Clinical trial NCT03527745
Conditions: Trichuriasis Hookworm Infections
Sponsor: Jennifer Keiser
Start date: 2018-10-23; Completion date: 2019-04-17
Enrollment: 700 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a single-blind randomized clinical trial conducted in rural Côte d'Ivoire. This study aims at providing evidence on the dose-response of increasing oral albendazole dosages against whipworm (T. trichiura) and hookworm infections in preschoolers (2-5 years), school-aged children (6-12 years) and adults (≥ 21 years).

The primary objective is to determine cure rates (primary end point, i.e. conversion from being egg positive pre-treatment to egg negative post-treatment). Secondary objectives involve the determination of egg reduction rates (the reduction in the number of excreted eggs from baseline (prior to treatment) to follow-up) and the assessment of safety of ascending dosages of albendazole (secondary end points). In addition, key pharmacokinetic parameters will be determined from blood samples collected with a micro-sampling device (secondary end point).

Detailed description:
This study is a single-blind randomized clinical trial conducted in Côte d'Ivoire. This study aims at providing evidence on the efficacy and safety of ascending oral albendazole dosages in children and adults infected with T. trichiura and hookworm. In preschool-aged children (2-5 years) (i) 200 mg, (ii) 400 mg and (iii) 600 mg; in schoolchildren (6-12 years) and adults (≥ 21 years) (i) 200 mg (only for hookworm infections), (ii) 400 mg, (iii) 600 mg and (iv) 800 mg will be administered and efficacy, safety and pharmacokinetic parameters will be assessed.

The primary objective is to determine the dose-response based on cure rates of albendazole in preschool-aged children (2-5 years), school-aged children (6-12 years) and adults (≥ 21 years) infected with T. trichiura and hookworm.

The secondary objectives of the trial are to determine the efficacy based on egg reduction rates of albendazole in preschool-aged children, school-aged children and adults, to determine an exposure (including length of time that the drug concentration is above the MIC, Cmax, AUC)-response correlation of albendazole in preschool-aged children, school-aged children and adults, to evaluate the safety and tolerability of albendazole in preschool-aged children, school-aged children and adults, and to determine the efficacy against concomitant soil-transmitted helminthiasis (Ascaris lumbricoides).

After obtaining informed consent from individual/parents and/or caregiver, the medical history of the participants will be assessed with a standardized questionnaire, in addition to a clinical examination and venipuncture to examine biochemical parameters in the blood carried out by the study physician before treatment. Enrollment will be based on two stool samples that will be collected, if possible, on two consecutive days or otherwise within a maximum of 5 days.

All stool samples will be examined with duplicated Kato-Katz thick smears by experienced laboratory technicians. Randomization of participants into the treatment arms will be stratified according to intensity of infection. All participants will be interviewed before treatment, 3 and 24 hours and 3 weeks after treatment about the occurrence of adverse events. Children and adults will be sampled using finger pricking for micro-blood sampling at 0, 1, 2, 3, 4, 6, 8, 24 hours post-dosing.

The primary analysis will include all participants with primary end point data (available case analysis). Supplementary, a per-protocol analysis and an intention-to-treat analysis will be conducted. CRs will be calculated as the percentage of egg-positive subjects at baseline who become egg-negative after treatment. Differences among CRs will be analysed by using crude logistic regressions and adjusted logistic regressions (adjustment for age, sex, and height).

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 2,000 replicates will be used to calculate 95% confidence intervals (CIs) for differences in ERRs. Noncompartmental and nonlinear mixed-effects (NLME) modeling will be used to determine PK parameters.

Arms: arm 1: against T. trichiura in preschool-aged children or against hookworm infections in preschool-aged children, school-aged children and adults arm 2: against T. trichiura in preschool-aged children, school-aged children and adults or against hookworm infections in preschool-aged children, school-aged children and adults arm 3: against T. trichiura in preschool-aged children, school-aged children and adults or hookworm infections in preschool-aged children, school-aged children and adults arm 4: against T. trichiura in school-aged children and adults or against hookworm infections in school-aged children and adults arm 5: against T. trichiura in preschool-aged children, school-aged children and adults or hookworm infections in preschool-aged children, school-aged children and adults
Interventions: intervention 1: Albendazole intervention 2: Albendazole intervention 3: Albendazole intervention 4: Albendazole intervention 5: Placebo
Intervention descriptions: intervention 1: Single dose of albendazole (200mg, dependent on treatment cohort) intervention 2: Single dose of albendazole (400mg, dependent on treatment cohort) intervention 3: Single dose of albendazole (600mg, dependent on treatment cohort) intervention 4: Single dose of albendazole (800mg, dependent on treatment cohort) intervention 5: Matching placebo tablets will be obtained from Fagron, Germany.

Protocol documents:
Prot_SAP_000.pdf: 
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Efficacy and safety of ascending dosages of albendazole against hookworm 
and Trichuris trichiura in preschool- and school-aged children and adults: a 
randomized controlled trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Number 
1 
Version Number 
1.01 
Document Date 
22.01.2018 
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@unibas.ch 
 
Principle 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@unibas.ch 
 
Trial registration 
ClinicalTrials.gov: NCT03527745 


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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 (Swiss 
TPH) 
 
Unit head 
Principal 
Investigator 
Dr.  
Jean Coulibaly 
Swiss TPH and 
Université Félix 
Hophouët-Boigny-
Abidjan 
Group leader 
Co-PI 
Dr.  
Jessica Schulz 
Swiss TPH  
Postdoc 
Co-investigator  
Dr. 
Yves N'Gbesso 
Departement 
d'Agboville, Centre 
de Santé Urbain 
d'Azaguié, Azaguié 
Medical 
doctor 
Study physician 
Dr. 
Jan Hattendorf 
 
Swiss TPH  
 
Group leader 
Statistician 
MSc 
Chandni Patel  
Swiss TPH 
PhD Student 
Student 
 
 
 


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II. 
Signatures  
 
Statistician 
Signature 
 
 
 
 
 
Date of Signature  
22.01.2018 
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 
 
 
Principal investigator 
Signature 
 
 
 
 
Date of Signature  
22.01.2018 
Name  
Jennifer Keiser 
Title 
Prof. 
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 fulfill 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  
22.01.2018 
Name  
Jean Coulibaly 
Title 
Dr 
Institution 
Swiss Tropical and Public Health Institute/Université Félix Houphouët-Boigny 
Address 
23 BP 915 Abidjan 23 
Phone 
+225 0500 8223/+225 0209 1401 
 
 
Co- investigator 
Signature 
 
 
 
 
 
Date of Signature  
22.01.2018 
Name  
Jessica Schulz 
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 61 207 15 06 
 
 


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III. 
Table of contents 
 
1. General Information ........................................................................................................... 2 
2. Background information ....................................................................................................12 
3. Trial objective and purpose ...............................................................................................14 
4. Methodology .....................................................................................................................14 
4.1. Primary and secondary endpoint ................................................................................14 
4.2. Type of trial ................................................................................................................15 
4.3. Trial design ................................................................................................................15 
4.3.1. Baseline survey ...................................................................................................15 
4.3.2. Assessment of efficacy after treatment ................................................................17 
4.3.3. Pharmacokinetic studies ......................................................................................17 
4.4. Measure to minimize bias ..........................................................................................18 
4.5. Study duration and duration of subject participation ...................................................19 
4.6. Schedule of visits .......................................................................................................19 
5. Selection of the trial subjects ............................................................................................19 
5.1. Recruitment ...............................................................................................................19 
5.2. Inclusion criteria .........................................................................................................20 
5.3. Exclusion criteria ........................................................................................................20 
5.4. Criteria for discontinuation of trial ...............................................................................21 
5.5. Treatment of subjects.................................................................................................21 
5.6. Concomitant therapy ..................................................................................................22 
6. Assessment of safety .......................................................................................................22 
6.1. Adverse event definitions ...........................................................................................23 
6.1.1. Severity grading...................................................................................................23 
6.1.2. Relatedness ........................................................................................................24 
6.1.3. Expectedness ......................................................................................................24 
6.1.4. Serious adverse events .......................................................................................24 
6.1.5. Suspected unexpected serious adverse reactions ...............................................25 
6.2. Methods of recording and assessing adverse events .................................................25 


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6.3. Reporting of serious adverse events ..........................................................................26 
6.4. Safety reporting to Health Authorities and Ethics Committees ....................................27 
7. Statistics ...........................................................................................................................27 
7.1. Definition of primary endpoint .....................................................................................27 
7.2. Justification of number of trial subject ........................................................................27 
7.3. Description of statistical methods ...............................................................................28 
8. Data management and data quality control ......................................................................29 
8.1. Data collection ...........................................................................................................29 
8.2. Ethical, legal and security issues ...............................................................................30 
8.3. Data storage and preservation ...................................................................................30 
9. Duties of the investigator ..................................................................................................30 
9.1. Investigator’s confirmation .........................................................................................30 
9.2. Damage coverage ......................................................................................................31 
9.3. Project management ..................................................................................................31 
10. Ethical considerations .....................................................................................................31 
10.1. Independent Ethics Committee (IEC) .......................................................................31 
10.2. Evaluation of the risk-benefit ratio ............................................................................32 
10.3. Subject information and consent ..............................................................................32 
10.4. Subject confidentiality ..............................................................................................33 
10.5. Subjects requiring particular protection ....................................................................33 
10.6. Other aspects...........................................................................................................33 
11. Quality control and quality assurance .............................................................................33 
11.1. Monitoring and auditing ............................................................................................33 
11.2. Access to data, handling of data and samples (data protection), archiving (place, 
duration) and destruction ..................................................................................................34 
11.3. Data entered directly in the Case Report Form (CRF) – definition of source data ....34 
11.4. Data and safety monitoring board (WHO) / data monitoring committee (EU/FDA) ....35 
11.5. Study Documents: Translations - Reference language .............................................35 
12. Dissemination of results and publication .........................................................................35 
13. References .....................................................................................................................36 


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IV. 
Abbreviations 
 
 
 
AE 
Adverse event 
AUC 
Area under the curve 
CI 
Confidence interval 
CR 
Cure rate 
CRF 
Case report form 
DALYs 
Disability-adjusted life years 
DBS 
Dried blood spot 
DSMB 
Data and safety monitoring board 
EKNZ 
Ethikkomission Nordwest- und Zentralschweiz 
EPG 
Eggs per gram 
ERR 
Egg reduction rate 
GCP 
Good clinical practice 
Hb 
Hemoglobin 
ICH 
International council for harmonisation of technical requirements for 
pharmaceuticals for human use 
IEC 
Independent ethics committee 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry 
MIC 
Minimal inhibitory concentration 
NLME 
Nonlinear mixed-effects 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PKPD 
Pharmacometric-pharmacodynamic 
SAE 
Serious adverse event 
STH 
Soil-transmitted helminth 
WHO 
World Health Organization 
 


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V. 
Synopsis 
 
Study Title 
Efficacy and safety of ascending dosages of albendazole against 
T. trichiura and hookworm in preschool- and school-aged children 
and adults: a randomized controlled trial 
Short title 
Albendazole dose finding and pharmacokinetics in children and 
adults 
Study Type 
Phase 2 trial 
Sample size 
1040 
Indication 
T. trichiura and hookworm infection (eggs in stool) 
Investigational Product 
and Reference 
Treatment 
Albendazole 
Protocol Number, Date 
and Version 
1, 25.02.2018, v1.01 
Trial registration 
ClinicalTrials.gov: NCT03527745 
 
Study Rationale 
To determine the range of doses of albendazole against infection 
with T. trichiura and hookworm which are effective and tolerated 
by preschool-aged children, school-aged children and adults. 
Study Objectives 
To determine the efficacy and safety of ascending oral 
albendazole dosages in children and adults infected with T. 
trichiura and in children and adults infected with hookworm. In 
preschool-aged children: (i) 200 mg, (ii) 400 mg and (iii) 600 mg; 
and in schoolchildren and adults: (i) 200 mg (only for hookworm 
infections), (ii) 400 mg, (iii) 600 mg and (iv) 800 mg will be 
compared against both parasites (T. trichiura and hookworm). 
Additionally, albendazole disposition will be measured in children 
and adults using a microsampling device. 
 
Our primary objective is to determine the dose-response based 
on cure rates of albendazole in (i) preschool-aged children (2-5 
years), (ii) school-aged children (6-12 years) and (iii) adults (≥ 21 
years) infected with T. trichiura and in (i) preschool-aged children 
(2-5 years), (ii) school-aged children (6-12 years) and (iii) adults 
(≥ 21 years) infected with hookworm. 
 
The secondary objectives of the trial are: 
 
a) To determine the efficacy based on egg reduction 


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rates of albendazole in preschool-aged children, 
school-aged children and adults; 
b) To determine an exposure (including Cmax, AUC and 
tmax)-response correlation of albendazole in preschool-
aged (2-5 years), school-aged children (6-12 years), and 
adults (≥ 21 years); 
c) To evaluate the safety and tolerability of albendazole in 
preschool-aged children, school-aged children and adults; 
and 
d) To determine the efficacy against concomitant soil-
transmitted helminthiasis (Ascaris lumbricoides) 
e) To assess genetic heterogeneity in hookworm and T. 
trichiura populations with regard to the efficacy of different 
doses of albendazole. 
Study design 
Single blind, randomized controlled trial (participants and lab 
technicians are blinded) 
Study product / 
intervention 
Administration of a single oral dose of albendazole 
Comparator(s) 
Matching placebo (purchased from Fagron) 
Key inclusion / 
Exclusion criteria 
Inclusion: preschool-aged children (2-5 years), school-aged 
children (6-12 years) and adults (≥21 years) infected with T. 
trichiura or hookworm, absence of major systemic illnesses, 
written informed consent signed by parents and/or caregivers for 
minors; and oral assent by school-aged children. 
Exclusion: Any abnormal medical conditions or chronic disease, 
negative diagnostic result for T. trichiura and hookworm, 
pregnancy, no written informed consent. 
Primary Endpoints 
CR on T. trichiura and hookworm  
Secondary Endpoints 
ERR against T. trichiura and hookworm and safety, 
pharmacokinetic 
parameters, 
genetic 
heterogeneity 
in 
hookworm and T. trichiura populations  
Exploratory Endpoints 
None  
Interim Analyses 
None 
Study Duration 
6 months 
Schedule 
08/2018 of first-participant in (planned) 
04/2019 of last-participant out (planned) 
Measurements & 
procedures 
At baseline, two stool samples will be collected, if possible, on 
two consecutive days or otherwise within a maximum of 5 days. 
The medical history of the participants will be assessed with a 


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standardized questionnaire (for preschool-aged children this will 
be administered to the caregiver of the child). In addition a clinical 
examination will be performed by the study physician and 
venipuncture to examine biochemical parameters in the blood will 
be carried out by study nurses before treatment.  
Adults, children and caregivers of preschool-aged children will 
also be interviewed before treatment, 3 and 24 hours after 
treatment, and at follow-up (2-3 weeks after 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 
duplicate Kato-Katz thick smears. A subsample of children and 
adults will be sampled using finger pricking for micro-blood 
sampling at 0, 1, 2, 3, 4, 6, 8, 24 hours post-dosing to evaluate 
pharmacokinetic parameters. 
Statistical Analyses 
An available case analysis (full analysis set according to the 
intention to treat principle) will be performed, including all subjects 
with primary endpoint data. Supplementary, a per-protocol 
analysis will be conducted. CRs will be calculated as the 
percentage of egg-positive subjects at baseline who become egg-
negative after treatment.  
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. Emax models using the DoseFinding package of the 
statistical software environment R will be implemented to predict 
the dose-response curves in terms of CRs and ERRs. 
Noncompartmental and nonlinear mixed-effects (NLME) modeling 
will be used to determine PK parameters. 
GCP statement 
This study will be conducted in compliance with the protocol, the 
current version of the Declaration of Helsinki, ICH-GCP E6 (R2) 
guidelines 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 an infection with T. 
trichiura and hookworm occurs most often in children and they 
are the main targets of preventive chemotherapy programs. 
Moreover, the exact dosage of albendazole in preschool and 
school-aged children has not yet been determined. 
Recruitment procedure 
Participants will be recruited from rural communities situated in 
Côte d’Ivoire and identified to have at least a moderate infection 
risk (prevalence: 10-49%) of T. trichiura or hookworm. 


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Coverage of damages 
Winterthur Police Nr. 4746321, BERACA Côte d’Ivoire, No: to be 
issued 
Storage of data and 
samples 
for 
future 
research aims 
After the study has been completed all samples will be destroyed 
and case report forms will be kept for a minimum of 15 years 
(chapter 10). 
 
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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2. Background information 
Parasitic worm diseases such as infection with soil-transmitted helminths (STHs) that include 
infection with Ascaris lumbricoides, Trichuris trichiura, and hookworm still affect hundreds of 
millions of people mostly in the tropics and subtropics [1]. In terms of morbidity, they 
contribute to an estimated 3.3 million disability-adjusted life years (DALYs) lost globally 
according to recent estimates [2]. The symptoms of STH infections are non-specific and may 
only be apparent in heavily infected individuals. Infection is typically most intense and 
debilitating in children. Chronically infected children might suffer from malnutrition, physical 
and cognitive retardation, and reduced work performance in older age [3]. 
For disease control, preventive chemotherapy represents the cornerstone and is advocated 
by the World Health Organization (WHO) as a strategy with a rapid impact on morbidity 
control and easily implementable at a large scale by trained personnel outside the health 
sector (e.g. teachers) [4]. Currently there are five drugs on the WHO model list of essential 
drugs against STH infections and these drugs have been widely and effectively used [4, 5]. 
Among these five, albendazole and mebendazole, which belong to the benzimidazoles, are 
considered as treatment of choice against A. lumbricoides, T. trichiura and hookworm 
infections [4]. However, both drugs show only limited efficacy against T. trichiura infection 
(cure rates of 30% and 42%, respectively) [5] and only albendazole is moderately efficacious 
against hookworm when used as single oral doses.  
Surprisingly, little is known on albendazole. The optimal dosages, as for many other 
anthelminthics, were never determined for albendazole and the 400 mg dose widely used is 
rather empirical. Unpublished data suggest higher efficacy when albendazole is used at 
higher dosages (John Horton, unpublished observation). Different dosages and regimen 
(single and multiple dose) of albendazole were tested against soil-transmitted helminthiasis 
but a thorough dose-response relationship study testing different doses in the same trial 
were not conducted to date [6]. A single dose of 800 mg albendazole was the highest single 
dose tested to date against soil-transmitted helminthiasis in school-aged children and adults 
[6] and other diseases e.g. Giardia infections [7], which represents a well-tolerated dose; 
therefore, was selected as the highest dose in our study for school-aged children and adults. 
Preschool-aged children will be treated with a slightly lower dose of 600 mg albendazole 
(John Horton personal communication), which will not pose any health risk as albendazole is 
an exceptionally safe drug. 400 mg is the standard dose for preschool-aged children, school-
aged children and adults recommended by WHO [5]. To be able to determine the dose 
response curve, 200 mg was selected as the lowest dose in the different cohorts. In addition, 
pharmacokinetic studies have not yet been conducted with albendazole in individuals 
infected with hookworm or T. trichiura; it is not known whether a pharmacokinetic 


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(PK)/pharmacodynamic relationship exists and whether there are differences in the behavior 
between different age groups.  
In view of remaining knowledge gaps in exact doses of albendazole in different population 
strata, our study aims at thoroughly investigating the safety and efficacy of ascending doses 
of albendazole (preschool-aged childreners: 200, 400 and 600 mg; school-aged children and 
adults: 200, 400, 600 and 800 mg) against T. trichiura and hookworm infections 
complemented by PK studies. 


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3. Trial objective and purpose 
 
The primary study objective is:  
To determine the dose-response of oral albendazole dosages: i) 200 mg, ii) 400 mg and iii) 
600 mg versus iv) placebo in preschool-aged children and i) 400 mg, ii) 600 mg and iii) 800 
mg versus v) placebo in school-aged children and adults infected with T. trichiura and i) 200 
mg, ii) 400 mg and iii) 600 mg versus iv) placebo in preschool-aged children and i) 200 mg ii) 
400 mg, iii) 600 mg and iv) 800 mg versus v) placebo in school-aged children and adults 
infected with hookworm.  
 
The secondary study objectives are: 
1.) To determine the efficacy based on egg reduction rates of albendazole in 
preschool-aged children, school-aged children and adults; 
 
2.) To measure albendazole disposition using a microsampling technology (DBS or 
Mitra®) to determine an exposure (including Cmax, AUC and tmax)-response 
correlation of albendazole in preschool-aged (2-5 years), school-aged children (6-12 
years) and adults (≥ 21 years); 
 
3.) To evaluate the safety and tolerability of albendazole in preschool-aged children, 
school-aged children and adults; 
 
4.) To determine the efficacy against concomitant soil-transmitted helminthiasis (Ascaris 
lumbricoides); and 
5.) To assess genetic heterogeneity in hookworm and T. trichiura populations with regard 
to the efficacy of different doses of albendazole. 
 
4. Methodology 
4.1. Primary and secondary endpoint 
Cure rate (CR) (primary endpoint, i.e. conversion from being egg positive pre-treatment to 
egg negative post-treatment) and egg reduction rate (ERR) (secondary endpoint). In 
addition, key pharmacokinetic parameters will be determined and safety of treatment 
evaluated (secondary endpoints).   


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4.2. Type of trial 
Single blind, randomized controlled trial 
4.3. Trial design 
4.3.1. Baseline survey 
Stool samples collection 
Two stool samples will be collected from each participant until a total of 560 hookworm-
infected participants (160 preschool-aged children, 200 school-aged children and 200 adults) 
and 480 T. trichiura infected participants (160 preschool-aged children, 160 school-aged 
children and 160 adults) are identified.  
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 
duplicate Kato-Katz thick smears (41.7 mg each) will be prepared [8]. The slides will be 
analyzed under a microscope by experienced technicians and a subsequent independent 
quality control of sample results (approximately 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) [9]. 
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 counts per gram of stool (EPG) will be 
calculated for each treatment arm. All microscopically analyzed quadruplicate Kato-Katz thick 
smears will be destroyed within one day (after passing the quality control). Since drug 
efficacy could be influenced by genetic aspects, ~2 g of stool sample from each participant 
will be preserved in ethanol for further genetic analyses of hookworm and T. trichiura in Côte 
d’Ivoire and Switzerland.  
Clinical examination and biological exams 
At baseline, the medical history of T. trichiura and hookworm-infected participants in the 
study will be assessed with a clinical and physical examination carried out by the study 
clinician, who will assess weight, height, body temperature, pulse rate and blood pressure. 
Rapid diagnostic tests for malaria will be done to assess the presence of a Plasmodium spp. 
co-infection. Hemoglobin (Hb) levels will be detected using HemoCue to exclude severely 
anemic participants (below 80 g/l and 70 g/l Hb in school-aged and preschool-aged children, 


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respectively, according to WHO). Female participants above 10 years will be asked to 
produce a urine sample for pregnancy testing. Vital organ (kidney, liver etc.) functions will be 
evaluated before treatment and between 14 and 21 days after treatment through a 
biochemical assessment of 4 ml of venous blood. We will assess urea, creatinine, bilirubin, 
azotemia, Alanine Amino Transferase (ALAT), Aspartate Amino Transferase (ASAT) and 
blood cell counts (hematocrit, erythrocyte, platelets). 
The six study cohorts (adults and school-aged children are summarized in one flow chart 
because the treatment schedule is identical) are presented in the figure below:  
 
 
 
 
 


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4.3.2. Assessment of efficacy after treatment 
The efficacy of the treatment will be determined 14-21 days post-treatment by collecting 
another two stool samples which will be microscopically examined for T. trichiura and 
hookworm and for co-infections (A. lumbricoides) using duplicate Kato-Katz thick smears.  
Participants will be considered T. trichiura and hookworm cured if no eggs have been found 
in the stool. 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 different treatment arms before and after 
treatment to assess the corresponding ERRs.  
At the end of the study, all participants remaining positive for T. trichiura or hookworm will be 
treated with 400 mg albendazole, the current standard treatment. 
 
4.3.3. Pharmacokinetic studies 
 


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Pharmacokinetic studies will be performed in a maximum of 20 participants per treatment 
arm (520 patients in total). Upon oral intake, albendazole gets metabolized first to sulfoxide 
and further to sulfone, whereas the sulfoxide is thought to be the most active compound to 
treat STH infection. In order to evaluate potential differences of PK parameters, including the 
metabolization rate in different populations, all three compounds, namely albendazole, 
albendazole sulfoxide and albendazole sulfone, will be quantified with time. Two blood micro-
sampling techniques, namely dried blood spot (DBS) and Mitra® are currently under 
investigation to quantify albendazole and its metabolites in human blood samples. 
Consequently, whole blood, plasma, DBS and Mitra® blood samples were collected in a 
previous clinical trial in rural Côte d'Ivoire with 10 adult volunteers who received the standard 
dose of albendazole. Methods to extract and quantify albendazole and its metabolites in all 
four matrixes are currently validated in order to demonstrate that the capillary and venous 
blood results correlate satisfactoryly. Once validation of the analytical method has been 
completed, the best blood micro-sampling device, DBS or Mitra®, will be chosen as a tool for 
these albendazole population pharmacokinetic studies in preschool-aged children, school-
aged children and adults.  
In more detail, capillary blood (± 0.1 ml) will be collected by middle or ring finger tip puncture 
using a finger pricker (e.g. Accu-chek Softclix Pro®, Roche). Sampling will be conducted at 
0, 1, 2, 3, 4, 6, 8, 24 hours post-dosing. The time points might be slightly adapted (shifted or 
reduced) in case the purpose for optimization is seen after the analyses of the samples of the 
10 adult patients has been completed. A few drops of blood will be transferred at each time 
point on DBS filter paper (Whatman) or Mitra® microsampling device and dried for 
approximately 1 hour. The DBS cards or Mitra® will be transported to Swiss TPH in Basel 
and stored at -80° C until analysis. Albendazole and its metabolites will be quantified using a 
validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug 
concentrations will be calculated by interpolation from a calibration curve with a foreseen limit 
of quantification of approximately 1-5 ng/ml. Quality control samples will be included in the 
study and its measured concentrations used to determine between-run and overall precision 
and accuracy of the analysis.  
4.4. Measure to minimize bias 
Study participants eligible for treatment will be randomly assigned to one of the treatment 
arms using a computer-generated, stratified block randomization code. The random 
allocation sequence with varying random blocks of 4 and 8 (or 5 and 10, respectively) 
stratified by 2 levels of baseline infection intensity (light and moderate T. trichiura and 
hookworm infections) will be provided by a statistician. Study-site investigators will be aware 


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of the study group assignment, whereas participants and laboratory technicians will be 
blinded.  
Placebo controlled trials reduce the risk of potential bias that can also interfere with the 
observed outcomes. In previous studies (e.g. Coulibaly et al. 2017 Lancet Global Health), we 
have observed moderate cure and egg reduction rates in placebo treated children likely due 
to the low sensitivity of anthelminthic diagnostics. Children treated with placebo will be 
treated at follow up (3-weeks post treatment) with 400 mg albendazole. This treatment delay 
does not cause any harm. 
4.5. Study duration and duration of subject participation 
The trial will last for a maximum of 6 months. The screening for the baseline will start four to 
six 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. 
4.6. Schedule of visits 
 
Screening 
 
Follow up 
 
-28 to -1 
days 
Hours 
2-3 weeks 
 
0 
Randomization and treatment 
1-8 
24 
 
Informed consent 
X 
 
 
 
 
Diagnosis (stool examination) 
X 
 
 
 
X 
Demographics 
X 
 
 
 
 
Medical history 
 
X 
 
 
 
Clinical examination 
 
X 
 
 
 
Biochemical parameter 
 
X 
 
 
X 
PK sampling 
 
X 
X 
X 
 
Capturing AEs 
 
 
X (3h) 
X 
X 
Capturing SAE 
 
 
X (3h) 
X 
X 
5. Selection of the trial subjects 
5.1. Recruitment 
The study will be carried out in different age groups in areas endemic for T. trichiura and 
hookworm in Côte d’Ivoire. Age groups investigated include preschool-aged children 2-5 
years old, school-aged children 6-12 years old and adults of 21 years or more. 


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The parents/guardians of the children and potential participating adults will be invited to 
participate in an informational meeting. Community members will be encouraged to ask 
questions in an open discussion forum. The parents/guardians will then be approached 
individually to explain and discuss the purpose and procedures of the study, including 
potential benefits and risks. 
5.2. Inclusion criteria 
1. Male and female preschool-aged children (2-5 years), school-aged children 
(6-12 years) and adults (≥21 years) infected with T. trichiura/hookworm. 
2. Written informed consent signed by study participant/parent/guardian and 
written assent in the case of school-aged children. 
3. Positive for T. trichiura/hookworm by at least two slides of the quadruple Kato-
Katz thick smears and infection intensities of at least 100 eggs per gram of 
stool (EPG). 
4. Agree to comply with study procedures, including provision of two stool 
samples at the beginning (baseline) and approximately three weeks after 
treatment (follow-up). 
5.3. Exclusion criteria 
1. Presence of acute or uncontrolled systemic illnesses (e.g. severe anemia, 
infection, clinical malaria) as assessed by a medical doctor, upon initial clinical 
assessment and liver function tests. 
2. Known or reported history of chronic illness such as HIV, acute or chronic 
hepatitis, cancer, diabetes, chronic heart disease or renal disease. 
3. Prior treatment with anthelmintics (eg, diethylcarbamazine [DEC], suramin, 
ivermectin, mebendazole or albendazole) within 4 weeks before planned test 
article administration.  
4. Received any investigational drugs or investigational devices within 4 weeks 
before administration of test article that may confound safety and/or efficacy 
assessments. 
5. Known or suspected allergy to benzimidazoles. 
6. Pregnant (urine testing) or breastfeeding women. 
 
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). Children suffering from 


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clinical malaria (fever plus positive diagnostic test) will be treated according to national 
guidelines but will not be included in the trial. 
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 child withdraws). 
2. At the discretion of the Principal Investigator, if the participant is not compliant to the 
requirements of the protocol or participation places the study subject at undue risk. 
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. 
5.5. Treatment of subjects 
400 mg chewable tablets of albendazole (Zentel®) will be obtained from Glaxo Smith Kline. 
Tablets will be split to obtain 200 mg and 600 mg dosages. Matching placebo tablets will be 
obtained from Fagron, Germany.  
Participants will receive a small breakfast two hours prior to treatment and breakfast and 
lunch during the day once absorption of the drug is complete.  
All drugs will be administered in the presence of the investigator(s), and ingestion confirmed. 
This will be recorded with the time and date of dosing. Subjects will be asked not to take any 
drugs other than those prescribed by the study medical team. After ingestion of the 
medication, 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.  
On each treatment day about 40 participants will be treated with the different dosages. In 
case any serious adverse events will be observed, the study will be put on hold until the data 
has been reviewed and a decision taken within the entire study team whether the study can 
be continued or has to be stopped. On the treatment day, participants presenting a serious 
medical situation as judged by the physician of the project will be kept at the hospital level 
under close supervision by the medical team, after the parents (for children) have been 
informed on the reasons for the prolonged hospitalization. Also, in order not to break the 
surveillance of the undesirable effects of those whom we will allow to go back home at the 
end of the treatment day, security measures will be taken: (i) a card containing at least three 
phone numbers of the investigators and the study physician will be given to the parents 


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(children) or the participant himself (adults). This card including the phone numbers on it will 
remain valid through the duration of the clinical trial; (ii) for the 24-hour period following 
treatment, a telephone unit transfer of at least 2000 CFA will be transferred to each 
participant or the participant’s parent so that they can call the investigators at any time; (iii) a 
medical team with an emergency kit will stay within the community for 24 hours following the 
treatment; and (iv) on the basis of an agreement to be signed with the responsible health 
district, an ambulance will be made available to enable rapid evacuation if necessary. All the 
financial implications of these arrangements will be fully supported by the project.  
The Principal Investigator 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. 
We will be working with children or adults in rural areas. Participants who are involved in 
agricultural activities and migrating between locations will be difficult to follow by the 
investigators. We will provide them with phone numbers and follow them up with the help of 
health workers in case adverse events occur. 
 
5.6. Concomitant therapy 
All medications taken one month before and during the study period must until the last stool 
examination between day 14 and 21 (follow-up) 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 or use of grapefruit juice against helminths are permitted during 
the trial 
 
6. Assessment of safety 
Few adverse events have been reported following albendazole administration in STH-
infected individuals. The most common adverse events were abdominal cramps, headache, 
nausea, diarrhea, fever and vertigo [10]. The safety profile of albendazole will be assessed 
through the recording, reporting and analysis of baseline medical conditions, adverse events 
and a physical and clinical examination as described in section 4.3.1. 


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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 and clinical examination and whole blood 
analysis. 
 
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 be considered baseline 
medical conditions. 
 
The observation time for adverse events starts when the treatment is initiated until the last 
follow-up examination (21 days after 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 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf): 
 
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. 


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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 event which is not reasonably related to the study treatment. A 
reasonable alternative explanation must be available. 
 
6.1.3. Expectedness 
Expected adverse event: Any adverse event of albendazole 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 1). 
Unexpected adverse event: Any adverse event, 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 
According to the ICH “Clinical Safety Data Management: Definitions and standards for 
expedited 
Reporting 
E2A” 
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/
E2A_Guideline.pdf), a serious adverse event (SAE) includes any event that: 
 
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 hospitalization or prolongation of existing hospitalization; 


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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 the last follow-up examination 
(14-21 days post-treatment).  
 
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 the 
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 
reaction which also meets the definition of serious adverse events.  
 
6.2. Methods of recording and assessing adverse events 
Subjects will be kept for observation for at least 3 hours following treatment for any acute 
adverse events. If there is any abnormal finding, the local study physician will perform a full 
clinical and physical examination and findings will be recorded. An emergency kit will be 
available on site to treat any medical conditions that warrant urgent medical intervention. 
Adults, school-aged children and the mother of preschool-aged children will also be 
interviewed 3 and 24 hours after treatment and at follow-up (2-3 weeks after treatment) about 
the occurrence of adverse events (see chapter 4.6). 
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) that serves as 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 
and iii) an assessment of intensity of adverse events will be judged by the study physician. 


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All serious adverse events 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, 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 principal study sponsor-investigator and co-
principal investigator:  
 
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 
 
Dr. Jean T. Coulibaly (Co-principal investigator) 
Université Félix Houphouët-Boigny 
Tel.: +225 0500 8223 / +225 0209 1401 
E-mail: couljeanvae@yahoo.fr 
 
The co-principal investigator must immediately notify by phone the local ethical authorities 
(Comité National d’Éthique de la Recherche (CNER) et au Département de la Pharmacie, du 
Médicament et des Laboratoires (DPML) about serious adverse events. Following 24 hours, 
the local co-principal investigator must provide to the 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).  
 


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6.4. 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 ‘Ethikkomission Nordwest- und Zentralschweiz’ (EKNZ, Switzerland) and the 
ethics committee and the ‘Direction de la Pharmacie, du Médicament et des Laboratoires 
(DPML)’ in Côte d’Ivoire according to national rules. Fatal or life-threatening serious adverse 
events or SUSARs will be reported within 24 hours after the event followed by a complete 
report within 7 additional calendar days. The sponsor will suspend dosing of further 
participants (until review by the PI and study physician(s)), if there is sufficient cause as 
determined by the investigators including the study physician, which attests that the 
continuity of the study will jeopardize the health or safety of participants. The study will be 
suspended pending a new positive decision by the two accredited local aforementioned 
institutions. The investigator will take care to inform all participants. Participants already 
enrolled in the study will complete the trial. 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 is the primary outcome of our study. Since these might be influenced by infection 
intensity, treatment allocation will be stratified by baseline infection intensity. 
7.2. Justification of number of trial subject 
Since the existence of a drug effect is well known, the main aim of the study is the 
elucidation of the nature of the dose–response relationship. A series of simulations was 
carried out to determine the required sample size. We assumed a true cure rate against 
hookworm of 5%, 30%, 50%, 70% and 80% (for 0, 200, 400, 600 and 800 mg) and of 5%, 
10%, 20%, 30% and 40% against T. trichiura and loss to follow up of 5%. We estimated that 
enrolling 40 participants per arm will be sufficient to predict the dose response curve with a 
precision (defined as median distance between prediction and confidence band) of about 10 
percentage points. The suggested sample size is also in line with the recommendations from 
Klingenberg et al. 2009 [11]. This sample size is sufficiently high to determine the key PK 
parameters as well as PK/PD relationships.  
 


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7.3. 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. In addition, a per-protocol analysis will be conducted. CRs will be 
calculated as the percentage of egg-positive participants 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 (ERR = (1-(mean at follow-up/mean at baseline))*100).  
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 point estimates. 
Emax models using the DoseFinding package of the statistical software environment R will be 
implemented to predict the dose-response curves in terms of CRs and ERRs.  
On the basis of the LC-MS/MS measurements, the following PK parameters for plasma will 
be calculated:  
Cmax 
maximal plasma concentration 
tmax 
time to reach Cmax 
AUC 
area under the curve, from 0 to 24h and 0 to inf 
T1/2 
elimination half-life 
Cmax and Tmax will be observed values derived from the plasma concentration time profile. 
AUC and T1/2 will calculated with the software WinNonlin (Version 5.2, Pharsight Corporation, 
USA) using noncompartmental analysis. The elimination half-life will be estimated by the 
equation: T1/2 = ln2/, where  will be determined by performing a regression of the natural 
logarithm of the concentration values during the elimination period.  
Further PK analysis will be undertaken fitting a structural compartmental PK model with the 
software NONMEM 7 via nonlinear mixed effects modeling (allowing for both between patient 
variation and random effects). This model will describe the blood drug levels in time, allowing 
one to investigate variation between patients in drug levels. In addition, pharmacometric-
pharmacodynamic (PKPD) analysis will be undertaken via NONMEM to investigate the 
drivers of cure and/or burden reduction and potentially any covariates with drug levels.  
Adverse events will be evaluated descriptively as the difference of proportion reporting 
adverse events before and after treatment. 
If possible, a sensitivity analysis will be conducted where double infections enrolled in one 
trial will be included in the other trial. 


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8. Data management and data quality control 
The investigators are responsible for an adequate data quality. Prior to the initiation of the 
study, a short investigators meeting will be held with the investigators and their study 
coordinators and a member of the Swiss TPH. This meeting will include a detailed discussion 
of the protocol, performance of study procedures, CRF completion, specimen collection and 
diagnostic methods. 
8.1. Data collection 
The data produced from this research project will fall into the following categories:  
 
1. Eggs counts of hookworm, Ascaris lumbricoides and Trichuris trichiura found in 
participants’ stool samples using the Kato-Katz technique before (baseline) and after 
(follow-up) treatment. 
2. Personal information such as name, age and gender of trial participants. 
3. Anthropometric and clinical characteristics of the trial participants collected using the 
study’s case report form (CRF) such as weight, height, blood pressure, temperature 
hemoglobin levels, any abnormal medical condition or chronic disease. 
4. Number and type of adverse events registered in the CRF and actively probed for 
3and 24,hours after treatment. The same data will be collected during the collection 
of the first sample at follow-up. 
5. Pharmacokinetic parameters such as Cmax, AUC or tmax analyzed from dry blood 
spots or Mitra® at 0, 1, 2, 3, 4, 6, 8, 24 hours post-dosing. 
Data from categories 1-4 will be paper-captured and subsequently doubled entered (data 
entry SOP) into ACCESS data entry masks by two independent people for quality assurance. 
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 entered into ACCESS 
databases will only be accessible to authorized personnel directly involved with the study by 
use of a password. Data in category 1 will be saved both in .mdb, .xlsx and .csv. Data in 
category 2, 3 and 4 will be double-entered using an EpiInfo mask and saved in .mdb, .xlsx 
and .csv. All categories will be merged into a single master filed saved in .xlsx and .csv. Data 
will then be analysed as described in section 7. PK parameters derived from analyzing 
microblood samples will be merged and saved as a .xlsx file. Hard copies of the data such as 
parasitological sheets and CRFs will remain at IHI. 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 CSRS. All data is expected to not exceed 5GB. 


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8.2. Ethical, legal and security issues  
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 pseudonymized data and will only be 
accessible to the local principal investigator. 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; 
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. 
8.3. Data storage and preservation  
After the study has been completed all samples will be destroyed. 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. 
Essential infrastructure such as lockable cabinets for safe storage of hardcopy data will be 
made available. Storage and backup will be in three places: personal laptops of Jennifer 
Keiser and Jessica Schulz, Swiss TPH shared server and SWICTHdrive. Archiving 
conditions will be made strictly confidential by password protection. 
 
9. Duties of the investigator 
9.1. Investigator’s confirmation 
This trial will be conducted in accordance with the protocol, International Council for 
Harmonisation of technical requirements for pharmaceuticals for human use harmonized 
guidelines of 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 or any Investigator. The Investigator will provide the reasons 
for the proposed amendment in writing and will discuss with the Sponsor and the Principal 
Investigator. Any protocol amendment must be approved and signed by the Sponsor and the 
Principal Investigator 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 


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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). 
9.2. Damage coverage 
A general liability insurance of the Swiss TPH is in place (Winterthur Police Nr. 4746321). A 
trial insurance will be arranged in Côte d’Ivoire. 
9.3. Project management 
The trial team will include the PI (Prof. Jennifer Keiser), a trial and data manager (Dr. Jean 
Coulibaly), a trial statistician (Dr. Jan Hattendorf), as well as a physician (Dr. Yves N'Gbesso) 
and laboratory technicians. Prof. Jennifer Keiser and Dr. Jean Coulibaly 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. Dr. Jean Coulibaly is 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. Dr. Jessica Schulz will be responsible for the 
pharmacokinetic studies. Dr. Yves Koutouan N'Gbesso will be responsible for all medical 
aspects of the study, including the decision for inclusion and exclusion of study participants.  
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. 
 
10. Ethical considerations 
10.1. Independent Ethics Committee (IEC) 
The study will be submitted for approval by the institutional research commission of the 
Swiss TPH, the ethical committees of Switzerland (EKNZ) and Côte d’Ivoire and the Ministry 


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of Health in Côte d’Ivoire. The study will be undertaken in accordance with the Declaration of 
Helsinki and good clinical practice (GCP). 
10.2. Evaluation of the risk-benefit ratio 
Albendazole is a well-known, widely used drug in mass treatment programs against filariasis, 
and has little and mainly mild adverse events (headache, abdominal pain etc.). All 
community members enrolled in the study will benefit from a clinical examination and 
treatment against STHs. All participating subjects remaining positive for T. trichuria, 
hookworm and concomitant STH will be treated with albendazole (according to WHO 
recommendations). 
Biological sampling (stool, blood) is always associated with potential risk of disease 
transmission. For this reason, only qualified persons with expertise will be involved in sample 
collection. They will only use sterilized material. Note that, painful swelling and/or numbness 
of the arm may occasionally occur as a result of blood sampling. These effects are usually 
transient. This procedure can also occasionally trigger reactions such as mild discomfort and 
weakness. These reactions are usually benign, short-lived and limited to feelings of 
weakness, accompanied by sweating. However, biological tests suggested in this work will 
provide important data on the health of the participants.  
10.3. Subject information and consent 
All parents or caregivers of eligible children and all adult participants (≥21 years) will be 
asked to sign a written informed consent sheet. Caregivers must have attained their majority 
(21 years in Côte d’Ivoire). In case the person is illiterate, an impartial witness that can read 
and write has to sign the consent and the illiterate participant to give a thumb print. Parents 
or caregivers will have sufficient time for reflection of their child’s participation. Additionally, 
school-aged children (6-12 years) will be briefed verbally and written assent sought in form of 
their name written down or, if illiterate, by providing a thumb print. Community meetings will 
be conducted to explain the purpose and procedures of the study. The parents attending this 
meeting will receive a small provision to cover their costs for transportation to the study site 
(~US$ 2). Information sheets are printed in French but will additionally be verbally translated 
into local languages (i.e. Abbé, Attié, Dioula, Moré) during community meetings. Participation 
is voluntary and participants 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. 
Data collected until date of potential withdrawal will be analyzed and once analysis 
performed fully anonymized. 


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10.4. 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. 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. 
The investigators have all been trained in GCPs. None of the investigators declare to have 
any conflicts of interest. 
10.5. Subjects requiring particular protection 
This study will be carried out in preschool- and school-aged children, since T. trichuria and 
Hookworm infection occurs often in children; hence, these age groups are at high risk of 
infection.  Pharmacokinetic and dose-finding studies have not been conducted to date in this 
population. Since PK parameters vary between children and adults these studies cannot be 
obtained by carrying out the trial on adults. Our trial will pave the way for a safe and effective 
treatment of STH infections in children. 
10.6. Other aspects 
We will include one arm of each study cohort treated with placebo. However, this group will 
be treated with a standard treatment of 400 mg single dose albendazole at the end of the 
study (3-4 weeks later); hence, this does not cause any medical concern. Patients generally 
are treated only in yearly intervals to reduce morbidity from chronic infections. A treatment 
delay of 3-4 weeks is not expected to cause any harm. 
11. Quality control and quality assurance 
11.1. 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. Source data/documents will be accessible to 
monitors and questions will be answered during monitoring. 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 


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Investigator agrees to allow inspectors from regulatory agencies or ethics committees to 
review records and is encouraged to assist the inspectors in their duties, if requested. 
11.2. 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 (access 
restricted, password protected, as mentioned in chapter 7.3). 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 black ink. All corrections must be initialed 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 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 principal 
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 
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. 
11.3. 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 (CRF) is considered a source document. All CRFs will be kept for at least 15 
years. 


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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. 
11.4. Data and safety monitoring board (WHO) / data monitoring committee 
(EU/FDA) 
In our study no DSMB will be established, since we work with well-known drugs in a small 
sample size and using a single dose treatment.     
 
11.5. Study Documents: Translations - Reference language 
- Protocol: Master document in English, all further language versions are translations thereof 
- CRF: Master document in English, all further language versions are translations thereof 
- ICF: no English version available; master document in French, all further language versions 
are translations thereof 
12. Dissemination of results and publication 
The final results of this study will be published in a scientific journal and presented at 
scientific conferences. All results from this investigation are considered confidential and shall 
not be made available to any third part by any member of the investigating team before 
publication. 


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13. References 
 
1. 
Jourdan PM, Lamberton PHL, Fenwick A, Addiss DG: Soil-transmitted helminth 
infections. Lancet 2017. 
2. 
Murray CJ, et al: Global, regional, and national disability-adjusted life years (DALYs) 
for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 
1990-2013: quantifying the epidemiological transition. Lancet 2015, 386(10009):2145-
2191. 
3. 
Bethony J, Brooker S, Albonico M, Geiger SM, Loukas A, Diemert D, Hotez PJ: Soil-
transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 2006, 
367(9521):1521-1532. 
4. 
WHO: Prevention and control of schistosomiasis and soil-transmitted helminthiasis: 
report of a WHO expert committee, vol. No. 912. Geneva: World Health Organization; 
2002. 
5. 
Moser W, Schindler C, Keiser J: Efficacy of recommended drugs against soil 
transmitted helminths: systematic review and network meta-analysis. BMJ (Clinical 
research ed) 2017, 358:j4307. 
6. 
Horton J: Albendazole: A review of anthelmintic efficacy and safety in humans. 
Parasitology 2000, 121:S113-S132. 
7. 
Pengsaa K, Limkittikul K, Pojjaroen-anant C, Lapphra K, Sirivichayakul C, Wisetsing 
P, Nantha-aree P, Chanthavanich P: Single-dose therapy for giardiasis in school-age 
children. Southeast Asian J Trop Med Public Health 2002, 33(4):711-717. 
8. 
Katz N, Chaves A, Pellegrino J: A simple device for quantitative stool thick-smear 
technique in schistosomiasis mansoni. Rev Inst Med Trop Sao Paulo 1972, 
14(6):397-400. 
9. 
Speich B, Ali SM, Ame SM, Albonico M, Utzinger J, Keiser J: Quality control in the 
diagnosis of Trichuris trichiura and Ascaris lumbricoides using the Kato-Katz 
technique: experience from three randomised controlled trials. Parasit Vectors 2015, 
8(1):82. 
10. 
Speich B, Ame SM, Ali SM, Alles R, Huwyler J, Hattendorf J, Utzinger J, Albonico M, 
Keiser J: Oxantel pamoate-albendazole for Trichuris trichiura infection. The New 
England journal of medicine 2014, 370(7):610-620. 
11. 
Klingenberg B: Proof of concept and dose estimation with binary responses under 
model uncertainty. Statistics in medicine 2009, 28(2):274-292.