Efficacy and Safety of a New Chewable Tablet of Mebendazole Versus the Swallowable, Standard Tablet of Mebendazole Against Hookworm Infections in Children: a Randomized Controlled Trial
Phase: PHASE2
Conditions: Hookworm Infections
Sponsor: Swiss Tropical & Public Health Institute

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Study protocol (amended)  
CHEW MEB PEMBA 
NTC03995680 
26.08.2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Protocol 
 
 
Efficacy and safety of a new chewable tablet of 
mebendazole versus the swallowable, standard 
tablet of mebendazole against hookworm infections 
in children on Pemba Island, Tanzania: a randomized 
controlled trial  
 
 
Protocol Number 
4 
Version Number 
4.01 
Document Date 
26.08.2019 
Sponsor Contact 
Prof. Dr. Jennifer Keiser,  Swiss Tropical and Public Health 
Institute, Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@swisstph.ch 
Principal Investigator 
Prof. Dr. Jennifer Keiser,  Swiss Tropical and Public Health 
Institute, Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@swisstph.ch 
Study site 
Wawi, Mvumoni, Bwagamoyo, Piki and Mzambarauni schools, 
Pemba, Tanzania and Public Health Laboratory Ivo de Carneri, 
Pemba, Tanzania 
Funding Agency 
Swiss National Science Foundation (SNF) 

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1. General information 
 
1.1. List of investigators and other persons involved 
Title 
Names 
Institution 
Position 
Function in trial 
Prof. Dr. 
Jennifer Keiser 
Swiss Tropical and 
Public Health Institute 
(Swiss TPH) 
Unit head 
Principal Investigator 
MSc  
Marta Palmeirim 
Swiss TPH 
PhD-student 
Co-PI 
MSc 
Said Ali 
Public Health Laboratory 
Ivo de Carneri (PHL-IdC) 
Foundation 
CEO 
Co-PI 
PhD 
Shaali Ame 
PHL-IdC Foundation 
Head 
laboratory 
Services 
Co-PI 
Dr. 
Jan Hattendorf 
Swiss TPH 
Project leader 
Statistician 
 
 
 
 
 

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1.2. Signatures   
Trial statistician 
 
Signature 
 
 
 
 
 
Date of Signature  
26.08.2019 
Name  
Jan Hattendorf 
Title 
Dr.  
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
CH- 4002 Basel, Switzerland  
Phone 
+41 61 284-8193 
 
 
 
Sponsor and Principal investigator (PI) 
 
Signature 
 
 
 
 
Date of Signature  
26.08.2019 
Name  
Jennifer Keiser 
Title 
Prof. Dr. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
CH- 4002 Basel, Switzerland  
Phone 
+41 61 284-8218 
 
 
 
I have read this protocol and agree that it contains all necessary details for carrying out this 
trial. I will conduct the trial as outlined herein and will complete the trial within the time 
designated. I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this trial. I will discuss this material with them 
to ensure they are fully informed regarding the drug and the conduct of the trial. 
I will use only the informed consent forms approved by the Sponsor or its representative and 
will fulfil all responsibilities for submitting pertinent information to the Independent Ethics 
Committees responsible for this trial. I agree that the Sponsor or its representatives shall 
have access to any source documents from which Case Report Form information may have 
been generated. 
 

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Co-Principal investigator 
 
Signature 
 
Date of Signature  
26.08.2019 
Name  
Marta Palmeirim 
Title 
MSc  
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
CH- 4002 Basel, Switzerland  
Phone 
+41 61 284 82 86 
 
 
Co-Principal investigator 
 
Signature 
 
 
Date de Signature  
26.08.2019 
Name  
Said Ali 
Title 
MSc  
Institution 
Public Health Laboratory Ivo de Carneri 
Address 
Public Health Laboratory Ivo de Carneri 
P.O. Box 122 Wawi, Chake Chake 
Pemba, Zanzibar (Tanzania) 
Phone 
+255 24 245-2003 
 
 
Co- Principal investigator 
 
Signature 
 
 
Date de Signature  
26.08.2019 
Name  
Shaali Ame 
Title 
PhD  
Institution 
Public Health Laboratory Ivo de Carneri 
Address 
Public Health Laboratory Ivo de Carneri 
P.O. Box 122 Wawi, Chake Chake 
Pemba, Zanzibar (Tanzania) 
Phone 
+255 24 245-2003 
 
 

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1.3. Abbreviations 
AE: adverse event 
CI: confidence interval 
Co-PI: co-principal investigator 
CR: cure rate 
CRF: case report form 
EPG: egg per gram 
ERR: egg reduction rate 
GCP: Good Clinical Practice 
Hb: haemoglobin 
 
ICH: International Council for Harmonisation 
IEC: independent ethics committee 
PHL-IdC: Public Health Laboratory Ivo de Carneri 
PI: Principal Investigator 
SAE: serious adverse event  
Swiss TPH: Swiss Tropical and Public Health Institute 
STH: soil-transmitted helminths 
WHO: World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.4. Synopsis 
Study title 
Efficacy and safety of a new chewable tablet of mebendazole 
versus the swallowable, standard mebendazole tablet against 
hookworm infections in children: a randomized controlled trial 
Short title 
Efficacy of chewable and swallowable MEB tablets 
Protocol number, 
version and date  
V4.01, 26.08.2019 
Trial registration 
Will be registered on http://clinicaltrials.gov/ 
Study type 
Phase 2 trial 
Sample size  
400 
Indication 
Hookworm infection 
Investigational product 
and reference treatment 
Mebendazole 
Study rationale 
To provide evidence on the safety and efficacy of a chewable 
tablet of mebendazole compared to the standard tablet in 
preschool- and school-aged children infected with hookworm. 
Study objectives 
To compare the efficacy and safety of two formulations of 
mebendazole: (i) single dose of 500 mg chewable tablet, and (ii) 
single dose of 500 mg standard swallowable tablet of 
mebendazole in participants aged 3-12, inclusive, infected with 
hookworm.  
 
The primary objective is to comparatively assess the efficacy in 
terms of egg reduction rates (ERRs) against hookworm infections 
using the duplicate Kato-Katz thick smear method on two stool 
samples among preschool- and school-aged children 14-21 days 
after the following oral treatment regimens: 
 
500 mg swallowable tablet of mebendazole 
 
500 mg chewable tablet of mebendazole 
 

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The secondary objectives of the trial are:  
 
To evaluate the safety and tolerability of the two 
formulations 
 
To evaluate the cure rates (CRs) of the two formulations 
against hookworm 
 
To determine the CRs and ERRs against Ascaris 
lumbricoides and Trichuris trichiura 
 
To investigate the acceptability and age-appropriateness 
of both formulation when administered to children 
between 3 and 12 years of age 
 
The exploratory objectives of this study are: 
 
To assess how well caregivers understand the clinical 
trials aim, procedures, their rights, risks and potential 
benefits 
 
To compare the effect of different methods of providing 
information on their understanding of the clinical trial 
Study design 
Randomized controlled, open-label, parallel-group, superiority 
trial (outcome assessors are blinded). 
Study product  / 
intervention 
Administration of a single oral dose of a 500 mg chewable tablet 
of mebendazole 
Comparator(s) 
500 mg swallowable tablet of mebendazole 
Key inclusion / 
exclusion criteria 
Inclusion: preschool- and school-aged children (3-12 years) with 
hookworm with at least two slides of quadruplicate Kato-Katz 
thick smears positive and infection intensities of at least 50 eggs 
per gram of stool (EPG), with written informed consent signed by 
the caregiver, able and willing to by examined by a study 
physician before treatment and to provide two stool samples at 
baseline. 
 
Exclusion: pregnant, any abnormal conditions or history of major 
systemic or chronic illnesses, severely anaemic (Hb < 80 g/l), 
received anthelminthic treatment or metronidazole within the past 
four weeks, or is attending any other clinical trial during this 

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study. 
Primary endpoints 
ERRs on hookworm, assessed 14-21 days post treatment 
Secondary endpoints 
CRs against hookworm, assessed 14-21 days post treatment 
CRs and ERRs against A. lumbricoides and T. trichiura 
Safety, assessed 14-21 days post treatment 
Acceptability and age-appropriateness of the tablets, assessed 
during treatment 
Exploratory endpoints 
Caregivers understanding of the clinical trial in general and by 
caregiver group, assessed during the informed consenting 
procedure 
Interim analyses 
None 
Study duration 
12 weeks total; up to 10 weeks per participant 
Schedule 
02/2019 of first-participant in (planned) 
05/2019 of last-participant out (planned) 
Study site 
Wawi, Mvumoni, Bwagamoyo, Piki and Mzambarauni schools, 
Pemba, Tanzania 
Measurements & 
procedures 
A first stool sample will be collected and if the participant is found 
positive for hookworm a second stool sample will be requested, if 
possible the next day. The medical history of the participating 
individuals will be assessed with a standardized questionnaire 
contained in the case report form, in addition to a clinical and 
physical examination carried out by the study physician before 
treatment. This examination also includes pricking subjects’ 
fingers to measure haemoglobin (Hb) levels and, in the case of 
female participants aged ≥ 10 years, a urine pregnancy test.  
Randomization of participants into the two treatment arms will be 
stratified according to intensity of infection.  
Participants will be interviewed before treatment for clinical 
symptoms and 3, and 24 hours after treatment to assess 
occurrence of adverse events (AEs). The efficacy of the 
treatment will be determined 14-21 days post-treatment by 

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collecting another two stool samples. All stool samples will be 
examined with duplicated Kato-Katz thick smears for hookworm, 
A. lumbricoides and T. trichiura eggs.  
During treatment, a sheet will be filled out for each participant to 
record his/her behaviour during the process of swallowing the 
tablet. School-aged children will be asked a few questions about 
their receptivity and the adequacy of the formulation of 
mebendazole they received, immediately after treatment.  
Statistical analyses 
The primary analysis will use the full analysis set (available case 
population) according to the intention to treat principle defined as 
all randomized subjects which provide any follow-up data. Only 
subjects which were negative at baseline and erroneously 
randomized will be excluded from the analysis. Because 
palatability and ease of swallowing are critical attributes in 
children; therefore, a per-protocol analysis will be conducted 
additionally to disentangle drug efficacy from adherence effects. 
Geometric mean egg counts will be calculated for the different 
treatment arms before and after treatment to assess the 
corresponding ERRs. Bootstrap resampling with 5,000 replicates 
will be used to calculate 95% confidence intervals (CIs) for ERRs 
and the difference between the two ERRs.  
Differences in CRs will be assessed using unadjusted logistic 
regressions. In a subsequent analysis an adjusted logistic 
regression (adjustment for age, sex, weight and strata) will be 
performed.  
GCP statement 
This study will be conducted in compliance with the protocol, the 
current version of the Declaration of Helsinki, ICH-GCP E6 as 
well as all national legal and regulatory requirements. 
Key explanation for the 
inclusion of children 
This study will be carried out in children since infection with 
hookworm and other soil-transmitted helminths occurs most often 
in this age group and they will be the population group treated 
with the new formulation. 
Recruitment procedure 
This school-based trial will be carried out in five primary schools 
with kindergarten (Wawi, Mvumoni, Bwagamoyo, Piki and 

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Mzambarauni) on Pemba Island, Tanzania. 
Coverage of damages 
Winterthur Police Nr. 4746321, National Insurance Cooperation 
of Tanzania LTD, GTA No: 00062. 
Storage of data and 
samples for future 
research aims 
After the study has been completed all samples will be destroyed 
and the trial master file will be kept for a minimum of 15 years.  
Conflict of interest in 
relation to the 
investigated drugs 
We declare no conflict of interest in relation to the investigated 
drugs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1. 
General information ........................................................................ 3 
1.1. 
List of investigators and other persons involved ...................................................... 3 
1.2. 
Signatures ............................................................................................................... 4 
1.3. 
Abbreviations .......................................................................................................... 6 
1.4. 
Synopsis ................................................................................................................. 7 
2. 
Background information ................................................................ 14 
3. 
Trial objective and purpose ........................................................... 15 
4. 
Methodology ................................................................................. 16 
4.1. 
Primary and secondary endpoint ............................................................................16 
4.2. 
Type of trial ............................................................................................................16 
4.3. 
Trial design ............................................................................................................16 
4.3.1. 
Baseline survey and screening ........................................................................16 
4.3.2. 
Assessment of efficacy after treatment ............................................................18 
4.4. 
Measure to minimize bias .......................................................................................19 
4.5. 
Study duration ........................................................................................................20 
4.6. 
Schedule of visits ...................................................................................................20 
5. 
Selection of the trial subjects ........................................................ 21 
5.1. 
Recruitment ............................................................................................................21 
5.2. 
Inclusion criteria .....................................................................................................21 
5.3. 
Exclusion criteria ....................................................................................................21 
5.4. 
Criteria for discontinuation of trial ...........................................................................22 
5.5. 
Treatment of subjects .............................................................................................22 
5.6. 
Concomitant therapy ..............................................................................................23 
6. 
Safety assessments ...................................................................... 24 
6.1. 
Adverse event definitions .......................................................................................24 
6.1.1. 
Severity grading ..............................................................................................24 
6.1.2. 
Relatedness ....................................................................................................25 
6.1.3. 
Expectedness..................................................................................................25 
6.1.4. 
Serious adverse events (SAEs) .......................................................................26 
6.1.5. 
Suspected unexpected serious adverse events (SUSARs) .............................26 
6.2. 
Methods of recording and assessing adverse events .............................................26 

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6.3. 
Reporting of serious adverse events ......................................................................27 
6.4. 
Safety reporting to health authorities and ethic committees ....................................28 
7. 
Data management and data quality control ................................... 28 
7.1. 
Source data ............................................................................................................28 
7.2. 
Data collection and documentation .........................................................................29 
7.3. 
Ethical, legal and security issues ............................................................................30 
7.4. 
Data storage and preservation ...............................................................................30 
8. 
Statistical analysis ........................................................................ 31 
8.1. 
Definition of primary endpoint .................................................................................31 
8.2. 
Justification of number of trial subjects ...................................................................31 
8.3. 
Description of statistical methods ...........................................................................31 
9. 
Duties of the investigator .............................................................. 32 
9.1. 
Investigator’s confirmation ......................................................................................32 
9.2. 
Damage coverage ..................................................................................................33 
9.3. 
Project management ..............................................................................................33 
10. Ethical considerations ................................................................... 33 
10.1. 
Independent Ethics  Committees ........................................................................33 
10.2. 
Evaluation of risk-benefit ratio .............................................................................34 
10.3. 
Subject information and consent .........................................................................34 
10.4. 
Subjects requiring particular protection ...............................................................34 
11. Monitoring and auditing ................................................................. 34 
12. Dissemination of results and publication ....................................... 35 
13. References ................................................................................... 35 
 
 
 

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2. Background information 
 
Soil-transmitted helminthiases are caused by one of the three soil-transmitted helminths 
(STH), Ascaris lumbricoides, Trichuris trichiura and hookworm (Ancylostoma duodenale and 
Necator americanus). Currently, STH still infect about two billion people worldwide, mostly in 
tropical and subtropical regions [1]. The global burden of STH infections reached over three 
million disability-adjusted life years in 2016 [2]. Children living in less developed settings, with 
crowded living conditions, inadequate sanitation and the lack of access to clean water, 
harbour the most intense infections [3-6]. These diseases can cause considerable burden 
including dietary deficiencies, anaemia, physical and cognitive retardation in children and 
reduction in work performance in adulthood [4, 7-10]. Currently, the main strategy to control 
STH infections is preventive chemotherapy which consists on the regular administration of 
either mebendazole (500 mg) or albendazole (400 mg) to children living in regions were 
these parasites are highly prevalent (WHO 2017). Preventive chemotherapy is promoted by 
the World Health Organization (WHO), due to its simple implementation and strong impact 
on morbidity by decreasing worm burden. WHO aims at reducing the prevalence of moderate 
and heavy STH infections in preschool and school-aged children to below 1% by 2020 [11]. 
However, there is a lack of appropriate paediatric formulations against soil-transmitted 
helminths; the mebendazole tablets currently used in mass drug administration programmes 
are solid (swallowable), which may make them inappropriate for younger age groups to 
swallow. 
The European Medicines Agency recommends swallowable tablets for children aged 
6 years or older [12]  and the WHO recommends only administering chewable tablets to 
children aged 5 or younger [13]. Indeed, in the UK, children aged 6 years and older are 
willing to take tablets of any size (Ranmal et al 2016). However, children as young as 3 years 
old have been found to easily swallow conventional tablets [14-16] and children above 6 
years of age have reported difficulties [17]. A survey in Nigeria found that caregivers prefer 
liquid formulations because they are sweet and do not require further preparation (Orubu et 
al 2017). However, solid tablets have significant advantages: they have a lower risk of 
incorrect administration (Walsh et al 2011) and are easily stored, transported and distributed 
(WHO 2012). In low-resource settings, as are most of those requiring preventive 
chemotherapy, the ease of storage, transport and distribution of the drugs is particularly 
important. Thus, ideally, a formulation which could be transported and stored in a solid form 
but administered in a semi-solid or liquid form could be a solution for young children.  
The WHO’s call for a more child-friendly formulation of mebendazole resulted in the 
development of a chewable 500 mg table by Johnson & Johnson (VermoxTM). In the case of 
young children, the WHO recommends crushing the tablet on a spoon, adding 2-3ml of clean 

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water and waiting for two minutes until it becomes a soft mass with semi-solid consistency 
which can more easily be administered. On the other hand, WHO recommends that older 
children should be encouraged to chew it (but never swallow it whole). Randomized, double-
blind, placebo-controlled trials which took place in Ethiopia and Rwanda have established 
safety and effectiveness against A. lumbricoides and T. trichiura in children aged 1-16 years 
[18, 19]. The efficacy of this chewable tablet of mebendazole against hookworm has not yet 
been studied. This formulation aims at making it easier for pre-school and school-aged 
children (PSAC and SAC) to swallow the drug but its acceptability has not yet been explored. 
Thus, in this study we will compare the efficacy, safety, and acceptability and age-
appropriateness of the two tablets (swallowable and chewable) of mebendazole and explore 
caregivers’ perceptions about both formulations.  
 
3. Trial objective and purpose 
The overall goal of this study is to determine if a chewable formulation of mebendazole is 
superior to a swallowable formulation tablet of mebendazole (standard of care) against 
hookworm in children. 
 
We hypothesize that the chewable formulation of mebendazole has a higher efficacy against 
hookworm infections than the swallowable one. Better absorption and bioavailability as well 
as better palatability are expected to contribute to superior efficacy. 
 
The primary objective of the study is to compare the egg reduction rates (ERRs) of two 
different mebendazole formulations against hookworm in children (3 - 12 years old): (i) 500 
mg of a single chewable mebendazole tablet and (ii) 500 mg of a single solid mebendazole 
tablet.  
 
The secondary objectives of the trial are:  
 
To evaluate the safety and tolerability of the two formulations 
 
To evaluate the CR of the two formulations against hookworm 
 
To determine the CRs and ERRs against Ascaris lumbricoides and Trichuris trichiura 
 
To investigate the acceptability and age-appropriateness of both formulation when 
administered to children between 3 and 12 years of age 
 
The exploratory objectives of this study are: 
 
To assess how well caregivers understand the clinical trials aim, procedures, their 
rights, risks and potential benefits 

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 
To compare the effect of different methods of providing information on their 
understanding of the clinical trial 
 
4. Methodology  
 
4.1. 
Primary and secondary endpoint 
The primary endpoint of the study is the ERRs of these two formulations of mebendazole 
against hookworm assessed before and 14 to 21 days post-treatment using the duplicate 
Kato-Katz technique. Secondary endpoints are the CR against hookworm, CRs and ERRs 
against A. lumbricoides and T. trichiura (assessed 14-21 days post-treatment), safety 
(assessed 3 and 24 hours post-treatment), and acceptability and age-appropriateness of the 
two formulations of mebendazole (assessed during treatment). Exploratory endpoints are 
how well caregivers understood the clinical trial’s informed consent form and its content, and 
which of the informing methods increase caregivers understanding the most (assessed 
during the informed consenting process). 
 
4.2. Type of trial 
Randomized controlled, open-label, parallel-group, superiority, phase 2 trial. 
 
4.3. Trial design 
4.3.1. Baseline survey and screening 
This will be a mainly school-based clinical trial that will take place in four primary schools 
with kindergarten (Wawi, Mvumoni, Bwagamoyo, Piki and Mzambarauni) on Pemba Island, 
Tanzania. Children aged 3 to 4 years old may yet be attending school, in which case they will 
be recruited directly in the communities of the same schools. Children for whom informed 
consent was obtained will receive an empty container at school, which they should return the 
following morning with a stool sample. If this first stool sample is positive for hookworm, a 
second sample will be requested, if possible the next day. Stool samples will be collected 
and transported by car to the central laboratory in Chake Chake (Public Health Laboratory 
Ivo de Carneri, PHL-IdC), if possible the next day. The stool sample collection will be done 
on different days to adequately cover the egg shedding cycle of 24-48 hours. Sampling will 
continue until a total of 400 hookworm-infected participants have been identified. Participants 
may be co-infected with A. lumbricoides and/or T. trichiura. The prevalence for hookworm 

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infected individuals is expected to be between 30% and 50% [20-23], hence we anticipate 
screening around 800-1,300 individuals to reach the total number of participants. The 
number of screened individuals will depend on the prevalence of the parasite. 
All stool samples will be prepared and analysed in the PHL-IdC on Pemba, United 
Republic of Tanzania. The Kato-Katz technique will be used for the quantitative assessment 
of STH infections. A first stool sample will be collected from each participant and if the 
participant is found positive for hookworm a second stool sample will be requested, if 
possible the next day. From each stool sample duplicate Kato-Katz thick smears (41.7 mg 
each) will be prepared [24]. All Kato-Katz thick smears will be microscopically analysed by 
experienced technicians within the first 60 minutes and will then be destroyed within a few 
days (after passing the quality control). A subsequent independent quality control of sample 
results for hookworm and concomitant STH will be conducted (described in section 4.3.2).  
 
 
Figure 1: Mebendazole efficacy study-flow. 
 
Participants found to be positive for hookworm and eligible (hookworm eggs per gram 
of stool (EPG) > 100 and more than one slide with hookworm eggs), will be invited for the 
physical and clinical examination day which will either take place the day before treatment or 
on the treatment day itself, but before treatment. All invited subjects will visit one of the study 
physicians and nurses to undergo a physical examination. Participant’s medical history, 
haemoglobin levels (using HemoCue), and, in the case of female participants, a pregnancy 
test (girls aged ≥ 10 years will be asked to provide a urine sample) will be recorded. Severely 
anaemic participants (below 70 g/l Hb in children aged 6-59 months and below 80 g/l Hb in 
children aged 5-12 years, according to WHO definition) and pregnant girls will be excluded. 
Stool examination (2 samples of stool analyzed with Kato-Katz) 
N = 800-1,300 
400 subjects enrolled (2 samples of stool analyzed with Kato-Katz) 
5 weeks 
Follow-up (2 samples of stool analyzed with Kato-Katz) 
14-21 days 
Mebendazole 
Chewable 500 mg tablet 
N = 200 
Mebendazole 
Solid 500 mg tablet 
N = 200 

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Pregnant participants will be given the option of receiving a similar looking tablet which does 
not contain any drug to avoid any stigmatization and severely anaemic participants will 
receive 
the 
combination 
of 
ivermectin 
and 
albendazole 
(according 
to 
WHO 
recommendations). 
 
4.3.2. Kato-Katz slide reading quality control 
To ensure quality of hookworm diagnosis, 10% of the samples will be divided into two stool 
containers; one of the containers will keep its original participant ID, whereas the second 
container will be labeled with a new ID (assigned by the co-PI). Duplicate Kato-Katz will be 
prepared from both containers and the findings compared. For hookworm, results are 
considered correct if no difference in presence/absence if found. In the case of A. 
lumbricoides and T. trichiura, 10% of slides will be re-read by another laboratory technician. 
Results are considered correct if the following tolerance margin is not exceeded:  egg counts 
are +/-10 eggs for counts ≤100 eggs or +/-20% for counts >100 eggs (for each species 
separately) [25]. In case discrepancies above the tolerance margin are noted in one or more 
slides, these slides will be re-read by the local technicians. The new results will be 
discussed, so that in case of discordant results, slides can be re-evaluated to reach 
consensus. All microscopically analysed quadruplicate Kato-Katz thick smears will be 
destroyed within one day after passing the quality control. 
 
4.3.3. Assessment of efficacy after treatment 
The efficacy of the treatment in participants will be determined 14-21 days post-treatment by 
collecting another two stool samples, which will be microscopically examined for STH using 
duplicate Kato-Katz thick smears, creating a total of four slides for this time point 
assessment. Participants will be considered hookworm cured if no eggs were found in the 
follow-up stool samples. 
EPG will be assessed by adding up the egg counts from the quadruplicate Kato-Katz 
thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean 
egg counts will be calculated for the two treatment arms before and after treatment to assess 
the corresponding ERRs. Individuals will not be included in the trial if the hookworm EPG < 
100 (total of the four slides) and/or if there is only one Kato-Katz thick smear slide with a 
hookworm egg. 
Once all follow-up samples have been analysed, all participants who were still found 
STH-positive will receive albendazole (400 mg single dose) and ivermectin (200 µg/kg), 
which is currently recommended against STH by the WHO’s Essential Medicines List. 

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4.3.4. Treatment acceptability and age-appropriateness assessment 
To compare the acceptability and age-appropriateness of each formulation two methods will 
be used: (1) an observer will fill in an observational sheet to record the participant’s reaction 
to treatment (Appendix 3) (age-appropriateness), and (2) the participant him/herself (if aged 
6 years or older) will respond to a brief questionnaire about the tablet he/she received 
(acceptability) (Appendix 3). 
 
4.3.5. Caregiver knowledge assessment 
In this clinical trial we will embed a parallel study focused on (1) assessing whether 
caregivers understand the content of the study (and its ICF) and (2) exploring different 
methods of transmitting the information we intend caregivers to understand before deciding 
whether their child should participate in our clinical trial and comparing their performance. 
Caregivers who show up will be randomly assigned to one of four groups with different types 
of information interventions: (i) no information, (ii) oral information session, (iii) information 
session with slideshow, and (iv) oral information session plus a theatre. The theatre will be 
performed by members of the local community with guidance of the research staff regarding 
its content. Caregivers’ understanding will be measured using a short questionnaire which 
will be pre-tested in a local community (Appendix 5). This questionnaire also includes asset 
socioeconomic questions.  
Interviewers will receive specific training. Caregivers assigned to the control group (no 
information group) will not have attended any of the three types of information sessions by 
the time they respond to the questionnaire. However, before they are invited to sign the ICF, 
they will have to attend an information session with slideshow. 
 
4.4. Measure to minimize bias 
Study participants eligible for treatment will be randomly assigned to one of the two treatment 
arms using a computer-generated stratified block randomization code. The random allocation 
sequence with varying random blocks of four or eight and stratified by 2 levels of baseline 
infection intensity (light: 1-1999 EPG, and moderate plus heavy:  2000 EPG hookworm 
infections) will be provided by a statistician. Both treatment arms will have an equal number 
of participants with light infection intensity, although the number of light versus 
moderate/heavy infections are not expected to be equal within each arm, depending on the 
distribution of infection intensity in the recruited cohort.  

Protocol_CHEW_MEB_V4.01_26.08.2019 
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4.5. Study duration  
The trial is estimated to last 12 weeks with each participant’s involvement lasting up to 10 
weeks. The screening for the baseline will start about five weeks prior to the treatment. 
Follow-up screening will take place 14-21 days post-treatment. Schedules of visits are 
summarized below. 
 
4.6. Schedule of visits 
Table 1 briefly presents the distribution of tasks along the trial.  
 
 
 
 
 
Table 1. Schedule of visits during treatment period. 
 
Baseline  
Examination/Treatment/Safety 
Follow-up 
 
Hours 
 
Days 
-35 to -1/0 
0 
3 
24 
Days 
14 to 21 
Days 
22 to 29 
Sample collection and 
diagnosis 
X 
 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
Caregiver 
questionnaires 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
Physical and clinical 
examination 
 
X 
 
 
 
 
Hb level and pregnancy 
assessment 
 
X 
 
 
 
 
Randomization and  
treatment 
 
X 
 
 
 
 

Protocol_CHEW_MEB_V4.01_26.08.2019 
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Capturing AEs/ SAEs 
 
 
X 
X 
X* 
 
Administration of 
ALB+IVM (if still 
infected at follow-up) 
 
 
 
 
 
X 
Observational sheet 
 
X 
 
 
 
 
* Passive collection of AEs/SAEs (only when a child/caregiver contacts a staff member). 
 
5. Selection of the trial subjects  
5.1. Recruitment 
The study will be carried out in preschool- and school-aged children (age: 3-12 years) in five 
primary schools with kindergarten (Wawi, Mvumoni, Bwagamoyo, Piki and Mzambarauni) on 
Pemba, Tanzania, a hookworm endemic area [20-22, 26, 27]. The study will be school-
based. Caregivers of potential participants will be invited to participate in an information 
session where the research staff will explain the purpose and procedures of the study, as 
well as potential benefits and risks of participating. Particular emphasis will be given to the 
fact that caregivers should oversee the sample collection to avoid sample mix ups. 
Caregivers will be encouraged to ask questions in an open discussion forum.  
Caregivers interested in having their child/children participate in the study will be 
invited to complete the process of informed consent by signing the informed consent form 
(ICF) (Appendix 1). See section 10.3 for further details on obtaining informed consent. Only 
participants who have written informed consent will be assessed for study eligibility criteria 
during screening procedures. 
 
5.2. Inclusion criteria 
 
Male of female children aged between 3 and 12 years; 
 
Written informed consent signed by caregiver; 
 
Was examined by a study physician before treatment; 
 
Provided two stool samples at baseline; 
 
Hookworm EPG ≥ 50 and at least two Kato-Katz thick smears slides with more than 
one hookworm egg; 
 
5.3. Exclusion criteria 

Protocol_CHEW_MEB_V4.01_26.08.2019 
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 
Pregnant; 
 
Presence or history of major systemic or chronic illnesses, as assessed by a medical 
doctor, such as can upon initial clinical assessment; 
 
Suffers from severe anemia (Hb < 80 g/l); 
 
Received anthelminthic treatment or metronidazole within past four weeks. 
 
Attending other clinical trials during the study. 
 
Participants who were diagnosed with hookworm, A. lumbricoides and/or T. trichiura but 
were excluded from the clinical trial due to one or several of the above-mentioned exclusion 
criteria, including withdrawals, will be offered standard anthelminthic treatment (combination 
of albendazole and ivermectin), except for pregnant girls. In the presence of major systemic 
or chronic illnesses, besides providing the standard anthelminthic treatment, we will facilitate 
the best locally available care and/or support. 
 
5.4. Criteria for discontinuation of trial 
A subject can be discontinued from the study for the following reasons: 
 
Withdraws from the study (this can happen anytime as participation is voluntary and 
there are no further obligations once a participant withdraws); data obtained prior to 
the withdrawal will be included in the analysis to ensure the validity of the trial. Data 
of withdrawn participants are filly anonymised once analysis is complete. 
 
At the discretion of the PI or co-PI, if the participant is not compliant to the 
requirements of the protocol. 
Discontinued subjects will not be replaced. If, for any reason, a subject is discontinued from 
the study before the end of treatment evaluations, the adverse event (AE) assessment will 
still be conducted.  
 
5.5. Treatment of subjects 
Both mebendazole tablet formulations will be donated by the WHO. Tablets will be kept in 
their original packing until they are administered to participants. However, we will cut the 
sheet of encapsulated tablets so that we have them individualized but still in the capsule. To 
ensure the treatment allocation is concealed, prior to the trial initiation, two subjects 
independent to the study will prepare sealed, opaque and sequentially numbered envelopes 
containing the correct encapsulated tablet (chewable or swallowable) for each participant.  

Protocol_CHEW_MEB_V4.01_26.08.2019 
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On treatment day, one 500 mg tablet will be orally administered to each participant. 
However, the mode of administration will depend on (i) whether the child is 3-5 year old or 6-
12 year old and (ii) on the treatment arm he/she has been allocated to: 
 
3-5 year olds allocated to the swallowable tablet arm will be given the crushed 
tablet on a spoon mixed with a small amount of clean water; 
 
6-12 year olds allocated to the swallowable tablet arm will be given the whole tablet 
to swallow with a glass of clean water; 
 
3-5 year olds allocated to the chewable tablet arm will be encouraged to chew  the 
tablet and swallow it without water; if they cannot chew it then a small amount of 
water will be added to the tablet in a spoon; 
 
6-12 year olds allocated to the chewable tablet arm will be encouraged to chew the 
tablet and then swallow it without water. 
The staff administering treatment will be trained in case any child chokes. Treatment arm, 
date and time will be recorded in the case report form (CRF) (Appendix 2). All drugs will be 
administered in the presence of at least one study investigator, and ingestion confirmed. The 
individual observational sheet will be filled out by the co-PI administering the drugs during the 
treatment of each participant, and as soon as the participant is done with treatment one staff 
member will pose him/her questions concerning the tablet to explore the acceptability 
(Appendix 3). This questionnaire will only be administered to the participant if he/she is aged 
between 6-12 years. 
Subjects will be asked not to take any drugs other than those prescribed by the study 
medical team until they have provided the two follow-up stool samples. After ingestion of the 
medication, which will be done at school, the subjects will be observed for 3 hours to ensure 
retention of the drug. Vomiting within one hour post-dosing will require re-dosing. The 
subjects will not be allowed more than one repeated dose. No re-administration will be 
needed for subjects vomiting after one hour. The site co-PI is responsible for drug 
accountability at the study site. Maintaining drug accountability includes careful and 
systematic study drug storage, handling, dispensing and documentation of administration. 
Any study product that is unused at the conclusion of the study will be destroyed. 
 
5.6. Concomitant therapy 
All medications taken one month before and during the study period until the last stool 
examination between day 14 and 21 (follow-up) must be recorded with indication, dose 
regimen, date and time of administration. 
Medication(s)/treatment(s) permitted during the trial: 

Protocol_CHEW_MEB_V4.01_26.08.2019 
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 
Analgesics and antipyretics are allowed to be given to the subjects in case of fever, 
antiemetics to prevent nausea and vomiting and/or antibiotics to prevent or treat 
bacterial superinfection. 
Medication(s)/treatment(s) NOT permitted during the trial:  
 
No other active drugs against helminths are permitted during the trial.  
 
Metronidazole.  
 
6. Safety assessments 
Few AEs have been reported following mebendazole administration. The most common 
reported AEs are abdominal cramps, headache, diarrhoea, fever and fatigue [22, 28, 29].  
The chewable mebendazole has previously caused convulsions but only in infants below the 
age of one year which are not included in this study. The concomitant administration of the 
chewable mebendazole and metronidazole has caused neutropenia and agranulocytosis 
[30]. The safety profile of mebendazole will be assessed through the recording, reporting and 
analysis of baseline medical conditions, a physical examination and active questioning at 3 
and 24 hours post-treatment (see section 6.2).  
 
6.1. Adverse event definitions 
The term “adverse event” could include any of the following events which develop or 
increase in severity during the course of the study, after administration of the study product: 
 
Any unfavourable and unintended signs, symptoms or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the condition 
under study and the study product; 
 
Any abnormality detected during physical examination. 
The medical conditions present at the initial trial visit that do not worsen in severity or 
frequency during the trial will not be defined as AEs but as be considered baseline medical 
conditions. For the purpose of this trial, disease progression and relapse will be considered 
as treatment failure, not as an AE.  
 
6.1.1. Severity grading 
Adverse signs or symptoms will be graded by the Investigator as mild, moderate, severe or 
life threatening according to the following definitions:  

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Grade 
Definition 
1 
Mild: the subject is aware of the event or symptom, but the event or symptom is 
easily tolerated. 
2 
Moderate: the subject experiences sufficient discomfort to interfere with or 
reduce his or her usual level of activity. 
3 
Severe: significant impairment of functioning: the subject is unable to carry out 
his or her usual activities. 
4 
Life threatening or disabling  
5 
Death related to adverse events 
 
 
6.1.2. Relatedness 
Relatedness will be assessed as defined below based on the temporal relationship between 
the AE and the treatment, known side effects of treatment, medical history, concomitant 
medication, course of the underlying disease and trial procedures. 
Possibly related: an AE which can medically (pharmacologically/clinically) be attributed to 
the study treatment. 
Unrelated: an adverse even which is not reasonably related to the study treatment. A 
reasonable alternative explanation must be available. 
An AE that is determined to be related to the administration of a study product is referred to 
as an “adverse drug reaction.” 
 
6.1.3. Expectedness 
Expected adverse drug reaction: Any AE possibly related to the administration of 
mebendazole reported in the literature or on the drug package leaflet and listed in the 
consent form. These AEs are detailed in the drug package leaflet (Appendix 4). 

Protocol_CHEW_MEB_V4.01_26.08.2019 
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Unexpected adverse drug reaction: Any AE possibly related to the study product 
administration, the nature, frequency, specificity or severity of which is unanticipated and not 
consistent with the available risk information described for these drugs.  
 
6.1.4. Serious adverse events (SAEs) 
According to the ICH “Clinical Safety Data Management: Definitions and standards for 
expedited Reporting E2A” [31], a serious adverse event (SAE) includes any event 
(experience) or reaction in any untoward medical occurrence that at any dose: 
 
Results in death; 
 
Is life threatening, meaning, the subject was, in the view of the Investigator, at 
immediate risk of death from the reaction as it occurred, i.e. it does not include a 
reaction that, had it occurred in a more serious form, might have caused death; 
 
Results in persistent or significant disability/incapacity, i.e. the event causes a 
substantial disruption of a person’s ability to conduct normal life functions; 
 
Requires in patient hospitalisation or prolongation of existing hospitalisation; 
 
Creates a congenital anomaly or birth defect (not relevant for this study); 
 
Is an important medical event, based upon appropriate medical judgment, that may 
jeopardize the patient or subject or may require medical or surgical intervention to 
prevent one of the other outcomes defining serious. 
A “severe” adverse event does not necessarily meet the criteria for a “serious” adverse event 
(SAE). SAE are reported from consent to 24 hours post-treatment. SAE that are still ongoing 
at the end of the study period will be followed up to determine the final outcome. The 
causality of any SAE that occurs after the study period and its possible relatedness to the 
study treatment or study participation will also be assessed by investigators as described in 
section 6.1.2. 
 
6.1.5. Suspected unexpected serious adverse events (SUSARs) 
A suspected unexpected serious adverse reaction (SUSAR) is an unexpected adverse drug 
reaction which also meets the definition of SAE.  
 
6.2. Methods of recording and assessing adverse events 
Patients will be kept for observation for 3 hours following treatment for any acute AEs. 
3h post-treatment participants will be actively questioned about any unfavorable changes in 

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the subject’s condition. Any reported changes will be recorded as an AE, whether reported 
by the subject or observed by the Investigator. In case of any abnormal finding, the local 
study physician will perform a full clinical examination and findings will be recorded. An 
emergency kit will be available on site to treat any medical conditions that warrant urgent 
medical intervention. In addition, patients will be also interviewed by a nurse and/or a 
physician about the occurrence of AEs 24 hours. Information on all AEs (onset, duration, 
intensity and causality) will be immediately entered in the appropriate AE module of the CRF 
which is considered as a source document, regardless of whether they are thought to be 
associated with the study or the drug under investigation. Associated with the use of the drug 
means that there is a reasonable possibility that the event may have been caused by the 
drug (see also relatedness definitions below). For all AEs, sufficient information will be 
pursued and/or obtained so as to permit (i) an adequate determination of the seriousness of 
the event (i.e. whether the event should be classified as a SAE), (ii) an assessment of the 
casual relationship between the AE and the study treatments (i.e. whether the event should 
be classified as an adverse drug reaction), and (iii) an assessment of intensity of AEs by the 
study physician. Additionally, participants will be encouraged to notify study staff of any AEs 
that may occur outside of scheduled safety assessments. All SAEs, unexpected adverse 
drug reactions, or SUSARs must be reported as described in Section 6.3.  
 
6.3. Reporting of serious adverse events  
Any study-related unanticipated problem posing risk of harm to subjects or others (including 
all unexpected adverse drug reactions), and any type of SAE will be immediately (within a 
maximum of 24 hours after becoming aware of the event) notified to the study PI and co-PI: 
 
Prof. Dr. Jennifer Keiser (PI) 
Swiss Tropical and Public Health Institute 
Socinstrasse 57, 4051 Basel, Switzerland 
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@swisstph.ch 
 
Mr. Said Ali (Co-PI) 
Public Health Laboratory Ivo de Carneri 
P.O. Box 122 Wawi, Chake Chake 
Pemba, Zanzibar (Tanzania) 

Protocol_CHEW_MEB_V4.01_26.08.2019 
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Tel.: +255 24 245-23 
Fax: +255 24 245-2003 
Mobile: +255 77 741-6867 
E-mail: saidmali2003@yahoo.com 
 
Within the following 48 hours, the local co-PI must provide to study PI further information on 
the SAE or the unanticipated problem in the form of a written narrative. This should include a 
copy of a completed SAE form, and any other diagnostic information that will assist the 
understanding of the event. In exceptional circumstances, a SAE may be reported by 
telephone. In these cases, a written report must be sent immediately thereafter by fax or e-
mail. Names, addresses and telephone for SAE reporting will be included in the trial-specific 
SAE form. Relevant pages from the CRF may be provided in parallel (e.g., medical history, 
concomitant medications).  
 
6.4. Safety reporting to health authorities and ethic committees 
The PI will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. Additionally, this information will be provided to the ‘Ethik 
Komission Nordwest- und Zentralschweiz’ (EKNZ, Switzerland) and ‘Zanzibar Health 
Research Institute (ZHRI, Tanzania) according to national rules. Fatal or life-threatening 
SAEs or SUSARs will be reported within 24 hours to ZHRI, followed by a complete report 
within 7 additional calendar days. Other SAEs and SUSARs that are not fatal or life-
threatening will be filed as soon as possible but no later than 14 days after first knowledge by 
the sponsor. 
 
7. Data management and data quality control 
7.1. Source data 
Source data are the clinical findings and observations, laboratory data maintained at the 
study site. Source data are contained in source documents. Local authorities are allowed to 
access the source data. Source data will be entered directly onto different documents: 
 
CRF where all the clinical and physical examination data, together with treatment 
information, adverse events and follow-up results are recorded. Each subject 
enrolled into the clinical study will have a CRF. One of the investigators will review, 
and approve each completed CRF. All data requested on the CRF must be recorded. 

Protocol_CHEW_MEB_V4.01_26.08.2019 
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 
Laboratory parasitology sheets where egg counts for each STH species are 
recorded. 
 
Observational sheet which an observer will record every child’s reaction to 
treatment (age-appropriateness). Every participant who received treatment will have 
an observational sheet. 
 
Acceptability questionnaire and observation which the participant responds to if 
aged between 6-12 years and a staff member fills out (the observation section) for all 
participants. 
 
Consent questionnaire which every caregiver will respond to assess their 
understanding of the study their child is enrolled in. This also includes socioeconomic 
data (asset possession). 
All source data documents will be kept for at least 15 years. The study site will retain a copy 
of the documents to ensure that local collaborators can provide access to the source 
documents to a monitor, auditor, or regulatory agency. 
 
7.2. Data collection and documentation 
Collected data will fall into one of the following categories: 
a) Anthropometric and clinical characteristics of the trial participants collected using the 
study’s CRF such as weight, height, blood pressure, temperature, pregnancy status 
(for female subjects ≥ 10 years of age), overall health status and any abnormal 
medical condition or disease. 
b) Egg counts of hookworm (Necator americanus and Ancylostoma duodenale, the 
differentiation of the two species will not be made), T. trichiura and A. lumbricoides. 
c) Observational data concerning the child’s receptivity to the tablet. 
d) Participant answers to the acceptability and adequacy questionnaire. 
e) Asset possession and household characteristics of each participant. 
f) Caregivers’ answers to the knowledge assessment questionnaire. 
Data in above categories (a) and (b) will be paper-captured, whereas data in 
categories (c), (d), (e) and (f) will be collected directly into tablets using Open Data Kit (ODK; 
free electronic data collection software) and uploaded to a server hosted at Swiss TPH. In 
paper-based data collection, all missing data must be explained. If a space on the CRF is left 
blank because the procedure was not done or the question was not asked “N/D” will be 
entered. If the item is not applicable to the individual case “N/A” will be written. All entries will 
be printed in black ink. All corrections must be initialled and dated. Paper-captured data will 
be subsequently double entered, using the EpiInfo data entry template, into ACCESS data 

Protocol_CHEW_MEB_V4.01_26.08.2019 
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entry masks by two independent staff members for quality assurance. The EpiInfo mask will 
be tested before use. Both databases will then be cross-checked using the Data Compare 
utility of EpiInfo; any discrepancies will be corrected by consulting the hard copy. Data will be 
entered at the study site. Data entered into ACCESS databases will only be accessible to 
authorized personnel directly involved with the study by use of a password. All data will be 
exported and saved in the following formats: .mdb, .xlsx and .csv. Hard copies of the data 
such as parasitological sheets and CRFs will remain at PHL-IdC. Digital copies along with 
the databases will be transferred to the Swiss TPH after a Material Transfer Agreement has 
been signed by both the Swiss TPH and PHL-IdC. Data will then be analyzed as described in 
section 8. 
 
7.3. Ethical, legal and security issues 
Screened participants will be listed in a confidential “subject screening log” and attributed a 
unique study ID. The codes will be linked with the participant’s identity on a separate file 
(subject identification list) and filed in a secured place at PHL-IdC and will only be accessible 
to investigators. Personal data will be coded for data analysis. No names will be published at 
any time, and published reports will not allow for identification of single subjects. 
Confidentiality will be ensured throughout the entire research project. All databases will be 
password secured. None of the investigators declare to have any conflicts of interest. 
 
7.4. Data storage and preservation 
Each stool sample will be destroyed once a duplicate Kato-Katz thick smear has been 
prepared. Slides will be destroyed up to one day after the examination and quality control are 
complete. Data and related material will be preserved for a minimum of 15 years to enable 
understanding of what was done, how and why, which allow the work to be assessed 
retrospectively and repeated if necessary. The primary data storage and backup will be in the 
Swiss TPH shared server and secondary data storage will be: personal laptops of Jennifer 
Keiser and Marta Palmeirim, Swiss TPH shared server, and SWICTHdrive. All files stored in 
these locations will be password protected. Archiving conditions will be made strictly 
confidential by password protection. 
 
7.5. Study documents: translations – reference language 
- 
ICF: Master-document English, all language version are translation thereof. 

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- 
Caregiver knowledge assessment questionnaire: Master-document English, all 
language version are translation thereof. 
 
8. Statistical analysis 
8.1. Definition of primary endpoint 
The primary endpoint of this study is the ERR of mebendazole against hookworm assessed 
14 to 21 days post-treatment using the duplicate Kato-Katz thick smear method.  
 
8.2. Justification of number of trial subjects 
Because the primary outcome – difference in egg reduction rates (ERR) – does not follow a 
known distribution we ran a series of conservative simulations using data from Speich et al. 
[22] to determine the required sample size. An initial round of simulations showed that 
differences in ERRs are associated with substantial higher power compared to CRs. We 
used Monte Carlo resampling techniques to simulate CR of 10 and 20%, respectively, which 
translates roughly into ERRs of 38% and 64%. We estimated that 160 patients per arm are 
required to detect a statistical significant difference with 80% power. To account for potential 
loss to follow up (which was low in our previous studies in this setting) of 10% and to include 
a safety margin of 14% we aim to recruit in total 200 participants per trial arm.  
 
8.3. Description of statistical methods 
The primary analysis will use the full analysis set (available case population) according to the 
intention to treat principle defined as all randomized subjects which provide any follow-up 
data. Only subjects which were negative at baseline and erroneously randomized will be 
excluded from the analysis. Palatability and ease of swallowing are critical attributes in 
children; therefore, a per-protocol analysis will be conducted additionally to disentangle drug 
efficacy from adherence effects. 
Geometric mean egg counts will be calculated for the different treatment arms before and 
after treatment to assess the corresponding ERRs. The ERR will be calculated as: 
 
𝐸𝑅𝑅=  1 − 
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝 + 1) −1
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 1)      −1  

Protocol_CHEW_MEB_V4.01_26.08.2019 
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Bootstrap resampling with 5,000 replicates will be used to calculate 95% confidence intervals 
(CIs) for ERRs and the difference between the two ERRs. Superiority will be claimed if the 
95% confidence interval of the difference in ERRs does not include unity (primary 
hypothesis). 
Differences in CRs will be assessed using unadjusted logistic regressions. In a subsequent 
analysis an adjusted logistic regression (adjustment for age, sex, weight and strata) will be 
performed.  
AEs will be evaluated descriptively as the difference of proportion reporting AEs before and 
after treatment. 
 
 
9. Duties of the investigator 
The investigators are responsible for an adequate data quality. Prior to the initiation of the 
study, a short investigator’s meeting will be held with the investigators and their study 
coordinators and a member from Swiss TPH. This meeting will include a detailed discussion 
of the protocol, performance of study procedures (SOPs from previous studies available on 
site), CRF completion, and specimen collection and diagnostic methods.  
 
9.1. Investigator’s confirmation 
This trial will be conducted in accordance with the protocol, International Conference on 
Harmonisation Good Clinical Practice E6 (R2) (ICH-GCP) and the current version of the 
Helsinki Declaration. 
All protocol modifications must be documented in writing. A protocol amendment can be 
initiated by either the PI or any Investigator. The Investigator will provide the reasons for the 
proposed amendment in writing and will discuss with the PI and Co-PIs. Any protocol 
amendment must be approved and signed by the PI and must be submitted to the 
appropriate Independent Ethics Committee (IEC) for information and approval, in accordance 
with local requirements, and to regulatory agencies if required. Approval by IEC must be 
received before any changes can be implemented, except for changes necessary to 
eliminate an immediate hazard to trial subjects, or when the change involves only logistical or 
administrative aspects of the trial, e.g. change of telephone number(s). 
 

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9.2. Damage coverage 
A general liability insurance of the Swiss TPH is in place (Winterthur Police Nr. 4746321) and 
a patient liability insurance will be issued by the National Insurance Cooperation of Tanzania 
LTD, which will cover any eventual study related injuries or deaths. 
 
9.3. Project management 
The trial team will include the PI (Prof. Jennifer Keiser), a trial and data manager (Marta 
Palmeirim), a trial statistician (Dr. Jan Hattendorf), as well as a physician (Dr. Sauda Kassim 
Omar), nurses and laboratory technicians. Prof. Jennifer Keiser and Marta Palmeirim will be 
responsible for staff management, communication with the collaborative group, recruitment 
monitoring, data management, safety reporting, analysis, report writing and dissemination of 
the trial results. Marta Palmeirim will monitor all field activities at the study site. Dr. Sauda 
Kassim will be responsible for clinical examinations and AEs monitoring. Dr. Shaali Ame and 
Said Ali (Co-PI in Tanzania) are responsible for supervision of the lab and field technicians, 
staff management, recruitment monitoring, supply of the material, contact to the local 
authorities and participating schools to obtain necessary permissions before beginning 
recruitment. 
The investigator team is responsible for ensuring that the protocol is strictly followed. The 
investigator should not make any changes without the agreement of the PI and co-PIs, 
except when necessary to eliminate an apparent immediate hazard or danger to a study 
participant. The investigator will work according to the protocol and GCP. The investigator 
may take any steps judged necessary to protect the safety of the participants, whether 
specified in the protocol or not. Any such steps must be documented. During the treatment 
the records are maintained by the responsible medical doctor. All entries have to be made 
clearly readable with a pen. The investigator must be thoroughly familiar with the properties, 
effects and safety of the investigational pharmaceutical product.  
 
10. Ethical considerations 
The investigators have all been trained in GCP. None of the investigators declare to have 
any conflicts of interest. 
 
10.1. Independent Ethics  Committees 

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The study will be submitted for approval by the institutional research commission of the 
Swiss TPH and the ethics committees of Switzerland (EKNZ) and Zanzibar (ZHRI). The 
study will be undertaken in accordance with the Declaration of Helsinki and good clinical 
practice (GCP).  
 
10.2. Evaluation of risk-benefit ratio 
Few AEs have been reported for mebendazole (package leaflet Appendix 4). The most 
common reported AEs are abdominal cramps, headache, diarrhoea, fever and fatigue [22, 
28, 29]. All participants will benefit from a clinical examination and a treatment against STHs. 
All participants in whose stool we still find hookworm eggs will be treated with the 
combination of albendazole and ivermectin (according to WHO recommendations). 
 
10.3. Subject information and consent 
Community meetings will be conducted to explain to caregivers the purpose and procedures 
of the study.  Caregivers attending this meeting will receive a small provision to cover their 
costs for transportation (3,000 TSh). Their level of comprehension of the trial’s purpose, 
procedures, risks, benefits and content of the ICF will then be assessed using a short 
multiple-choice questionnaire. Finally, caregivers of an eligible individual will be invited to 
sign a written ICF (translated into the local language, i.e. Kiswahili) after having had sufficient 
time for reflection of their child’s participation. In case the caregiver is illiterate, an impartial 
witness that can read and write has to sign the consent and the caregiver has to give a 
thumb print. Participation is voluntary and individuals have the right to withdraw from the 
study at any given point in time with no further obligations. Participation itself will not be 
awarded with compensation. Only after the ICF is signed will participants undergo any 
screening procedures. 
 
10.4. Subjects requiring particular protection 
This study will include subjects requiring particular protection: children aged 3-1 years. It is 
important to include this age group because hookworm infections are common in this age 
group and they are at high risk of infection. Our trial will produce more evidence to support 
the search of safer and more effective treatment of STH infections in children. 
 
11. Monitoring and auditing 

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We will work with a locally based monitor. He/she will conduct site visits to the investigational 
facilities for the purpose of monitoring the study. Details will be described in a separate 
monitoring plan. The investigator will permit her/him access to study documentation and the 
clinical supplies dispensing and storage area. Monitoring observations and findings will be 
documented and communicated to appropriate study personnel and management. A 
corrective and preventative action plan will be requested and documented in response to any 
audit observations. No sponsor initiated audits are foreseen, but audits and inspections may 
be conducted by the local regulatory authorities or ethics committees. The Investigator 
agrees to allow inspectors from regulatory agencies to review records and is encouraged to 
assist the inspectors in their duties, if requested.  
 
12. Dissemination of results and publication 
The final results of this study will be published in a scientific journal and presented at 
scientific conferences. The European Research Council will be acknowledged as study 
funder. All results from this investigation are considered confidential and shall not be made 
available to any third party by any member of the investigating team before publication. A 
summary of study conclusions will be shared with the local ethics committee, ZHRI. 
 
 
 
 
 
 
 
 
 
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Global Burden of Disease Study 2016. The Lancet, 2017. 390: p. 1260-344. 

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3. 
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WHO, Action against worms: deworming young children. 2007. 
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Chewable, Rapidly-Disintegrating Tablet for Ascaris lumbricoides and Trichuris 
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Placebo-Controlled, Phase 3 Study. Am J Trop Med Hyg, 2017. 97(6): p. 1851-1856. 
19. 
Friedman, A.J., S.M. Ali, and M. Albonico, Safety of a New Chewable Formulation of 
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Moser, W., et al., Efficacy and safety of oxantel pamoate in school-aged children 
infected with Trichuris trichiura on Pemba Island, Tanzania: a parallel, randomised, 
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Speich, B., et al., Efficacy and safety of albendazole plus ivermectin, albendazole 
plus mebendazole, albendazole plus oxantel pamoate, and mebendazole alone 

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against Trichuris trichiura and concomitant soil-transmitted helminth infections: a four-
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Speich, B., et al., Oxantel pamoate-albendazole for Trichuris trichiura infection. N 
Engl J Med, 2014. 370(7): p. 610-20. 
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Palmeirim, M.S., et al., Efficacy and Safety of a Single Dose versus a Multiple Dose 
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Wu, Z.X., Y.Y. Fang, and Y.S. Liu, [Effect of a novel drug--enteric coated 
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Xiao, S.H., et al., [Clinical observation on 899 children infected with intestinal 
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Knopp, S., et al., Albendazole and mebendazole administered alone or in 
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30. 
Johnson&Johnson. U.S. FDA Approves Vermox™ Chewable (Mebendazole) For 
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from: 
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14.  Appendixes 
 
Appendix 1. Informed consent form (ICF) 
Appendix 2. Case report form (CRF) 
Appendix 3. Acceptability questionnaire and observation 

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Appendix 4. Package leaflets (chewable and swallowable) 
Appendix 5. Caregiver knowledge assessment questionnaire