Clinical trial NCT03245398
Conditions: Hookworm
Sponsor: Jennifer Keiser
Start date: 2017-07-25; Completion date: 2017-09-15
Enrollment: 186 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a double-blind randomized clinical trial which aims at providing evidence on the efficacy and safety of two regimens of mebendazole in school-aged children. Thus, our primary objective is to assess the efficacy and safety of: i) 100 mg solid tablets twice a day for 3 days, and ii) one dose of 500 mg solid tablets of mebendazole in participants aged 6-12, inclusive, infected with hookworm.

The primary endpoint of the trial is the cure rate (CR) of the 3-day regimen of mebendazole against hookworm and a single dose mebendazole treatment.

The secondary objectives are to determine if the multi-dose regimen is superior to the single dose regimen, evaluate the efficacy against concomitant soil-transmitted helminth infections, and assess the safety of both mebendazole regimens.

After obtaining informed consent from children's caregiver, the medical history of the participating individuals will be assessed with a standardized questionnaire, in addition to a clinical examination carried out by the study physician on the treatment day. Enrollment will be based on two stool samples which will be collected, if possible, on two consecutive days or otherwise within a maximum of 5 days apart. All stool samples will be examined with duplicated Kato-Katz thick smears by experienced laboratory technicians.

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 hours after every morning treatment and 24 hours after every morning treatment about the occurrence of adverse events. The efficacy of the treatment will be determined 14-21 days post-treatment by collecting another two stool samples.

The primary analysis will include all participants with primary end point data (available case analysis). Supplementary, two sensitivity analyses will be conducted imputing all missing endpoint data as treatment failures or all as treatment success. CRs will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. CRs will be compared by using unadjusted logistic regression. To assess model robustness with respect to covariates, adjusted logistic regressions (adjustment for age, sex, school, weight and strata) will be performed.

Geometric and arithmetic mean egg counts will be calculated for the different treatment arms before and after treatment to assess the corresponding ERRs. Bootstrap resampling method with 5,000 replicates will be used to calculate 95% confidence intervals (CIs) for ERRs and the difference of the ERRs.

Detailed description:

Arms: arm 1: In day 1 each child in this treatment arm will receive a 500 mg tablet of mebendazole plus one 100 mg placebo tablet in the morning. In the afternoon of day 1 they will only receive the placebo. In day 2 and 3 each child will receive one placebo twice a day (in the morning and in the evening) arm 2: In day 1 each child in this treatment arm will receive a 100 mg tablet of mebendazole plus one 500 mg placebo tablet in the morning. In the afternoon of day 1 they will only receive the 100 mg tablet of mebendazole. In day 2 and 3 each child will receive one 100 mg tablet of mebendazole twice a day (in the morning and in the evening).
Interventions: intervention 1: Treatment with one of the two regimens of mebendazole
Intervention descriptions: intervention 1: Once in the morning and once in the evening for 3 consecutive days

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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Study Protocol 
 
 
 
Efficacy and safety of a single-dose regimen and a multi-
dose 
regimen 
of 
mebendazole 
against 
hookworm 
infections in children: a randomized controlled trial 
Protocol Number 
2 
Version Number 
2.01 
Document Date 
17 July 2017 
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 
Public Health Laboratory Ivo de Carneri, Pemba, Tanzania 
Funding Agency 
PATH, Seattle, USA 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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1. General Information 
 
I. List of investigators and other persons involved 
 
Title 
Names 
Institution 
Position 
Function in trial 
Prof. Dr. 
Jennifer Keiser 
Swiss Tropical and 
Public Health Institute 
Unit head 
Principal Investigator 
MSc  
Marta Palmeirim 
Swiss Tropical and 
Public Health Institute 
PhD-student 
Co-PI 
MSc 
Said Ali 
Public Health Laboratory 
Ivo de Carneri 
Director 
Site Co-PI 
MSc 
Shaali Ame 
Public Health Laboratory 
Ivo de Carneri 
Group leader 
Site Co-PI 
Dr. 
Jan Hattendorf 
Swiss Tropical and 
Public Health Institute 
Project leader 
Statistician 
 
 
 
 
 


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Signatures  
 
Statistician 
 
Signature 
 
 
 
 
 
Date of Signature  
14 July 2017 
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 (Sponsor-Investigator) 
 
Signature 
 
 
 
 
Date of Signature  
14 July 2017 
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. 
 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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Co-Principal investigator 
 
Signature 
 
Date of Signature  
14 July 2017 
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  
14 July 2017 
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  
14 July 2017 
Name  
Shaali Ame 
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 
 
 
 
 
 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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III. 
Table of contents 
Efficacy and safety of a single-dose regimen and a multi-dose regimen of 
mebendazole against hookworm infections in children: a randomized controlled trial . 1 
1. General Information ........................................................................................................ 2 
2. Background information ................................................................................................11 
3. Trial objective and purpose ...........................................................................................13 
4. Methodology ...................................................................................................................14 
4.1 
Type of trial ............................................................................................................14 
4.2 
Trial design ............................................................................................................14 
4.2.1 Baseline survey and screening .............................................................................14 
4.2.2 Assessment of efficacy after treatment .................................................................16 
4.3. Measure to minimize bias ..........................................................................................17 
4.4. Study duration and duration of subject participation ...................................................17 
4.5. Schedule of visits .......................................................................................................17 
Table 2 briefly presents the distribution of tasks along the trial. Further detail is available in 
Appendix 2. ......................................................................................................................17 
5. Selection of the trial subjects ........................................................................................18 
5.1 Recruitment ................................................................................................................18 
5.2 Inclusion criteria ..........................................................................................................18 
5.3. Exclusion criteria .......................................................................................................19 
5.4. Criteria for discontinuation of trial ...............................................................................19 
5.5. Treatment of subjects ................................................................................................20 
5.6 Concomitant therapy ...................................................................................................21 
6. Safety assessments .......................................................................................................22 
6.1. Adverse event definitions ...........................................................................................22 
6.1.1. Severity grading ...................................................................................................22 
6.1.2. Relatedness .........................................................................................................23 
6.1.3. Expectedness ......................................................................................................23 
6.1.4. Serious adverse events .......................................................................................24 
6.1.5. Suspected unexpected serious adverse reactions ...............................................24 
6.2. Methods of recording and assessing adverse events .................................................24 
6.3. Reporting of serious adverse events ..........................................................................25 
6.5. Safety reporting to Health Authorities and Ethics Committees ...................................26 
7. Statistics .........................................................................................................................26 
7.1. Definition of primary endpoint ....................................................................................26 
7.2. Justification of number of trial subjects ......................................................................27 
7.3. Description of statistical methods ...............................................................................27 


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7.4. Description of data management ...............................................................................27 
8. Duties of the investigator ...............................................................................................28 
8.1. Investigator’s confirmation .........................................................................................28 
8.2. Damage coverage .....................................................................................................29 
8.3. Project management ..................................................................................................29 
9. Ethical considerations ...................................................................................................29 
9.1. Independent Ethics Committee (IEC) .........................................................................29 
9.2. Evaluation of the risk-benefit ratio ..............................................................................30 
9.3. Subject information and consent ................................................................................30 
9.4. Subject Confidentiality ...............................................................................................30 
9.5. Subjects requiring particular protection ......................................................................31 
10. Quality control and quality assurance ........................................................................32 
10.1. Monitoring and auditing............................................................................................32 
10.2. Access to data, handling of data and samples (data protection), archiving (place, 
duration) and destruction ..................................................................................................32 
10.3. Data entered directly in the Case Report Form (CRF) – definition of source data ....33 
11. Dissemination of results and publication ...................................................................33 
12. References ....................................................................................................................34 
Appendix 1: ......................................................................................................................38 
Stefan Mörgeli, administrative director Swiss TPH                    (Signature) ................. Error! 
Bookmark not defined. 
 
 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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Abbreviations 
 
AE: adverse event 
CI: confidence interval 
CR: cure rate 
CRF: case report form 
DALYs: disability-adjusted life years 
EMA: European Medicines Agency 
EPG: egg per gram 
ERR: egg reduction rate 
GCP: Good Clinical Practice 
HB: haemoglobin 
 
ICH: International Council for Harmonisation 
IEC: independent ethics committee 
MDA: mass drug administration 
PCR: polymerase chain reaction 
PHL: Public Health Laboratory 
PI: Principal Investigator 
SAE: serious adverse event 
 
SSL: Secure Sockets Layer 
STH: soil-transmitted helminths 
WHO: World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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Synopsis 
 
Study Title 
Efficacy and safety of a single-dose regimen and a multi-dose 
regimen of mebendazole against hookworm infections in 
children: a randomized controlled trial 
Study Type 
Phase 4 trial 
Indication 
Hookworm infection (eggs in stool) 
Sample size 
180 
Investigational Product 
and Reference 
Treatment 
Mebendazole  
100 mg solid tablets 
500 mg solid tablets 
Protocol Number, Date 
and Version 
14 July 2017, V2.01 
Trial registration 
Will be registered on (http://www.controlled-trials.com/) 
Study Rationale 
To provide evidence on the efficacy of a single dose regimen and 
a multiple dose regimen of mebendazole in children. 
Study Objectives 
To assess the efficacy and safety of two dose regimens of 
mebendazole: i) 100 mg solid tablets twice a day for 3 days, and 
ii) one dose of 500 mg solid tablets of mebendazole in 
participants aged 6-12, inclusive, infected with hookworm.  
The primary objective of the trial is to assess the cure rate (CR) 
of a 3-day regimen of mebendazole against hookworm and a 
single dose mebendazole treatment.  
The secondary objectives are to determine if the multi-dose 
regimen is superior to the single dose regimen, evaluate the 
efficacy against concomitant soil-transmitted helminth infections, 
and assess the safety of both mebendazole regimens. 
Study -design 
Double blind, randomized trial (both participants and outcome 
assessors are blinded) 
Study product  
intervention 
Mebendazole 
Comparator(s) 
None 
Key inclusion / 
Exclusion criteria 
Inclusion: individuals aged between 6 and 12 with a hookworm 
infection, absence of major systemic illnesses, written informed 
consent signed by parents/caregivers; and oral assent by the 
participants. 
Exclusion: Menarche, any abnormal medical conditions or 
chronic disease, negative diagnostic result for hookworm, no 
written informed consent 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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Primary Endpoints 
CR against hookworm 
Secondary Endpoints 
Egg reduction rate (ERR, based on geometric means) 
against hookworm, CR/ERR against A. lumbricoides and T. 
trichiura, safety 
Exploratory Endpoints 
 
Sensitivity of Kato Katz compared to quantitative polymerase 
chain reaction assays 
 
Prevalence of mebendazole genetic resistance markers 
 
Prevalence of STH species 
Interim Analyses 
None 
Study Duration 
12 weeks total; up to 8 weeks per participant 
Schedule 
07/2017 of first-participant in (planned) 
10/2017 of last-participant out (planned) 
Measurements & 
procedures 
Two stool samples will be collected if possible on two 
consecutive days or otherwise within a maximum of 5 days apart. 
The medical history of the participating individuals will be 
assessed with a standardized questionnaire, in addition to a 
clinical examination carried out by the study physician on the 
treatment day.  
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 hours 
after every morning treatment and 24 hours after every morning 
treatment about the occurrence of adverse events. The efficacy 
of the treatment will be determined 14-21 days post-treatment by 
collecting another two stool samples. All stool samples will be 
examined with duplicated Kato-Katz thick smears.  
Statistical Analyses 
The primary analysis will include all participants with primary end 
point data (available case analysis). Supplementary, two 
sensitivity analyses will be conducted imputing all missing 
endpoint data as treatment failures or all as treatment success. 
CRs will be calculated as the percentage of egg-positive 
participants at baseline who become egg-negative after 
treatment. CRs will be compared by using unadjusted logistic 
regression. To assess model robustness with respect to 
covariates, adjusted logistic regressions (adjustment for age, sex, 
school, weight and strata) will be performed.  
Geometric and arithmetic mean egg counts will be calculated for 
the different treatment arms before and after treatment to assess 
the corresponding ERRs. Bootstrap resampling method with 
5,000 replicates will be used to calculate 95% confidence 
intervals (CIs) for ERRs and the difference of the ERRs.  
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 
This study will be carried out in individuals aged 6-12 years old, 
since an infection with hookworm and other soil-transmitted 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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participants 
helminths occurs most often in this age group. 
Recruitment procedure The study will be carried out in primary schools in 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. 
Study site 
Public Health Laboratory Ivo de Carneri, Pemba, Tanzania 
 
 
 
 
 
 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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2. Background information 
 
The most recent estimates suggest that between 600 and 800 million people are infected 
with one or several of the common soil-transmitted helminths (STHs), which are 
A. lumbricoides, T. trichiura, and hookworm [1]. Recently, the global burden due to STHs has 
been estimated at 3.3 million disability-adjusted life years (DALYs) [2]. The symptoms of STH 
infections are non-specific and may only be apparent in heavily infected individuals. Children 
make up the age group which is most at risk of infection with helminths and infections in 
children are typically the most intense and debilitating [3].  Chronically infected children might 
suffer from malnutrition, physical and cognitive retardation, and reduced work performance 
[4]. 
Currently there are five drugs on the World Health Organization (WHO) model list of 
essential drugs against STH infections and these drugs have been widely and effectively 
used [5, 6]. Against A. lumbricoides, T. trichiura and hookworm infection, the two 
benzimidazoles (albendazole and mebendazole) are the treatment of choice; the other drugs 
used against these infections are levamisole and pyrantel pamoate [5-7]. Ivermectin is used 
to treat Strongyloides stercoralis infection, but it is also effective against A. lumbricoides 
infections and moderately effective against T. trichiura infection [8, 9]. Both albendazole and 
mebendazole are used at large scale, within the frame of preventive chemotherapy, which is 
the regular administration of anthelminthic drugs to at-risk populations (e.g. school-aged 
children). Preventive chemotherapy is advocated by WHO, because this strategy has a rapid 
impact on morbidity, and its ease of implementation; the drugs can be administered by 
personnel outside the health sector (e.g. teacher) independent of recipients body weight, e.g. 
albendazole or mebendazole are administered at a single oral dose [5].  
Mebendazole displays a broad spectrum of activity [6, 10, 11] and it interferes with cellular 
tubulin formation in the worms’ intestine leading to its death [12]. This drug has been 
extensively used worldwide for more than 30 years both alone and, more recently, in 
combination with drugs such as praziquantel and ivermectin [13-16]. Mebendazole has 
shown excellent cure rates (CR) against A. lumbricoides. In addition, it reveals low to 
moderate efficacy against T. trichiura and hookworm at single oral doses [6, 17].  
Through mass drug administration (MDA) campaigns for STH treatment, hundreds of millions 
of doses of mebendazole have been distributed worldwide, including to many pregnant 
women. Multiple studies have failed to find a statistically significant increase in congenital 
abnormalities among infants born to women exposed to mebendazole during pregnancy as 
compared to those born to untreated women [55-58].  Over 6,000 women treated with 
mebendazole are included in these studies, providing more data than for other anthelminthic 
drugs. Of particular relevance to the proposed trial, a study in Israel found no teratogenic 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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effects when either a single-dose or a three-day regimen of mebendazole was administered 
to women in pregnancy, including during the first trimester [57]. 
The WHO notes in its guidelines on MDA, Preventative chemotherapy in human 
helminthiasis, that “despite excellent empirical safety profiles, none of the anthelminthic 
drugs used in MDA campaigns, including mebendazole, is licensed for administration during 
pregnancy [59].  Nonetheless, risk-benefit analyses show that the advantages of treating 
women of reproductive age, including those who are pregnant, far outweigh the risks to their 
health and that of their unborn child.” [60]. 
WHO notes that using LMP is appropriate for identification of women who are pregnant and 
to determine the stage of pregnancy. However, among school-age children, defined as those 
aged 6 to 15 years, the WHO guidance has no requirements for pregnancy testing or 
screening. The mean age of menarche in Tanzania has been described as 14.3 ±1.1 years 
[61], but especially on Zanzibar, the location for this study, there is often a lengthy delay 
between menarche and sexual activity. The median age of first birth in Zanzibar is 21.7 years 
and it is clear from demographic surveys that pregnancy is rare among adolescents [62]. The 
population of Zanzibar is almost entirely Muslim and quite conservative culturally. Sexual 
activity before marriage is stigmatized and highly discouraged, so testing for pregnancy 
among 6 to 12 year old girls would be socially inappropriate. As a result, this study proposes 
to exclude all girls who have started their menses to avoid the possibility of exposure to 
mebendazole during the first trimester.   
Mebendazole can be administered in different doses. The present study will explore the 
efficacy of the single-dose (500 mg) and the triple-dose (six doses of 100 mg over three 
consecutive days twice per day) against hookworm. Like albendazole, both regimens of 
mebendazole (the single- and triple-dose) are included in the National Essential Medicine 
List for mainland Tanzania [18]. 
A summary of randomized controlled trials using a single dose of mebendazole (500 mg solid 
tablets) against hookworm is given in Table 1. The recorded CRs of single-dose 
mebendazole are very conflicting ranging from 7.6 to 91.1% [19, 20]. Of note, CRs and ERRs 
of mebendazole observed on Pemba are very low.  
 
 
Table 1. Randomized-controlled studies which assessed the efficacy of mebendazole (500 mg) against 
hookworm. 
 
 
Study 
Country 
Diagnostic 
approach 
Treatment 
evaluation 
Study 
design 
Age 
N 
CR 
ERR 
Abadi 1985 [19] 
Indonesia 
Kato-Katz 
and Harada 
Mori 
1-4 wk after 
treatment 
Double-
blinded 
2-70 
45 
91.1% 
98.3
% 


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Albonico et al., 2002 [21] 
Tanzania 
Kato-Katz 
21 d after 
treatment 
Not blinded 
9.5 
(mean) 
424 
13.2% 
67% 
Albonico et al., 2003 [20] 
Tanzania 
Kato-Katz 
21 d after 
treatment 
Not blinded 
7-18 
224 
7.6% 
52.1
% 
De Clercq et al., 1997 
[22] 
Mali 
Kato-Katz 
4 wk after 
treatment 
Single-
blinded 
5-54 
35 
22.9% 
0% 
Knopp et al., 2010 [23] 
Tanzania 
Kato-Katz 
3 wk after 
treatment 
Single-
blinded 
 5 
34 
35.3% 
78.7
% 
Sacko et al., 1999 [24] 
Mali 
Kato-Katz 
10 d after 
treatment 
Single-
blinded 
3-70 
35 
51.4% 
68.5
% 
Soukhathammavong et 
al., 2012 [25] 
Laos 
Kato-Katz 
21-23 d after 
treatment 
Not blinded 
6-12 
82 
17.6% 
76.3
% 
Speich et al., 2014 [17] 
Tanzania 
Kato-Katz 
18-23 d after 
treatment 
Double-
blinded 
6-14 
109 
17.4% 
58.7
% 
Steinmann et al., 2011 
[26] 
China 
Kato-Katz 
3-5 wk after 
treatment 
Not blinded 
 5 
81 
31% 
83.6
% 
 
 
We identified 22 studies exploring the efficacy of the triple-dose regimen of mebendazole 
[27-48]. These studies were conducted between 1973 and 2007 in Asia (N=14), North 
America (N=1), South America (N=3), Africa (N=2), Europe (N=1) and in the Pacific (N=1) 
using relatively small samples (average of 40 participants). CRs varied considerably ranging 
from 30.8% to 100% [36, 37]. Still, the lowest CR of this regimen was considerably higher 
than the lowest CR of the single-dose regimen CR=7.6%) (Table 1).  
The trial presented in this protocol would be, to our knowledge, the first randomized clinical 
trial comparing the single-dose (500 mg) to the triple-dose (100 mg twice a day for three 
days) of mebendazole. The fact that the efficacy of the different mebendazole regimens is 
still highly variable and, therefore, not entirely clear, points to the pressing need to perform 
further trials to increase evidence. Furthermore, it is important to note that our study will take 
place in an African setting where the prevalence of hookworm is particularly worrisome and 
where, up to date, few (2/22) trials testing the efficacy of the multiple dose regimen have 
taken place. On Pemba, where this trial will take place, the most recent studies have found a 
prevalence of hookworm ranging from 36 to 97% and the efficacy of a single dose 
mebendazole is low [17, 49, 50]. Thus, there is a pressing need to develop treatment 
alternatives. Albendazole is the current standard of care in Pemba for STH treatment; 
however mebendazole is used in many other settings because of its greater efficacy against 
infections such as pinworm and Trichinosis. There could be a great public health benefit if an 
effective mebendazole regimen was identified for the treatment of hookworm in Pemba as 
the drug would also be effective against numerous other concomitant STH infections.   
 
3. Trial objective and purpose 
 
We hypothesize that both regimens of mebendazole will be effective against hookworm and 
concomitant soil-transmitted helminths.   


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The primary objective of the study is to assess the CR (i.e. conversion from being egg 
positive pre-treatment to egg negative post-treatment) of two different mebendazole 
regimens against hookworm in children (6 - 12 years old): (i) 100 mg of mebendazole twice a 
day for 3 days and (ii) 500 mg of mebendazole single dose. Thus, the primary endpoint of 
the study is the CR of these two regimens of mebendazole against hookworm. 
 
Additional secondary endpoints are (1) the ERR of these two regimens against hookworm, 
(2) the CR and ERRs of both mebendazole regimens against concomitant soil-transmitted 
helminth infections, and (3) the safety of both mebendazole regimens. Exploratory 
endpoints include comparison of the sensitivity of Kato Katz to quantitative polymerase 
chain reaction assays, prevalence of genetic resistance markers among participants, and 
distribution of hookworm species among participants. 
 
 
4. Methodology  
 
4.1 Type of trial 
Double blind randomized trial. 
 
4.2 
Trial design 
4.2.1 Baseline survey and screening 
This trial will take place in the two primary schools (Bagamoyo School and Piki School) in 
Pemba, Tanzania, which have been found to have a high prevalence of hookworm in 
previous studies. Among those children for whom informed consent is obtained, each 
participant will receive an empty container at school, which they return the following day with 
a stool sample. Stool samples will be collected and transported by car to the central 
laboratory. Two stool samples will be collected from each participating individual on different 
days, to adequately cover the egg shedding cycle of 24-48 hours, until a total of 180 
hookworm-infected participants have been identified, preferable with A. lumbricoides and/or 
T. trichiura co-infections (Fig. 1). The prevalence for hookworm infected individuals is 
expected to be between 20% and 40% [17, 49, 50], hence we anticipate screening around 
500-1,000 individuals to reach the total number of participants. The number of screened 
individuals will depend on the prevalence of the parasite. 
The Kato-Katz technique will be used for the quantitative assessment of STH infections. Two 
stool samples will be collected from each participant before treatment and from each sample 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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duplicate Kato-Katz thick smears (41.7 mg each) will be prepared [51]. The slides will be 
analysed under a microscope by experienced technicians and a subsequent independent 
quality control of sample results (10%) will be conducted. Results are considered correct if 
the following tolerance margin is not exceeded: (i) No difference in presence/absence of 
hookworm, A. lumbricoides and T. trichiura, (ii) Egg counts are +/-10 eggs for counts ≤100 
eggs or +/-20% for counts >100 eggs (for each species separately) [52]. In case 
discrepancies above the tolerance margin are noted in one or more slides, all slides are re-
read by the local technicians. The new results are discussed, so that in case of discordant 
results, slides can be re-evaluated to reach consensus. Infection intensity expressed as the 
arithmetic and geometric mean egg count per gram of stool (EPG) will be calculated for each 
treatment arm.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Mebendazole efficacy study-flow. 
 
All stool samples will be prepared and analysed in the Public Health Laboratory Ivo de 
Carneri on Pemba, United Republic of Tanzania. All quadruplicate Kato-Katz thick smears 
will be microscopically analysed within the first 60 minutes and will then be destroyed within 
a few days (after passing the quality control). Also, two aliquots (about 1 g of stool each) of 
positive samples will be stored in ethanol. One aliquot will remain in Pemba as a “back-up” 
Stool examination (2 samples of stool analyzed with Kato-Katz) 
N = 500-1,000 
180 subjects enrolled (2 samples of stool analyzed with Kato-Katz) 
3 weeks 
Follow-up (2 samples of stool analyzed with Kato-Katz) 
14-21 days 
Mebendazole 
100 mg twice a day for 3 days 
N = 90 
Mebendazole 
500 mg single dose 
N = 90 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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sample and the other aliquot will be transported to the Swiss Tropical Public Health Institute 
for subsequent DNA extraction, diagnostic and assessment of drug resistance-associated 
single-nucleotide polymorphisms. Upon successful PCR analysis, the aliquot which was 
stored in Pemba will be destroyed. Finally, a Harada Mori culture will be prepared from one 
of the stool samples of each child at baseline and at follow-up to extract hatched larvae. 
Larvae will be stored in ethanol and will subsequently undergo the same process as the 
previously mentioned stool aliquots. 
Among those participants who tested positive for hookworm, the second stage of screening 
involves a physical examination and will occur one to three days before treatment is 
scheduled to begin. At baseline the medical history of STH-infected participants will be 
assessed at school during clinical examination carried out by the study clinician. Additionally, 
during this clinical examination, haemoglobin levels will be detected using HemoCue 
conducted by nurses to exclude severely anaemic participants (below 80 g/l Hb according to 
WHO definition). In all girls, the clinician will assess the possibility of pregnancy by asking if 
menarche has occurred.  If menarche has occurred and thus pregnancy cannot be ruled out, 
the participant will be excluded from the trial, but will still be given the option of receiving only 
placebo to avoid any stigmatization. 
4.2.2 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 and microscopically examined for STH using duplicate 
Kato-Katz thick smears, creating a total of four slides for this time point assessment. Kato-
Katz is the standard method used to diagnose STH and is the reference standard for much of 
the literature reporting anti-helminthic treatment efficacy. Kato-Katz thick smears are not as 
sensitive as more recently developed methodologies, such as quantitative PCR, and slides 
have to be read within a strict window for accurate results. Appendix 1 includes instructions 
that will be followed for Kato-Katz preparation and analysis.   
Individuals will be considered hookworm negative if EPG < 100 (total of the four slides) 
and/or if only one Kato-Katz thick smear slide with more than one hookworm egg. 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.  
Additionally, an aliquot from each participant stool sample positive for any of the soil-
transmitted helminths (A. lumbricoides, T. trichiura or hookworms) at either baseline or 
follow-up survey, will be stored at Public Health Laboratory Ivo de Carneri in absolute 
ethanol. Aliquots will be shipped to the Swiss Tropical Public Health Institute (Basel, 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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Switzerland) to undergo DNA extraction and quantitative polymerase chain reaction (PCR) 
analysis to perform molecular genotyping for drug resistance-associated single-nucleotide 
polymorphisms studies. At the end of the study all participants in whose post-treatment 
samples we still find hookworm eggs will be contacted at school with their test results and 
treated with albendazole (400 mg single dose), the current local standard drug against 
hookworm. 
 
4.3. 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 in each arm, depending on the 
distribution of infection intensity in the recruited cohort. The codes will be held in a locked 
cabinet at the Swiss Tropical and Public Health Institute. A copy of this code will be kept in a 
sealed envelope by one of the co-investigators (will only be unblinded in case there is a 
serious adverse event, determined by the principal investigator upon consultation with the 
co-investigators). The blinding will be maintained throughout the trial until data entry and 
processing are complete and the data have been verified. Following release of the final data, 
the randomization codes will be released. 
 
4.4. Study duration and duration of subject participation 
The trial will last twelve weeks with each participant’s involvement lasting up to eight weeks. 
The screening for the baseline will start three weeks prior to the treatment. Follow up 
screening will take place 14-21 days post-treatment and last for about three weeks. 
Schedules of visits are summarized below. 
 
4.5. Schedule of visits 
Table 2 briefly presents the distribution of tasks along the trial. Further detail is available in 
Appendix 2. 
 
Table 2. Schedule of visits during treatment period. 
 
 
Screening 
 
 
 
 
 
 
Follow-up 
 
- 21 
to -1 
-3 to 
-1 
D1 
D2 
D3 
D4 
D5 
14 to 21 days 
 
Hours 
 


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days 
days 
0 
3 
10 
0 
3 
10 
0 
3 
10 
0 
0 
Diagnosis (stool 
examination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
treatment/placebo 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
 
Physical Examination, 
including menarche 
and anemia 
assessments 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Capturing AEs/ SAE 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
Administration of 
albendazole (still 
infected at follow-up) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
5. Selection of the trial subjects 
 
5.1 Recruitment 
The study will be carried out in children (age: 6-12 years) in one primary school on Pemba, 
United Republic of Tanzania in areas endemic for hookworm [17, 21, 49, 50, 53]. 
The parents/caregivers of participants will be invited to participate in an information meeting 
to explain the purpose and procedures of the study, including potential benefits and risks. 
Parents/caregivers will be encouraged to ask questions in an open discussion forum. During 
this session, parents will be informed of preventive actions they can take to help protect their 
children from acquiring hookworm and other STH infections in the future (e.g., wearing 
shoes, hand washing procedures). 
Those parents/caregivers and their children who are interested in the study will be invited to 
complete the process of informed consent. See section 9.3 for details on obtaining informed 
consent. Only those participants who have written informed consent will be assessed for 
study eligibility criteria during screening procedures. 
 
5.2 Inclusion criteria 
1. 
Written informed consent signed by parents and/or caregiver; and oral assent 
by participant.  
2. 
Able and willing to be examined by a study physician at the beginning of the 
study. 
3. 
Able and willing to provide two stool samples at the beginning (baseline) and 
approximately three weeks after treatment (follow-up). 


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4. 
Positive for hookworm eggs in the stool (≥ 100 EPG and at least two Kato-
Katz thick smears slides with more than one hookworm egg). 
5. 
Absence of major systemic illnesses, e.g. diabetes, severe anemia (HB<8.0 
g/l) as assessed by a medical doctor at school, upon initial clinical 
assessment. 
6. 
No known or reported history of chronical illness as cancer, diabetes, chronic 
heart, liver or renal disease. 
7. 
No recent anthelminthic treatment (within past 4 weeks).  
8. 
No known allergy to study medications (mebendazole and albendazole). 
 
5.3. Exclusion criteria 
1. 
No written informed consent by parents and/or caregiver; no oral assent by 
participant.  
2. 
Menarche, based on self-report 
3. 
Presence of major systemic illnesses, e.g. diabetes, severe anemia (HB<8.0 g/l) 
as assessed by a medical doctor, upon initial clinical assessment. 
4. 
History of acute or severe chronic disease. 
5. 
Recent use of anthelminthic drug (within past 4 weeks). 
6. 
Attending other clinical trials during the study. 
7. 
Negative diagnostic result for hookworm eggs in the stool (< 100 EPG (total of 
the four slides) and/or only one Kato-Katz thick smear slide with more than one 
hookworm egg). 
 
 
Participants who were diagnosed with a STH infection, but who were excluded from the 
study due to one or several of the above-mentioned exclusion criteria, including withdrawals, 
will be offered standard anthelminthic treatment (albendazole). 
 
5.4. Criteria for discontinuation of trial 
A subject can be discontinued from the study for the following reasons: 
1. 
Withdraws from the study (this can happen anytime as participation is voluntary 
and there are no further obligations once a participant withdraws). 
2. 
At the discretion of the Principal Investigator (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 safety procedures planned (adverse 
events monitoring) will be conducted. 


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5.5. Treatment of subjects 
Mebendazole tablets (100 and 500 mg) will be commercially purchased from Johnson & 
Johnson (Zug, Switzerland) (expiration date 2019). Matching placebo tablets will be 
produced by our collaborators at the Pharmacenter of the University of Basel. Tablets will be 
put into sealed and labelled plastic bags by an independent pharmacist according to the 
randomisation list and will always be stored at room temperature together with silica gel 
(desiccant) against humidity. Because we do not have independent pharmacists in the study 
site, all plastic bags will be prepared prior to departure at the Swiss Tropical Public Health 
Institute (Basel, Switzerland) and labelled with their treatment ID. There will be six treatment 
time points: three mornings and three evenings (evening treatments will take place about 10 
hours after morning treatments), thus, a total of 1080 bags will be prepared (180 participants 
x 6 time points): 90 contain 500mg mebendazole and 100mg placebo, 90 contain 100mg 
mebendazole and 500mg placebo, 450 contain 100mg mebendazole, and 450 contain 
100mg placebo (see Table 3). At this point, all bags will be labelled with the treatment ID of 
each participant, e.g. participant number 13 will have six bags corresponding to the six time 
points (13.1, 13.2, 13.3, 13.4, 13.5, and 13.6). In the study site, the tablet bags will be kept in 
air conditioned rooms (up to 20ºC). Drugs will be administered up to one month prior to the 
preparation of the envelopes. 
Participants will stay all day at school for the morning and evening treatments. All drugs will 
be administered orally with a small amount of water in the presence of the investigator(s), 
and ingestion confirmed. This will be recorded with the time and date of dosing. On the first 
morning, depending on which treatment arm they were randomly allocated to, all participants 
will receive two tablets: one 100mg tablet (mebendazole or placebo) and one 500mg tablet 
(mebendazole or placebo). On the remaining five treatment points, also depending on which 
treatment arm they were allocated to, each participant will receive either one 100mg 
mebendazole tablet or one 100mg placebo tablet (Tables 2 and 3). Participants will be all 
day at school where the administration of mebendazole and capturing of AEs will take place. 
The morning dosing will occur when participants first arrive at school and the evening dosing 
will occur right before participants leave the school, approximately 10 hours later. 
 
Table 3. Distribution of the administration of mebendazole and placebo in both groups. 
 
 
Day 1 
Day 2 
Day 3 
 
Morning 
Evening 
Morning 
Evening 
Morning 
Evening 
Arm A 
MEB 100 + 
plac 500  
MEB 100 
MEB 100  
MEB 100  
MEB 100 
MEB 100  


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Arm B 
MEB 500 + 
plac 100 
plac 100 
plac 100  
plac 100  
plac 100  
plac 100  
 
Note: MEB 100, 100 mg of mebendazole; MEB 500, 500 mg of mebendazole; plac 100, placebo 
matching 100 mg mebendazole; plac 500, placebo matching 500 mg of mebendazole. 
 
Subjects will be asked not to take any drugs other than those prescribed by the study 
medical team. 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 1-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: 
- 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.  


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6. Safety assessments 
Few adverse events have been reported following mebendazole administration. The most 
common reported adverse events are abdominal cramps, headache, diarrhoea, fever and 
fatigue [17, 23, 26]. The safety profile of mebendazole will be assessed through the 
recording, reporting and analysis of baseline medical conditions, adverse events and a 
physical examination. Participants will be encouraged to notify study staff of any adverse 
events that may occur outside of scheduled safety assessments. The medical doctor will be 
responsible for this part of the trial. 
 
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: 
a) 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; 
b) 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 adverse events 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 Adverse Event.  
 
The observation time for adverse events starts when the treatment is initiated until day 5 (48 
hours after last drug administration).  
 
These data will be recorded on the appropriate CRF sections, 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).  
 
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 adverse event and the treatment, known side effects of treatment, medical history, 
concomitant medication, course of the underlying disease and trial procedures. 
 
Possibly related: an adverse event 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 adverse event 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 adverse event possibly related to the administration of 
mebendazole reported in the literature or on the drug package leaflet and listed in the 
consent form. These adverse events are detailed in the drug package leaflet (Appendix 3). 
Unexpected adverse drug reaction: Any adverse event 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.  
 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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6.1.4. Serious adverse events  
According to the ICH “Clinical Safety Data Management: Definitions and standards for 
expedited Reporting E2A” [54], a serious adverse event includes any event (experience) or 
reaction in any untoward medical occurrence that at any dose: 
1. results in death; 
2. 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; 
3. 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; 
4. requires in patient hospitalisation or prolongation of existing hospitalisation; 
5. creates a congenital anomaly or birth defect (not relevant for this study); 
6. 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. Serious adverse events are reported from consent to 48 hours post-treatment (Day 5).  
 
Serious adverse events that are still ongoing at the end of the study period will be followed 
up to determine the final outcome.  
 
The causality of any serious adverse event 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 reactions 
A suspected unexpected serious adverse reaction (SUSAR) is an unexpected adverse drug 
reaction which also meets the definition of serious adverse events.  
 
6.2. Methods of recording and assessing adverse events 
Patients will be kept for observation for at least 3 hours following each morning treatment for 
any acute adverse events. During the reporting period, any unfavorable changes in the 
subject’s condition will be recorded as adverse events, whether reported by the subject or 
observed by the Investigator. In case of any abnormal finding, the local study physician will 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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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 adverse events 24 hours after every morning treatment (before the next 
treatment) and 48 hours after the last treatment (day 5) (Table 2). 
Information on all adverse events (onset, duration, intensity, seriousness and causality) will 
be immediately entered in the appropriate adverse event module of the case report form 
(CRF) which is considered as a source document. For all adverse events, 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 serious adverse 
event); ii) an assessment of the casual relationship between the adverse event and the study 
treatments (i.e. whether the event should be classified as an adverse drug reaction); and iii) 
an assessment of intensity of adverse events by the study physician. 
 
All serious adverse events, 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 serious adverse event will be 
immediately (within a maximum of 24 hours after becoming aware of the event) notified to 
the study sponsor-investigator and co-PI: 
 
 
Prof. Dr. Jennifer Keiser (Sponsor-investigator) 
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) 
Tel.: +255 24 245-23 
Fax: +255 24 245-2003 


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Mobile: +255 77 741-6867 
Email: saidmali2003@yahoo.com 
 
 
Within the following 48 hours, the local co-investigator must provide to study sponsor-
investigator further information on the serious adverse event 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 serious adverse event 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 serious adverse event 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).  
 
6.5. Safety reporting to Health Authorities and Ethics Committees 
The sponsor-investigator 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 Medical Research and Ethical Committee’ (ZAMREC, Tanzania) according to 
national rules. Fatal or life-threatening serious adverse events or SUSARs will be reported 
within 24 hours followed by a complete report within 7 additional calendar days. Other 
serious adverse events 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. Statistics 
 
7.1. Definition of primary endpoint 
Cure rate of mebendazole against hookworm is the primary endpoint in our study. Since this 
might be influenced by infection intensity, treatment groups will be equally balanced in terms 
of infection intensity by 2 levels of baseline infection intensity (light infections and 
moderate/heavy infections).  
 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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7.2. Justification of number of trial subjects  
Sample size calculations for this study are based on the secondary objective comparing the 
efficacy of the two mebendazole regimens. Based on the published literature with special 
attention to studies conducted on Pemba Island, we assume that the cure rate of single dose 
mebendazole against hookworm infections is 20% compared to 40% in the triple treatment 
regimen [17, 33, 45, 46, 49]. To detect the difference with 80% power at a two-sided 5% 
significance level we require 79 participants per study arm. To account for potential loss to 
follow up (which was low in our previous studies in this setting) we aim to recruit in total 180 
participants.  
 
7.3. Description of statistical methods 
The primary available case analysis will include all participants with primary end point data. 
In addition, an intention-to-treat analysis will be conducted considering all participants with 
missing endpoint data as treatment failure or all as treatment success to ensure that the 
results are not sensitive to potential loss to follow-up bias. CRs will be calculated as the 
percentage of egg-positive children at baseline who become egg-negative after treatment. 
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. The ERR will be calculated as: 
 
𝐸𝑅𝑅=  1 − 
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝 + 1) −1
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 1)      −1  
 
In the primary model we estimate the difference among CRs by using unadjusted logistic 
regressions. In a subsequent analysis an adjusted logistic regression (adjustment for age, 
sex, school, weight and strata) will be performed.  
Geometric mean egg counts will be calculated for the different treatment arms before and 
after treatment to assess the corresponding ERRs. Bootstrap resampling method with 5,000 
replicates will be used to calculate 95% confidence intervals (CIs) for ERRs and the 
difference between the ERRs.  
Adverse events will be evaluated descriptively as the difference of proportion reporting 
adverse events before and after treatment. 
 
 
7.4. Description of data management 
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 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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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.  
Screened patients will be listed in a confidential “subject screening log”. Enrolled patients will 
be listed in a confidential “subject enrolment log” and attributed a unique study number; this 
document will constitute the only source to decode the pseudonymised data and will only be 
accessible to the local principal investigator. All data that have been hand-entered in the 
database will be verified by a double-key entry procedure in a validated electronic data base 
system and error, range and consistency checks will be programmed. Any discrepancies will 
be reviewed against the hard copy CRF and corrected. Electronic data files will be stored on 
secured network drives with restricted access for study personnel only. Data analysis will be 
conducted with pseudonymised data and reporting of findings will be fully anonymised.  
Essential infrastructure such as lockable cabinets for safe storage of hardcopy data will be 
made available. Network drives with restricted access for authorised personnel only and 
appropriate analysis software are available.  
 
 
8. Duties of the investigator  
 
8.1. 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 Sponsor/PI or any Investigator. The Investigator will provide the 
reasons for the proposed amendment in writing and will discuss with the Sponsor/PI and Co-
PIs. Any protocol amendment must be approved and signed by the Sponsor/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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8.2. 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. 
 
8.3. 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 adverse events monitoring. 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 Principal Investigator 
and the Co-Investigators, 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.  
 
9. Ethical considerations 
 
9.1. Independent Ethics Committee (IEC) 
The study will be submitted for approval by the institutional research commission of the 
Swiss TPH and the ethics committees of Switzerland (EKNZ: Ethical Commission of 
northwest/central Switzerland) and Zanzibar (ZAMREC: Zanzibar Medical Research and 
Ethics Committee). The study will be undertaken in accordance with the Declaration of 
Helsinki and good clinical practice (GCP).  
 


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9.2. Evaluation of the risk-benefit ratio 
Few adverse events have been reported for mebendazole (package insert Appendix 3). The 
most common reported adverse events are abdominal cramps, headache, diarrhoea, fever 
and fatigue [17, 23, 26]. 
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 albendazole 
(according to WHO recommendations). 
 
9.3. Subject information and consent 
Community meetings will be conducted to explain to caregivers the purpose and procedures 
of the study.  Parents or caregivers attending this meeting will receive a small provision to 
cover their costs for transportation (~US$ 2). Their level of comprehension of the trial’s 
purpose and procedures will then be assessed using a short multiple-choice questionnaire. 
Finally, one the parents/caregiver of an eligible individual will be asked to sign a written 
informed consent form (translated into the local language, i.e. Kiswahili) after having had 
sufficient time for reflection of their child’s participation. Even if the participant gives oral 
assent, the parent/caregiver has to sign the consent. In case the parent/caregiver is illiterate, 
an impartial witness that can read and write has to sign the consent and the parent/caregiver 
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 informed consent form is signed will 
participants undergo any screening procedures. 
 
9.4. Subject Confidentiality 
The obtained data will be handled strictly confidentially. Only members of the study team will 
have access to the data. Personal data will be coded for data analysis. The codes will be 
filled with the participant’s identity on a separate file (subject identification list) and filled in a 
secured place at the Public Health Laboratory Ivo de Carneri and will only be accessible to 
investigators. No names will be published at any time, and published reports will not allow for 
identification of single subjects. Confidentiality and anonymity will be ensured throughout the 
entire research project. 
The investigators have all been trained in GCP. None of the investigators declare to have 
any conflicts of interest. 


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9.5. Subjects requiring particular protection 
This study will be carried out in children, since an infection with hookworm often occurs 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. 
 


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10. Quality control and quality assurance 
10.1. Monitoring and auditing 
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 them 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.  
 
10.2. Access to data, handling of data and samples (data protection), archiving 
(place, duration) and destruction 
Information about study subjects will be kept confidential and managed accordingly. A CRF 
will be completed for each subject enrolled into the clinical study. The investigators will 
review, and approve each completed CRF. The study CRF is the primary data collection 
instrument for the study. All data requested on the CRF must be recorded. 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 blue ink. All corrections must 
be initialled and dated.  
All data on parasitology and questionnaires about adverse events and self-reported clinical 
signs and symptoms will be doubled entered into a database by two independent persons 
and cross-checked. Discrepancies between data entries will be corrected by consulting the 
hard copy.  
The collected data together with the hard copy CRFs, ICFs and other study documents will 
be stored at server of the Public Health Laboratory (PHL) in Pemba and are encrypted with 
Secure Sockets Layer (SSL).  
The results of the research study will be published, but subjects’ names or identities will not 
be revealed. Records will remain confidential. To maintain confidentiality, the Sponsor-
Investigator will keep records in locked cabinets and the results of tests will be coded to 
prevent association with participant’s names. Data entered into the ACCESS data entry 
mask will be accessible only by authorized personnel directly involved with the study and will 


Protocol_TRIPLEMEB_PEMBA_V2.01 
 
 
 
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be encoded. Subject-specific information may be provided to other appropriate medical 
personnel only with the subject’s permission. 
After the study has been completed all samples will be destroyed and research data and 
related material will be kept 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. 
 
10.3. Data entered directly in the Case Report Form (CRF) – definition of 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. Data will be entered directly onto the case report forms. The case 
report form is considered as a source document. All CRFs will be kept for at least 15 years. 
The study site will retain a copy of the CRF to ensure that local collaborators can provide 
access to the source documents to a monitor, auditor, or regulatory agency. 
 
10.4. Data and safety monitoring board (WHO)/ data monitoring committee 
(EU/FDA) 
In our study no data and safety monitoring board will be established, since we work in a 
small sample size and treatment will be completed after 3 days. This study is anticipated to 
be no greater than minimal risk to participants. 
 
11. Dissemination of results and publication 
 
The final results of this study will be published in a scientific journal and presented at 
scientific conferences. PATH 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, ZAMREC. 
 
 


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Nontasut, P., V. Singhasivanon, W. Maipanich, S. Yamput, and K. Visiassuk, 
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50. 
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60. 
Savioli L Crompton DWT, Neira M. Use of anthelminthic drugs during pregnancy. 
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Rebacz E. Age at menarche in schoolgirls from Tanzania in light of socioeconomic 
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http://dhsprogram.com/pubs/pdf/FR321/FR321.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1: Kato-Katz manual from the World Health Organization (assessed: 
http://www.who.int/neglected_diseases/preventive_chemotherapy/pctnewsletter11.pdf; 


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05.03.2013). 
 
 


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Appendix 2: Schedule of the mebendazole study procedures in Tanzania. 
 
 
 
 
 
Mo 
Tu 
We 
Th 
Fr 
Sa 
Su 
Mo 
Tu 
We 
Th 
Fr 
Sa 
Su 
Week 1 --           
  
  
Week 2 --  
  
  
Training Interviwers 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
Panflet distribution 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Invite for Consenting 
  
  
  
50 
50 
  
  
50 
50 
50 
50 
50 
  
  
Shows Info/Consenting 
  
  
  
20 
20 
  
  
20 
20 
20 
20 
20 
  
  
Consents/Questionnaires 
  
  
  
20 
40 
  
  
60 
80 
100 
120 
140 
  
  
Week 3 --  
  
  
Week 4 -- 
  
  
Invite for Consenting 
50 
50 
50 
200 
200 
  
  
200 
200 
200 
200 
200 
  
  
Shows Info/Consenting 
20 
20 
20 
120 
120 
  
  
120 
120 
120 
120 
120 
  
  
Consents/Questionnaires 
160 
180 
200 
120 
240 
  
  
360 
480 
600 
720 
840 
  
  
Week 5 --  
  
  
Week 6 --  
  
  
Cup distribution 
120 
120 
120 
120 
120 
  
  
120 
  
120 
120 
    
  
Baseline stool 1 
  
100 
100 
100 
100 
  
  
100 
  
100 
100 
100   
  
Stool 1 positives 
  
20 
20 
20 
20 
  
  
20 
  
20 
20 
20   
  
Baseline stool 2 
  
  
  
20 
20 
  
  20 + 20 
  
20 
  
20   
  
Stool 2 positives 
  
  
  
  
16 
  
  
16 
  16 + 16 
16 
    
  
Sum of positives 
  
  
  
  
16 
  
  
32 
  
64 
80 
    
  
Week 7 -- 
  
  
Week 8 -- 
  
  
Cup distribution 
120 
120 
120 
120 
120   
  
  
  
  
  
  
  
  
Baseline stool 1 
  
100 
100 
100 
100 
  
  
100 
  
  
  
    
  
Stool 1 positives 
  
20 
20 
20 
20 
  
  
20 
  
  
  
    
  
Baseline stool 2 
20 + 20 
  
  
20 
20 
  
  20 + 20 
  
20 
  
    
  
Stool 2 positives 
16 
16 + 
16 
  
  
16 
  
  
16 
16 + 16 
  
16 
    
  
Sum of positives 
96 
112 
  
  
128 
  
  
144 
176 
  
192 
    
  


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Week 9 -- 
  
  
Week 10 --  
  
  
Treatment 
  
  
....................................................... School holidays 
.................................... 
  
  
Week 11 -- 
  
  
Week 12 --  
  
  
Treatment * 
180 
180 
180   
  
  
  
  
  
  
  
  
  
  
AE's recording 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
Week 13 --  
  
  
Week 14 -- 
  
  
Cup distribution 
  
  
  
  
  
  
  
96 
96 
96 
96   
  
  
Follow up stool 1 
  
  
  
  
  
  
  
  
90 
90 
90 
90   
  
Follow up stool 2 
  
  
  
  
  
  
  
  
90 
90 
90 
90   
  
 
 


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Appendix 3: package leaflet mebendazole
 


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Appendix 4: English ICF prepared by funder 
 
 
Efficacy and safety of a single-dose regimen and a multi-dose 
regimen of mebendazole against hookworm infections in children: a 
randomized-controlled trial  
 
The Ministry of Health and Social Welfare (Zanzibar, Tanzania) has permitted this study after 
careful verification. The Zanzibar Medical Research and Ethical Committee has also 
reviewed and approved this study. 
 
Introduction 
You are being asked to take part in this study because your child is between the ages of 6 
and 12 years. This study is sponsored by the Swiss Tropical and Public Health Institute. The 
person in charge of this study at this site is Mr. Said Ali.  The enrollment process includes 
interview questions, stool sample collection, a finger prick blood test, and a physical exam.   
This is an enrollment consent form. It gives you information about the study product, study 
questions and exams, and what your child will need to do to be in the study.  The study staff 
will explain the exams and tests to you and what is expected of you and your child.  You are 
free to ask questions about the study at any time. If you agree for your child to take part in 
this study, you will be asked to sign this consent form or make your mark in front of a 
witness. You will be given a copy of this form to keep. 
 
Why Is This Study Being Done? 
Hookworm infection is an infection by a parasitic worm. These worms, and others like it, live 
in the small intestine of infected persons. The worms can cause malnutrition, poor growth 
and development, and reduced work performance later in life.  
On Pemba, most children are infected with one or even two or three different types of 
parasitic worms. This is the reason why children are regularly given drugs to kill these 
worms. However, the worms may acquire resistance to the drug when it is used for many 
years, meaning that the medicine loses its capacity to kill the worms. We would like to try two 
different doses of the same drug (mebendazole) to understand which one is best at killing the 
worms that your child suffers from. Mebendazole works by killing worms in the body, which 
are then passed through the stool. Mebendazole is an approved drug for parasitic worms and 
has been used for many years in Tanzania and other parts of the world for treatment. 
Mebendazole can be given at a low dose twice a day for 3 days or it can be given once at a 
high dose. 
We would like your child to take part in a research study. The aim of this study is to look at 
how well two different amounts of mebendazole kill the worms in the children’s bodies. 
Approximately 450 children will be screened for parasites by stool sample and 180 subjects 
with hookworm will join this treatment study. Your child will be tested to confirm that they are 
infected with hookworm before being treated. If your child is still infected with hookworm at 
the end of the study, your child will receive one dose of another anti-parasitic drug called 
albendazole.  Albendazole is also licensed in Tanzania and may cure hookworm infection 
that is not cured by mebendazole.   
An international health non-profit organization, PATH, is providing funds for this study to take 
place. Each subject will be in the study for a total of about 8 weeks: one month for screening, 
three days of treatment, and follow up 14 to 21 days after treatment. If your child is in the 
study, your child will have to attend 11 study visits at your child’s school. 


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What Is The Study Design? 
This study will compare the two forms of oral mebendazole. Mebendazole tablets (100 and 
500 mg) are from Johnson & Johnson (Zug, Switzerland). Both of these tablet forms of 
mebendazole are licensed in Tanzania.   
Neither you, your child, nor the study staff will know if your child is getting the low dose or 
high dose drug. This is called keeping the study “blinded.” Not even the study doctor will 
know, although he can find out if necessary.   
The study drugs will be given by mouth. The low dose medication will be given twice a day 
for 3 days and the high dose will be given once. To keep the study blinded, all subjects will 
receive a total of 6 small tablets (containing either drug or no medicine, called a “placebo”) 
and one large tablet (containing either drug or placebo).     
Your child will be assigned by chance (like flipping a coin) to be in one of 2 groups.  There 
will be 90 subjects in the low dose group and 90 in the high dose group. So there is an equal 
chance of being in either group. 
 
What Does My Child Have To Do If My Child Takes Part in the Study? 
If you agree for your child to be in the study, your child will have these study visits here at 
school: 
o Enrolment Visit 
o Day before treatment 
o Treatment days 1-3 
o Follow up visit for safety: to look at any signs and symptoms your child may suffer 
on days 4 and 5 
o Follow up visit for efficacy: stool exam between days 14 and 21 to check if your child 
is still infected. 
While your child is in the study, we will ask your child to come in for all study visits. We will 
also ask you and your child to follow the instructions of the study staff for taking the 
medications. 
 
Enrolment Visit 
Your child’s Enrolment Visit will continue today, after you read, discuss, and sign or make 
your mark on this form.  No study activities will be started before they have been fully 
explained to you, you have let us know that you understand the enrollment process and you 
have signed or made your mark on this form. 
The Enrollment visit will take about one to two hours.  You will be asked to do these things 
for the Enrollment Visit if you decide you want your child to be in the study: 
o Sign this form or make your mark on it after you have read it, understand it, and had 
the chance to ask questions about the study. 
o Tell the study staff how they can stay in contact with you. 
o Tell the study staff about any medical problems of your child. 
o Tell the study staff about any medicines your child is taking now. 
o For all girls, tell the study staff if they have ever had a menstrual period. 
o Have your child have a physical exam.  
o Have your child provide two stool samples for detection of parasites.  
o Have your child provide a finger stick blood sample for anemia testing.  


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If your child is diagnosed positive for the hookworm parasite and passes the other screening 
questions and tests, your child can participate in the study and will be assigned by chance to 
one of the two different treatment groups. 
 
Treatment Days 1, 2 and 3 
Your child will visit the study staff twice at school a day so he/she will spend all day at school 
during the three treatment days. Each day’s contact with study staff will take about 30 
minutes. At these treatment visits, your child will: 
o Tell the study staff how he or she feels and if there are any changes in his or her 
health since the last visit.   
o Take one large pill and one small pill on the first morning. Each pill will be taken by 
mouth with water.   
o Take one small pill in the morning and another one in the afternoon approximately 10 
hours later for the remaining days.  
o Tell the study staff about any medical problems 3 hours after treatment. 
 
Follow-up Safety Visits on Days 4 and 5 
These visits will take about 10 minutes each.  At these visits, we will ask your child to: 
o Tell the study staff about any medical problems. 
Contact the study doctor right away if your child has symptoms or you feel concerned about 
your child’s symptoms and health. 
 
Follow-up Stool Exam between Days 14 and 21 
During school hours, two stool cups and instructions on how to collect stool specimens will 
be provided to your child before the visit. Your child will then return the specimen cup with 
stool in it to the study team during school hours.  
 
Follow-up Albendazole Treatment 
If your child’s stool specimen is still positive for hookworm after the mebendazole treatment, 
you will be notified and your child will be given one tablet of albendazole at the end of the 
study (approximately 2 months from now). Albendazole is an approved medication in 
Tanzania for the treatment of hookworm. 
 
Can My Child Be Removed From The Study? 
The study doctor may need to take your child out of the study early without your permission 
if: 
o The investigators recommend that the study be stopped early for safety concerns.  
o Your child is not able to keep appointments. 
o Other reasons that may prevent your child from completing the study successfully. 


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What Are The Risks of Being in the Study? 
Mebendazole and albendazole are usually well tolerated.  The most common side effects are 
stomach/abdominal pain, vomiting, diarrhea, fever, headache, dizziness, or drowsiness. In 
any case, if anything were to happen your child is insured during the trial. Mebendazole is 
not recommended for use in the first trimester of pregnancy and anyone who might be 
pregnant should not participate in the study.  
 
Risk of Blood Draws: 
Your child may feel discomfort or pain when your child’s blood is pricked from his or her 
finger.   
 
Are There Benefits To Taking Part In This Study? 
Your child will receive a hemoglobin test for anemia, stool examinations and treatment for 
intestinal parasites free of charge.     
 
Alternatives To Participation 
Your child does not have to join this study. Your child’s alternative is not to join this study. 
Your child will receive regularly scheduled treatment for intestinal parasites at school.  
 
What About Confidentiality? 
Efforts will be made to keep your child’s personal information private.  If this study is 
published, your or your child’s names will not be used and your child will not be personally 
identified. Your child’s information will be labeled with an identification code for all data 
analysis. Your child’s records may be reviewed by the following institutions: 
o Swiss Tropical Public Health Institute 
o National Institute of Public Health or other health authorities 
o Study staff 
o Study monitors 
o Ethics committees 
o PATH 
However, your child’s personal files will always remain in the Public Health Laboratory Ivo de 
Carneri, in Pemba. 
 
What Are The Costs To Me? 
The study procedures will be provided at no cost to you or your child. Ask the study doctor to 
discuss the costs that will or will not be covered by the sponsor. 
 
Will I Receive Any Payment? 
The parents attending this meeting will receive a small provision to cover their costs for 
transportation (~US$ 2). Participation is voluntary and therefore itself will not be awarded 
with compensation. 


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What Happens If My Child Is Injured? 
If your child suffers an injury directly related to participation in this project, a general liability 
insurance of the Swiss Tropical Public Health Institute (Swiss TPH) and National Insurance 
Cooperation of Tanzania LTD will help you obtain medical treatment for your child’s specific 
injury and provide referrals to other health care facilities, as appropriate. Swiss TPH, the 
sponsor of the study, will provide reimbursement of reasonable medical expenses incurred 
as a result of your participation in this study. The sponsor will not pay for the treatment of 
other injuries including those cause by non-compliance with the protocol and study staff 
instruction, and any underlying diseases or conditions that your child may have.  No other 
compensation such as lost wages or pain and suffering will be provided. The study staff can 
give you more information about this if your child has a study injury. You are not precluded 
from seeking to collect compensation for injury related to malpractice, fault, or blame on the 
part of those involved in the research, including the hospital. 
 
Right To Withdraw 
Your child doesn’t have to be in this study.  Your child’s participation in this study is 
voluntary.  You or your child may decide not to have your child participate, or your child may 
leave the study at any time without further obligations.  You or your child’s decision will not 
result in any penalty or loss of benefits to which your child is entitled.  
• 
If you want your child to stop being in the study, or your child wants to stop being in 
the study, please tell us right away.  
• 
Leaving this study early will not stop your child from getting regular medical care.  
• 
If your child leaves the study early, information collected up to the date your child 
leaves the study can be used only as outlined in the confidentiality section of this 
consent form.  
• 
If your child leaves the study after taking the study medication, you and your child will 
be given contact information to reach the study doctor or the study coordinator if your 
child develops any illness that may be related to the study.  
 
What Do I Do If I have Problems or Questions? 
For questions about the screening exams and tests or if your child has a research-related 
injury, you should contact: 
Mr. Said Ali or Mr. Shaali Ame 
Public Health Laboratory Ivo de Carneri 
P.O. Box 122 Wawi, Chake Chake 
Pemba, Zanzibar (Tanzania) 
Phone:  +255 24 245-2003 
For questions about your rights as a research participant, contact: 
Zanzibar Medical Research and Ethical Committee (ZAMREC, Tanzania) 
Dr. Msafiri L. Marijani, Administrator 
Mnazi Mmoja Hospital, P.O. Box 672 
Zanzibar (Tanzania) 
Phone: +255 77 666-3303