Overview of the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children

Dr Rima Al-Saffer, Specialist Registrar, Paediatrics, UK

Dr Anna Louise Ridge, Technical Officer, Medicine Access and Rational Use, Department of Essential Medicines and Pharmaceutical Policies, WHO-HQ, Geneva

Contents

Introduction...... 1 Objective ...... 2 Methods ...... 3 Results ...... 4 Drug Name (s)...... 1 Studies reporting data for children...... 1 Efficacy data ...... 1 Safety data ...... 1 PK data...... 1 Doses reported ...... 1 Formulation(s) reported ...... 1 Mebendazole (MBZ) for the treatment of soil transmitted helminth infections...... 1 Levamisole (LVM) for the treatment of soil transmitted helminth infections ...... 1 Pyrantel (PYR) for the treatment of soil transmitted helminth infections...... 2 Niclosamide for the treatment of soil transmitted helminth infections...... 2 Systematic reviews of antihelminthics...... 2 Diethylcarbamazine (DEC) for the treatment of filarial diseases ...... 3 Ivermectin (IVM) for the treatment of filarial diseases...... 4 Systematic reviews for antifilarials...... 4 Praziquantel (PZQ) for the treatment of schistosomiasis ...... 5 Oxamniquine for the treatment of schistosomiasis ...... 6 Triclabendazole for the treatment of schistosomiasis ...... 6 Systematic reviews for treatment of schistosomiasis ...... 7 Metronidazole for the treatment of amoebiasis and giardiasis ...... 7 Studies reporting the metabolism or pharmacokinetics of metronidazole: ...... 7 Diloxanide for the treatment of amoebiasis ...... 8 Systematic reviews for antiamoebic and antigiardiasis medicines ...... 8 Pentamidine for the treatment of 1st stage African trypanosomiasis ...... 8 Suramin for the treatment of the initial phase of Trypanosomal brucei rhodensiense infection...... 9 Melarsoprol for the treatment of 2nd stage African trypanosomiasis...... 9 Eflornithine for the treatment of 2nd stage African Trypanosomiasis ...... 9 Systematic reviews for the treatment of Human African Trypanosomiasis (HAT)...... 10 Benznidazole for the treatment of American trypanosomiasis ...... 10 Nifurtimox for the treatment of American trypanosomiasis ...... 10 Systematic reviews of treatment of American trypanosomiasis (Chagas disease) ...... 10 Gaps in evidence...... 10 Conclusion...... 11 References...... 12 APPENDICES...... 20 Appendix A: ...... 20 WHO Model List of Essential Medicines for children...... 20 Current WHO dosing guidelines from the manual of preventative chemotherapy in human helminthiasis...... 21 Summary of evidence tables ...... 22 Appendix B: Details of search strategy...... 22 Appendix C: Flow diagrams for search results...... 33

i Acronyms

ALB Albendazole DEC Diethylcarbamazine EMLc Essential Medicines List for Children HAT Human African Trypanosomiasis IVM Ivermectin LEV Levamisole LVM Levamisole MBD Mebendazole MBZ Mebendazole MSF Médecins sans Frontières NTDs Neglected tropical diseases PSAC Pre‐school age children PYR Pyrantel PZQ Praziquantel RCT Randomized controlled trials WHO World Health Organization

ii What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Introduction

In October 20081 the Subcommittee of the Expert Committee for the Selection and Use of Essential Medicines reviewed the following medicines:

– Antischistosomals and antitrematode medications – Antiamoebic and antigiardiasis medications – Antitrypanasomal medicines

The lack of new medicines for treatment options was highlighted, as well as the lack of information (particularly in relation to the antitrypanasomal medications) about efficacy and safety for their use in the paediatric population. The Subcommittee therefore requested that the clinical evidence for these medicines should be reviewed. This recommendation was subsequently endorsed by the Expert Committee.

Neglected tropical diseases (NTDs) are a group of communicable diseases which thrive in impoverished settings and blight the lives of around one billion people worldwide, while threatening the health of millions more. Despite the numbers affected by tropical diseases there is currently very little in the way of new treatments to offer old diseases. WHO recently published a report that focuses on 17 neglected tropical diseases and disease groups.* The report found that there are currently 149 countries and territories where neglected tropical diseases are endemic, at least 100 of which are endemic for 2 or more of these diseases, and 30 countries that are endemic for 6 or more.

The diseases identified in the report as the main NTDs are: Dengue Rabies Trachoma Buruli ulcer Endemic treponematoses (including yaws) Leprosy Chagas disease (American trypanosomiasis) Human African trypanosomiasis (sleeping sickness) Leishmaniasis Cysticercosis Dracunculiasis (guinea‐worm disease) Echinococcosis Foodborne trematode infections Lymphatic filariasis (elephantiasis) Onchocerciasis (river blindness) Schistosomiasis (bilharziasis) Soil‐transmitted helminthiases (intestinal parasitic worms)

* WHO (2010). Working to overcome the global impact of neglected tropical diseases. First WHO report on neglected tropical diseases. Geneva: World Health Organization.

1

Gap analysis

The World Health Organization (WHO) recommends five public‐health strategies for the prevention and control of neglected tropical diseases:

1. Expansion of preventive chemotherapy 2. Intensified case‐detection and case management 3. Improved vector control 4. Appropriate veterinary public health measures 5. Provision of safe water, sanitation and hygiene

The purpose of this review is to identify existing evidence for the medicines currently included in the WHO Model List of Essential Medicines for Children and recommended for the treatment of schistosomiasis, soil‐transmitted helminthiasis, filarial diseases, amoebiasis, giardiasis, Human African trypanosomiasis and Chagas disease (American trypanosomiasis), in the paediatric population.2‐5

Objective

To identify evidence to support the use of medicines currently listed in the WHO Model List of Essential Medicines for Children for the treatment of the specified neglected tropical diseases in children 0‐18 years of age, with a particular focus on use in children less than 4 years of age.

2 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Methods

Search strategy

To identify efficacy and safety data for the specified medicines in children a systematic search of the literature was performed using the following electronic databases: the Cochrane Trials Register, Cochrane Database of Systematic Reviews, Medline/Pubmed (1950‐ present), Embase (1980‐present), Public Library of Science (PLoS) open access, WHO database, Royal Society of Medicine online catalogue, JAMA, Bulletin of the World Health Organization and Memórias do Instituto Oswaldo Cruz. In addition reference lists of the most relevant articles were searched. The full search strategy can be founding Appendix B.

Individual drugs and terms searched: (Appropriate MeSH terms and subject headings were identified for each database)

– Mebendazole, levamisole, pyrantel, niclosamide: helminths (including individual helminthic species). – Praziquantel, triclabendazole, oxamniquine: helminth, schisotosomiasis (S. Mansoni, S. Japonicum, S. Haematobium). – Ivermectin, diethylcarbamazine: filariasis (individual species), lymphatic filariasis, onchocerciasis, loasis. – Diloxanide: amoebiasis, entamoeba histolytica. – Metronidazole: giardiasis, neonates, sepsis. – Pentamidine: Trypanosoma brucei gambiense, sleeping sickness, Human African Trypanosomiasis. – Suramin sodium: Trypanosoma brucei rhodensiense (and terms as for pentamidine). – Eflornithine, melarsoprol: As above. – Benznidazole, nifurtimox: Chagas disease, American trypanosomiasis, Trypanosoma Cruzi.

The individual drug, relevant pathogen and neglected tropical disease search terms (as shown above) were then combined individually with the following: (children OR paediatrics OR neonates OR pre‐school age children) AND (safety OR efficacy) AND (pharmacokinetics OR pharmacodynamics) AND (dosing OR scheduling).

Selection criteria

To assess clinical efficacy all interventional studies with or without a control group (using either differing doses for comparison or other appropriate drugs) were deemed eligible for inclusion. With respect to safety data, all study designs where considered eligible for inclusion.

3

Gap analysis

Inclusion criteria:

– Studies including children (0‐18 years), from which paediatric data could be extracted. – Studies published in the English language. – Randomized controlled trials (RCT), quasi RCT, cohort studies, case control studies, case series, observational studies.

Exclusion criteria:

– Non‐English studies. – Studies including data for adults and children, where paediatric data were not reported separately. – Studies reporting adult data only.

Results

A summary of the available paediatric specific efficacy and safety data for each of the individual medicines is provided below (all tables can be found in Appendix A).

Table 1 provides an overview of the evidence.

4 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Table 1 Summary of available evidence Drug Name (s) Studies reporting data for Efficacy data Safety data PK data Doses reported Formulation(s) children reported Mebendazole 10 studies (9 RCTs6‐14, 1 All studies, except 3 studies reported No 200 mg tds; Tablet (MBZ) observational15; n=6856, age Flohr et al. 20077 adverse events as an 500 mg od (most 500 mg chewable range 6 mos to 70 yrs) showed treatment outcome. 6,8,9 No serious commonly used); tablet 2 studies included children <3 with MBZ to be adverse events reported. 600 mg multiple No other years6,9 effective Main problems: nausea, doses information abdominal distension provided and discomfort Levamisole (LVM) 3 studies (2 RCTs8,16, 1 All studies showed Adverse events No < 3 yrs 40 mg Tablet observational17; n=1633; age efficacy based on occurring once in 3‐9 yrs 60 mg range 1 to 19 yrs) reduction in egg different patients >9 yrs 80 mg 2 studies included children <4 counts. Albonico et (temperature rise, loose yrs16,17 al. 2003 showed stools, convulsion) not LVM to have reported to be directly smaller effect on related to LVM. No egg clearance other adverse events compared to MBZ reported or MBZ+LVM Pyrantel (PYR) 4 studies (3 RCTS11,12,20, 1 Effective in treating None of the studies No 10 mg/kg/day Tablet observational study14) ascaris provided any 11 mg/kg/day 3 included only children12,14,20 lumbricoides information about 12.5 mg/kg/day (n= 2074; age range 2 yrs to 10 Poor efficacy for adverse events/safety yrs treating hookworm 15‐20 kg: 150 mg 1 included adults and infections 21‐30 kg: 300 mg children11 (n=147; age range 3 Higher cure rate 31‐40 kg: 450mg yrs to 70 yrs) than MBZ for trichuriasis infection, but less effective than albendazole

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Gap analysis

Drug Name (s) Studies reporting data for Efficacy data Safety data PK data Doses reported Formulation(s) children reported Niclosamide No x x x x x Diethylcarbamizine 6 studies (3 RCTs25,28,29, 3 All studies showed Mild adverse events No 6 mg/kg No information (DEC) observational studies30,31,33; n= efficacy with a reported (nausea, reported >12000; age range 1 to 87 reduction in mf and vomiting, fever, years antiginaemia headache). No cessation of treatment required Ivermectin (IVM) 7 studies (4 RCTs24,26,27,29; 1 IVM treatment No serious adverse No Dose ranged from 3 mg tablets comparative field trial34, 1 alone had lower mf events reported. Most 150 mcg/kg to 400 follow up study32, 1 safety clearance rates than frequently reported side mcg/kg study35; n= age range 3 yrs to combination effects: headache, 87 yrs) therapy (IVM + swellings, arthralgia and 2 studies included children <4 albendazole) fever yrs29,32 Praziquantel (PZQ) 13 studies (8 RCTs39‐46, 1 safety Efficacy against S. 7 studies reported No 20 mg/kg single oral 200 mg tablet pilot study48, 1 observational haematobium adverse events as an dose study51, 1 clinical efficacy (cure rate of 88.5%; outcome40‐43,46,47,49. 20 mg/kg 2 oral trial49,50, 1 quasi RCT47) egg reduction rate Generally side effects doses 8 studies included only 98.2%) were mild and transient 20 mg/kg 3 oral children39,41,44‐46,49‐51 (n = 5181; PZA more (dizziness, headache, doses age range 4 yrs to 18 yrs) efficacious than abdominal pain, 40 mg/kg single 5 studies included adults and Niridazole, vomiting, diarrhoea). dose children40,42,43,47,48 (n= 5710; age Metrifonate and No cessation of 60 mg/kg split dose range 7 yrs to 60 yrs) placebo with treatment required 3 hrs apart ascorbic acid Praziquantel (PZQ) 5 observational studies All studies showed All studies reported No 40 mg/kg Tablet 600mg Additional 4 studies included pre‐school efficacy of PZQ adverse events as an 1‐3 yrs: 518 mg; 1 (crushed and information from age children98‐101 (n= 1748; age tablets and PZQ outcome. In general, tablet mixed with unpublished range 1 mth to 6 yrs) syrup with PZA tablets and/or >3‐5 yrs: 740 mg; 11/4 orange juice for studies 1 study included primary reduction in egg syrup were well tablet younger children school children97 (n= 5700 age counts in tolerated, with mild, >5‐6yrs: 977 mg; 12/3 unable to range 6 yrs to 12 yrs). consecutive stool/ transient side effects. tablet swallow tablets;

2 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Drug Name (s) Studies reporting data for Efficacy data Safety data PK data Doses reported Formulation(s) children reported urine samples. Reported side effects: required dosage Although, efficacy fatigue, dizziness, was broken into of PZQ tablets drowsiness, headache, smaller pieces or shown to be greater loss of appetite and crushed using than efficacy of stomach ache. 1 study mortar and PZQ syrup. PZA showed symptoms pestle. A honey treatment resulted were significantly based solution in significant higher among was added to reduction in overall uninfected children make a infection compared to those with suspension for prevalence (29.5% s.mansoni some of the to 5.68%) and children ) infection intensity Syrup 19.7 to 1.39 (EPIQUANTEL®) eggs/10ml urine. Oxamniquine 9 studies (4 RCTs52‐54,58, 4 More effective at Adverse events No 10 mg/kg bd for 1 Capsule clinical efficacy trials55‐57,59, 1 treating S. Mansoni generally mild and day or 2 days Suspension follow up study60) infection than S. transient. 15 mg/kg single 4 studies only included Haematobium Dizziness, headache and dose or bd for 1 children52,55,57,58 (n= 510; age In children, lower drowsiness were the day, 2 days or 8 range 2 yrs to 16 yrs) doses, not as most commonly days 5 studies included adults and successful in reported side effects. 20 mg/kg single oral children53,54,56,59,60 (n > 1261; age achieving cure as dose or bd for 1 day range 2 yrs to >20 yrs) same doses in or 3 days adults. Higher 800 mg/m2/day in 2 doses associated divided doses with an increase in (approx. 60 mg/kg) adverse events. Optimal dose for Better tolerated and children reported to more effective in be 30 mg/kg over 2 adult groups days (Ayele et al

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Gap analysis

Drug Name (s) Studies reporting data for Efficacy data Safety data PK data Doses reported Formulation(s) children reported 1986, n=162; age < 15yrs) Triclabendazole 3 studies (1 pilot study61, 1 Cure rate with No significant adverse No 10 mg/kg od or bd Oral community dose comparison single dose 74.9% events. Good No other study62; 1 case series63, n= 184; Higher cure rate tolerability information age range 2 yrs to 62 yrs). All (93.9%) with 2 reported the studies included adults doses and children Metronidazole 5 studies (1 RCT69; 1 All studies showed Adverse events mild, 4 studies. 15 mg/kg in 3 Oral route of prospective open label efficacy by transient and did not Preterm and divided doses for 7 administration. randomized trial70; 1 survey of parasitological require cessation of term infants days No other efficacy and adverse events71; assessment of stool treatment. Reported have a lower 20 mg/kg/day for 5 information 2 comparative trials72,73; n= age samples.. Cure side effects included: total body days provided range 7 mos to 12 yrs). Only 1 rates ranged from anorexia, nausea, clearance and 30 mg/kg bd for 7 study included children <2 80% to 97% vomiting, malaise and prolonged days yrs79 metallic taste half‐life, whereas children over 4 have PK parameters similar to adults. Dose should be decreased in malnourished children. Diloxanide 2 studies (1 comparative Unable to Most commonly No 25 mg/kg od for 10 Oral. No other trial79, n= 39; age range 7 mos determine efficacy reported side effect: days information to 10 yrs; 1 retrospective data from flatulence. Fewer provided study80 n= 4371 treatment information adverse events reported

4 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Drug Name (s) Studies reporting data for Efficacy data Safety data PK data Doses reported Formulation(s) children reported courses from 1977 to 1990) reported in in those aged 20 mos to comparative trial 10 yrs than those aged >10 yrs Pentamidine 3 studies (1 clinical study86, 1 Not reported No serious adverse No 4 mg/kg i.m once Intramuscular phase II clinical trial87, 1 events reported daily for 7 days injection retrospective study88; n = 3133; age range 0 to > 15yrs Suramin No x x x x x Melarsoprol 4 studies (2 RCT82,84, 1 phase II melarsoprol + Significantly toxic. No Over 26 days: 3 Intravenous clinical trial87, 1 retrospective eflornithine not as Some deaths series of 4 daily i.v infusion analysis88; n= 3035; age range 0 effective as attributable to infusions starting at to 62 yrs. All the studies nifurtimox + complications of 1.2 mg/kg, included both adults and eflornithine (cure treatment. increasing to 3.6 children rates 44% vs. 94% Poorly tolerated by all mg/kg with a 7 day respectively) age groups. Very young interval between (<2 yrs) more prone to series jaundice and rash than 1.8 mg/kg/d for 10 adults. days Lower incidence of 2.2 mg/kg/d for 10 encephalopathic days syndrome in PSAC, but higher mortality rate in those that did develop it Eflornithine 5 studies (3 RCTs82,83,85, 1 Eflornithine has Number of adverse No 100 mg/kg 6 hourly Oral retrospective study88, 1 clinical equal efficacy to evnts increased with for either 7 or 14 Intravenous trial89; n = 3509; age range 0 to melarsoprol longer duration of days infusion 77 yrs) treatment, but only 200mg/kg 12 hourly 2 studies included children < 2 statistically significant for 14 days yrs88,89 for diarrhoea and 100 mg/kg i.v 6 infections. hourly for 14 days, Less toxic than followed by 75

5

Gap analysis

Drug Name (s) Studies reporting data for Efficacy data Safety data PK data Doses reported Formulation(s) children reported melarsoprol mg/kg orally 6 hourly for 21 days

Benznidazole 7 studies (4 RCTs90‐93, 1 follow 3 studies90‐92 Minor adverse events No 2.5 mg/kg bd for 60 Tablets up study94, 1 observational showed efficacy in (gastrointestinal days 100 mg tablets study95, 1 control program comparison to disorders; rash). 5 mg/kg/d ground up and study96 (MSF project); n= age placebo in children No deaths reported 7.5 ,g/kg once daily capsules filled range newborn to 18 yrs) with indeterminate for 30 or 60 days with 8, 10, 13 and or early stage 7.5 mg/kg bd or tds 15 mg powder to trypanosome cruzi for 60 days treat neonates Maximum dose according to 300mg/d weight Nifurtimox (N) 2 studies (2 RCTs82,85; n> 54; Only used in Combination of N+E No 15 mg/kg/d 8 hourly Oral age range 5 yrs to 62 yrs). Not combination with well tolerated. Low for 10 days possible to extract paediatric eflornithine (E) or fatality rate compared to 20 mg/kg/d 8 hourly specific data from either study melarsoprol (M) melarsoprol (0.76% vs. for 10 days N+ E more effective 6%) than M + E (cure rates 94% vs. 44% respectively) Abbreviations used in table: RCT = randomized controlled trial; mos = months; yrs = years; tds = 3 time daily; od = once daily; bd = twice daily; mf = microfilarial load; d = day

6 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Mebendazole (MBZ) for the treatment of soil transmitted helminth infections

Ten studies were identified that included childrenʹ nine RCTs (4 of which were double blinded and placebo controlled)6‐14 and one observational study.15 The age of participants ranged from 6 months to 18 years; the number of participants ranged from 96 to 3028 (Refer to Table 2). Only 2 studies, Montresor et al.9 and Stoltzfus et al.6 included children in the pre‐ school age group (starting from 6 months of age). A variety of different doses were used across the studies:

– MBZ 500 mg tablet (described as oral intake) single dose. – MBZ 200 mg taken 3 times daily orally. – MBZ 600 mg taken orally ʺmultiple dosesʺ.

The 500 mg dose of MBZ was the most commonly used (8/10 studies).6‐9,11‐12,14 None of the studies provided evidence for the dosing and scheduling of MBZ in children. The pharmacokinetic data identified referred only to adults. The only formulation that was used in the studies was a tablet dosage form (regardless of patient age). Only one study reported using a chewable tablet (Stoltzfus et al6). No information was provided in the studies regarding how the tablets were administered to the different age groups.

All the studies, with one exception (Flohr et al.7), showed treatment with MBZ to be effective with a reduction in prevalence and intensity of STH infections. Efficacy was measured by reduction or absence of helminth eggs in the faeces.

Three studies (Albonico et al.8, Montresor et al.9, Cañete et al.13) reported adverse events as well as efficacy. No serious adverse events were noted in any of the studies. The adverse events that were documented required no medical intervention and were mainly symptoms of nausea, abdominal distension and discomfort.

Despite an informal consultation by the WHO in 2002 evaluating the evidence for safety and efficacy of MBZ use in the under 24 months age group there have been no new randomized controlled trials since that of Montresor et al. 2002.9 There was one observational study by Morrone et al.15 in 96 preschool age children, but the results were not stratified into age groups. The aim of this study was to determine use and frequency of chemotherapeutic agents within that age group, and efficacy and safety was not specifically evaluated.

Levamisole (LVM) for the treatment of soil transmitted helminth infections

Three studies were identified that included childrenʹ two RCTs (Albonico et al.8 and Thein‐ Lang et al.16) and one observational study (Lionel et al.17). Both the RCTs used a valid method of randomization, but only Albonico et al.8 had a placebo control arm. Both studies were non‐blinded. The age of participants ranged from 1 to 19 years. In the case series study by Lionel et al.17 nine children under 2 were included, but the lower limit of the age range was not reported (Table 3). Doses of LVM used in the studies ranged from 40 mg to 80 mg depending on the childʹs age. In one study (Thein‐Lang 16) the dose used was not reported ‐ only documented as ʺper manufacturers guidelinesʺ. No information was given about how the tablets were administered to the children.

1

Gap analysis

All studies showed there was efficacy based on reduction in egg counts. Albonico et al.8 (n=914, age range 7‐18 years) that LVM had a smaller effect on egg clearance when compared to treatment with MBZ or combined MBZ/LVM.

At the dosages reported above few adverse events were reported. Thein‐Lang et al.16 reported a temperature rise, loose stools and convulsions occurring once in different patients; on each occasion it was found to not be related to LVM.

There are data describing the long‐term effects of LVM use in childhood nephrotic syndrome18‐19 indirectly giving further evidence of safety of its use in children. The studies showed LVM to be well tolerated with minimal side effects. These studies were reviewed, but not reported in Table 3 as dosing regimens, scheduling and efficacy outcomes were unrelated to aim of this review.

Pyrantel (PYR) for the treatment of soil transmitted helminth infections

Four studies were found that reported efficacy data for childrenʹ three RCTs and one longitudinal evaluation (Table 4). Forrester et al20, Albonico et al.12 and Northrop‐Clewes et al.14 recruited children for their studies, age range 2 to 10 years. Sacko et al.11 included children and adults, with an age range of 3 to 70 years. The number of participants ranged from 147 to 1329.

The reported dose of pyrantel used in the studies varied from 10 mg/kg/day to 12.5 mg/kg/day. One study12 stratified the dosing by weight bands: 15 to 20 kg – 150 mg tablet; 21 to 30 kg ‐ 300 mg tablet and 31 to 40 kg ‐ 450 mg tablet. The range across the different weights is therefore 10 mg/kg to 14.5 mg/kg.

The only formulation reported in the studies was a tablet. Pyrantel overall showed good efficacy in the treatment of soil transmitted helminths, but in the study by Forrester et al.20 it was found to be less effective against Trichuriais infection compared with albendazole. In the other studies pyrantel was shown to have comparative cure rates to mebendazole in treatment of A. Lumbricoides, Trichuria trichuris and human hookworm infections.

None of the studies reviewed reported adverse events.

Niclosamide for the treatment of soil transmitted helminth infections

No studies were identified that met the inclusion criteria.

Systematic reviews of antihelminthics

A systematic review by Keiser et al.21 reviewed the efficacy of single oral albendazole, mebendazole, levamisole, and pyrantel against A. lumbricoides, hookworm and T. trichuria infections. Twenty RCTs were included in the systematic review, of which 9 included children. The review concluded that treatment success was dependent on the type of soil transmitted nematode that was being treated. Albendazole, mebendazole and pyrantel were

2 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children? all effective at curing A. lumbricoides (cure rate 88‐93%), but were less successful in producing cure rates for T. trichuria and human hookworm infections (15‐36%).

Taylor‐Robinson et al.22 evaluated the effects of treatment on school performance. Adverse events were reported as a secondary outcome. Adverse events were found to be mild and transient and not requiring cessation of treatment. Nausea and abdominal discomfort were the most commonly reported side effects.

Albonico et al.23 did a review summarizing the data available to support the use of antihelminthics in pre‐school age children. They reviewed 17 published reports on the prevalence of STH in pre‐school age children and evaluated the safety and efficacy of medication used in children. The review highlighted issues that needed to be addressed urgently:

1. Monitoring safe administration 2. Monitoring efficacy 3. Need for paediatric formulations.

Refer to Table 5 for further details.

Diethylcarbamazine (DEC) for the treatment of filarial diseases

Six studies reported efficacy and/or safety data for the use of DEC in children. Three RCTs.25,28,29 One study, although initially a double‐blinded placebo controlled RCT, had its placebo arm terminated early when efficacy of treatment became evident.29 The remaining 3 studies were monitoring/evaluation studies of the impact of community mass drug administration programmes and included both adults and children 30‐31,33(Table 6).

The reported dose of DEC administered in all the studies was 6 mg/kg. The age range across the studies was 1 to 87 years, with sample sizes ranging from 82 to 18,415 participants. A monitoring study by Weil et al.30 reported the impact of mass drug administration with DEC and albendazole in the 2‐5 year age group. All the studies using DEC as a treatment arm showed efficacy with a reduction in microfilaria and antiginaemia in the younger age groups.28,30,33 Babu et al31 reported adverse events of nausea, vomiting, fever, headache, however no cessation of treatment was required. Kshirsaga et al.25 assessed the safety of DEC in 5‐12 year olds. They concluded that there was a good safety profile with good tolerability. However, it was not possible to determine the type and frequency of the adverse events from what was reported in the study.

Despite the inclusion of children in the community mass drug administration evaluation and monitoring studies, children under six years of age frequently did not have blood tests to determine microfilaria load. The burden of microfilaria in those less than six years was not reported and the evaluation of the impact of mass drug administration on microfilaria in these children was not possible following subsequent rounds of treatment.

Apart from the dose, no information was reported about how the medicine was administered to pre school age children. Data for efficacy and safety for children under 4

3

Gap analysis years of age could not be extracted as results were not stratified by age. No studies were found that reported pharmacokinetic data for the paediatric population (specifically in those <4 years)

Ivermectin (IVM) for the treatment of filarial diseases

Seven studies were identified that included children in treatment groups. Four RCTs24,26,27,29, 1 follow up study32, 1 comparative field trial34, and 1 safety study35. Only two studies included children less than 4 years (Ramaiah et al.29 and Ndyomugyeni et al.32). Results were stratified for Ramaiah et al.29 as percentage microfilaria in the 0‐5 age range and as <10 years in the Ndoyomugyeni et al.32 study. Two RCTs (Beach et al.24 and Simonsen et al.26) evaluated IVM efficacy in children aged 5 to 18 years (Table 6).

The age range of participants across the studies was 3 to 87 years and the number of participants ranged from 182 to 5,055 participants. The dosage of IVM used in the studies ranged from 150 mcg/kg to 400 mcg/kg. Tablets were the only formulation mentioned. No information was provided about how the tablets were administered to younger children.

Efficacy was measured in terms of microfilarial clearance. IVM treatment alone compared to combination therapy had lower microfilarial clearance rates. Four studies specifically mentioned adverse events associated with treatment (Simonsen et al.26, Asio et al.27, Vyungumana et al.34, Mohammed et al.35) but only Vyungumana et al.34 reported the frequency and type of adverse events. The most frequently reported side effects were headache, swellings, arthralgia and fever. In general side effects were mild and transient and all the studies described ivermectin as well tolerated.

Systematic reviews for antifilarials

The systematic review by Adinarayan et al.36 evaluated the effect of DEC medicated salt on infection with lymphatic nematodes. Twenty‐one RCTs were included. Extraction of paediatric data from the review was difficult, since the study descriptions lacked details of age ranges. Outcomes measured were microfilaria prevalence, adverse events, disease status, and change in vector infection or infectivity rates. The authors concluded that DEC‐ medicated salt was an effective intervention with minimal side effects and good tolerability. Tisch et al.37 examined what drug interventions were most effective in reducing circulating microfilaria. Forty‐three RCTs and fourteen field trials were included. No age range was specified, but it was assumed that children had been included in the community trials. Safety and tolerability of the drugs were not reported (Table 7)

A review by Olsen38 of 31 studies and 2 abstracts evaluated the efficacy and safety of combinations of various medicines, including of albendazole (ALB)‐praziquantel (PZQ), ivermectin (IVM), diethylcarbamazine (DEC) and mebendazole, in the treatment of schistosomiasis, soil‐transmitted helminthiasis, lymphatatic filariasis or onchocerciasis. Sample size across the studies ranged from 25 to 2000; age range 2 to 98 years. There were no significant pharmacokinetic interactions when ALB‐PZQ, ALB‐DEC, ALB‐IVM or ALB‐ IVM‐PZQ were co‐administered. Efficacy of IVM in the treatment of lymphatic filariasis was enhanced by combination with DEC.

4 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

No systematic review of studies exclusively in the paediatric population was identified.

Praziquantel (PZQ) for the treatment of schistosomiasis

Thirteen studies were identified with efficacy and or safety data reported separately for children (Table 8): 8 randomized blinded placebo controlled trials39‐46, 1 study was described as a RCT, but the method used for randomization was not reported47, 1 safety pilot study48, 2 clinical trials of efficacy49,50 and 1 longitudinal intervention study.51

The age range across the studies was 4 to 60 years; sample size ranged from 80 to 5,055 participants. The majority of the studies only included children; exceptions were: Hou et al.43, Ferrari et al.40, Mohammed et al.48, Davis et al.47 and Inyang‐Etoh et al.42. However, in the study by Davis et al47 (n=80) only 4 out of 80 participants were >16 (age range 7‐22 years). None of the trials included children under the age of four.

Dosages of PZQ used varied from 20‐60 mg/kg/dose, administered as either a single dose or divided into 2‐3 doses over the course of either a single day or over a course of several weeks (refer to Table 8 for further details). The medication was administered orally and only available in tablet form. Davis et al.47 evaluated the effectiveness of different doses of PZQ (single dose versus 2 doses versus 3 doses, each ʺdoseʺ 20 mg/kg). All the doses showed high efficacy in clearance of S. haematobium and no serious adverse effects were reported.

Efficacy of treatment was determined by intensity and prevalence of infection (egg counts in faeces/urine or hatching test). Of the 13 studies reviewed 7 reported adverse events as an outcome (Ferrari et al.40, Sissoko et al.41, Hou et al.43, Midzi et al.49, Inyang‐Etoh et al.42, Keiser et al.46 and Davis et al.47). These 7 studies reported that adverse events were minimal, with no need to withdraw treatment. Side effects such as dizziness, headache, abdominal pain, vomiting and diarrhoea were described as transient and mild, not requiring cessation of treatment. No studies were identified that reported pharmacokinetic data for PZQ in children.

Additional information following a WHO meeting to review results from studies on the treatment of young children for schistosomiasis

A meeting was held at WHO‐HQ on 13th‐14th September 2010 to discuss the results from 5 observational studies undertaken in 5 different countries (Egypt, Sudan, Niger, Zimbabwe and Uganda) investigating safety and efficacy of PZA treatment in young children with schistosomiasis (n= 7448; age range 0.1 mth to 12 years)97‐101. All studies showed efficacy of PZQ tablets and/or PZQ syrup with reduction in egg counts in consecutive stool and urine samples. However, cure rates were lower among Egyptian school children treated with PZQ suspension than those treated with PZQ tablets under all circumstances (Barakat et al.97). Egg reduction rates were the same regardless of whether child received suspension or tablet.

All studies reported adverse events as an outcome (see Table 8). In general, PZA tablets and/or syrup were well tolerated, with mild, transient side effects. Reported side effects included fatigue, dizziness, drowsiness, headache, loss of appetite and stomach ache. One study (Kabatereine et al.100) showed reported symptoms post treatment to be significantly higher among uninfected children compared to those with S. mansoni.

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Gap analysis

Administration of praziquantel to pre‐school‐age children was shown to be acceptable, safe and efficacious in the context of individual case management and large group settings.

Oxamniquine for the treatment of schistosomiasis

Nine studies were identified that reported paediatric safety and/or efficacy data: 4 RCTs52‐ 54,58, 4 clinical trials of efficacy55‐57,59 and one 2‐year follow up study of an efficacy trial.60 The studies by Ayele et al52, Axton et al.55, Katz et al.(1991)57 and Lambertucci et al.58 only included children, age range 6 to 16 years. The remaining trials recruited both adults and children, age range across the studies 2 to >20 years.53,54,56,59,60 The number of participants ranged from 57 to 1,138 (Table 9).

Doses of oxamniquine ranged from 10 mg/kg to 60 mg/kg across the various studies. The mode of administration was oral, either in a capsule form or suspension for the young children. The age of those receiving suspension rather than tablet form was not reported. The doses were given once daily or in divided doses either over several hours or over 2 days. Reported adverse events were mild and transient: dizziness and drowsiness were the most frequently.

Oxamniquine in children at lower doses did not appear to be as effective as in adults in achieving cure rates. The higher doses were associated with an increase in adverse events. The optimal dose for treatment as determined by Ayele et al.146 was 30 mg/kg over 2 days. The consensus from the studies that included both adult and children was that oxamniquine was better tolerated and more effective in the adult groups. No studies were identified that reported pharmacokinetic data for the use of oxamniquine in children.

Triclabendazole for the treatment of schistosomiasis

Three studies reported data relating to efficacy and safety of triclabendazole: 1 pilot study,61 1 community dose comparison study,62 1 case series63. All the studies included a mixture of adult and paediatric participants but none of the studies stratified the results by age. The age range of participants in the studies was 2 to 62 years of age, with the number of participants ranging from 10 to 134 participants (Table 10). None of the studies were randomized or had a control arm. The studies found that triclabendazole was effective for the clearance of fascioliasis cysts. The study by El‐Morshedy et al.62 provided more convincing efficacy data, as the sample group was larger (134 participants). Cure rates for single dose and 2 doses 24 hours apart were 74.9% and 93.9% respectively. Tolerability was reported to be good and no significant adverse events were reported.

A case series by El‐Karaksy et al.63 looked at the effectiveness and tolerability of triclabendazole for the treatment of fasciola hepatica in Egyptian children. The series demonstrated that a 78% cure rate was achievable with minimal side effects. The age range of this population was 4 to 15 years of age.

6 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Systematic reviews for treatment of schistosomiasis

Saconata et al.64 analysed thirteen RCTs in their systematic review. The aim was to determine the efficacy of PZQ and oxamniquine in the treatment of S. mansoni. The conclusion was that both treatments were effective treatment options with minimal adverse events documented. Paediatric data were difficult to extract.

Danso‐Appia et al.65 reviewed treatment options of PZQ, metrifonate, artemisinin derivatives or albendazole alone or in combination for urinary schistosomiasis. Twenty‐ four trials were included; 19 of which reported the use of PZQ in children >5 years. Only one trial in the review described treatment of children <5 years (Wilkins et al.66) but information about administration of treatment for those under 5 years could not be extracted. Refer to Table 11 for further details.

Metronidazole for the treatment of amoebiasis and giardiasis

Six studies were identified with extractable paediatric data: 1 prospective open labelled randomized trial, 1 RCT69, 1 prospective open label randomized trial70, 1 survey study of efficacy and adverse events71, and 3 comparative studies.72,73,79 The studies reported treatment outcomes for either amoebiasis or giardiasis. The age range of the participants in the reviewed studies was 7 months to 12 years of age, with a sample size of 39 to 122 participants. Only one study by Rubidge et al.79 included children under the age of 2 years (Table 13). Dosing regimens for metronidazole were different in all the studies; 15 mg/kg in 3 divided doses for 7 days, 20 mg/kg/day for 5 days and 30 mg/kg twice daily for 7 days. Dosing appeared to be via the oral route, but it was difficult to ascertain from some studies and no further information about formulation was reported. Treatment with metronidazole was assessed by parasitological clearance of cysts in all the studies. Adverse events were considered mild, transient and did not require cessation of treatment. Adverse events of anorexia, nausea, vomiting, malaise, and metallic taste were reported by Sadjjadi et al.73, the other studies mentioned nausea as the most frequently reported side effect. Refer to tablets 12 and 13 for more information.

Studies reporting the metabolism or pharmacokinetics of metronidazole:

Alestig et al.74 (1980) measured serum concentrations and urinary excretion of metronidazole after single dose therapy in patients with giardiasis in 10 adults and 6 children (ages not stated). Results were reported as an average of all participants and not age specific.

Lares‐Asseff et al.75 (1992) published a study evaluating at the pharmacokinetics of metronidazole in severely malnourished and nutritionally rehabilitated children that suggested that the dose of metronidazole should be reduce in malnourished children.

Lau et al.76 (1992) (only abstract available) reviewed the historical pharmacokinetic studies for metronidazole, including data obtained from specific chromatographic techniques to measure parent drug and metabolite activity. The main finding of the review was that preterm and term infants have a lower total body clearance and prolonged half‐life, whereas children over 4 have pharmacokinetic parameters similar to adults. Children who were

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Gap analysis malnourished also had delayed clearance of the drug. The study found that also the oral bioavailability is close to 100%.

There have been suggestions that infants as young as 6 weeks metabolize metronidazole in a similar manner to adults.77 Amon et al.78 (1983) assessed children aged 6 weeks to 14 years in whom treatment with metronidazole was started and their findings suggested that there was little difference in kinetic parameters between children and adults.

Diloxanide for the treatment of amoebiasis

Two relevant studies were found from which paediatric data could be extracted, 1 randomized comparative trial79 and 1 retrospective analysis of efficacy and safety data80 (Table 13). A comparative trial by Rubidge et al79 evaluated children (n= 39) between 7 months to 10 years of age. Twenty participants received treatment with metronidazole, with the remaining participants being given a combination of treatments, one of which was diloxanide. It was not possible to extract efficacy and safety data for diloxanide from this study; however the author concluded that metronidazole was an effective and well‐tolerated treatment.

A study by McCauley et al.80 analysed efficacy and adverse event data associated with diloxanide treatment and found that fewer adverse effects were reported for persons aged 20 months to 10 years than for persons aged > 10 years (6/206 versus 89/763) with 86% of those treated achieving parasitological cure. Reported adverse events included flatulence, dizziness, diarrhoea or cramping, nausea and headache. No cessation of treatment was required. The study demonstrated that diloxanide was a safe and effective treatment in children for clearance of E. Histolytica cysts.

Systematic reviews for antiamoebic and antigiardiasis medicines

A systematic review by Gonzales,81 evaluated antiamoebic medicines for treating amoebic colitis (37 studies, n= 4487). Of those trials, 10 included only children (<15 years) and 10 included both adults and children. Results for children alone were not extractable from the review. The overall finding of the review was that tinidazole reduced clinical failure compared to metronidazole (8 studies, n=477) and caused fewer side effects. The trials reviewed were reported to be inadequate or unclear in methodological quality (Table 14).

Pentamidine for the treatment of 1st stage African trypanosomiasis, (Trypanosoma brucei gambiense infection)

Three efficacy studies including children, were identified, 1 clinical study86, 1 clinical trial (phase ii)87, and 1 retrospective analysis88 (Table 15). Sample sizes ranged from 523 to 1952; age range of participants ranged from 0 to 15 years. Only 1 study (Eperon et al)88 stratified the participants by age groups and reported the results according to these age stratifications. The dose of pentamidine administered in all the studies was 4 mg/kg given intramuscularly. The overall results showed use of pentamidine in all age groups was safe and effective with no reports of serious adverse events.

8 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Suramin for the treatment of the initial phase of Trypanosomal brucei rhodensiense infection

No studies from which paediatric data could be extracted were found.

Melarsoprol for the treatment of 2nd stage African trypanosomiasis

Four studies were found with extractable safety and efficacy data for children, 2 randomized clinical trials82,84, 1 phase II clinical trial87 and 1 retrospective comparative analysis.88 The age range across the studies was 0 to 62 years and sample sizes ranged from 52 to 1958 patients (Table 15). Eperon et al.88 was the only study to present results specifically for pre‐school age children.

The dose of melarsoprol used varied from 1.2 mg/kg to 3.6 mg/kg, with the most commonly used dose of 2.2 mg/kg being administered as an intravenous infusion. The results from all the reviewed studies showed that melarsoprol was poorly tolerated by all age groups, with the very young (<2 years) being prone to jaundice and rash more commonly than the adults treated.88 Eperon et al.88 found that there was a lower incidence of encephalopathic syndrome in pre‐school age children, but those who did develop it had a higher mortality rate. All studies found melarsoprol to be significantly toxic, with some deaths attributable to the complication of adverse effects of the treatment.

Ongoing studies are currently evaluating alternatives to treatment for late stage Human African Trypanosomiasis, which include the combination of nifurtimox and eflornithine compared to melarsoprol in children as well.

Eflornithine for the treatment of 2nd stage African Trypanosomiasis (Trypanosomiasis brucei gambiense)

Five studies were identified that had extractable safety and efficacy data for children, 3 RCTS, 1 retrospective study and 1 clinical efficacy trial.82‐83,85,88‐89 Two studies (Eperon et al.88 and Milord et al.89) included children under the age of 2 years. The age range of participants was 0 to 77 years. The population size ranged from 54 to 1928 participants. Each study used a different dose of eflornithine (Table 15).

Adverse events were noted in all studies, however the overall conclusion was that eflornithine was an effective treatment with less toxic side effects to melarsoprol. Only Eperon et al.88 stratified the results by the different age groups. Further trials are underway examining combination therapy of nifurtimox and eflornithine as a more effective treatment with a lower toxicity profile as shown by Priotto et al.82

Pepin et al.83 studied different dosage scheduling for eflornithine and found that a 7‐day treatment duration was effective for treatment and with an improved adverse event profile (i.e. diarrhoea and infections) in comparison to the longer 14‐day treatment duration that has been used in previous studies.

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Gap analysis

Systematic reviews for the treatment of Human African Trypanosomiasis (HAT)

There are currently no published systematic reviews on African trypanosomiasis. There is an ongoing NECT trial in the Democratic Republic of Congo that includes children of all ages.

Benznidazole for the treatment of American trypanosomiasis

Seven studies were reviewed looking at the efficacy and safety of benznidazole use. Paediatric data was extractable from all the studies, 4 RCTs90‐93, 1 follow up study of the Andrade et al. 1996 RCT94, 1 observational trial95 and 1 control program study96 (Médecins sans Frontièresʹ project). The age of participants ranged from newborn to 18 years of age, and the number of participants ranged from 106 to 2,444. Dosages varied from 2.5 mg/kg twice a day for 60 days to 7.5 mg/kg once a day for 30 days or twice a day for 60 days. Trials by Sosa‐ Estani et al.90, Andrade et al.91 and Galvão et al.92 were able to show efficacy of benznidazole in comparison to a placebo treatment in children with both indeterminate stage or early stage trypanosome cruzi infection (Table 16).

Chippaux et al.93 studied 253 newborns using antibody titres as a marker for cure. No adverse events were noted with treatment in this age group, but antibody titres were noted to be present in non parasataemic infants of seropositive mothers for a period of up to 8 months. Escriba et al.95 examined children between 9 months to 12 years and noted minor adverse events, such as gastrointestinal disorders and rash. They noted that those <10 years of age tended to take longer to seroconvert.

Administration of treatment was oral, with tablets being crushed to the nearest appropriate dose. No further information was provided regarding different formulations.

Nifurtimox for the treatment of American trypanosomiasis

No studies were found describing the use of nifurtomox in the treatment of American trypanosomiasis in children. Two studies were identified that reported us of nifurtimox in combination with eflornithine for the treatment of late stage HAT gambiense (n= 54, age range 5 to 62 years).82,85 It was not possible to extract paediatric data from either study (Table 16).

Systematic reviews of treatment of American trypanosomiasis (Chagas disease)

There were no systematic reviews describing treatment in children. The only two paediatric studies that were included in reviews of Chagas disease treatment were by Sosa‐Estani et al.90 and Andrade et al.91, described above. The reviews concluded that there was a lack of sufficient evidence regarding treatment, dosing schedules and a paucity of RCTs evaluating treatment of chronic and indeterminant Chagasic disease (Table 17).

Gaps in evidence

Only a limited number of RCTs/clinical trials evaluating the safety and efficacy for each NTD medicine in the paediatric population were identified. Some relevant studies may have been missed due to the fact that the search was limited to English language papers. Several potentially relevant studies in Spanish or Portuguese were not reviewed.

10 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

The gaps identified in the evidence for use of these medicines in children include:

• Lack pharmacokinetic and pharmacodynamic data for these medicines in the paediatric population, especially <4‐year age group. • In all medicine groups most of the studies poorly described and/or reported age stratification within the participant groups. • In many of the community studies there was a lack of stratification of the results according to different age groups. • The method of administration of the medicine to children, especially the younger age groups, not clearly described. • Lack of paediatric friendly formulations (benznidazole is an example of where crushed tablets are being used to treat neonates).

Future research requirements have been identified as:

1. Pharmacokinetic data in the paediatric population, especially pre‐school age children (< 4 years). 2. Improved reporting of paediatric data in clinical trials and community MDA programmes. All data for children should be stratified and reported by age group.

Conclusion

The purpose of this review was to determine whether or not there was sufficient evidence to support the use of the current dosages and formulations of medicines included on the WHO Essential Medicine List for the treatment of neglected tropical diseases in the paediatric population. In general it was found that there is a lack of high quality clinical trials in the paediatric population and there is a paucity of pharmacokinetic data for the reviewed medicines within the 0‐5 age group.

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56. Katz N., Zicker F., Pereira J.P. Field trials with oxamniquine in a schistosomiasis mansoni‐endemic area. Am J trop Med Hyg (1977) 26(1); 234‐237. 57. Katz N., Rocha R.S., De Souza C.P., Coura Filho P., Bruce J.I., Coles G.C., Kinotie G.K. Efficacy of alternating therapy with osamniquine and praziquantel to treat schistosoma Mansoni in children follwing failure of first treatment. Am J Trop Med Hyg (1991) 44(5); 509‐512. 58. Lambertucci J.R., Greco D.B., Pedrosa E.R.P, da Costa Rocha M.O., Salazar H.M., De Lima D.P. A double blind trial with oxamniquine in chronic schistosomiasis mansoni. Trans Roy Soc Trop Med Hyg (1982) 76(6); 751‐755. 59. Gryseels B., Nkulikyinka L., Coosemans M.H. Field trials of praziquantel and oxamniquine for treatment of schistosomiasis mansoni in Burundi. Trans Roy Soc Trop Med (1987) 81; 641‐44. 60. Gryseels M., Nkulikyinka L. Two‐year follow‐up of schistosoma mansoni infection and morbidity after treatment with different regimens of oxamniquine and praziquantel. Trans Roy Soc Trop Med Hyg (1989) 83; 219‐228. 61. Hammouda N.A, El‐Mansoury S.T., El‐Azzouni M.Z., El‐Gohari Y. Therapeutic effect of tricalbendazole in patients with fascioliasis in Egypt a preliminary study. J. Egyption Soc Parasit. Vol.25 (1) 1995: 137‐143. 62. El‐Morshedy H., farghaly A, Sharaf S., Abou‐Basha L., Barakat R. Triclabendazole in the treatment of human fascioliasis: a community‐based study. La Revue de Santé de la Méditerranée orientale. 5(5) 1999; p888‐894. 63. El‐Karaksy H, Hassanein B, Okasha S, Beheiry B, Gadallah I. Human fascioliasis in Egyptian children: successful treatment with triclabendazole. J Trop Pediatr 1999; 45, 3; Proquest Health and medical complete p 135 –139. 64. Saconato H, Atallah AN. Interventions for treating shistosomiasis mansoni. Cochrane Database of Systematic Reviews 1999, issue 3 Art. No.:CD000528. DOI: 10.1002/14651858.CD000528. 65. Danso‐Appia A, Utzinger J, Liu J, Olliaro P. Drugs for treating urinary schistosomiasis (review). Cochrane database of systematic reviews 2008, issue 3. Art. No.: CD000053. DO!: 10.1002/14651858.CD000053.pub 2. 66. Wilkins HA, Moore PJ. Comparative trials of regime for treatment of urinary schistosomiasis in The Gambia. J. Trop Med Hyg 1987; 90(2): 83‐92 67. Ming‐Gang C. Use of Praziquantel for clinical treatment and morbidity control of schistosomiasis japonica in China: a review of 30 years’ experience. Acta Tropica (2005) 96:168‐176. 68. Fenwick A, Webster JP. Schistosomiasis: challenges for control, treatment and drug resistance. Curr Opin Infect Dis 2006; 19:577‐582. 69. Ortiz JJ, Ayoub A, Gargala G, Chegne NL, Favennec L. Randomized clinical study of niazoxanide compared to metronidazole in the treatment of symptomatic giardiasis in children from Northern Peru. Alim Pharmac Therap 2001; 15(9):1409‐1415. 70. Dinleyici E.C. , Eren M. , Yargic Z.A., Dogan N., Vandenplas Y. Clinical Efficacy of Saccharomyces boulardii and Metronidazole Compared to Metronidazole Alone in Children with Acute Bloody Diarrhea Caused by Amebiasis: A Prospective, Randomized, Open Label Study. Am. J. Trop. Med. Hyg.2009, 80(6): 953–955.

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71. Talri SA, Momtazmanesh N, Talebian A, Khorshidi A, Taghavi A, Fakharian E, Talari MR, Mokhtari Z. Comparison of metronidazole and furazolidone against Giardia lamblia in children. J Med Sci 2006; 6(3): 378‐381. 72. Suntornpoch V, Chavalittamrong B. Treatment of giardiasis in children with tinidazole, ornidazole and metronidazole. Southeast Asian J Trop Med Pub Health 1981; 12(2):231‐235). 73. Sadjjadi SM, Alborzi AW, Mostovfi H. Comparative clinical trial of mebendazole and metronidazole in Giardiasis of children. J Trop Pediat 2001; 47(3): 176‐178. 74. Alestig K, Freij L, Arnold E. Absorption and excretion of metronidazole after administration of metronidazole benzoate mixture. Scand J Infect Diseases 1980; 12(2): 149‐152). 75. Lares‐Asseff I, Cravioto J, Santiago P, Perez‐Ortiz B. Pharmacokinetics of metronidazole in severely malnourished and nutritionally rehabilitated children. Clin Pharm Therap 1992;51(1):42‐50. 76. Lau AH, Lam NP, Piscitelli SC, Wilkes L, Danziger LH. Clinical pharmacokinetics of metronidazole and other nitroimidazole anti‐infectives. Clinical Phamaracokinetics 1992; 23(5): 328‐364. 77. Upadhyaya P, Bhatnager V, Basu N. Pharmacokinetics of intravenous metronidazole in neonates. J Pediat Surg 1988;23:263–5. 78. Amon I, Amon K, Scharp H. Disposition kinetics of metronidazole in children. Eur J Clin Pharm 1983; 24 (1): 113‐119. 79. Rubidge CJ, Scragg JN, Powell SJ. Treatment of children with acute amoebic dysentery: comparative trial of metronidazole against a combination of dehydroemetine, tetracycline and diloxanide furoate. Arch dis child. 1970; 45: 196‐197. 80. McAuley J.B. Herwaldt B.L. Stokes S.L. Becher J.A. Roberts J.M. Michelson M.K. Juranek D.D. Diloxanide furoate for treating asymptomatic Entamoeba histolytica cyst passers: 14 Yearsʹ experience in the United States. Clinical Infectious Diseases (1992). 15 (3): 464‐468. 81. Gonzales MLM, Dans LF, Martinez EG. Antiamoebic drugs for treating amoebic colitis. Cochrane database of systematic reviews 2009, issue 2. Art. No.: CD006085. DOI: 10.1002/14651858.CD006085.pub 2. 82. Priotto G, Fogg C, Balasegaram M, Erphas O, Louga A, Checchi F, Ghabri S, Piola P. Three drug combinations for late‐stage Trypanosoma brucei gambiense sleeping sickness: a randomized controlled trial in Uganda. PloS Clin Trials 2006; 1(8): e39. doi: 10.1371/journal.pctr.0010039. 83. Pépin J, Khonde N, Maiso F, Doua F, Jaffar S, Ngampo S, Mpia B, Mbulamberi D, Kuzoe F. Short‐course eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial. Bull World Health Organ 2000; 78:1284‐1295. 84. Burri C, Nkunku S, Merolle A, Smith T, Blum J, Brun R. Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial. The Lancet 2000; 355: 1419‐1425. 85. Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, Ghabri S et al. Nifurtimox‐eflornithine combination therapy for second‐stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non‐inferiority trial. The Lancet 2009; 374: 56‐64.

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100. Kabatereine et al. Treatment of intestinal schistosomiasis using praziquantel syrup versus crushed praziquantel tablet in Ugandan preschool children. 2010 (unpublished data). 101. Garba et al. Assessing tolerance to and efficacy of EPIQUANTEL® syrup (praziquantel) on S. Haematobium and S.mansoni infected pre‐school children in Niger. 2010 (unpublished data).

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APPENDICES

Appendix A:

WHO Model List of Essential Medicines for children3

Levamisole: tablet 50 mg; 150 mg (as hydrochloride) Mebendazole: tablet (chewable) 100 mg; 500 mg Niclosamide: tablet (chewable) 500 mg (listed for use when praziquantel treatment fails) Praziquantel: tablet 150 mg; 600 mg Pyrantel: oral liquid 50 mg (as embonate)/ml; tablet (chewable) 250 mg (as embonate) Ivermectin: tablet (scored) 3 mg, 6 mg Diethycarbamazine (complementary list): tablet 50 mg; 100 mg (dihydrogen citrate) Triclabendazole: tablet 250 mg Oxamniquine (complementary list): capsule 250 mg; oral liquid 250 mg/5ml (for use when praziquantel treatment fails) Diloxanide: tablet 500 mg (furoate) >25 kg Metronidazole: injection 500 mg in 100ml vial; oral liquid 200 mg (as benzoate)/5 ml; tablet 200 mg to 500 mg Medicines for treatment of 1st stage of African Trypanosomiasis Pentamidine: powder for injection 200 mg (pentamidine isetionate) in vial. Suramin Sodium: powder for injection 1g in vial Medicines for the treatment of 2nd stage African Trypanosomiasis Eflornithine: Injection 200 mg (hydrochloride)/ml in 100ml bottle Melarsoprol: Injection 3.6% solution in 5 ml ampoule (180 mg of active compound) Benznidazole: tablet 100 mg Nifurtimox: tablet 30 mg; 120 mg; 250 mg

20 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Current WHO dosing guidelines from the manual of preventative chemotherapy in human helminthiasis4,5,6:

Preschool age children (1-5 years)

Albendazole (ALB) 200 mg for children aged 12‐23 months 400 mg for children aged 2‐5 years

Mebendazole (MBD) 500 mg for children ≥1year

Levamisole (LVM) 2.5 mg/kg for children ≥1year

Pyrantel (PYR) 10 mg/kg for children aged ≥1year

Niclosamide if ≤2years 500 mg, 2‐6 years 1g

Praziquantel (PZQ) for >4years 10‐25 mg/kg depending on infection up to 50 mg/kg in 3 daily divided doses for cysticercosis

School-age children (aged 6-15 years) and adults (aged >15 years)

ALB 400 mg MBD 500 mg LEV 2.5 mg/kg standard dose for school‐age children 80 mg PYR 10 mg/kg PZQ according to height starting from >94 cm

For further details on dosing and scheduling details were taken from the WHO Model Formulary 6.

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Summary of evidence tables

22 Table 1 Summary of available evidence

Drug Name (s) Studies reporting Efficacy data Safety data PK data Doses reported Formulation(s) data for children reported Mebendazole (MBZ) 10 studies (9 RCTs6‐14, All studies, except 3 studies reported No 200 mg tds; Tablet 1 observational15; Flohr et al. 20077 adverse events as an 500 mg od 500 mg chewable n=6856, age range 6 showed treatment outcome. 6,8,9 No (most tablet mos to 70 yrs) with MBZ to be serious adverse commonly No other 2 studies included effective events reported. used); information children <3 years6,9 Main problems: 600 mg provided nausea, abdominal multiple doses distension and discomfort Levamisole (LVM) 3 studies (2 RCTs8,16, 1 All studies Adverse events No < 3 yrs 40 mg Tablet observational17; showed efficacy occurring once in 3‐9 yrs 60 mg n=1633; age range 1 to based on different patients >9 yrs 80 mg 19 yrs) reduction in egg (temperature rise, 2 studies included counts. Albonico loose stools, children <4 yrs16,17 et al. 2003 showed convulsion) not LVM to have reported to be smaller effect on directly related to egg clearance LVM. No other compared to MBZ adverse events or MBZ+LVM reported Pyrantel (PYR) 4 studies (3 Effective in None of the studies No 10 mg/kg/day Tablet RCTS11,12,20, 1 treating ascaris provided any 11 mg/kg/day observational study14) lumbricoides information about 12.5 mg/kg/day 3 included only Poor efficacy for adverse children12,14,20 (n= 2074; treating events/safety 15‐20 kg: 150 age range 2 yrs to 10 hookworm mg Drug Name (s) Studies reporting Efficacy data Safety data PK data Doses reported Formulation(s) data for children reported yrs infections 21‐30 kg: 300 1 included adults and Higher cure rate mg children11 (n=147; age than MBZ for 31‐40 kg: 450mg range 3 yrs to 70 yrs) trichuriasis infection, but less effective than albendazole Niclosamide No x x x x x Diethylcarbamizine 6 studies (3 RCTs25,28,29, All studies Mild adverse events No 6 mg/kg No information (DEC) 3 observational showed efficacy reported (nausea, reported studies30,31,33; n= with a reduction vomiting, fever, >12000; age range 1 to in mf and headache). No 87 years antiginaemia cessation of treatment required Ivermectin (IVM) 7 studies (4 IVM treatment No serious adverse No Dose ranged 3 mg tablets RCTs24,26,27,29; 1 alone had lower events reported. from 150 comparative field mf clearance rates Most frequently mcg/kg to 400 trial34, 1 follow up than combination reported side mcg/kg study32, 1 safety therapy (IVM + effects: headache, study35; n= age range 3 albendazole) swellings, arthralgia yrs to 87 yrs) and fever 2 studies included children <4 yrs29,32 Praziquantel (PZQ) 13 studies (8 RCTs39‐46, Efficacy against S. 7 studies reported No 20 mg/kg single 200 mg tablet 1 safety pilot study48, haematobium adverse events as an oral dose 1 observational (cure rate of outcome40‐43,46,47,49. 20 mg/kg 2 oral study51, 1 clinical 88.5%; egg Generally side doses efficacy trial49,50, 1 reduction rate effects were mild 20 mg/kg 3 oral quasi RCT47) 98.2%) and transient doses Drug Name (s) Studies reporting Efficacy data Safety data PK data Doses reported Formulation(s) data for children reported 8 studies included PZA more (dizziness, 40 mg/kg single only children39,41,44‐46,49‐ efficacious than headache, dose 51 (n = 5181; age range Niridazole, abdominal pain, 60 mg/kg split 4 yrs to 18 yrs) Metrifonate and vomiting, dose 3 hrs apart 5 studies included placebo with diarrhoea). No adults and ascorbic acid cessation of children40,42,43,47,48 (n= treatment required 5710; age range 7 yrs to 60 yrs)

Praziquantel (PZQ) 5 observational All studies All studies reported No 40 mg/kg Tablet 600mg Additional studies showed efficacy of adverse events as 1-3 yrs: 518 mg; (crushed and information from 4 studies included PZQ tablets and an outcome. In 1 tablet mixed with >3-5 yrs: 740 mg; unpublished pre‐school age PZQ syrup with general, PZA tablets orange juice for 11/4 tablet 98‐101 studies children (n= 1748; reduction in egg and/or syrup were >5-6yrs: 977 mg; younger children age range 1 mth to 6 counts in well tolerated, with 12/3 tablet unable to yrs) consecutive stool/ mild, transient side swallow tablets; 1 study included urine samples. effects. Reported required dosage primary school Although, efficacy side effects: fatigue, was broken into children97 (n= 5700 age of PZQ tablets dizziness, smaller pieces or range 6 yrs to 12 yrs). shown to be drowsiness, crushed using greater than headache, loss of mortar and efficacy of PZQ appetite and pestle. A honey syrup. PZA stomach ache. 1 based solution treatment resulted study showed was added to in significant symptoms were make a reduction in significantly higher suspension for overall infection among uninfected some of the prevalence (29.5% children compared children ) Drug Name (s) Studies reporting Efficacy data Safety data PK data Doses reported Formulation(s) data for children reported to 5.68%) and to those with Syrup infection intensity s.mansoni (EPIQUANTEL®) 19.7 to 1.39 eggs/10ml urine. Oxamniquine 9 studies (4 RCTs52‐ More effective at Adverse events No 10 mg/kg bd for Capsule 54,58, 4 clinical efficacy treating S. generally mild and 1 day or 2 days Suspension trials55‐57,59, 1 follow up Mansoni infection transient. 15 mg/kg single study60) than S. Dizziness, headache dose or bd for 1 4 studies only Haematobium and drowsiness day, 2 days or 8 included In children, lower were the most days children52,55,57,58 (n= doses, not as commonly reported 20 mg/kg single 510; age range 2 yrs successful in side effects. oral dose or bd to 16 yrs) achieving cure as for 1 day or 3 5 studies included same doses in days adults and adults. Higher 800 mg/m2/day children53,54,56,59,60 (n > doses associated in 2 divided 1261; age range 2 yrs with an increase in doses (approx. to >20 yrs) adverse events. 60 mg/kg) Better tolerated Optimal dose and more effective for children in adult groups reported to be 30 mg/kg over 2 days (Ayele et al 1986, n=162; age < 15yrs) Triclabendazole 3 studies (1 pilot Cure rate with No significant No 10 mg/kg od or Oral study61, 1 community single dose 74.9% adverse events. bd No other dose comparison Higher cure rate Good tolerability information study62; 1 case series63, (93.9%) with 2 reported Drug Name (s) Studies reporting Efficacy data Safety data PK data Doses reported Formulation(s) data for children reported n= 184; age range 2 yrs doses to 62 yrs). All the studies included adults and children Metronidazole 5 studies (1 RCT69; 1 All studies Adverse events 4 studies. 15 mg/kg in 3 Oral route of prospective open label showed efficacy mild, transient and Preterm and divided doses administration. randomized trial70; 1 by parasitological did not require term infants for 7 days No other survey of efficacy and assessment of cessation of have a lower 20 mg/kg/day information adverse events71; 2 stool samples.. treatment. total body for 5 days provided comparative trials72,73; Cure rates ranged Reported side clearance and 30 mg/kg bd for n= age range 7 mos to from 80% to 97% effects included: prolonged 7 days 12 yrs). Only 1 study anorexia, nausea, half‐life, included children <2 vomiting, malaise whereas yrs79 and metallic taste children over 4 have PK parameters similar to adults. Dose should be decreased in malnourished children. Diloxanide 2 studies (1 Unable to Most commonly No 25 mg/kg od for Oral. No other comparative trial79, n= determine efficacy reported side effect: 10 days information 39; age range 7 mos to data from flatulence. Fewer provided 10 yrs; 1 retrospective information adverse events study80 n= 4371 reported in reported in those treatment courses comparative trial aged 20 mos to 10 Drug Name (s) Studies reporting Efficacy data Safety data PK data Doses reported Formulation(s) data for children reported from 1977 to 1990) yrs than those aged >10 yrs Pentamidine 3 studies (1 clinical Not reported No serious adverse No 4 mg/kg i.m Intramuscular study86, 1 phase II events reported once daily for 7 injection clinical trial87, 1 days retrospective study88; n = 3133; age range 0 to > 15yrs Suramin No x x x x x Melarsoprol 4 studies (2 RCT82,84, 1 melarsoprol + Significantly toxic. No Over 26 days: 3 Intravenous phase II clinical trial87, eflornithine not as Some deaths series of 4 daily infusion 1 retrospective effective as attributable to i.v infusions analysis88; n= 3035; nifurtimox + complications of starting at 1.2 age range 0 to 62 yrs. eflornithine (cure treatment. mg/kg, All the studies rates 44% vs. 94% Poorly tolerated by increasing to 3.6 included both adults respectively) all age groups. mg/kg with a 7 and children Very young (<2 yrs) day interval more prone to between series jaundice and rash 1.8 mg/kg/d for than adults. 10 days Lower incidence of 2.2 mg/kg/d for encephalopathic 10 days syndrome in PSAC, but higher mortality rate in those that did develop it Eflornithine 5 studies (3 RCTs82,83,85, Eflornithine has Number of adverse No 100 mg/kg 6 Oral 1 retrospective equal efficacy to evnts increased with hourly for either Intravenous study88, 1 clinical melarsoprol longer duration of 7 or 14 days infusion Drug Name (s) Studies reporting Efficacy data Safety data PK data Doses reported Formulation(s) data for children reported trial89; n = 3509; age treatment, but only 200mg/kg 12 range 0 to 77 yrs) statistically hourly for 14 2 studies included significant for days children < 2 yrs88,89 diarrhoea and 100 mg/kg i.v 6 infections. hourly for 14 Less toxic than days, followed melarsoprol by 75 mg/kg orally 6 hourly for 21 days

Benznidazole 7 studies (4 RCTs90‐93, 3 studies90‐92 Minor adverse No 2.5 mg/kg bd for Tablets 1 follow up study94, 1 showed efficacy in events 60 days 100 mg tablets observational study95, comparison to (gastrointestinal 5 mg/kg/d ground up and 1 control program placebo in disorders; rash). 7.5 ,g/kg once capsules filled study96 (MSF project); children with No deaths reported daily for 30 or with 8, 10, 13 and n= age range newborn indeterminate or 60 days 15 mg powder to to 18 yrs) early stage 7.5 mg/kg bd or treat neonates trypanosome cruzi tds for 60 days according to Maximum dose weight 300mg/d Nifurtimox (N) 2 studies (2 RCTs82,85; Only used in Combination of No 15 mg/kg/d 8 Oral n> 54; age range 5 yrs combination with N+E well tolerated. hourly for 10 to 62 yrs). Not eflornithine (E) or Low fatality rate days possible to extract melarsoprol (M) compared to 20 mg/kg/d 8 paediatric specific N+ E more melarsoprol (0.76% hourly for 10 data from either study effective than M + vs. 6%) days E (cure rates 94% vs. 44% respectively) Abbreviations used in table: RCT = randomized controlled trial; mos = months; yrs = years; tds = 3 time daily; od = once daily; bd = twice daily; mf = microfilarial load; d = day What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Appendix B: Details of search strategy

Search PubMed EMBASE* RSM Set 1 Helminth* Helminth* Helminth* 2 Mebendazole*; AND/OR helminth; Mebendazole*; AND/OR helminth; Mebendazole*; AND/OR helminth; AND/OR children/PSAC/Paediatrics; AND/OR children/PSAC/Paediatrics; AND/OR children/PSAC/Paediatrics; AND/OR safety and efficacy; AND/OR safety and efficacy; AND/OR safety and efficacy; pharmacokintetics/dynamics; all pharmacokintetics/dynamics; all pharmacokintetics/dynamics; all alone and in combination; individual alone and in combination; individual alone and in combination; individual helminth species used in search as helminth species used in search as helminth species used in search as well well well. 3 Levamisole*; and all of the above Levamisole*; and all of the above Levamisole*; and all of the above search strategies used search strategies used search strategies used 4 Pyrantel*; and all of the above search Pyrantel*; and all of the above search Pyrantel*; and all of the above search strategies used strategies used strategies used 5 Niclosamide* ; all of the above search Niclosamide*; all of the above search Niclosamide*; all of the above search strategies used strategies used strategies used 6 Praziquantel*; all of the above search Praziquantel*; all of the above search Praziquantel*; all of the above search strategies uses; combination and strategies uses; combination and strategies uses; combination and single searches with schistosomiasis single searches with schistosomiasis single searches with schistosomiasis (different schistosome species) (different schistosome species) (different schistosome species) 7 Triclabendazole*; all of the above Triclabendazole*; all of the above Triclabendazole*; all of the above search categories used for PZQ search categories used for PZQ search categories used for PZQ 8 Oxamniquine*; all of the above search Oxamniquine*; all of the above search Oxamniquine*; all of the above search categories used for 7&8 categories used for 7&8 categories used for 7&8 9 Ivermectin*; AND/OR Ivermectin*; AND/OR Ivermectin*; AND/OR children/PSAC; AND/OR filariasis children/PSAC; AND/OR filariasis children/PSAC; AND/OR filariasis (including individual searches for (including individual searches for (including individual searches for each species); lymphatic filariasis*; each species); lymphatic filariasis*; each species); lymphatic filariasis*; AND/OR onchocerciasis*; AND/OR AND/OR onchocerciasis*; AND/OR AND/OR onchocerciasis*; AND/OR Loasis*; AND/OR safety and efficacy; Loasis*; AND/OR safety and efficacy; Loasis*; AND/OR safety and efficacy; AND/OR AND/OR AND/OR pharmacokinetics/pharmacodynamics pharmacokinetics/pharmacodynamics pharmacokinetics/pharmacodynamics 10 Diethylcarbamazine*; all of the search Diethylcarbamazine*; all of the search Diethylcarbamazine*; all of the search categories above used as well as categories above used as well as categories above used as well as Onchocerca Volvulus Onchocerca Volvulus Onchocerca Volvulus 11 Diloxanide*; AND/OR Diloxanide*; AND/OR Diloxanide*; AND/OR children/PSAC; AND/OR amoebiasis; children/PSAC; AND/OR amoebiasis; children/PSAC; AND/OR amoebiasis; AND/OR entamoeba histolytica; AND/OR entamoeba histolytica; AND/OR entamoeba histolytica; AND/OR safety and efficacy; AND/OR safety and efficacy; AND/OR safety and efficacy; AND/OR AND/OR AND/OR pharmacokinetics/pharmacodynamics pharmacokinetics/pharmacodynamics pharmacokinetics/pharmacodynamics 12 Metronidazole*; AND/OR Metronidazole*; AND/OR Metronidazole*; AND/OR children/PSAC; AND/OR neonates; children/PSAC; AND/OR neonates; children/PSAC; AND/OR neonates; AND/OR giardiasis; AND/OR safety AND/OR giardiasis; AND/OR safety AND/OR giardiasis; AND/OR safety and efficacy; AND/OR and efficacy; AND/OR and efficacy; AND/OR pharmacokinetics/pharmacodynamics pharmacokinetics/pharmacodynamics pharmacokinetics/pharmacodynamics 13 Pentamidine *; AND/OR T.b. Pentamidine *; AND/OR T.b. Pentamidine *; AND/OR T.b. gambiense; AND/OR sleeping gambiense; AND/OR sleeping gambiense; AND/OR sleeping sickness; AND/OR Human African sickness; AND/OR Human African sickness; AND/OR Human African Trypnaosomiasis; AND/OR Trypnaosomiasis; AND/OR Trypnaosomiasis; AND/OR children/PSAC; AND/OR children/PSAC; AND/OR children/PSAC; AND/OR pharmacokinetics/dynamics; pharmacokinetics/dynamics; pharmacokinetics/dynamics; AND/OR safety and efficacy AND/OR safety and efficacy AND/OR safety and efficacy

31

Gap analysis

With EMBASE and Pub Med the appropriate search terms were determined for input by first searching for the MeSH terms on Pub Med or for the appropriate subject heading and explosion on EMBASE

The following search term was used in Pub Med when searching for children AND the drug of interest: PubMed

ʺChildʺ[Mesh] OR ʺMaternal‐Child Health Centersʺ[Mesh] OR ʺChild Nutrition Sciencesʺ[Mesh] OR ʺChild Health Servicesʺ[Mesh] OR ʺChild Nutritional Physiological Phenomenaʺ[Mesh] OR ʺChild Nutrition Disordersʺ[Mesh] OR ʺChild Mortalityʺ[Mesh] OR ʺChild Welfareʺ[Mesh] OR ʺChild Careʺ[Mesh] OR ʺChild Reactive Disordersʺ[Mesh] OR ʺChild Guidanceʺ[Mesh] OR ʺChild Reactive Disordersʺ[Mesh] OR ʺChild Behavior Disordersʺ[Mesh] OR ʺChild, Orphanedʺ[Mesh] OR ʺChild, Institutionalizedʺ[Mesh] OR ʺChild, Hospitalizedʺ[Mesh] OR ʺChild Developmentʺ[Mesh] OR ʺChild Behaviorʺ[Mesh] OR ʺDevelopmental Disabilitiesʺ[Mesh] OR ʺMental Disorders Diagnosed in Childhoodʺ[Mesh] OR ʺDisabled Childrenʺ[Mesh] OR ʺchildrenʺ [TIAB] OR ʺnewborn*ʺ [TIAB] OR ʺchildhoodʺ [TIAB] OR ʺbabyʺ [TIAB] OR ʺbabiesʺ[TIAB] OR ʺtoddlerʺ[TIAB] OR ʺtoddlersʺ[TIAB] OR ʺinfantsʺ[TIAB] OR ʺinfantʺ[TIAB] OR ʺinfantileʺ [TIAB] OR ʺyoung patientʺ [TIAB] OR ʺyoung patientsʺ[TIAB] OR ʺPediatric Nursingʺ[Mesh] OR ʺPediatric Assistantsʺ[Mesh] OR ʺHospitals, Pediatricʺ[Mesh] OR ʺIntensive Care Units, Pediatricʺ[Mesh] OR ʺPediatricsʺ[Mesh] OR ʺPediatriciansʺ [TIAB] OR ʺpaediatriciansʺ [TIAB] OR ʺPediatricianʺ [TIAB] OR ʺpaediatricianʺ [TIAB] OR ʺPediatricsʺ [TIAB] OR ʺpaediatricsʺ [TIAB] OR ʺPediatricʺ [TIAB] OR ʺpaediatricʺ [TIAB]

EMBASE Child ʹchildʹ/exp OR ʹchildʹ OR ʹchildrenʹ/exp OR ʹchildrenʹ OR ʹyouthʹ/exp OR ʹyouthʹ OR youth* OR newborn* OR ʹnewbornʹ/exp OR ʹnewbornʹ OR ʹnew bornʹ OR ʹchildhood diseaseʹ/exp OR ʹchildhood diseaseʹ OR ʹbabyʹ/exp OR ʹbabyʹ OR babies OR ʹinfantʹ/exp OR ʹinfantʹ OR infant* OR childhood* OR toddler* OR kid OR kids OR ʹyoung patientʹ OR boy* OR girl* OR ʹyoung ageʹ OR pediatr* OR paediatr* OR ʹchild deathʹ/exp OR ʹchild deathʹ OR ʹchild healthʹ/exp OR ʹchild healthʹ OR ʹchild careʹ/exp OR ʹchild careʹ OR ʹchildhood mortalityʹ/exp OR ʹchildhood mortalityʹ OR ʹchild hospitalizationʹ/exp OR ʹchild hospitalizationʹ OR ʹpediatric hospitalʹ/exp OR ʹpediatric hospitalʹ OR child*

32 What is the evidence for safety and efficacy of medicines for the treatment of neglected tropical diseases in children?

Appendix C: Flow diagrams for search results

33 Mebendazole Search Results

Records identified through database searching n=706

Records after duplicates removed N=204

Records excluded as not

Relevant records screened fitting inclusion criteria N=57 N=46

Full text article assessed for eligibility N=11

1 systematic review 9 RCT 1 prospective observational study Levamisole Search Results

Records identified through

database searching

n=175

Records after duplicates removed N=75

Records excluded as not

Relevant records screened fitting inclusion criteria N=12 N=6

Full text article excluded Full text article assessed as not part of inclusion for eligibility criteria or relating to N=6 different disease process N=2

1 systematic review 2 RCT 1 observational study

Pyrantel search results

Records identified through

database searching

N=134

Records after duplicates removed N=101

Records excluded as Relevant records not fitting inclusion screened criteria N=48

Full text article assessed for eligibility N=5

1 systematic review 3 RCTs 1 observational study

Niclosamide search results

Records identified through database searching N=29

Records after duplicates removed N=12

Relevant records screened Records excluded as N=12 not fitting inclusion criteria N=12

No study found to fit inclusion criteria

Praziquantel search results

Records identified through database searching N=452

Records after duplicates removed N=140

Relevant records screened Records excluded as not N=140 fitting inclusion criteria N=107

Full text article assessed for Records excluded as not eligibility fitting inclusion criteria N=33 N=18

2 systematic reviews 8 RCT 1 RCT (randomization method not described) 2 clinical trials of efficacy 1 interventional longitudinal study 1 safety study (pilot study) Triclabendazole search results

Records identified through database searching N=26

Records after duplicates removed N= 21

Records excluded as not Relevant records screened fitting inclusion criteria N=14 N=7

Full text article assessed Records excluded as not for eligibility fitting inclusion criteria N=7 N=4

1 pilot study 1 community dose comparison study 1 case series Oxamniquine search results

Records identified through database searching N= 69

Records after duplicates removed N= 48

Relevant records Records excluded as screened not fitting inclusion N=22 criteria N=9

Records excluded as not Full text article fitting inclusion criteria assessed for eligibility N=3 N=13

1 systematic review 4 RCTs 4 efficacy trials 1 follow up study Ivermectin search results

Records identified through

database searching

N=82

Records after duplicates removed N=14

Records excluded as

Relevant records screened not fitting inclusion

N= 14 criteria

N=3

Full text article excluded Full text article assessed for as not part of inclusion eligibility criteria or relating to N=11 different disease process N=4

4 RCTs 3 observational studies

Diethylcarbamazine search results

Records identified through

database searching

N=208

Records after duplicates removed N=126

Records excluded as not Relevant records screened fitting inclusion criteria N=86 N=63

Full text article assessed for Full text article excluded eligibility as not part of inclusion N=23 criteria N=17

3 RCTs 3 observational studies

Metronidazole search results

Records identified through database searching N= 1556

Records after duplicates removed N=700

Relevant records Records excluded as not screened fitting inclusion criteria N=350 N=318

Full text article assessed Full text article excluded for eligibility as not part of inclusion N=32 criteria N=22

1 systematic review 1 RCT 2 comparative clinical efficacy studies 1 survey of efficacy/adverse events 4 PK studies 1 prospective open label randomized trial Diloxanide studies reviewed

Records identified through database searching N= 11

Records after duplicates removed N=6

Relevant records screened Records excluded as not

N=6 fitting inclusion criteria

N=4

1 comparative study 1 retrospective analysis Pentamidine studies reviewed

Records identified through database searching N=33

Records after duplicates removed N=29

Records excluded as not Relevant records screened fitting inclusion criteria N=11 N=6

Full text article assessed for Full text article excluded eligibility as not part of inclusion N=5 criteria N=2

1 clinical study 1 phase ii clinical trial 1 retrospective analysis Suramin studies reviewed

Records identified through database searching N=30

Relevant records screened N=11

Full text article assessed for eligibility N=1

No paediatric studies identified Melarsoprol studies reviewed

Records identified through database searching N=23

Records after duplicates removed N=17

Records excluded as not

Relevant records screened fitting inclusion criteria

N=11 N=4

Full text article assessed for Full text article excluded eligibility as not part of inclusion N=7 criteria N=3

2 RCT 1 clinical trial (phase II) 1 retrospective analysis Eflornithine studies reviewed

Records identified through database searching N=47

Records after duplicates removed N=39

Records excluded as not Relevant records screened fitting inclusion criteria N=19 N=9

Full text article excluded Full text article assessed for as not part of inclusion eligibility criteria N=10 N=5

3 RCTs 1 retrospective analysis 1 open label trial Benznidazole studies reviewed

Records identified through database searching N= 36

Records after duplicates removed N=32

Records excluded as Records screened not fitting inclusion N=28 criteria N=17

Full text article Full text article assessed for excluded as not part of eligibility inclusion criteria N=11 N=4

4 RCT 1 follow up study 1 observational study 1 control program study (MSF project) Nifurtimox studies reviewed

Records identified through database searching N=32

Records after duplicates removed N=30

Records excluded as Records screened not fitting inclusion N=9 criteria N=9

No paediatric studies identified