BMJ
Confidential: For Review Only
Efficacy of recommended drugs against soil -transmitted helminths: systematic review and network meta-analysis
Journal: BMJ
Manuscript ID BMJ.2017.037871.R1
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the Author: 26-Jul-2017
Complete List of Authors: Moser, Wendelin; Schweizerisches Tropen- und Public Health-Institut Schindler, Christian; Swiss Tropical and Public Health Institute, ; University of Basel, Keiser, Jennifer; Swiss Tropical and Public Health Institute, Department of Medical Parasitology and Infection Biology; University of Basel,
Soil-transmitted helminthiasis, albendazole, mebendazole, hookworm, Keywords: Ascaris lumbricoides, Trichuris trichiura, cure rate, egg reduction rate
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1 2 3 1 Efficacy of recommended drugs against soil-transmitted helminths: systematic review 4 5 2 and network meta-analysis 6 7 3 8 4 WendelinConfidential: Moser, Christian Schindler, Jennifer For Keise r Review Only 9
10 5 11 Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health 12 6 13 7 Institute, P.O. Box, CH 4002 Basel, Switzerland and University of Basel P.O. Box, CH 4003 14
15 8 Basel, Switzerland, Wendelin Moser, PhD student and Jennifer Keiser, Professor, Department 16 9 of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, P.O. Box, CH 17 18 10 4002 Basel and University of Basel, P.O. Box, CH 4002 Basel, Switzerland, Christian Schindler 19 20 11 Professor 21 12 22 23 13 24
25 14 26 15 27 28 16 29 17 30 31 18 32 33 19 34 20 35 36 21 Correspondence to: 37 Jennifer Keiser, [email protected] 38 22 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1
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1 2 3 23 Abstract 4 5 24 Objective 6 7 25 To evaluate efficacies of anthelmintic drugs used against soil transmitted helminthiasis in terms 8 26 of Confidential:cure rates (CR) and egg reduction rates For (ERR). Review Only 9 10 27 Design 11 Systematic review and network meta analysis 12 28 13 29 Data Sources 14 15 30 PubMed , ISI Web of Science, Embase, ScienceDirect, the Cochrane Central Register of Clinical 16 31 Trials and the World Health Organization Library Database from 1960 until 31 December 2016. 17 18 32 Study Selection 19 20 33 Randomised controlled trials evaluating the efficacy of a single dose regimen of albendazole, 21 34 mebendazole, levamisole and pyrantel pamoate against Ascaris lumbricoides , hookworm 22 23 35 (Necator americanus and Ancylostoma duodenale ) and Trichuris trichiura. The primary outcome 24 included CRs analysed by network meta analysis using mixed logistic regression models and 25 36 26 37 the ERRs using mixed linear models. 27 28 38 Results 29 39 56 and 45 RCTs were included in the analysis of CRs and ERRs, respectively. All drugs were 30 31 40 highly efficacious against A. lumbricoides . Albendazole showed the highest efficacy against 32 33 41 hookworm with a CR of 79.5% (95% confidence interval, 71.5 to 85.6) and a ERR of 89.6% 34 42 (81.9 to 97.3). Only low efficacy was observed for all drugs against T. trichiura , with 35 36 43 mebendazole demonstrating the highest CR of 42.1% (25.9 to 60.2) and ERR of 66.0% (54.6 to 37 77.3). Albendazole showed significantly reduced ERR and CR against T. trichiura over time. 38 44 39 45 Conclusions 40 41 46 The four recommended drugs show limitations in their efficacy profile, while only albendazole 42 47 revealed good efficacy against hookworm, all drugs had low efficacy against T. trichiura . Our 43 44 48 finding indicate the need for strengthening drug discovery efforts with a special focus on drugs 45 46 49 against T. trichiura . 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2
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1 2 3 50 What is already known on this topic 4 5 51 The current strategy against STHs is preventive chemotherapy mainly using albendazole, 6 7 52 mebendazole, and to a lesser extent levamisole and pyrantel pamoate. 8 53 A Confidential: previous systematic review presented For summary Review estimates on cure ratesOnly of these major 9 10 54 anthelminthics based on a small number of randomised controlled trials. 11
12 55 13 56 What this study adds 14 15 57 We provide up to date estimates on cure rates and for the first time on egg reduction rates 16 58 using network meta analysis. Albendazole and mebendazole reveal shortcoming in their 17 18 59 efficacy profile, e.g. mebendazole has low efficacy against hookworm (cure rate of 32.5%, egg 19 20 60 reduction rate of 61.0%) and both show low performance against Trichuris trichiura (egg 21 61 reduction rates of 49.9% and 66.0% for albendazole and mebendazole, respectively). 22 23 62 Alarmingly, our date show that efficacy of the most commonly used drugs for preventive 24 chemotherapy albendazole and mebendazole decreased over the past decades against T. 25 63 26 64 trichiura . 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3
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1 2 3 65 Introduction 4 5 66 Soil transmitted helminthiasis is caused by infections with the nematodic worms Ascaris 6 7 67 lumbricoides , the hookworms Necator americanus and Ancylostoma duodenale and Trichuris 8 68 trichiuraConfidential:. An estimated 5.3 billion of people For are at risk, Review while 1.5 billion are infectedOnly with at least 9 10 69 one of the soil transmitted helminths (STHs) [1]. Despite a global decline in infections, Asia 11 remains with highest prevalence, followed by Sub Saharan Africa and Latin America [1]. STH 12 70 13 71 infections affect particularly pre and school aged children, living under poor conditions in the 14 15 72 least developed countries, where households lack adequate facilities and clean water. Morbidity 16 73 correlates with the number of worms harboured by infected individuals. In more detail, while 17 18 74 light infections commonly remain asymptomatic, moderate and heavy infections cause severe 19 20 75 morbidity [2] including growth stunting, intellectual retardation, cognitive and educational 21 76 deficits, malnutrition and iron deficiency anaemia [3]. In 2015, the global burden of infections 22 23 77 with STH has been estimated at 3.4 million disability adjusted life years (DALYs) [4]. 24 The goal of the World Health Organization (WHO) is to reduce the prevalence of moderate and 25 78 26 79 heavy STH infections in pre and school aged children to a level below 1% by 2020 [5–7]. To 27 28 80 achieve this goal, children in endemic areas are regularly treated in so called preventive 29 81 chemotherapy programs [5,6,8]. In more detail, in 2015 about 573 million children received 30 31 82 preventive chemotherapy against STHs, corresponding to a global coverage of 59.5% [9]. The 32 33 83 ultimate target is to cover at least 75% of school aged children in need for treatment [6]. 34 84 Albendazole, mebendazole, levamisole and pyrantel pamoate are currently on the WHO list of 35 36 85 essential medicines for the treatment of STH infections [6,7], while the two benzimidazoles 37 albendazole and mebendazole are the most widely used drugs in preventive chemotherapy 38 86 39 87 programs against STH infections [8]. 40 41 88 The efficacy of albendazole, mebendazole and pyrantel pamoate has been assessed in a 42 89 systematic review for different dose regimens [10] and by means of meta analysis using 43 44 90 randomised controlled trials (RCTs) for single doses [11]. Albendazole, mebendazole and 45 46 91 pyrantel pamoate revealed high efficacy against A. lumbricoides in terms of cure rates (CR). 47 92 Only albendazole was found to be efficacious in single dose regimen against hookworm (CR 48 49 93 72%). Both albendazole and mebendazole indicated unsatisfactory results against T. trichiura at 50 51 94 single doses with CRs of 28% and 36%, respectively [11]. Concerningly, recent results from 52 95 randomised trials on Pemba revealed even lower CRs of albendazole (2.6%) and mebendazole 53 54 96 (11.8%) against T. trichiura [12]. 55 97 The aim of this review is to update the findings from the two systematic reviews [10,11] 56 57 98 including new evidence, by applying network meta analysis methodology. The comparison of 58 59 60 4
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1 2 3 99 intervention effects among RCTs using conventional meta analysis is limited by the constraint 4 5 100 that only drugs tested in the same study can be compared [11]. In contrast, network meta 6 7 101 analysis draws strength from direct and indirect comparisons via common comparators (e.g. 8 102 placebo).Confidential: Furthermore, multiple drugs canFor be compar Reviewed and ranked [13–17]. Only In addition, we 9 10 103 meta analysed for the first time egg reduction rates (ERR), the standard key drug efficacy 11 parameter [18]. Our results provide current evidence on anthelminthic drug efficacy, which are 12 104 13 105 of considerable relevance to policy makers since they call for an adaptation of current treatment 14 15 106 guidelines. 16 107 17 18 108 Methods 19 20 109 Search strategy and selection criteria 21 110 This review and meta analysis is based on the Preferred Reporting Items for Systematic 22 23 111 Reviews and Meta Analysis (PRISMA) extension statement for network meta analysis [19] . The 24 study protocol is available in the appendix. We conducted an electronic literature search on 25 112 26 113 PubMed , ISI Web of Science, Embase, ScienceDirect, the Cochrane Central Register of Clinical 27 28 114 trials and the World Health Organization Library Database. All studies from 1960 until 31 29 115 December 2016 were considered. The search was not restricted to any language and in case of 30 31 116 non English articles, native speakers were consulted for full text translations. The triple MeSH 32 33 117 search terms included “albendazole”, “mebendazole”, “levamisole” and “pyrantel pamoate” 34 118 combined with either “trial”, “study” or “case report” and “ Ascaris lumbricoides ”, “ascariasis, 35 36 119 “hookworm”, “ Ancylostoma duodenale ”, “ Necator americanus ”, “ Trichuris trichiura ”, “trichuriasis” 37 or “soil transmitted helminths” (appendix table S1). 38 120 39 121 Only level 1 RCTs (https://www.elsevier.com/__data/promis_misc/Levels_of_Evidence.pdf) 40 41 122 were eligible, which reported the efficacy against A. lumbricoides , hookworm and T. trichiura in 42 123 terms of cure rates (CR), egg reduction rates (ERR) or both outcome measures. RCTs, which 43 44 124 included at least one treatment arm of the currently recommended [7,10,20] single dose 45 46 125 regimens of albendazole (400 mg), mebendazole (500 mg), levamisole (80 mg or 2.5 mg/kg) or 47 126 pyrantel pamoate (10 mg/kg) were selected for this review. Studies were included without any 48 49 127 restrictions on age. Studies were excluded, if they were not RCTs; used different drug regimens; 50 51 128 combined different drugs; or if the follow up was shorter than one or longer than 6 weeks. 52 129 53 54 130 Patient involvement 55 131 There was no patient involvement in this study. 56 57 132 58 59 60 5
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1 2 3 133 Data extraction and assessment of risk bias 4 5 134 From each eligible RCT following information was extracted: number of infected participants at 6 7 135 baseline, number of cured participants at follow up, mean number of eggs at baseline, mean 8 136 numberConfidential: of eggs at follow up, percentage Forof egg redu Reviewction, measure of central Only tendency (MCT, 9 10 137 arithmetic, geometric or not described), percentage of egg reduction, information on the number 11 of treatment arms, number of eligible treatment arms, year of publication, country, diagnostic 12 138 13 139 method, age range and time between treatment and follow up. 14 15 140 Two independent reviewers (WM and JK) screened titles and abstracts for potential studies. In 16 141 case the articles met the inclusion criteria, the entire manuscripts were scrutinized and for 17 18 142 eligible trials the data was extracted independently by the same reviewers. All included RCTs 19 20 143 were assessed for the quality by two different methodologies i) as described by Jadad and 21 144 colleagues [21] with scores ranging between 1 (lowest level) and 5 (highest level) and ii) 22 23 145 according to the Cochrane Collaboration Handbook (appendix table S2) [22]. The latter criteria 24 assess studies for risk of bias in six different domains: random sequence generation, allocation 25 146 26 147 concealment, blinding of participants and personnel, blinding of outcome assessment, 27 28 148 incomplete outcome data and selective reporting. Each domain is categorised into low risk, high 29 149 risk or unclear risk of bias. In case of discrepancies for extracting data or scoring of the study 30 31 150 quality, a third person was involved and the results discussed until consensus was reached. 32 33 151 34 152 Data synthesis and statistical analysis 35 36 153 The advantage of a network meta analysis is the simultaneous combination of direct and 37 indirect estimate of the treatment effect in one analysis. In data from clinical trials with direct 38 154 39 155 estimates for drug A versus B and other trials comparing A versus C, the relative treatment 40 41 156 effect of B versus C can be estimated and all three drugs can be ranked [13,23]. To illustrate the 42 157 network geometry, a separate plot for CR and ERRs was constructed (figure 1) [23]. For the 43 44 158 network meta analysis of the CRs, we used a method proposed by Kessels and colleagues [24]. 45 46 159 The method consists in rebuilding the original data sets based on sample sizes and case 47 160 numbers retrieved from the publications. All data sets from studies with one, two or more 48 49 161 treatment arms were then pooled and mixed logistic regression models were applied to the final 50 51 162 pooled dataset. With this method even studies with only one eligible treatment arm can be 52 163 included. The models included treatment as a fixed factor, random effects for studies and for 53 54 164 treatment arms within studies. To mimic meta regression analysis, we additionally included the 55 165 respective regressor variable and its interactions with the treatments. 56 57 58 59 60 6
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1 2 3 166 All ERRs were directly taken from the articles. Mixed linear models were used for the meta 4 5 167 analysis of the ERRs. These models included the fixed factors treatment, infection intensity 6 7 168 (dichotomized as above vs. below median of baseline egg counts), MCT (arithmetic mean, 8 169 geometricConfidential: mean or not described) and randomFor effects Review for studies. Baseline Only infection intensity 9 10 170 was considered to increase precision and to achieve approximate normality of regression 11 residuals. 12 171 13 172 Average CRs and ERRs (table 1) per treatment derived from the underlying regression models 14 15 173 as marginal estimates. One sided 95% confidence intervals (CI) are given, if the limits of the 16 174 respective 2 sided interval exceeded 0 or 100%. One to one comparisons of CRs and ERRs 17 18 175 were done by looking at the differences of the respective regression coefficients (figure 2). In 19 20 176 the case of CRs these differences were converted into odds ratios (OR) by exponentiation. We 21 177 also conducted a simple, pairwise meta analysis of CRs for the one to one comparison using 22 23 178 the command ‘metan’ of Stata. The respective summary ORs, I squared and tau squared 24 statistics are provided in the appendix (table S4, figure S2), where they are compared with the 25 179 26 180 corresponding OR estimates from network meta analysis. 27 28 181 In a second stage, analysis for CRs and ERRs were stratified according to continent, place of 29 182 the study, sensitivity of diagnostic method, quality of the study, length of follow up, baseline 30 31 183 infection intensity and year of publication (details are described in appendix table S5 S11). By 32 33 184 letting the treatment interact in the mixed regression model separately with study size and year, 34 185 we obtained estimated CRs and ERRs for small (n=30) and large (n=300, appendix table S12) 35 36 186 studies and for years 1995 and 2015 (appendix table S13), to address publication bias and 37 evaluate the potential trends of efficacy over time. 38 187 39 188 The consistency between OR estimates from direct and indirect comparisons was assessed by 40 41 189 adding indicator variables for the two respective parallel treatments to the mixed logistic 42 190 regression models. The difference of their regression coefficients was exponentiated, to obtain 43 44 191 the ratio between the OR from direct and the one from indirect comparison (referred to as ratio 45 46 192 of odds ratios (ROR)). The two variables were obtained as the product of the respective 47 193 treatment indicator variable and the indicator variable for studies having compared both 48 49 194 treatments directly. The RORs and their 95% CI, measuring inconsistency between direct and 50 51 195 indirect estimates, are displayed in a forest plot in the appendix (figure S3). All analysis were 52 196 done using STATA version 14.0 (Stata Corporation; College Station, USA). 53 54 197 55 198 Results 56 57 199 Characteristics of included studies and bias assessment 58 59 60 7
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1 2 3 200 Overall 301 potential studies including albendazole, mebendazole, levamisole and pyrantel 4 5 201 pamoate for treating STH infections were identified in the literature search (figure 1). 245 6 7 202 studies were excluded; 82 were not randomised, 87 used a different dose regimen, 37 studies 8 203 hadConfidential: a longer follow up than 6 weeks, 23 Forused only dReviewrug combinations and Onlyfrom 16 studies the 9 10 204 data were not extractable (appendix table S3). From the remaining 56 studies, one only 11 presented only ERRs, while 10 did not report the ERRs. A total of 44 studies had CR data for A. 12 205 13 206 lumbricoides , while 38 for hookworm and T. trichiura , respectively. For analysing ERRs 34 14 15 207 studies were included for hookworm and 33 for A. lumbricoides and T. trichiura . Studies 16 208 including placebo plus albendazole and albendazole plus mebendazole were most common. 17 18 209 We did not find any evidence of inconsistencies between the ORs of CRs from direct and 19 20 210 indirect comparisons for the different pairs of drugs (appendix figure S3). 21 211 The percentages of studies in the lowest categories of bias risk were 41.1% for random 22 23 212 sequence generation, 30.4% for allocation concealment and 51.8% for incomplete outcome 24 data. The percentage of studies in the highest category of bias risk was largest for blinding of 25 213 26 214 participants and personnel (25.6%). The category of unclear risk was largest in all criteria other 27 28 215 than “incomplete outcome data”. This was especially pronounced among studies published 29 216 before the year 2000 (appendix table S14). 30 31 217 32 A. lumbricoides 33 218 Drug efficacy against 34 219 We evaluated 44 studies with an average Jadad score of 2.5 and a total number of 7273 A. 35 36 220 lumbricoides positive participants (detailed numbers are presented in the appendix table S15) to 37 evaluate the effect of the four anthelminthics against A. lumbricoides (figure 1). Pooled 38 221 39 222 estimates were based on 19 studies with only one treatment [25–43], 22 studies including two 40 41 223 [12,43–63] and three studies with three eligible treatments [64–66]. 42 224 The four anthelminthics investigated showed highly significant superiority (all p<0.001) over 43 44 225 placebo, whose average CR was 12.7% (95% CI; 6.7 to 22.7, table 1). Estimated average CRs 45 46 226 were 95.7% (93.2 to 97.3) for albendazole, 96.2% (92.3 to 98.1) for mebendazole, 97.3% (84.2 47 227 to 99.6) for levamisole and 92.6% (85.6 to 96.3) for pyrantel pamoate. There were no significant 48 49 228 differences among the four treatments in the one to one comparison (figure 2). 50 51 229 Thirty three studies reported ERRs [12,25,26,29,31,32,34–38,43–49,51,52,54–62,64,66,67] 52 230 (figure 3). All treatment arms revealed significantly higher ERRs (p<0.001) compared to placebo 53 54 231 with 20.7% (14.7 to 26.7, table 1), while there were no significant differences between the ERRs 55 232 of the four treatments (figure 2). Highest ERR of 98.5% (94.9 to 100.0) was demonstrated for 56 57 58 59 60 8
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1 2 3 233 albendazole, followed by 98.0% (94.0 to 100.0) for mebendazole, 96.4% (82.3 to 100.0) for 4 5 234 levamisole and 94.3% (88.3 to 100.0) for pyrantel pamoate. 6 7 235 8 236 DrugConfidential: efficacy against hookworm For Review Only 9 10 237 For estimating the drug efficacy against hookworm, data from 7178 individuals from 38 studies 11 (table 1, appendix table S15) with an average Jadad score of 2.8 were considered. Pooled 12 238 13 239 estimates included 12 studies with one treatment [25,26,30–32,34,36,38,42,43,68], 21 studies 14 15 240 with two treatments [12,43,44,46–58,62,63,68–70] and five studies with three treatments [64– 16 241 66,71,72]. 17 18 242 For placebo a CR of 15.2% (9.3 to 23.9, table 1) was calculated. The CR of levamisole (10.3%; 19 20 243 2.4 to 35.2) did not significantly differ from placebo. A significantly higher CR compared to 21 244 placebo was observed for albendazole (79.5%; 71.5 to 85.6, p<0.001), mebendazole (32.5%; 22 23 245 20.8 to 46.9, p=0.011) and pyrantel pamoate (49.8%; 29.5 to 70.1, p=0.001). The one to one 24 comparison of CRs showed a strongly increased odds of being cured after the administration of 25 246 26 247 albendazole compared to mebendazole (p<0.001), levamisole (p<0.001) and pyrantel pamoate 27 28 248 (p=0.005, figure 2). Levamisole exhibited significantly lower odds in comparison to pyrantel 29 249 pamoate (p=0.016). 30 31 250 Data from 34 studies [12,25,26,30–32,34,36,38,43,44,46–49,51,52,54–58,62,64,66–72] (figure 32 33 251 3) was used to determine an ERR of 16.2% (5.3 to 27.1) for placebo, which was significantly 34 252 lower than the ERRs of all treatments (table 1). Albendazole reached the highest average ERR 35 36 253 with 89.6% (81.9 to 97.3), followed by pyrantel pamoate (71.9%; 54.7 to 89.0), levamisole 37 (61.8%; 30.3 to 93.3) and mebendazole (61.0%; 52.0 to 69.9). The one to one comparison 38 254 39 255 revealed a significant difference between albendazole and mebendazole (p<0.001, figure 2). 40 41 256 42 257 Drug efficacy against T. trichiura 43 44 258 38 studies (average Jadad score of 2.6) including 8841 T. trichiura positive participants (table 1, 45 46 259 appendix table S15) were used for analysing the CRs of the four drugs against T. trichiura . 47 260 Pooled estimates were based on 16 trials with one treatment [25,26,29–33,35– 48 49 261 38,40,42,43,73,74], 19 studies including two treatments [12,43,44,46–51,53–59,62,63,75] and 50 51 262 three studies three with treatments [64–66]. 52 263 We determined a CR of 8.6% (4.1 to 17.1) for treatment with placebo, which was not 53 54 264 significantly different from the CRs of levamisole (29.5%; 6.1 to 72.9) and pyrantel pamoate 55 265 (20.2%; 7.3 to 44.7, table 1). Albendazole and mebendazole showed significantly higher efficacy 56 57 266 than placebo with estimated CRs of 30.7% (21.0 to 42.5, p<0.001) and 42.1% (25.9 to 60.3, 58 59 60 9
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1 2 3 267 p<0.001), respectively. No significant differences among the CRs of the four treatments were 4 5 268 found comparing them one to one (figure 2). 6 7 269 Thirty three studies were used for analysing the ERRs [12,25,26,29,31,35–38,43,44,46– 8 270 49,51,54–58,62–64,66,67,73–76]Confidential: (figure For 3). For plac Reviewebo, an average ERR Only of 19.2% (6.9 to 9 10 271 31.4) was calculated, which was significantly lower than the ERRs of albendazole (p<0.002), 11 mebendazole (p<0.001) and pyrantel pamoate (p=0.008) but comparable with the one of 12 272 13 273 levamisole (28.3%; 6.7 to 49.8, table 1). The highest ERR of 66.0% (54.6 to 77.3) was shown 14 15 274 for mebendazole, which was significantly higher than the ERRs of albendazole (49.9%; 39.6 to 16 275 60.6, p<0.001) and levamisole in the one to one comparison (figure 2). For pyrantel pamoate an 17 18 276 ERR of 47.5% (25.5 to 69.6) was estimated. 19 20 277 21 278 Discussion 22 23 279 Summary of key findings 24 We present up to date evidence on the efficacy of the four recommended anthelminthic drugs, 25 280 26 281 albendazole, mebendazole and the less widely used levamisole and pyrantel pamoate, based 27 28 282 on a thorough review of the literature, using for the first time a network meta analysis. In 29 283 addition, in this review, we present first meta analysed summary estimates on ERR, a key 30 31 284 parameter on helminth drug efficacy [18]. 32 33 285 We confirmed the high efficacy, both in terms of CR and ERR, of the most widely used 34 286 anthelminthic drug albendazole against A. lumbricoides and hookworm. With about 134 million 35 36 287 distributed doses in 2015, mebendazole is the second most widely administered drug for 37 infections with STHs [77]. Our review validates the high efficacy of mebendazole against A. 38 288 39 289 lumbricoides and confirms its low activity against hookworm . Levamisole and pyrantel pamoate 40 41 290 showed high efficacy against A. lumbricoides and pyrantel pamoate moderate efficacy against 42 291 hookworm. The weakness of the currently available drugs is their low efficacy against T. 43 44 292 trichiura, of which mebendazole showed the highest performance. This finding emphasizes the 45 46 293 urgent need of new drugs with higher efficacy against T. trichiura for preventive chemotherapy 47 294 programs [10,11]. 48 49 295 50 Strength and limitations 51 296 52 297 The main strength of this study was the innovative data analysis including the two measures of 53 54 298 helminth drug efficacy, CRs and ERRs. By applying a network meta analysis we could increase 55 299 the evidence by including the efficacy results of a higher number of randomised controlled trials 56 57 58 59 60 10
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1 2 3 300 compared to a previous meta analysis [11]. Furthermore, the model from Kessels and 4 5 301 colleagues [24] allowed the inclusion of studies with only one eligible treatment arm. 6 7 302 The reviewed RCTs cover the past 50 years of research in this field. This inevitably leads to 8 303 hugeConfidential: qualitative differences among the studies,For whi chReview reflects the main challenge Only and limitation 9 10 304 of our analyses. There are major disparities among the included studies, which affect drug 11 efficacy, for instance diagnostic method, baseline infection intensity, statistical analyses and 12 305 13 306 sample size. 14 15 307 In more detail, the diagnostic methods used by the reviewed studies ranged from lowest 16 308 sensitivity methods, such as the direct smear, up to multiple Kato Katz thick smears, which has 17 18 309 a reasonable sensitivity. The sensitivity of diagnostic methods is associated with the baseline 19 20 310 infection intensity, i.e. Kato Katz has a reduced sensitivity for low egg counts [78]. Both, the 21 311 diagnostic method and baseline infection intensity directly influence CRs and ERRs [79–81]. 22 23 312 While the efficacy results stratified by infection intensities did not show a clear tendency in this 24 review, the sensitivity of the diagnostic method had an impact. After stratifying the efficacy by 25 313 26 314 low and moderate sensitivity of the diagnostic method, albendazole showed significantly 27 28 315 decreased CRs against A. lumbricoides (p=0.044) and hookworm (p=0.023). However, we 29 316 cannot explain the increase in ERR of albendazole (p=0.024) against T. trichiura (appendix 30 31 317 table S6). 32 33 318 An additional limitation of the diagnostic methods (Kato Katz, McMaster etc.) is their incapability 34 319 to distinguish between the human hookworm species A. duodenale and N. americanus . Only 35 36 320 very few included studies were reporting hookworm species specific efficacies. The overall 37 efficacies might differ according to the hookworm species. For example, while both hookworm 38 321 39 322 species are somewhat susceptible to pyrantel pamoate, N. americanus is reported to be less 40 41 323 sensitive [82]. The commonly higher abundance of N. americanus in Africa compared to Asia 42 324 [83], might have led to the borderline significant difference (p=0.053) in CRs of pyrantel 43 44 325 pamoate in Asia (64%) and Africa (27%, appendix table S4). 45 46 326 The network meta analysis for ERRs was limited by the lack of precision estimates in most of 47 327 the studies and by the different choices of the MCT (arithmetic or geometric mean). There is an 48 49 328 ongoing debate about advantages and disadvantages of the two systematically different means, 50 51 329 while WHO now recommends the arithmetic mean [18,86]. Few, mainly older studies did not 52 330 even report the MCTs, which they have used. In the absence of standard errors and confidence 53 54 331 intervals, we could not optimize the precision of meta analytic estimates. Moreover, as 55 332 arithmetic and geometric means are systematically different, we had to adjust analyses of ERRs 56 57 333 for the type of mean. 58 59 60 11
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1 2 3 334 To address potential publication bias, results of smaller and larger studies were compared in an 4 5 335 interaction analysis. We might have slightly overestimated the effect of albendazole against 6 7 336 hookworm, where the CR showed an almost significant negative association with study size 8 337 (P=0.053).Confidential: While the CRs of A. lumbricoides For showed Review positive or stable associations Only with study 9 10 338 size for all treatments, those of T. trichiura after treatment with albendazole and mebendazole 11 slightly decreased with increasing study size, yet not significantly. Thus, we did not find 12 339 13 340 consistent evidence of publication bias (appendix table S11). The small number of available and 14 15 341 eligible studies for levamisole is another limitation of our work. Nonetheless, we present the first 16 342 pooled efficacy estimates for levamisole against hookworm, revealing a low CR of 10.3% and 17 18 343 an ERR of 61.8%, contrasting the fact that the drug is recommended for the treatment of 19 20 344 hookworm [3,11]. 21 345 22 23 346 Clinical implications 24 Anthelmintic drug efficacy is defined by CRs and ERR. For ranking the efficacy of the drugs for 25 347 26 348 each helminth species both parameters have to be taken into consideration and the ranking was 27 28 349 done qualitatively. Against A. lumbricoides no significant differences were found and all drugs 29 350 revealed high efficacy. Albendazole ranked first against hookworm with significant higher CRs, 30 31 351 followed by pyrantel pamoate and last levamisole and mebendazole. With regard to T. trichiura 32 33 352 infections mebendazole reached the highest, yet only moderate efficacy, with significantly 34 353 higher ERRs compared to the second ranking albendazole. Levamisole and pyrantel pamoate 35 36 354 showed low CRs, which did not even differ from placebo. 37 Moreover, after stratification by year, we found a significant decrease in CRs of albendazole 38 355 39 356 against T. trichiura (p=0.039) and a remarkable reduction against hookworm (appendix table 40 41 357 S10). These results were even more pronounced in the interaction analysis. The CR of 42 358 albendazole against T. trichiura remained significant lower (p=0.027). Furthermore, ERRs of 43 44 359 albendazole (p=0.027) against hookworm and of albendazole (p=0.049) and mebendazole 45 46 360 (p=0.014) against T. trichiura (appendix table S12) significantly decreased over time, which 47 361 might be attributed to drug resistance [84]. Several studies correlated reduced benzimidazole 48 49 362 efficacies [58,64,70–72,85] with emerging resistance, however confounding factors related to 50 51 363 statistical analysis, diagnostic methodology, drug regimen, parasite or host characteristics might 52 364 also have influenced the results [18]. In veterinary medicine, frequently repeated treatment with 53 54 365 benzimidazoles caused resistance in numerous nematode species [86–88]. However, 55 366 resistance to anthelminthics in human medicine has not yet been demonstrated. 56 57 367 58 59 60 12
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1 2 3 368 Conclusion 4 5 369 Our data confirms that the most widely used drugs albendazole and mebendazole reveal 6 7 370 shortcomings in their efficacy profile, especially against hookworm and T. trichiura . Alarmingly, 8 371 theConfidential: efficacy of albendazole and mebendazole For has decReviewreased over time. TakingOnly into account, 9 10 372 that the two most widely distributed drugs in preventive chemotherapy albendazole and 11 mebendazole are used since almost 50 years the threat of resistance is real and immediate. For 12 373 13 374 a careful monitoring of potential resistance, our summary estimates might help to revise current 14 15 375 efficacy reference figures [18]. 16 376 There is an eminent need to fill the empty anthelminthic drug discovery pipeline and strengthen 17 18 377 drug discovery efforts for STH . Alternatively, old and new drugs, e.g. tribendimidine, oxantel 19 20 378 pamoate, moxidectin or ivermectin with different efficacy profiles could be used in combination 21 379 with the recommended drugs to successfully tackle all three soil transmitted helminths [12,89]. 22 23 380 We would like to emphasize that only with an integrated approach combining improved 24 sanitation, health education [90–92] and scaling up of research for new anthelminthic drugs and 25 381 26 382 use of drug combinations for preventive chemotherapy will achieve the ultimate goal to control 27 28 383 STH infections. Furthermore, future RCTs should follow a harmonized design in order to reduce 29 384 confounders as suggested by WHO [18], which will yield improved summary estimates of 30 31 385 anthelminthic drug efficacy. 32 33 386 34 387 Contributors: WM, CS and JK conceptualized and designed the study. WM and JK conducted 35 36 388 the study. WM and CS analysed and interpreted the data. WM and JK wrote the first draft of the 37 paper and CS revised the manuscript. 38 389 39 390 Role of funding source: This review was supported by the unrestricted grant from the Swiss 40 41 391 National Science Foundation. 42 392 Competing interests: All authors have completed the ICMJE uniform disclosure form at 43 44 393 www.icmje.org/coi_disclosure.pdf and declare: this work was founded by the Swiss National 45 46 394 Science Foundation; all other authors declare no financial relationships with any organisations 47 395 that might have an interest in the submitted work in the previous three years, and no other 48 49 396 relationships or activities that could appear to have influenced the submitted work. 50 Ethical approval: Not required. 51 397 52 398 Data sharing: No additional data available. 53 54 399 Transparency: The lead authors (WM and JK) affirms that the manuscript is an honest, 55 400 accurate, and transparent account of the study being reported; that no important aspects of the 56 57 58 59 60 13
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1 2 3 401 study have been omitted; and that any discrepancies from the study as planned (and, if 4 5 402 relevant, registered) have been explained. 6 7 403 This is an Open Access article distributed in accordance with the Creative Commons Attribution 8 404 NonConfidential: Commercial (CC BY NC 3.0) license, For which permit Reviews others to distribute, Only remix, adapt, build 9 10 405 upon this work non commercially, and license their derivative works on different terms, provided 11 the original work is properly cited and the use is non commercial. See: 12 406 13 407 http://creativecommons.org/licenses/ by nc/3.0/. 14 408 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 14
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1 2 3 651 Figure 1. Flowchart and network showing the procedure for the identification of the 4 5 652 relevant publications. 6 7 653 Each treatment is indicated by a circular node whose size indicates the amount of respective 8 654 evidence.Confidential: Numbers in brackets behind theFor treatments Review indicate the number Only of pooled studies 9 10 655 with only one eligible treatment arm. The size and number in the edges indicates the number of 11 direct treatment comparisons within the same study. 12 656 13 657 14 15 658 Figure 2. Drug comparison based on the network meta-analysis 16 659 Odds ratios for the one to one comparisons of the cure rates and difference for the one to one 17 18 660 comparisons of the egg reduction rates based on the network meta analysis for albendazole 19 20 661 (Alb), mebendazole (Meb), levamisole (Lev) and pyrantel pamoate (PyP) against Ascaris 21 662 lumbricoides , hookworm and Trichuris trichiura (Significance level for odds ratios and 22 23 663 differences *p<0.05, **p<0.01 and ***p<0.001). 24
25 664 26 665 Figure 3. Egg reduction rates of albendazole, mebendazole, levamisole and pyrantel 27 28 666 pamoate 29 667 Median, third quartile interval (light grey), second quartile interval (dark grey) and individual 30 31 668 study specific egg reduction rates (ERR, black dots) under placebo (Plc), albendazole (Alb), 32 33 669 mebendazole (Meb), levamisole (Lev) and pyrantel pamoate (PyP) against Ascaris 34 670 lumbricoides , hookworm and Trichuris trichiura . Negative values of ERRs were set to zero in 35 36 671 this figure. 37
38 672 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 21
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1 2 3 673 Table 1. Average cure rates (CR) and egg reduction rates (ERR) of albendazole, 4 5 674 mebendazole, levamisole and pyrantel pamoate against Ascaris lumbricoides , hookworm 6 Trichuris trichiura 7 675 and based on the network meta-analysis. 8 676 Confidential: For Review Only 9 10 Treatment Cure rates Egg reduction rates 11 No. of No. of CR 95% No. of No. of EER 95% 12 included included (%) CI included included (%) CI 13 studies participants studies participants 14 Ascaris lumbricoides 15 16 Placebo 14 842 12.7 6.7 9 525 20.7 14.7 17 22.7 26.7 18 Albendazole 34 3360 95.7*** 93.2 26 2854 98.5*** 94.9 19 97.3 100.0 20 Mebendazole 13 1548 96.2*** 92.3 13 1529 98.0*** 94.0 21 98.1 100.0 22 Levamisole 2 149 97.3*** 84.2 1 125 96.4*** 82.3 23 99.6 100.0 24 25 Pyrantel pamoate 11 1374 92.6*** 85.6 6 284 94.3*** 88.3 26 96.3 100.0 27 Total 44 7273 33 5137 28 Hookworm 29 Placebo 18 1309 15.2 9.3 14 1046 16.2 5.3 30 23.9 27.1 31 Albendazole 30 3104 79.5*** 71.5 26 2839 89.6*** 81.9 32 85.6 97.3 33 Mebendazole 14 2305 32.5* 20.8 14 2263 61.0*** 52.0 34 35 46.9 69.9 36 Levamisole 2 230 10.3 2.4 1 202 61.8* 30.3 37 35.2 93.3 38 Pyrantel pamoate 7 230 49.8** 29.5 5 144 71.9*** 54.7 39 70.1 89.0 40 Total 38 7178 34 6494 41 Trichuris trichiura 42 Placebo 11 1417 8.6 4.1 28 1049 19.2 6.9 43 17.1 31.4 44 45 Albendazole 33 4432 30.7*** 21.0 29 3407 49.9*** 39.0 46 42.5 60.6 47 Mebendazole 13 2514 42.1*** 25.9 14 2507 66.0*** 54.6 48 60.2 77.3 49 Levamisole 2 203 29.5 6.1 1 197 28.3 6.7 50 72.9 49.8 51 Pyrantel pamoate 6 275 20.2 7.3 4 158 47.5** 25.5 52 44.7 69.6 53 Total 38 8841 33 7318 54 55 677 *p<0.05, **p<0.01, ***p<0.001 for the comparison with placebo 56 678 57 58 59 60 22
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1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 Figure 1
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1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Figure 2 27 28 338x190mm (300 x 300 DPI) 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 25 of 64 BMJ
1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 218x122mm (300 x 300 DPI) 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 26 of 64
1 2 Supplementary Appendix 3 4 5 6 Efficacy of recommended drugs against soil-transmitted helminths: systematic review 7 8 Confidential:and network meta-analysis For Review Only 9 10 11 12 Moser et al. 13 14 15 16 Table of contents 17
18 19 Study protocol ...... 2 20 21 Appendix Table S1 – Search terms ...... 4 22 23 Appendix Table S2 – Study characteristics ...... 6 24 Appendix Table S3 – Excluded studies ...... 9 25 26 Appendix Table S4 – CR comparison between network and pairwise meta-analysis ...... 25 27 Appendix Table S5 – Stratification by continent ...... 26 28 29 Appendix Table S6 – Stratification by place of the study ...... 27 30 Appendix Table S7 – Stratification by sensitivity of diagnostic method ...... 28 31 32 Appendix Table S8 – Stratification by quality of the study ...... 29 33 34 Appendix Table S9 – Stratification by length of follow-up ...... 30 35 Appendix Table S10 – Stratification by baseline infection intensity ...... 31 36 37 Appendix Table S11 – Stratification by publication year ...... 32 38 Appendix Table S12 – Influenece of study size (interaction analysis) ...... 33 39 40 Appendix Table S13 – Influenece of study year (interaction analysis) ...... 34 41 Appendix Table S14 – Bias assessment ...... 35 42 43 Appendix Table S15 – Cumulative cure rates ...... 36 44 45 Appendix figure S1 – One-to-one comparison based on network meta-analysis ...... 37 46 Appendix figure S2 – Network and pairwise meta-analysis plot ...... 38 47 48 Appendix figure S3 – Inconsistency plot ...... 39 49 50 51 52 53 54 55 56 57 58 59 60 1 https://mc.manuscriptcentral.com/bmj Page 27 of 64 BMJ
1 2 Study protocol 3 4 5 6 Version 7: 01.01.2017 7 8 Confidential: For Review Only 9 Efficacy of Drugs for Preventive Chemotherapy against Soil-Transmitted Helminths: 10 Systematic Review and Network Meta-Analysis 11 12 13 14 15 Objective 16 To assesse the efficacy in terms of cure rates (CRs) and egg-reduction rates (ERR) of 17 18 albendazole (Alb), mebendazole (Meb), levamisole (Lev) and pyrantel pamoate (PyP) 19 against soil-transmitted helminths ( Ascaris lumbricoides , hookworm and Trichuris trichiura . 20 21 22 Inclusion criteria 23 24 Study type 25
26 27 Only level 1 (https://www.elsevier.com/__data/promis_misc/Levels_of_Evidence.pdf) 28 randomized controlled trials (RCTs) will be eligible for this review. The included RCTs 29 30 do not necesserally have to be placebo controlled. If a RCT contains only one eligible 31 32 treatment arm, only this one will be included for pooling the results. 33 34 35 36 Participants 37 38 • There will be no restriction on age classes and all RCT including preschool-aged 39 children, school-aged children, adolescents and adults or a mix will be included. 40 41 • If possible, we will perform sub-group analyses for each of the four drugs (e.g., 42 different continents, different time periode etc.). 43 44 45 Parasites 46 47 The review will focus on soil-transmitted helminths including: 48 • 49 Ascaris lumbricoides ; 50 • Necator americanus ; 51 52 • Ancylostoma duodenale; and 53 • 54 Trichuris trichiura 55 56 57 Drugs 58 Only RCTs using a single dose regimen will be included: 59 60 2 https://mc.manuscriptcentral.com/bmj BMJ Page 28 of 64
1 2 • albendazole (400 mg) 3 • mebendazole (500 mg) 4 5 • levamisole (80 mg or 2.5 mg/kg) 6 • 7 pyrantel pamoate (10 mg/kg) 8 Confidential: For Review Only 9 10 Diagnostic methods 11 • All different diagnostic methods will be included in the review. 12 13 14 Follow-up time 15 16 • The follow-up time will be restricted to 1-6 weeks a slight extend than the official 17 World Health Organizations suggestion of 2-3 weeks [1]. 18 19 20 Outcome measures 21 22 i) Cure rates (CR), percentage of infected participant at baseline, who got cured 23 at follow-up (free of eggs); 24 25 ii) Egg-reduction rates (ERR), percentage of reduction in mean egg counts from 26 27 baseline to follow-up, measured as arithmetic, geometric or unspecified mean. 28 29 30 31 • The CRs will be extracted from the articles and included in the database. Two 32 33 variables to calculate the CRs will be recorded: number of participants positive at 34 baseline and number of participants cured at follow-up. In case the number of positive 35 36 participants at baseline and the CR in percentage is given by the article, the number 37 of cured participants at follow-up will be calculated. 38 39 • The ERRs will be extracted from each article if available. Two variables will be 40 41 recorded: mean egg count at baseline and the percentage of reduction at follow-up. If 42 only the mean egg count at follow-up is given, the percentage will be calculated. For 43 44 each ERR the measurement of central tendency (MCT) will be noted seperatly, as 45 arithmetic or geometric mean. In case the MCT is not indicated, the ERR will be 46 47 defined as “unspecified”. 48 49 50 Publication type 51 • Full published papers will be eligible without any language restrictions. 52 53 54
55 56 Search methods 57 58 59 60 3 https://mc.manuscriptcentral.com/bmj Page 29 of 64 BMJ
1 2 3 We will search the following electronic databases: 4 5 • PubMed; 6 • 7 ISI Web of Science; 8 Confidential:• Embase For Review Only 9 10 • ScienceDirect 11 • 12 Cochrane Central Register of Clinical trials 13 • World Health Organization library database 14 15 16 There will be no restriction on language or year of publication, hence, we will search for all 17 18 publications published before the 31.12.2016. 19 20 21 All combination from the three parts will be searched, 22 e.g. “Lev” + “study” + “Trichuris trichiura” 23 24 25 Appendix Table S1 – Search terms 26 27 Summary of the keywords for the search of the electronic databases. 28 29 30 31 Anthelmitic drug Study Parasite/disease • 32 • Alb • trial Ascaris lumbricoides 33 • Meb • study • ascariasis 34 • Lev • case report • hookworm 35 • PyP • Ancylostoma duodenale 36 • Necator americanus 37 • Trichuris trichiura 38 • trichuriasis
39 • soil -transmitted helminth 40 41 42 43 Data collection 44 45 Two reviewers (WM and JK) was independently review the titles of all studies found on 46 PubMed and ISI Web of Science. If the study is considered clearly irrelevant to our meta- 47 48 analysis, the study will be excluded at this stage. From the remaining studies, the abstracts 49 will be inspected and excluded if the study is considered irrelevant. In the final stage, a full- 50 51 text examination will be done by the same two reviewers’ in an independend manner. In 52 cases of disagreement, a third reviewer will read the article and the results will be discussed 53 54 until consensus will be reached. 55 56 57 58 59 60 4 https://mc.manuscriptcentral.com/bmj BMJ Page 30 of 64
1 2 From each eligible study the following information will be recorded in a database: number of 3 infected participants at baseline, number of cured participants at follow up, mean number of 4 5 egg counts at baseline, mean number of egg counts at follow-up (or the percentage of 6 reduction from baseline to follow up), measure of central tendency, information on the 7 8 Confidential:number of treatment arms, the number For of eligible Review treatment arms, year Only of publication, 9 country, diagnostic method, age range and time between treatment and follow-up. 10 11 12 Quality assessment 13 14 Only level 1 randomized controlled trials will be included in this review 15 (https://www.elsevier.com/__data/promis_misc/Levels_of_Evidence.pdf). Addtionally, each 16 17 study will be categorized according to the Jadad score [2]. 18 19 20 Statistical analysis 21 22 For the meta-analysis of the CRs we will use a logistic regression with random effects for 23 each soil-transmitted helminth. The model was previously described by Kessels and 24 25 colleagues.[3] If a study has only one eligible treatment arm, the result will be used for 26 pooling. All treatments will be compared to Plc and in a second all treatment will be 27 28 compared in a one-to-one manner. Additional, stratification according to the publication year 29 (two categories: 1960-1999 and 2000-2016) and continent (Africa and Asia) will be done. 30 31 The ERR with a mixed linear model. Publication bias will be estimated with a stratified 32 analyse (small vs. large studies). All analysis will be done using STATA version 14.0 (Stata 33 34 Corporation; College Station, USA). 35 36 37 References 38 1 WHO. Assessing the efficacy of anthelminthic drugs against schistosomiasis and soil- 39 transmitted helminthiases. Geneva World Health Organzation 2013. 40 41 2 Halpern SH, Douglas MJ, editors. Appendix: Jadad Scale for Reporting Randomized 42 Controlled Trials. In: Evidence-based Obstetric Anesthesia . Blackwell Publishing Ltd 2005. 43 237–8. doi:10.1002/9780470988343.app1 44 45 3 Kessels AGH, ter Riet G, Puhan MA, et al. A simple regression model for network meta- 46 analysis. OA Epidemiol 2013; Jul 22 :7. 47 48
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1 2 Appendix Table S2 – Study characteristics 3 All included randomised controlled trials including the study caracteristics and quality 4 assessment in terms of Jadad score and Cochrane ris of bias assessment. 5
6 7 8
Confidential:) and For Review Only 9 10 /
11
12 T. trichiura 13 14 15
16 Publication Study (No.size treated for lumbricoides A. hookworm/ treatment Follow-up period (days) Age Sex School(S)/Community (C) Diagnostic method Jadad Random sequence generation (selectionbias) Allocation concealment (selectionbias) Blinding of participantsand personnel (performance Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selectivereporting (reportingbias) 17 Adams et al. -/-/31 Alb 28 6- M S 6 4 18 2004, South 16 ,F + + + ? ? + 19 Africa 20 Adegnika et al. 39/13/50 Alb 42 4- M S 1 3 + + ? + ? ? 21 2014, Gabon 14 ,F 22 Albonico et al. 818/1048/1138 Alb 21 6- M S 1 3 23 1994, 730/1011/1095 Meb 12 ,F + + - ? + ? 24 Tanzania 25 Albonico et al. ERR only 21 6- M S 1 1 26 1995, 12 ,F ? ? ? ? ? ? 27 Tanzania 28 Albonico et al. 103/417/369 Plc 21 6-9 M S 1 3 29 2002, 107/424/404 Meb ,F + + - ? + ? 30 Tanzania 31 Albonico et al. 138/233/227 Plc 21 6- M S 1 3 32 2003, 141/224/214 Meb 12 ,F + + - ? + ? Tanzania 125/202/197 Lev 33 Albonico et al. 135/210/346 Alb 21 SC M C 1 2 34 ? + - ? + + 2007, Nepal ,F 35 Beach et al. 62/16/86 Plc 35 5- M S 6 4 + + + ? + + 36 1999, Haiti 62/12/93 Alb 11 ,F 37 Belizario et al. 99/-/149 Alb 6- 7- M S 1 2 38 2003, 12 14 ,F + ? - ? - + 39 Philipines 40 Bell and Nassif 22/-/- Plc 8- >5 M C 6 1 ? ? ? ? ? ? 41 1971, Agypt 48/-/- PyP 10 ,F 42 Bwibo and 36/34/25 Plc 21 SC M S 1 3 43 Pamba 1982, 40/34/31 Alb ,F ? ? + ? + ? 44 Kenya 45 Chien et al. 41/41/41 Plc 28 8-9 M S 3 1 46 1989, 41/41/41 Alb ,F ? ? ? ? ? ? 47 Malaysia 48 De Clercq et -/31/- Plc 28 ≥2 M C 1 2 49 al. 1997 -/35/- Meb ,F ? ? - ? + ? 50 -/29/- PyP 51 Ekenjoku et al. 19/42/7 Meb 7 4- M S 6 2 52 2013, Nigeria 24/28/6 Lev 12 ,F - ? - ? + ? 53 31/31/6 PyP 54 El-Masry et al. 7/23/- Plc 14 NA M C 6 2 1983, Egypt 11/19/- Alb , ? ? + ? ? ? 55 F 56 Farahmandian 48/48/- PyP 21 NA M C 6 1 ? ? ? ? ? ? 57 et al. 1977, , 58 59 60 6 https://mc.manuscriptcentral.com/bmj BMJ Page 32 of 64
1 2 Iran F 3 Flohr et al. -/51/- Plc 14 7- M S 5 5 4 2007, Vietnam -/47/- Alb 11 , + + + + + + 5 F 6 Flohr et al. -/78/- Plc 14 16- M C 5 4 7 2007, Vietnam -/90/- Meb 75 , + + - + + + 8 Confidential: ForF Review Only Fox et al. 97/31/156 Plc 35 5- M S 6 5 9 + ? + ? + + 10 2005, Haiti 91/26/166 Alb 11 ,F 11 Hadju et al. 31/-/- Plc 21 6- M S 1 3 12 1996, 32/-/- PyP 10 - ? + ? + ? Indonesia 13 Ioli et al. 1987, 25/-/- Alb 7 16- M C 6 1 14 ? ? ? ? ? ? Italy 63 ,F 15 Jackson et al. ERR only 10 2- M C 4 3 16 1998, South 12 ,F + ? - + + ? 17 Africa 18 Jongsuksuntig 13/51/43 Alb 14 3- M C 1 1 19 ul et al. 1993, 17/53/37 Meb 80 ,F ? ? ? ? ? ? 20 Thailand 21 Juan et al. 35/-/19 Alb 21- 2- M C 1 2 ? ? ? ? ? ? 22 2002, Peru 30 11 ,F 23 Kale 1977, 35/27/31 Plc 42 6- M S 6 1 ? ? ? ? ? ? 24 Nigeria 64/55/63 PyP 17 ,F 25 Knopp et al. 14/39/132 Alb 21 PS M S 2 5 26 2010, 18/34/138 Meb ,F + + + + + + 27 Tanzania Legesse et al. 234/-/244 Alb 21 2- M C 1 3 28 + ? ? ? + ? 29 2002, Ethiopia 80 ,F Legesse et al. 107/-/123 Alb 21 SC M S 1 3 30 + + ? ? + ? 31 2004, Ethiopia 113/-/118 Meb ,F 32 Lubis et al. 123/-/- Alb 7 PS M S 1 2 33 2012, 106/-/- Meb ,F + ? ? ? ? ? 34 Indonesia Morgan et al. -/25/- Plc 21 6- M S 1 3 35 ? ? + ? + ? 1983, Malawi -/28/- Alb 19 ,F 36 37 Namwanje et -/-/83 Alb 21 5- M S 1 1 al. 2011, -/-/90 Meb 14 ,F ? + ? ? ? ? 38 Uganda 39 Nanivadekar 626/-/48 PyP 14- 1- M C 1 2 40 et al. 1984, 28 60 ,F ? ? ? ? + ? 41 India 42 Ndyomugyenyi 2/178/12 Alb 21 AD F C 1 2 43 et al. 2008, ? ? - ? + ? 44 Uganda 45 Nontasut et al. 48/-/- Alb 14- 6- M S 1 1 46 1989, Thailand 28 14 , ? ? ? ? - ? 47 F 48 Olds et al. 229/198/308 Plc 45 4- M C 2 5 49 1999, Africa 219/172/297 Alb 19 , + + + + + + 50 and Asia F 51 Oyediran and 24/29/29 Plc 14 8- M S 1 4 52 Oyejide 1983, 27/26/29 Alb 17 , + + + ? + + 53 Nigeria F 54 Pugh et al. -/25/- Plc 21 6- M S 1 3 55 1986, Malawi -/26/- Alb 19 , ? ? + ? ? ? 56 F Pugh et al. -/15/- Alb 21 8- M S 1 2 57 ? ? + ? ? ? 1986, Malawi 17 , 58 59 60 7 https://mc.manuscriptcentral.com/bmj Page 33 of 64 BMJ
1 2 F 3 Sacko et al. -/36/- Plc 10 4- M C 1 2 4 1999, Mali -/37/- Alb 71 ,F ? ? - ? + ? 5 -/35/- Meb Sarmah 1988, 85/-/- PyP 14 SC M S 1 1 6 ? ? ? ? ? ? 7 India ,F 8 SinniahConfidential: and 71/41/62 PyP 21 For 6- M SReview 6 1 Only 9 Sinniah 1981, 12 , ? ? ? ? ? ? 10 Malaysia F 11 Sinniah et al. 10/5/10 Plc 21 6- M S 6 1 12 1990, 56/16/52 Alb 13 , ? ? ? ? ? ? Malaysia 47/8/52 PyP F 13 Sirivichayakul -/-/33 Alb 21- 9- M C 1 1 14 et al. 2001, 28 42 ,F - - - ? ? ? 15 Thailand 16 Sorensen et 71/59/84 Alb 21 3- M C 1 1 17 al. 1996, Sri 84/67/88 Meb 15 ,F ? ? - ? ? ? 18 Lanka 19 Soukhathamm 28/89/39 Alb 21- 6- M S 2 3 20 avong et al. 30/82/43 Meb 23 12 ,F + - - ? + + 21 2012, PRD 22 Lao 23 Speich et al . 135/9/7 Plc 18- 7- M S 2 5 + + + ? + + 24 2012, Tazania 9/11/131 Alb 23 15 ,F 25 Speich et al. 75/112/114 Alb 18- 6- M S 2 5 + + + ? + + 26 2014, Tanzaia 68/109/110 Meb 23 14 ,F 27 Speich et al. 44/41/107 Meb 18- 6- M S 2 3 28 2015, 23 14 ,F + + - ? + + 29 Tanzania 30 Steinmann et 78/55/65 Alb 21- ≥5 M C 2 3 31 al. 2011, 71/58/63 Meb 28 ,F + - - + + + 32 China Tankhiwale et 284/-/- PyP 21 1- M C 1 1 33 ? ? ? ? ? ? al. 1989, India 60 ,F 34 Tefera et al. 50/17/51 Alb 14 SC M S 5 3 35 2015, Ethiopia 64/23/45 Alb ,F + ? ? ? + ? 36 48/23/61 Alb 37 Wang et al. 41/-/- Alb 10 1-3, M C 6 1 38 1987, China 16- ,F ? ? ? ? ? ? 39 25 40 Zani et al. 42/41/38 Alb 20 ≥2 M C 1 1 ? ? ? ? + ? 41 2004, Brazil ,F 42 Zhang et al. 491/593/553 Alb 7 SC M C 6 1 43 1998, China +A ,F ? ? ? ? ? ? 44 D 45 Zu et al. 1992, 47/-/39 Alb 14 AA M C 1 1 46 China 47/44/18 PyP , ? ? ? ? ? ? 47 F 48 Zu et al. 1992, 77/43/94 Alb 14 AA M C 1 1 49 China , ? ? ? ? ? ? 50 F 51 Age: PS (Primary school children); SC (School-aged children), AD (Adults), AA (All ages); N.A. (not 52 appliciable) 53 Method: 1 (one sample Kato-Katz), 2 (two samples Kato-Katz), 3 (direct microscopy), 4 (Formol-Ether method), 5 (McMaster), 6 (other) 54 Cochrane ris of bias assessment: + (low risk of bias), - (high risk of bias), ? (unclear risk of bias) 55 56 57 58 59 60 8 https://mc.manuscriptcentral.com/bmj BMJ Page 34 of 64
1 2 Appendix Table S3 – Excluded studies 3 Details of all studies, which were relevant and screened by two authors. Studies were 4 excluded in case they were not randomised, included a wronge dose, data were not 5 6 extractable (reporting), the follow-up exceeded 6 weeks or the drugs were given in 7 combination. One reason per study was listed below. 8 Confidential: For Review Only 9 Excluded 10 11 12 13
14 Fist author Year Coutry Included not randomised dose Wrong Reporting Follow-up Combination 15 Abadi [1] 1985 Indonesia x 16 Adams [2] 1994 Kenya x 17 Adams [3] 2004 South Africa x 18 Adegnika [4] 2014 Gabon x 19 Adoubryn [5] 2012 Ivory coast x 20 Ahmad [6] 1986 Pakistan x 21 Ahmed [7] 1983 Sudan x 22 Al-Issa [8] 1977 Irak x 23 Albonico [9] 1994 Tanzania x 24 Albonico [10] 1995 Tanzania x 25 Albonico [11] 1999 Tanzania x 26 Albonico [12] 2002 Tanzania x 27 Albonico [13] 2002 Tanzania x 28 Albonico [14] 2003 Tanzania x 29 Albonico [15] 2007 Nepal x 30 Albonico [16] 2013 Tanzania x 31 Al-Mekhlafi [17] 2008 Malaysia x 32 Amato Neto [18] 1983 Brazil x 33 Anantaphruti [19] 2007 Thailand x 34 Andunga [20] 2007 Ethiopia x 35 Anjaneyulu [21] 1989 India x 36 Asalou [22] 1991 Nigeria x 37 Awasthi [23] 2000 India x 38 Bahibulaya [24] 1977 Thailand x 39 Balasuriya [25] 1990 Sri Lanka x 40 Banerjee [26] 1972 India x 41 Baranski [27] 1976 Brazil x 42 Barbieri [28] 1993 Brazil x 43 Bartoloni [29] 1993 Bolivia x 44 Bassily [30] 1984 Egypt x 45 Bastidas [31] 1982 Venezuela x 46 Beach [32] 1999 Haiti x 47 Beasley [33] 1999 Tanzania x 48 Bekana[34] 2015 Ethiopia x 49 Belizario [35] 2003 Philipines x 50 Bell [36] 1971 Kenya x 51 Bell [37] 1971 Agypt x 52 Bell [38] 1972 Agypt x 53 Bhaibulaya [39] 1977 x 54 Bhargava [40] 2003 Tanzania x 55 Biagi [41] 1988 Mexico x 56 Borda [42] 1978 Argentina x 57 Botero [43] 1973 Colombia x 58 59 60 9 https://mc.manuscriptcentral.com/bmj Page 35 of 64 BMJ
1 2 Pene [44] 1981 Senegal x 3 Brutus [45] 2007 Madagascar x 4 Bundy [46] 1985 Santa Lucia x 5 Bunnag [47] 1977 Thailand x 6 Bwibo [48] 1984 Kenya x 7 Cabrera [49] 1980 Philipines x 8 Confidential:Camilo-Coura [50] 1981 Mexico For Review x Only 9 Carneiro [51] 1993 Brazil x 10 Casey [52] 2009 Vietnam x 11 Cervoni [53] 1971 Puerto Rico x 12 Chai [54] 1985 South Korea x 13 Chai [55] 2009 Laos x 14 Chan [56] 1992 Malaysia x 15 Chandiwana [57] 1983 Zimbabwe x 16 Chavarria [58] 1973 Costa Rica x 17 Chege [59] 1974 Kenya x 18 Chen [60] 1984 Taiwan x 19 Chien [61] 1989 Malaysia x 20 Chitchang [62] 1983 Thailand x 21 Choi [63] 1979 Korea x 22 Chongsuphajaisiddhi [64] 1978 Thailand x 23 Cleary [65] 2007 Peru x 24 Cline [66] 1984 USA x 25 Cortes [67] 1982 Costa rica x 26 Coulaud [68] 1984 Multi x 27 Dalal [69] 1980 India x 28 Davidson [70] 1979 Australia x 29 Davis [71] 2013 Russia x 30 De Clercq [72] 1997 Mali x 31 Diaz Jidy [73] 1990 Cuba x 32 Dissanaike [74] 1978 Malaysia x 33 Dissanaike 1978 Malaysia x 34 Domingo [75] 1983 Philipines x 35 Dossa [76] 2001 Benin x 36 Dotsenko [77] 1989 Russia x 37 Ekenjoku [78] 2013 Nigeria x 38 El-Masry [79] 1983 Egypt x 39 Evans [80] 1987 South Africa x 40 Farahmandian [81] 1977 Iran x 41 Farid [82] 1977 Egypt x 42 Farid [83] 1984 Egypt x 43 Feldmeier [84] 1982 different x 44 Flohr [85] 2007 Vietnam x 45 Flohr [85] 2007 Vietnam x 46 Flores [86] 1990 Mexico x 47 Forrester [87] 1989 Mexico x 48 Forrester [88] 1998 Mexico x 49 Fox [89] 2005 Haiti x 50 Friedman [90] 2012 Tanzania x 51 Friis [91] 2003 Kenya x 52 Gan [92] 1992 China x 53 Garcia [93] 1978 N.A. x 54 Garg [94] 2002 Kenya x 55 Gatti [95] 1972 Congo x 56 Gazder [96] 1987 India x 57 Ghadirian [97] 1972 Iran x 58 Gilgen [98] 2001 Bangladesh x 59 60 10 https://mc.manuscriptcentral.com/bmj BMJ Page 36 of 64
1 2 Gil-Grande [99] 1993 Spain x 3 Griffin [100] 1982 Kenya x 4 Guggenmoos [101] 1978 Cameroon x 5 Guyatt [102] 2001 Tanzania x 6 Gyorkos [103] 2013 Peru x 7 Hadidjaja [104] 1998 Indonesia x 8 Confidential:Hadju [105] 1996 Indonesia For x Review Only 9 Hall [106] 1994 Bangladesh x 10 Halwindi [107] 2011 Zambia x 11 Hanjeet [108] 1991 Malaysia x 12 Haswell-Elkins [109] 1988 India x 13 Hatchuel [110] 1973 South Africa x 14 Hlaing [111] 1987 Burma x 15 Holland [112] 1996 Nigeria x 16 Holzer [113] 1987 Sri Lanka x 17 Homeida [114] 1994 Sudan x 18 Humphries [115] 2011 Gahna x 19 Humphries [116] 2013 Gahna x 20 Huq [117] 1982 Bangladesh x 21 Hutchinson [118] 1975 England x 22 Ioli [119] 1987 Italy x 23 Islam [120] 1984 Bangladesh x 24 Ismid [121] 1981 Indonesia x 25 Jackson [122] 1998 South Africa x 26 Choudhuri [123] 1988 India x 27 Jeske [124] 2000 Poland x 28 Jinabhai [125] 2001 South Africa x 29 Jongsuksuntigul [126] 1993 Thailand x 30 Juan [127] 2002 Peru x 31 Kale [128] 1977 Nigeria x 32 Kale [129] 1982 N.A. x 33 Kan [130] 1983 Malaysia x 34 Katz [131] 1973 Brazil x 35 Kightlinger [132] 1995 Madagascar x 36 Kihara [133] 2004 Kenya x 37 Kilpatrick [134] 1981 Egypt x 38 Kinugh'hi [135] 2015 Tanzania x 39 Kleiner [136] 1990 Brazil x 40 Knopp [137] 2010 Tanzania x 41 Koukounari [138] 2006 Uganda x 42 Koukounari [139] 2007 Burkina Faso x 43 Krepel [140] 1993 Togo, Gahna x 44 Krepel [141] 1992 Togo x 45 Krepel [142] 1995 Togo x 46 Kurup [143] 2010 Saint Lucia x 47 Lai [144] 1995 N.A. x 48 Larocque [145] 2006 Peru x 49 Le Huong [146] 2007 Vietnam x 50 Lechat [147] 1974 Congo x 51 Legesse [148] 2002 Ethiopia x 52 Legesse [149] 2004 Ethiopia x 53 Lengyel [150] 1975 Germany x 54 Levecke [151] 2014 Brazil x 55 Liabsuetrakul [152] 2009 Thailand x 56 Linklater [153] 1992 Burma x 57 Lionel [154] 1969 Sri Lanka x 58 Lionel [155] 1975 Sri Lanka x 59 60 11 https://mc.manuscriptcentral.com/bmj Page 37 of 64 BMJ
1 2 Lubis [156] 2012 Indonesia x 3 Maqbool [157] 1975 USA x 4 Maipanich [158] 1997 Thailand x 5 Maissoneuve [159] 1981 Tunisia x 6 Maissoneuve [160] 1984 Tunisia x 7 Maissoneuve [161] 1985 Tunisia x 8 Confidential:Mani [162] 1993 India For Review Onlyx 9 Margono [163] 1980 N.A. x 10 Marti [164] 1996 Tanzania x 11 Mbendi [165] 1985 Congo x 12 Mekonnen [166] 2013 Ethiopia x 13 Migasena [167] 1978 Thailand x 14 Mihrshahi [168] 2009 Vietnam x 15 Miller [169] 1974 USA x 16 Miller [170] 1978 N.A. x 17 Misra [171] 1995 India x 18 Moens [172] 1978 Multi x 19 Morgan [173] 1983 Malawi x 20 Muchiri [174] 2001 Kenya x 21 Musgrave [175] 1979 South Africa x 22 Muttalib [176] 1981 Bangladesh x 23 Nagalingam [177] 1976 Malaysia x 24 Nagaty [178] 1978 Iran x 25 Nahmias [179] 1989 Israel x 26 Namwanje [180] 2011 Uganda x 27 Nanivadekar [181] 1984 India x 28 Ndenecho [182] 2002 Cameroon x 29 Ndyomugyenyi [183] 2008 Uganda x 30 Nga [184] 2009 Vietnam x 31 Nontasut [185] 1987 Thailand x 32 Nontasut [186] 1989 Thailand x 33 Nontasut [187] 1997 Thailand x 34 Nontasut [188] 2000 Thailand x 35 Nooman [189] 1972 England x 36 Norhayati [190] 1995 Malaysia x 37 Norhayati [191] 1997 Malaysia x 38 Northrop-Clewes [192] 2001 Bangladesh x 39 Ochoa [193] 1989 Colombia x 40 Okelo [194] 1984 Keny x 41 Olds [195] 1999 Multi x 42 Olson [196] 2009 Uganda x 43 Ortega [197] 1982 Mexico x 44 Ovedoff [198] 1984 Philipines x 45 Ovedoff [198] 1984 Taiwan x 46 Ovedoff [198] 1984 Taiwan x 47 Ovedoff [198] 1984 Indonesia x 48 Ovedoff [198] 1984 Malaysia x 49 Ovedoff [198] 1984 Malaysia x 50 Ovedoff [198] 1984 Thailand x 51 Ovedoff [198] 1984 Thailand x 52 Oyedrian [199] 1983 nigeria x 53 Pamba [200] 1987 Kenya x 54 Pamba [201] 1989 Kenya x 55 Partono [202] 1974 Indonesia x 56 Payne [203] 2016 Cameroon x 57 Pene [204] 1982 France x 58 Periago [205] 2015 Brazil x 59 60 12 https://mc.manuscriptcentral.com/bmj BMJ Page 38 of 64
1 2 Pion [206] 2015 Congo x 3 Prasad [207] 1985 India x 4 Pugh [208] 1986 Malawi x 5 Pugh [208] 1986 Malawi x 6 Pugh [208] 1986 Malawi x 7 Purnomo [209] 1981 Indonesia x 8 Confidential:Raccurt [210] 1990 Cameroon For Review x Only 9 Raccurt [210] 1990 Cameroon x 10 Rafi [211] 1997 Pakistan x 11 Rahman [212] 1996 Malaysia x 12 Ramaginam [213] 1983 Malaysia x 13 Rao [214] 1973 India x 14 Reynoldson [215] 1997 Australia x 15 Lenoble [216] 1982 Gabon x 16 Rim [217] 1978 South Korea x 17 Rim [218] 1984 South Korea x 18 Rohner [219] 2010 Côte d'Ivoire x 19 Rossignol [220] 1983 Multi x 20 Rowbotton [221] 2012 Venezuela x 21 Sacko [222] 1999 Mali x 22 Saif [223] 1984 Egypt x 23 Samuel [224] 2014 Ethiopia x 24 Sargent [225] 1975 Colombia x 25 Sarmah [226] 1988 India x 26 Scherrer [227] 2009 Côte d'Ivoire x 27 Scragg [228] 1977 South Africa x 28 Scragg [229] 1978 South africa x 29 Seah [230] 1976 Canada x 30 Seo [231] 1977 South Korea x 31 Seo [232] 1978 South Korea x 32 Seo [233] 1980 South Korea x 33 Seo [234] 1983 South Korea x 34 Singhal [235] 1975 India x 35 Sinniah [236] 1980 Malaysia x 36 Sinniah [237] 1981 Malaysia x 37 Sinniah [238] 1984 Malaysia x 38 Sinniah [236] 1990 Malaysia x 39 Sirivichayakul [239] 2001 Thailand x 40 Sirivichayakul [240] 2003 Thailand x 41 Sitthichareonchai [241] 1984 Thailand x 42 Sorensen [242] 1996 Sri Lanka x 43 Soukhathammavong [243] 2012 Laos x 44 Sousa-Figueiredo [244] 2011 Uganda x 45 Speich [245] 2012 Tanzania x 46 Speich [246] 2014 Tanzania x 47 Speich [247] 2015 Tanzania x 48 Staathoff [248] 2004 South Africa x 49 Staudacher [249] 2014 Rwanda x 50 Steinmann [250] 2011 China x 51 Stephenson [251] 1989 Kenya x 52 Stephenson [252] 1990 Kenya x 53 Stephenson [253] 1993 Kenya x 54 Stephenson [254] 1993 Kenya x 55 Stolzfus [255] 1997 Tanzania x 56 Stolzfus [256] 2004 Tanzania x 57 Stothard [257] 2009 Tanzania x 58 Sunish [258] 2015 India x 59 60 13 https://mc.manuscriptcentral.com/bmj Page 39 of 64 BMJ
1 2 Tankhiwale [259] 1989 India x 3 Taylor [260] 2001 South Africa x 4 Tefera [261] 2015 Ethiopia x 5 Thienpont [262] 1969 Indonesia x 6 Tian [263] 2012 China x 7 Tokmalaev [264] 1994 Russia x 8 Confidential:Udonsi [265] 1985 Nigeria For Review Only x 9 Upatham [266] 1989 Thailand x 10 Urquiaga [267] 1982 Mexico x 11 Vakil [268] 1975 India x 12 Van der Werff [269] 2014 Cuba x 13 Vandepitte [270] 1972 Congo x 14 Vazquez [271] 1988 Mexico x 15 Vercruysse [272] 2011 Multi x 16 Viravan [273] 1982 Thailand x 17 Walson [274] 2008 Kenya x 18 Walson [275] 2012 Kenya x 19 Wang [276] 1987 China x 20 Wen [277] 2008 China x 21 Wesche [278] 1994 PNG x 22 Wiria [279] 2013 Indonesia x 23 Wolfe [280] 1974 Bahamas x 24 Wu [281] 2006 China x 25 Xu [282] 1992 China x 26 Xu [282] 1992 China x 27 Xu [283] 2014 China x 28 Yangco [284] 1981 USA x 29 Yap [285] 2013 China x 30 Zani [286] 2004 Brazil x 31 Zawde [287] 1987 Ethiopia x 32 Zhang [288] 1998 China x 33 Total 56 82 87 16 37 23 34 35
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1 2 Appendix Table S4 – CR comparison between network and pairwise meta-analysis 3 Odds ratios of cure between different treatments obtained by network meta-analysis on the 4 one hand and pairwise meta-analysis based on direct comparisons on the other hand, for 5 placebo (Plc), albendazole (Alb), mebendazole (Meb), levamisole (Lev) and pyrantel 6 pamoate (PyP) against for Ascaris lumbricoides , hookworm and Trichuris trichiura. 7 8 Confidential:Treatment Network meta-anaysis For Pairwise Review meta-analysis 1 Only 9 comparison Odds ratio 95% CI Odds ratio 95% CI Heterogeneity 10 I2 (%) τ2 11 Ascaris lumbricoides 12 Plc Alb 151.9 66.9-344.8 73.0 19.0-280.5 85.4 3.1 13 Meb 171.5 62.8-468.5 103.1 50.8-209.4 0.0 0.0 14 15 Lev 246.3 33.8-1792.9 149.3 58.2-382.9 N.A. N.A. 16 PyP 85.4 32.4-225.3 131.3 75.3-380.8 0.0 0.0 17 Alb Meb 1.1 0.5-2.5 0.9 0.5-1.5 17.6 0.1 18 Lev 1.6 0.2-11.3 N.A. N.A. N.A. N.A. 19 PyP 0.6 0.2-1.3 0.2 <0.1-2.9 66.9 2.6 20 Meb Lev 1.4 0.2-10.3 1.6 0.6-4.1 N.A. N.A. 21 PyP 0.5 0.2-1.4 N.A. N.A. N.A. N.A. 22 Lev PyP 0.3 0.1-2.6 N.A. N.A. N.A. N.A. 23 24 Plc Alb 21.5 11.0-42.0 16.4 6.6-40.9 82.8 1.9 25 Meb 2.7 1.3-5.7 2.4 1.2-4.7 66.8 0.4 26 Lev 0.6 0.1-3.2 9.6 1.2-77.2 N.A. N.A. 27 PyP 5.5 2.0-15.2 3.5 1.5-7.9 0.0 0.0 28 Alb Meb 0.1 <0.1-0.3 0.2 0.2-0.3 35.3 0.1 29 Lev <0.1 <0.1-0.1 N.A. N.A. N.A. N.A. 30 PyP 0.3 0.1-0.7 0.2 <0.1-0.4 N.A. N.A. 31 Meb Lev 0.2 <0.1-1.1 0.1 <0.1-2.3 92.5 4.4 32 33 PyP 2.1 0.7-6.0 0.5 <0.1-14.7 94.1 5.6 34 Lev PyP 8.6 1.5-50.0 3.8 1.1-12.6 N.A. N.A. 35 36 Plc Alb 4.7 2.2-10.2 4.0 1.9-8.6 76.1 0.7 37 Meb 7.8 3.1-19.7 12.8 0.2-762.2 88.2 7.8 38 Lev 4.5 0.6-31.0 20.4 1.2-355.9 N.A. N.A. 39 PyP 2.7 0.7-10.0 0.7 0.2-2.5 20.6 0.3 40 Alb Meb 1.6 0.8-3.3 2.3 1.1-4.9 90.7 1.2 41 Lev 0.9 0.1-6.2 N.A. N.A. N.A. N.A. 42 PyP 0.6 0.2-1.9 0.2 0.1-0.4 0.0 0.0 43 Meb Lev 0.6 0.1-3.8 0.2 0.1-0.4 N.A. N.A. 44 PyP 0.3 0.1-1.4 N.A. N.A. N.A. N.A. 45 Lev PyP 0.6 0.1-4.9 N.A. N.A. N.A. N.A. 46 1conducted using the command “metan” of Stata. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25 https://mc.manuscriptcentral.com/bmj Page 51 of 64 BMJ
1 2 Appendix Table S5 – Stratification by continent 3 Estimated cure rates and egg reduction rates stratified by continent (Asia and Africa) for 4 placebo, albendazole, mebendazole, levamisole and pyrantel pamoate against A. 5 6 lumbricoides , hookworm and T. trichiura . 7 8 Confidential: ForCure rates Review Only 9 Treatment Asia Africa P- 10 No. CR 95% CI No. CR 95% CI value* 11 studies (%) low up studies (%) low up 12 Ascaris lumbricoides 13 Placebo 3 8.2 0.8 50.9 8 13.3 7.6 22.2 0.679 14 Albendazole 14 96.1 91.8 98.2 14 95.4 92.0 97.4 0.725 15 Mebendazole 5 97.8 91.2 99.5 8 94.1 89.9 96.7 0.205 16 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 17 Pyrantel pamoate 8 90.0 78.1 95.8 3 96.9 90.5 99.0 0.104 18 19 Hookworm 20 Placebo 4 30.8 14.0 54.8 11 9.1 4.8 16.8 0.017 21 Albendazole 10 73.9 60.7 83.9 16 80.2 69.2 88.0 0.405 22 Mebendazole 5 29.5 15.6 48.7 9 33.9 20.6 50.3 0.712 23 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 24 Pyrantel pamoate 4 64.1 39.3 83.1 3 28.6 11.5 55.2 0.053 25 Trichuris trichiura 26 Placebo 2 4.9 0.6 30.7 6 9.1 3.2 23.3 0.597 27 Albendazole 12 34.3 21.4 50.1 15 21.6 10.7 38.8 0.235 28 Mebendazole 4 36.2 21.4 54.2 9 42.7 21.4 67.0 0.669 29 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 30 Pyrantel pamoate 4 12.9 5.7 26.5 2 22.4 2.8 74.4 0.597 31 Egg reduction rates 32 Treatment Asia Africa p- 33 No. ERR 95% CI No. ERR 95% CI value 34 studies (%) low up studies (%) low up 35 Ascaris lumbricoides 36 37 Placebo 3 23.6 6.9 40.2 4 15.3 7.6 23.0 0.377 38 Albendazole 12 95.0 83.3 100.0 10 100.0 93.8 100.0 0.446 39 Mebendazole 5 94.8 78.3 100.0 8 98.9 93.3 100.0 0.649 40 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 41 Pyrantel pamoate 5 90.3 77.9 100.0 1 99.7 86.3 100.0 0.315 42 Hookworm 43 Placebo 4 24.1 12.7 35.4 8 2.3 - 18.9 0.034 44 14.4 45 Albendazole 10 94.7 86.4 100.0 12 85.5 72.6 98.5 0.243 46 Mebendazole 5 73.2 64.9 81.5 9 59.2 44.5 74.0 0.106 47 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 48 Pyrantel pamoate 4 73.3 60.3 86.3 1 100.0 66.6 100.0 0.091 49 Trichuris trichiura 50 Placebo 2 5.0 -21.1 31.1 4 22.5 2.1 42.9 0.301 51 Albendazole 11 46.1 20.3 72.0 13 58.1 39.6 76.7 0.459 52 Mebendazole 4 48.7 22.6 74.9 10 78.5 60.0 97.0 0.068 53 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 54 Pyrantel pamoate 4 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 55 2 56 *Chi -test of the difference between stratum-specific estimates 57 58 59 60 26 https://mc.manuscriptcentral.com/bmj BMJ Page 52 of 64
1 2 Appendix Table S6 – Stratification by place of the study 3 Estimated cure rates and egg-reduction rates stratified by place of the study (community or 4 school based) for placebo, albendazole, mebendazole, levamisole and pyrantel pamoate 5 6 against A. lumbricoides , hookworm and T. trichiura . 7 8 Confidential: ForCure rates Review Only 9 Treatment Community School P- 10 No. CR 95% CI No. CR 95% CI value* 11 studies (%) low up studies (%) low up 12 Ascaris lumbricoides 13 Placebo 3 11.6 2.2 43.1 11 12.0 6.9 20.0 0.966 14 Albendazole 15 97.3 94.3 98.8 19 93.9 90.1 96.4 0.080 15 Mebendazole 3 97.4 86.4 99.5 10 94.4 89.7 97.0 0.412 16 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 17 Pyrantel pamoate 5 93.1 80.5 97.8 6 92.4 84.3 96.4 0.877 18 19 Hookworm 20 Placebo 5 26.1 13.4 44.6 13 11.7 6.4 20.4 0.068 21 Albendazole 12 79.3 69.6 86.6 18 78.6 67.1 86.9 0.915 22 Mebendazole 5 33.1 18.4 52.1 9 35.0 20.8 52.6 0.879 23 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 24 Pyrantel pamoate 3 76.2 51.7 90.5 4 24.8 9.7 50.3 0.004 25 Trichuris trichiura 26 Placebo 1 29.1 16.5 46.0 10 6.2 2.5 14.5 0.003 27 Albendazole 14 39.0 25.1 54.9 19 26.0 14.8 41.6 0.222 28 Mebendazole 3 42.6 25.9 61.2 10 38.3 19.4 61.6 0.773 29 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 30 Pyrantel pamoate 2 18.2 6.2 42.8 4 20.7 5.1 56.1 0.874 31 Egg reduction rates 32 Treatment Community School p- 33 No. ERR 95% CI No. ERR 95% CI value 34 studies (%) low up studies (%) low up 35 Ascaris lumbricoides 36 37 Placebo 1 -6.2 -12.1 -0.3 8 25.7 19.0 32.3 <0.001 38 Albendazole 11 98.8 95.6 100.0 15 99.8 93.1 100.0 0.789 39 Mebendazole 3 98.8 95.6 100.0 10 98.5 92.5 100.0 0.914 40 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 41 Pyrantel pamoate 3 95.7 90.9 100.0 3 95.0 84.4 100.0 0.906 42 Hookworm 43 Placebo 4 3.7 -18.4 25.0 10 20.5 5.5 35.5 0.201 44 Albendazole 10 90.3 73.0 100.0 15 88.7 76.9 100.0 0.882 45 Mebendazole 5 64.5 44.8 84.2 9 59.7 45.2 74.3 0.703 46 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 47 Pyrantel pamoate 3 80.3 41.2 100.0 2 65.7 36.6 94.9 0.557 48 Trichuris trichiura 49 Placebo 0 N.A. N.A. N.A. 8 23.8 7.9 39.7 N.A. 50 Albendazole 11 76.2 49.2 100.0 17 54.7 39.4 70.0 0.175 51 Mebendazole 4 92.7 64.6 100.0 10 70.9 56.3 85.6 0.178 52 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 53 Pyrantel pamoate 2 7.1 0.0 61.2 2 83.9 37.6 100.0 0.034 54 2 55 *Chi -test of the difference between stratum-specific estimates 56 57 58 59 60 27 https://mc.manuscriptcentral.com/bmj Page 53 of 64 BMJ
1 2 Appendix Table S7 – Stratification by sensitivity of diagnostic method 3 Estimated cure rates and egg-reduction rates stratified by the sensitivity of diagnostics. i.e. 4 low sensitivity (direct microscopy, Formol-Ether and others) and moderate sensitivity (Kato- 5 6 Katz and McMaster) for placebo, albendazole, mebendazole, levamisole and pyrantel 7 pamoate against A. lumbricoides , hookworm and T. trichiura . 8 Confidential: For Review Only 9 10 Cure rates 11 Treatment Low sensitivity Moderate sensitivity P- 12 No. CR 95% CI No. CR 95% CI value* 13 studies (%) low up studies (%) low up 14 Ascaris lumbricoides 15 Placebo 7 13.4 5.3 30.0 7 14.1 5.8 30.4 0.935 16 Albendazole 11 97.9 95.0 99.1 23 94.2 90.7 96.4 0.044 17 Mebendazole 1 100.0 N.A. N.A. 12 95.8 91.5 97.9 N.A. 18 Levamisole 1 100. N.A. N.A. 1 95.8 73.7 99.5 N.A. 19 Pyrantel pamoate 6 96.9 91.4 98.9 5 85.3 69.8 93.6 0.020 20 21 Hookworm 22 Placebo 6 15.3 6.3 32.5 12 15.8 9.3 25.6 0.948 23 Albendazole 9 89.6 78.8 95.3 21 74.5 65.2 82.0 0.023 24 Mebendazole 1 91.2 53.0 99.0 13 27.9 17.8 40.8 0.005 25 Levamisole 1 16.9 2.2 64.6 1 11.3 1.4 54.0 0.769 26 Pyrantel pamoate 5 48.8 26.8 71.3 2 63.3 29.2 87.8 0.500 27 Trichuris trichiura 28 Placebo 5 8.5 1.6 34.2 6 8.3 3.5 18.5 0.984 29 Albendazole 10 47.9 21.6 75.5 23 24.6 16.3 35.2 0.120 30 Mebendazole 1 100.0 N.A. N.A. 12 34.1 20.5 50.9 N.A. 31 Levamisole 1 100.0 N.A. N.A. 1 12.6 1.7 54.3 N.A. 32 Pyrantel pamoate 4 29.8 6.5 72.3 2 25.4 5.6 66.3 0.862 33 Egg reduction rates 34 Treatment Low sensitivity Moderate sensitivity p- 35 No. ERR 95% CI No. ERR 95% CI value 36 studies (%) low up studies (%) low up 37 Ascaris lumbricoides 38 39 Placebo 5 12.0 3.3 20.8 4 24.6 96.1 30.1 0.017 40 Albendazole 6 100.0 89.7 100.0 20 98.7 94.5 100.0 0.562 41 Mebendazole 0 N.A. N.A. N.A. 13 97.9 93.9 100.0 N.A. 42 Levamisole 0 N.A. N.A. N.A. 1 96.5 90.9 100.0 N.A. 43 Pyrantel pamoate 4 99.1 87.0 100.0 2 70.7 63.7 77.7 <0.001 44 Hookworm 45 Placebo 5 39.2 26.7 51.8 9 7.6 -8.0 23.1 0.002 46 Albendazole 5 100.0 86.8 100.0 20 88.0 77.2 98.9 0.136 47 Mebendazole 0 N.A. N.A. N.A. 14 61.7 49.9 73.5 N.A. 48 Levamisole 0 N.A. N.A. N.A. 1 58.7 18.8 98.6 N.A. 49 Pyrantel pamoate 3 88.8 68.7 100.0 2 84.7 38.5 100.0 0.876 50 Trichuris trichiura 51 Placebo 4 2.4 -25.4 30.2 4 23.9 8.0 39.8 0.189 52 Albendazole 6 27.3 -0.2 54.8 22 62.8 48.8 76.8 0.024 53 Mebendazole 1 53.4 20.6 86.2 13 76.1 62.6 89.6 0.211 54 Levamisole 0 N.A. N.A. N.A. 1 37.3 17.4 57.2 N.A. 55 Pyrantel pamoate 3 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 56 2 57 *Chi -test of the difference between stratum-specific estimates 58 59 60 28 https://mc.manuscriptcentral.com/bmj BMJ Page 54 of 64
1 2 3 Appendix Table S8 – Stratification by quality of the study 4 Estimated cure rates and egg-reduction rates stratified by quality assed by the Jadad score 5 6 low (1-2) and high (3-5) for placebo, albendazole, mebendazole, levamisole and pyrantel 7 pamoate against A. lumbricoides , hookworm and T. trichiura . 8 Confidential: For Review Only 9 Cure rates 10 Treatment Low quality High quality P- 11 No. CR 95% CI No. CR 95% CI value* 12 studies (%) low up studies (%) low up 13 Ascaris lumbricoides 14 Placebo 5 7.7 2.0 25.6 9 14.1 7.3 25.5 0.410 15 Albendazole 17 95.5 91.1 97.7 17 96.0 93.0 97.8 0.770 16 Mebendazole 3 99.5 95.0 99.9 10 95.1 90.7 97.5 0.064 17 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 18 Pyrantel pamoate 10 93.7 86.3 97.3 1 72.1 22.0 96.0 0.150 19 Hookworm 20 Placebo 7 12.9 6.3 24.6 11 17.3 9.3 29.9 0.523 21 Albendazole 13 85.0 77.1 90.4 17 71.7 57.6 82.6 0.053 22 23 Mebendazole 4 34.3 18.2 55.0 10 33.8 20.1 50.9 0.973 24 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 25 Pyrantel pamoate 7 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 26 Trichuris trichiura 27 Placebo 3 10.4 2.8 31.6 8 6.7 2.7 15.6 0.578 28 Albendazole 15 33.9 21.3 49.4 18 26.2 15.3 41.2 0.439 29 Mebendazole 3 38.8 22.7 57.9 10 39.3 21.2 60.8 0.976 30 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 31 Pyrantel pamoate 6 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 32 Egg reduction rates 33 Treatment Low quality High quality p- 34 No. ERR 95% CI No. ERR 95% CI value 35 studies (%) low up studies (%) low up 36 Ascaris lumbricoides 37 Placebo 3 2.6 -2.8 8.0 6 21.0 14.2 27.7 <0.001 38 Albendazole 14 98.7 93.3 100.0 12 100.0 95.8 100.0 0.417 39 Mebendazole 4 98.7 93.3 100.0 9 99.5 93.6 100.0 0.833 40 41 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 42 Pyrantel pamoate 5 87.4 82.0 92.7 1 67.0 58.1 75.9 <0.001 43 Hookworm 44 Placebo 6 -0.2 -19.5 19.1 8 25.1 9.2 41.1 0.048 45 Albendazole 13 90.9 75.1 100.0 12 84.1 69.3 98.9 0.536 46 Mebendazole 5 55.6 35.2 76.1 9 60.5 46.2 74.8 0.704 47 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 48 Pyrantel pamoate 5 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 49 Trichuris trichiura 50 Placebo 2 28.3 -6.1 62.6 6 28.7 12.5 45.0 0.980 51 Albendazole 13 69.3 35.4 100.0 15 57.7 42.6 72.9 0.540 52 Mebendazole 4 85.5 51.5 100.0 10 73.5 58.7 88.2 0.524 53 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 54 Pyrantel pamoate 4 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 55 *Chi 2-test of the difference between stratum-specific estimates 56 57 58 59 60 29 https://mc.manuscriptcentral.com/bmj Page 55 of 64 BMJ
1 2 Appendix Table S9 – Stratification by length of follow-up 3 Estimated cure rates and egg-reduction rates stratified by the length of follow-up to short (1-3 4 weeks) and long (4-6 weeks) for placebo, albendazole, mebendazole, levamisole and 5 6 pyrantel pamoate against A. lumbricoides , hookworm and T. trichiura . 7 8 Confidential: ForCure rates Review Only 9 Treatment Short follow -up Long follow -up P- 10 No. CR 95% CI No. CR 95% CI value* 11 studies (%) low up studies (%) low up 12 Ascaris lumbricoides 13 Placebo 5 4.4 0.9 19.7 9 4.4 0.9 19.7 0.113 14 Albendazole 13 96.4 91.0 98.6 18 96.4 91.0 98.6 0.510 15 Mebendazole 5 98.6 92.0 99.7 8 98.6 92.0 99.7 0.174 16 Levamisole 1 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 17 Pyrantel pamoate 5 93.8 78.9 98.4 5 93.8 78.9 98.4 0.842 18 Hookworm 19 Placebo 9 14.6 7.3 27.2 8 16.3 7.9 30.6 0.821 20 Albendazole 12 77.7 64.7 86.8 15 74.9 61.9 84.5 0.729 21 Mebendazole 6 41.6 23.3 62.5 7 34.8 18.7 55.3 0.635 22 Levamisole 1 16.9 2.2 65.2 1 21.4 3.7 66.0 0.849 23 Pyrantel pamoate 2 65.9 28.9 90.2 4 46.1 22.2 72.0 0.404 24 Trichuris trichiura 25 26 Placebo 3 16.2 5.5 39.0 8 6.6 2.7 15.3 0.198 27 Albendazole 11 30.7 13.3 56.0 19 29.8 19.8 42.3 0.948 28 Mebendazole 5 45.4 20.8 72.5 8 34.3 17.4 56.5 0.536 29 Levamisole 1 N.A. N.A. N.A. 1 7.3 0.5 53.3 N.A. 30 Pyrantel pamoate 2 10.8 2.6 35.8 3 18.8 5.2 49.5 0.544 31 Egg reduction rates 32 Treatment Short follow-up Long follow-up p- 33 No. ERR 95% CI No. ERR 95% CI value 34 studies (%) low up studies (%) low up 35 Ascaris lumbricoides 36 Placebo 2 -6.2 -11.2 -1.2 7 24.7 18.7 30.7 <0.001 37 Albendazole 9 100.0 95.0 100.0 17 99.2 94.4 100.0 0.834 38 Mebendazole 4 99.7 93.2 100.0 9 99.1 93.9 100.0 0.895 39 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 40 Pyrantel pamoate 2 99.7 94.7 100.0 4 91.8 83.1 100.0 0.123 41 Hookworm 42 43 Placebo 7 -1.3 -20.2 17.6 6 37.2 25.5 48.9 0.001 44 Albendazole 10 87.2 70.1 100.0 15 92.4 85.1 99.7 0.580 45 Mebendazole 5 48.2 32.0 64.4 8 82.4 73.0 91.9 <0.001 46 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 47 Pyrantel pamoate 1 N.A. N.A. N.A. 3 81.6 65.3 97.8 N.A. 48 Trichuris trichiura 49 Placebo 2 8.0 -28.9 44.9 6 30.8 15.4 46.2 0.264 50 Albendazole 10 35.8 0.1 71.6 18 64.9 51.4 78.5 0.136 51 Mebendazole 5 54.5 18.2 90.7 9 81.1 67.5 94.7 0.178 52 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 53 Pyrantel pamoate 1 N.A. N.A. N.A. 3 44.8 13.1 76.5 N.A. 54 *Chi 2-test of the difference between stratum-specific estimates 55 56 57 58 59 60 30 https://mc.manuscriptcentral.com/bmj BMJ Page 56 of 64
1 2 Appendix Table S10 – Stratification by baseline infection intensity 3 Estimated cure rates and egg-reduction rates stratified by baseline infection intensity (below 4 and above the median of baseline infection intensity) for placebo, albendazole, 5 6 mebendazole, levamisole and pyrantel pamoate against A. lumbricoides , hookworm and T. 7 trichiura . 8 Confidential: For Review Only 9 Cure rates 10 Treatment Low infection intensity High infection intensity P- 11 No. CR 95% CI No. CR 95% CI value* 12 studies (%) low up studies (%) low up 13 Ascaris lumbricoides 14 Placebo 5 14.2 7.9 24.2 9 12.1 4.5 28.6 0.773 15 Albendazole 9 97.7 95.8 98.8 25 94.6 90.6 96.9 0.042 16 Mebendazole 5 94.7 90.4 97.2 8 97.3 92.3 99.0 0.293 17 Levamisole 1 96.3 90.4 98.6 0 N.A. N.A. N.A. N.A. 18 Pyrantel pamoate 1 97.8 78.0 99.8 10 91.7 83.0 96.2 0.302 19 Hookworm 20 Placebo 5 21.8 15.5 29.8 13 11.7 5.2 24.2 0.134 21 Albendazole 6 73.3 66.9 78.8 24 81.8 69.7 89.8 0.190 22 23 Mebendazole 5 31.3 25.5 37.8 9 31.3 11.5 61.5 0.996 24 Levamisole 1 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 25 Pyrantel pamoate 0 N.A. N.A. N.A. 7 N.A. N.A. N.A. N.A. 26 Trichuris trichiura 27 Placebo 4 7.5 3.4 15.8 7 7.5 2.6 20.1 0.992 28 Albendazole 8 25.0 16.3 36.2 25 30.2 17.9 46.3 0.551 29 Mebendazole 5 23.1 13.2 37.4 8 53.2 28.5 76.3 0.037 30 Levamisole 1 4.5 0.9 20.2 0 N.A. N.A. N.A. N.A. 31 Pyrantel pamoate 0 N.A. N.A. N.A. 6 N.A. N.A. N.A. N.A. 32 Egg reduction rates 33 Treatment Low infection intensity High infection intensity p- 34 No. ERR 95% CI No. ERR 95% CI value 35 studies (%) low up studies (%) low up 36 Ascaris lumbricoides 37 Placebo 5 18.1 11.6 24.6 4 27.1 16.0 38.3 0.170 38 Albendazole 9 98.7 93.2 100.0 17 98.5 92.2 100.0 0.967 39 Mebendazole 6 98.6 92.1 100.0 7 97.4 90.5 100.0 0.796 40 41 Levamisole 1 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 42 Pyrantel pamoate 1 99.7 85.2 100.0 5 93.1 85.1 100.0 0.738 43 Hookworm 44 Placebo 5 26.6 5.6 47.6 9 6.4 -1.1 13.9 0.075 45 Albendazole 6 90.8 73.1 100.0 19 88.4 81.6 95.2 0.807 46 Mebendazole 5 56.5 37.4 75.6 9 69.6 60.9 78.3 0.223 47 Levamisole 1 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 48 Pyrantel pamoate 0 N.A. N.A. N.A. 5 N.A. N.A. N.A. N.A. 49 Trichuris trichiura 50 Placebo 4 29.3 15.8 42.7 4 26.7 - 72.6 0.917 51 19.1 52 Albendazole 8 58.9 48.5 69.4 20 67.4 22.0 100.0 0.722 53 Mebendazole 6 76.3 64.2 88.5 8 82.6 36.3 100.0 0.799 54 Levamisole 1 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 55 Pyrantel pamoate 0 7.1 -26.4 40.6 4 83.2 -0.1 100.0 0.096 56 *Chi 2-test of the difference between stratum-specific estimates 57 58 59 60 31 https://mc.manuscriptcentral.com/bmj Page 57 of 64 BMJ
1 2 Appendix Table S11 – Stratification by publication year 3 Estimated cure rates and egg-reduction rates stratified by publication year of the study 4 (1960-1999 and 2000-2016) for placebo, albendazole, mebendazole, levamisole and 5 6 pyrantel pamoate against A. lumbricoides , hookworm and T. trichiura . 7 8 Confidential: ForCure rates Review Only 9 Treatment 1960 -1999 2000 -2016 P- 10 No. CR 95% CI No. CR 95% CI value* 11 studies (%) low up studies (%) low up 12 Ascaris lumbricoides 13 Placebo 10 11.7 5.3 23.9 4 9.3 4.0 20.3 0.697 14 Albendazole 16 96.1 92.6 98.0 18 95.3 91.8 97.3 0.636 15 Mebendazole 3 98.4 92.0 99.7 10 94.9 90.3 97.4 0.201 16 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 17 Pyrantel pamoate 10 91.1 82.5 99.7 1 N.A. N.A. N.A. N.A. 18 Hookworm 19 Placebo 12 14.1 7.7 24.3 6 24.7 12.6 42.7 0.201 20 Albendazole 16 83.0 74.0 89.4 14 70.5 54.5 82.6 0.108 21 Mebendazole 5 31.4 15.9 52.5 9 38.7 23.5 56.5 0.577 22 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 23 Pyrantel pamoate 6 55.1 34.3 74.3 1 8.6 1.7 33.8 0.008 24 Trichuris trichiura 25 26 Placebo 7 23.0 12.1 39.2 4 2.3 0.5 9.1 0.002 27 Albendazole 13 44.9 29.4 61.5 20 23.7 14.2 36.7 0.039 28 Mebendazole 3 50.4 31.8 68.9 10 33.2 17.3 54.3 0.230 29 Levamisole 0 N.A. N.A. N.A. 2 N.A. N.A. N.A. N.A. 30 Pyrantel pamoate 5 16.7 8.1 31.4 1 N.A. N.A. N.A. N.A. 31 Egg reduction rates 32 Treatment 1960-1999 2000-2016 p- 33 No. ERR 95% CI No. ERR 95% CI value 34 studies (%) low up studies (%) low up 35 Ascaris lumbricoides 36 Placebo 6 16.0 2.0 30.0 3 21.2 16.0 26.3 0.494 37 Albendazole 13 98.0 84.3 100.0 13 98.6 94.6 100.0 0.930 38 Mebendazole 4 97.5 83.1 100.0 9 98.0 93.6 100.0 0.948 39 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 40 Pyrantel pamoate 6 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 41 Hookworm 42 43 Placebo 9 6.6 -9.8 23.0 5 27.2 11.4 43.0 0.077 44 Albendazole 15 96.1 80.5 100.0 10 77.1 63.4 90.7 0.072 45 Mebendazole 6 63.8 45.2 82.3 8 58.0 44.4 71.7 0.624 46 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 47 Pyrantel pamoate 5 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 48 Trichuris trichiura 49 Placebo 4 22.0 -5.2 49.1 4 26.1 8.7 43.5 0.801 50 Albendazole 12 51.0 23.9 78.2 16 59.1 43.4 74.8 0.617 51 Mebendazole 5 68.2 39.7 96.8 9 72.4 57.0 87.8 0.799 52 Levamisole 0 N.A. N.A. N.A. 1 N.A. N.A. N.A. N.A. 53 Pyrantel pamoate 4 N.A. N.A. N.A. 0 N.A. N.A. N.A. N.A. 54 *Chi 2-test of the difference between stratum-specific estimates 55 56 57 58 59 60 32 https://mc.manuscriptcentral.com/bmj BMJ Page 58 of 64
1 2 Appendix Table S12 – Influenece of study size (interaction analysis) 3 Estimated cure rates and egg-reduction rates. for small (n=30) and large (n=200) studies 4 from a model including interactions of treatments and study size to adress potential 5 6 publication bias in the effects of placebo, albendazole, mebendazole, levamisole and 7 pyrantel pamoate on A. lumbricoides , hookworm and T. trichiura . 8 Confidential: For Review Only 9 Cure rates 10 Treatment Small studies Large studies p-value* 11 CR (%) 95% CI CR (%) 95% CI 12 low up low up 13 Ascaris lumbricoides 14 Placebo 7.4 3.7 14.5 48.8 21.0 77.3 0.002 15 Albendazole 94.2 90.9 96.3 96.6 94.6 98.9 0.010 16 Mebendazole 95.6 91.3 97.8 96.8 94.0 98.3 0.230 17 Levamisole N.A. N.A. N.A. N.A. N.A. N.A. N.A. 18 Pyrantel pamoate 92.0 84.3 96.1 91.5 84.2 95.6 0.815 19 Hookworm 20 Placebo 17.2 10.0 27.8 12.7 6.0 25.2 0.427 21 Albendazole 82.2 74.6 87.9 77.2 68.4 84.1 0.053 22 23 Mebendazole 34.9 21.2 51.8 30.1 19.1 44.0 0.235 24 Levamisole 11.9 1.4 56.9 7.9 0.7 52.3 0.809 25 Pyrantel pamoate 54.2 31.4 75.3 97.8 <0.1 100.0 0.552 26 Trichuris trichiura 27 Placebo 5.8 2.0 15.9 6.9 3.1 14.7 0.719 28 Albendazole 33.9 23.2 46.5 27.6 19.1 38.0 0.109 29 Mebendazole 47.5 28.4 67.4 39.3 24.3 56.6 0.119 30 Levamisole N.A. N.A. N.A. N.A. N.A. N.A. N.A. 31 Pyrantel pamoate N.A. N.A. N.A. N.A. N.A. N.A. N.A. 32 Egg reduction rates 33 Treatment ERR 95% CI ERR 95% CI p-value 34 (%) low up (%) low up 35 Ascaris lumbricoides 36 Placebo 15.4 7.8 23.0 39.2 21.6 56.7 0.028 37 Albendazole 97.1 90.6 100.0 97.6 92.1 100.0 0.802 38 Mebendazole 96.7 89.9 100.0 97.2 91.4 100.0 0.788 39 Levamisole 83.3 63.4 100.0 100.0 87.9 100.0 0.028 40 41 Pyrantel pamoate 90.8 79.1 100.0 100.0 27.2 100.0 0.713 42 Hookworm 43 Placebo 17.2 4.3 30.2 20.5 2.8 38.2 0.688 44 Albendazole 90.7 79.6 100.0 91.5 81.1 100.0 0.789 45 Mebendazole 56.4 44.2 68.6 61.3 50.3 72.3 0.145 46 Levamisole 61.0 20.5 100.0 64.3 26.2 100.0 0.688 47 Pyrantel pamoate 73.6 51.5 95.7 54.4 0.0 100.0 0.856 48 Trichuris trichiura 49 Placebo 32.7 15.3 50.1 29.4 14.9 43.9 0.622 50 Albendazole 56.5 41.6 71.3 62.4 49.0 75.8 0.141 51 Mebendazole 68.6 53.9 83.4 74.7 61.6 87.7 0.152 52 Levamisole 39.8 16.3 63.4 36.6 15.9 57.3 0.622 53 Pyrantel pamoate N.A. N.A. N.A. N.A. N.A. N.A. N.A. 54 *Wald-test of the difference between stratum-specific estimates 55 56 57 58 59 60 33 https://mc.manuscriptcentral.com/bmj Page 59 of 64 BMJ
1 2 Appendix Table S13 – Influenece of study year (interaction analysis) 3 Estimated cure rates and egg-reduction rates for old (1995) and new studies (2015) from a 4 model including interactions of treatments and year. to evaluate potential trends of efficacy 5 6 over time for placebo, albendazole, mebendazole, levamisole and pyrantel pamoate against 7 A. lumbricoides , hookworm and T. trichiura . 8 Confidential: For Review Only 9 Cure rates 10 Treatment 1995 2015 p-value* 11 CR (%) 95% CI CR (%) 95% CI 12 low up low up 13 Ascaris lumbricoides 14 Placebo 12.7 6.7 22.9 17.3 4.5 48.5 0.559 15 Albendazole 95.3 92.5 97.1 96.6 92.5 98.5 0.473 16 Mebendazole 97.3 90.1 99.2 95.2 86.5 98.4 0.566 17 Levamisole N.A. N.A. N.A. N.A. N.A. N.A. N.A. 18 Pyrantel pamoate 90.7 79.5 96.1 85.6 39.6 98.2 0.513 19 Hookworm 20 Placebo 16.1 9.9 25.1 35.5 15.3 62.5 0.050 21 Albendazole 80.6 72.4 86.9 70.6 53.5 83.4 0.172 22 23 Mebendazole 31.4 16.4 51.6 39.4 20.7 61.7 0.608 24 Levamisole N.A. N.A. N.A. N.A. N.A. N.A. N.A. 25 Pyrantel pamoate 40.5 21.6 62.7 23.9 4.7 67.0 0.250 26 Trichuris trichiura 27 Placebo 9.5 4.6 18.6 3.0 0.6 12.9 0.089 28 Albendazole 38.6 26.2 52.7 16.4 7.7 31.3 0.027 29 Mebendazole 47.5 23.1 73.1 29.2 12.4 54.5 0.365 30 Levamisole N.A. N.A. N.A. N.A. N.A. N.A. N.A. 31 Pyrantel pamoate 37.8 12.9 71.3 64.8 6.0 98.1 0.340 32 Egg reduction rates 33 Treatment ERR 95% CI ERR 95% CI p-value 34 (%) low up (%) low up 35 Ascaris lumbricoides 36 Placebo 17.1 11.6 22.6 44.9 30.0 55.8 <0.001 37 Albendazole 99.5 94.7 100.0 95.4 88.2 100.0 0.295 38 Mebendazole 99.7 93.3 100.0 94.8 87.3 100.0 0.352 39 Levamisole 86.2 72.6 99.8 100.0 96.0 100.0 <0.001 40 41 Pyrantel pamoate 84.3 73.8 94.7 72.8 50.6 95.0 0.090 42 Hookworm 43 Placebo 15.1 3.2 27.1 37.5 14.6 60.4 0.060 44 Albendazole 95.6 85.3 100.0 77.1 62.5 91.7 0.027 45 Mebendazole 69.4 54.3 84.6 51.8 35.3 68.2 0.156 46 Levamisole 53.5 16.4 90.7 75.9 39.0 100.0 0.060 47 Pyrantel pamoate 78.4 50.2 100.0 87.4 21.8 100.0 0.682 48 Trichuris trichiura 49 Placebo 38.9 18.2 59.6 20.0 -3.9 44.0 0.282 50 Albendazole 72.6 53.7 91.5 43.4 23.5 63.3 0.049 51 Mebendazole 91.4 72.9 100.0 54.7 34.6 74.8 0.014 52 Levamisole 45.2 19.9 70.6 26.4 -3.0 55.7 0.282 53 Pyrantel pamoate N.A. N.A. N.A. N.A. N.A. N.A. N.A. 54 *Wald-test of the difference between stratum-specific estimates 55 56 57 58 59 60 34 https://mc.manuscriptcentral.com/bmj BMJ Page 60 of 64
1 2 Appendix Table S14 – Bias assessment 3 Bias assessment according to the Cochrane Collboration Handbook for the 56 included 4 studies, stratified by publication year (before and after the year 2000). 5 6 Bias Total (%) Before 2000 (%) After 2000 (%) 7 Random sequence generation 8 Confidential: For Review Only (selection bias) 9 10 Low risk of bias 23 (41.1) 5 (15.6) 18 (75.0) 11 Unclear risk of bias 30 (53.6) 25 (78.1) 5 (20.8) 12 High risk of bias 3 (5.4) 2 (6.3) 1 (4.2) 13 Allocation concealment 14 (selection bias) 15 Low risk of bias 17 (30.4) 4 (12.5) 13 (54.2) 16 Unclear risk of bias 36 (64.3) 27 (84.4) 9 (37.5) 17 High risk of bias 3 (3.4) 1 (3.1) 2 (8.3) 18 Blinding of participants and personnel 19 (performance bias) 20 Low risk of bias 15 (26.8) 9 (28.1) 6 (25.0) 21 Unclear risk of bias 25 (44.6) 17 (53.1) 8 (33.3) 22 High risk of bias 16 (25.6) 6 (18.8) 10 (41.7) 23 Blinding of outcome assessment 24 (detection bias) 25 Low risk of bias 7 (12.5) 2 (6.3) 5 (20.8) 26 Unclear risk of bias 49 (87.5) 30 (93.8) 19 (79.2) 27 High risk of bias - - - 28 Incomplete outcome data 29 30 (attrition bias) 31 Low risk of bias 29 (51.8) 12 (37.5) (17 (70.8) 32 Unclear risk of bias 25 (44.6) 19 (59.4) 6 (25.0) 33 High risk of bias 2 (3.6) 1 (3.1) 1 (4.2) 34 Selective reporting 35 (reporting bias) 36 Low risk of bias 15 (26.8) 3 (9.4) 12 (50.0) 37 Unclear risk of bias 41 (73.2) 29 (90.4) 12 (50.0) 38 High risk of bias - - - 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 35 https://mc.manuscriptcentral.com/bmj Page 61 of 64 BMJ
1 2 Appendix Table S15 – Cumulative cure rates 3 Total numbers of participants, cured participants and cumulative cure rates for placebo, 4 albendazole, mebendazole, levamisole and pyrantel pamoate against A. lumbricoides , 5 6 hookworm and T. trichiura . 7 8 Confidential:Parasite Treatment For Total no- ReviewTotal no- OnlyCure rate (%) 9 participants participants 10 cured 11 A. lumbricoides Placebo 188 842 22.3 12 Albendazole 3194 3360 95.1 13 Mebendazole 1493 1548 96.4 14 Levamisole 142 149 95.3 15 Pyrantel pamoate 1239 1374 90.2 16 Total 7273 17 Hookworm Placebo 251 1309 19.2 18 Albendazole 1989 3104 64.1 19 Mebendazole 510 2305 22.1 20 Levamisole 13 230 5.7 21 Pyrantel pamoate 118 230 51.3 22 Total 7178 23 T. trichiura Placebo 179 1417 12.6 24 Albendazole 1075 4432 24.3 25 26 Mebendazole 548 2514 21.8 27 Levamisole 14 203 6.9 28 Pyrantel pamoate 87 275 31.6 29 Total 8841 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 36 https://mc.manuscriptcentral.com/bmj BMJ Page 62 of 64
1 2 Appendix figure S1 – One-to-one comparison based on network meta-analysis 3 Odds ratios of cure and differences in egg reduction rates for the one-to-one comparisons for 4 treatments with placebo, based on network meta-analysis. 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 37 https://mc.manuscriptcentral.com/bmj Page 63 of 64 BMJ
1 2 Appendix figure S2 – Network and pairwise meta-analysis plot 3 Odds ratios of cure between different treatments obtained by network meta-analysis on the 4 one hand and pairwise meta-analysis based on direct comparisons on the other hand, for 5 placebo (Plc), albendazole (Alb), mebendazole (Meb), levamisole (Lev) and pyrantel 6 pamoate (PyP) against for Ascaris lumbricoides , hookworm and Trichuris trichiura. 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 38 https://mc.manuscriptcentral.com/bmj BMJ Page 64 of 64
1 2 Appendix figure S3 – Inconsistency plot 3 The inconsistency plot shows the ratios between the odds ratios from direct and from indirect 4 comparisons within the network meta-analysis, along with their 95%-confidence intervals. 5 6
7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 39 https://mc.manuscriptcentral.com/bmj