actual doses in preschool-aged children (blue symbols) and school-aged children (red symbols). Figure 20 mg/kg and 40 mg/kg could be recommended to treat S2. Predicted probability of being cured by baseline infection intensity in PSAC for S. haematobium and S. mansoni infections, preschool children (blue lines) and school-aged children (red lines). respectively. (DOCX 231 kb) In PSAC we observed a high CR in the placebo arm similar to what was observed in our S. mansoni study [24]. Abbreviations AM: Arithmetic mean; CR: Cure rate; ERR: Egg reduction rate; GM: The probability of being cured for placebo-treated Geometric mean; PSAC: Preschool-aged children; SAC: School-aged children was particularly high in children with low egg children; WHO: World Health Organization loads despite using a relatively strong diagnostic ap- Acknowledgements proach at baseline and follow-up by collecting per child We are grateful to all participating children and their parents. We thank the three consecutive urine samples for each time point mothers of the PSAC from the study of all five villages and the teachers from (baseline and follow-up). On the other hand, no cured Mopé and Nyan for their support. Moreover, we are thankful to our staff of doctors, nurses, technicians, volunteers and drivers, whose expertise and individual was observed in placebo-treated children dedication were indispensable. We are grateful to the European Research with heavy infection intensity at baseline. The high CR Council for financial support. This work was supported by the donation of observed in the placebo treatment arm among PSAC Cesol® tablets provided by Merck KGaA, Darmstadt, Germany. was thus likely reflective of the low sensitivity of the Funding urine filtration method for light infections [40, 41]. Our This work was supported by the European Research Council (grant number findings underscore the value of adding a placebo ERC-2013-CoG 614739-A_HERO). group in Schistosoma drug efficacy trials—the overesti- Availability of data and materials mation of CRs due to potential false negatives in light The datasets supporting the conclusions of this article are included within infections is visible. More importantly, our observations the article. emphasise the need for Schistosoma species-related Authors’ contributions standard operating procedures including reliable diag- JTC, JH and JK designed the study; JTC, GP, RBY, YKN, BB, JK and JKo conducted nostic tools, suitable for drug efficacy assessment for the study; JTC, JH and JK analysed and interpreted the data; JTC and JK wrote low infection intensities [40–42]. the first draft of the manuscript; GP, RBY, BB, YKN and JH revised the manuscript. Coulibaly et al. BMC Medicine (2018) 16:81 Page 9 of 10 All authors read and approved the final version of the manuscript. Merck KGaA, 11. World Health Organization. Preventive chemotherapy in human Darmstadt, Germany reviewed the manuscript for medical accuracy only before helminthiasis: coordinated use of anthelminthic drugs in control journal submission. The authors are fully responsible for the content of this interventions: a manual for health professionals and programme managers. manuscript, and the views and opinions described in the publication reflect solely Geneva: WHO; 2006. those of the authors. 12. Lelo AE, Mburu DN, Magoma GN, Mungai BN, Kihara JH, Mwangi IN, Maina GM, Kinuthia JM, Mutuku MW, Loker ES, et al. No apparent reduction in Ethics approval and consent to participate schistosome burden or genetic diversity following four years of school- Approval was obtained by the Comité d’Ethique et de la Recherche of the based mass drug administration in Mwea, Central Kenya, a heavy Ministry of Health in Côte d’Ivoire (CNER, reference no. 037/MSLS/CNER-dkn) transmission area. PLoS Negl Trop Dis. 2014;8:e3221. and the Ethical Committee of Northwestern and Central Switzerland (EKNZ, 13. Leenstra T, Coutinho HM, Acosta LP, Langdon GC, Su L, Olveda RM, reference no. 162/2014). McGarvey ST, Kurtis JD, Friedman JF. Schistosoma japonicum reinfection Information provided to communities and written informed consent and assent after praziquantel treatment causes anemia associated with inflammation. procedures were conducted as described elsewhere [24]. Infect Immun. 2006;74:6398–407. 14. Stothard JR, Gabrielli AF. Schistosomiasis in African infants and preschool Consent for publication children: to treat or not to treat? Trends Parasitol. 2007;23:83–6. Consent to publish from the participant (or legal parent or guardian for children) 15. Stothard JR, Sousa-Figueiredo JC, Betson M, Bustinduy A, Reinhard-Rupp J. to report individual patient data was obtained. Schistosomiasis in African infants and preschool children: let them now be treated! Trends Parasitol. 2013;29:197–205. Competing interests 16. Coulibaly JT, N'Gbesso YK, Knopp S, Keiser J, N'Goran EK, Utzinger J. 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