Efficacy and Safety of Combination Moxidectin and Albendazole, Ivermectin and Albendazole and Albendazole Alone in Adolescents and Adults Infected With Trichuris Trichiura: a Randomized Controlled Trial
Phase: PHASE3
Conditions: Trichuriasis, Ascariasis, Hookworm Infections
Sponsor: Jennifer Keiser

Efficacy and safety of combination moxidectin and albendazole, 
ivermectin and albendazole and albendazole alone in adolescents 
and adults infected with Trichuris trichiura: a randomized controlled 
trial 
 
NCT Number: NCT04726969 
 
Document date: 06 May 2021 

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Efficacy and safety of combination moxidectin and albendazole, ivermectin 
and albendazole and albendazole alone in adolescents and adults infected 
with Trichuris trichiura: a randomized controlled trial 
Protocol Number 
1 
Version Number 
2.0 
Document Date 
06 May 2021 
Sponsor Contact 
Prof. Dr. Jennifer Keiser, 
Swiss Tropical and Public Health Institute, 
Tel.: +41 61 284 82 18 
Fax: +41 61 284 81 05 
E-mail: jennifer.keiser@unibas.ch 
Principle Investigator 
Prof. Dr. Jennifer Keiser, 
Swiss Tropical and Public Health Institute, 
Tel.: +41 61 284 82 18 
Fax: +41 61 284 81 05 
E-mail: jennifer.keiser@unibas.ch 
Funding Agency 
Bill and Melinda Gates Foundation 

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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), Basel, 
Switzerland 
Unit head 
Principal 
Investigator 
Dr. 
Eveline 
Hürlimann 
Swiss TPH 
Senior 
Scientific 
Collaborator 
Co-PI 
Dr. 
Jean T. Coulibaly 
Swiss TPH and 
Université Félix 
Hophouët-Boigny-
Abidjan 
Group 
Leader 
Co-PI 
MSc 
Viviane Sprecher 
Swiss TPH 
Doctoral 
student 
Co-PI 
Dr. 
Pierre H. H. 
Schneeberger 
Swiss TPH 
Post-doc 
Co-investigator 
Dr. 
Daniela Hofmann 
Swiss TPH 
Post-doc 
Co-investigator 
Dr. 
Yves Koutouan 
N’Gbesso 
Centre de Santé 
Urbain d’Azaguié 
Medical 
Doctor 
Study Physician / 
Local PI 
Dr. 
Jan Hattendorf 
Swiss TPH 
Group leader 
Statistician 
 

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II. 
Signatures 
 
Statistician 
Signature 
 
 
 
 
 
Date of Signature 
06 May 2021 
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 81 93 
 
Principal investigator 
Signature 
 
Date of Signature 
06 May 2021 
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 82 18 
 
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 
06 May 2021 
Name 
Eveline Hürlimann 
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 87 04 
 
Co-Principal investigator 
Signature 
 
Date of Signature 
06 May 2021 
Name 
Jean T. 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-Principal investigator 
Signature 
 
Date of Signature 
06 May 2021 
Name 
Viviane Sprecher 
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 
 
Study physician/Local PI 
Signature 
 
Date of Signature 
06 May 2021 
Name 
Yves Koutouan N’Gbesso 
Title 
MD 
Institution 
Centre de Santé Urbain (CSU) d’Azaguié 
Address 
BP 84 Azaguié 
Phone 
+225 0272 9236/+225 0744 2207 
 

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Co-investigator 
Signature 
 
Date of Signature 
06 May 2021 
Name 
Pierre H. H. Schneeberger 
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 83 23 
 
Co-investigator 
Signature 
 
Date of Signature 
06 May 2021 
Name 
Daniela Hofmann 
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 83 14 
 

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Table of contents 
 
1. 
General information ........................................................................................................................ 2 
2. 
Background information ................................................................................................................ 17 
3. 
Trial objective and purpose ........................................................................................................... 18 
4. 
Methodology ................................................................................................................................. 19 
4.1 
Primary and secondary endpoint ........................................................................................... 19 
4.2 
Type of trial ........................................................................................................................... 20 
4.3 
Trial design ............................................................................................................................ 20 
4.3.1 
Diagnosis ....................................................................................................................... 21 
4.3.2 
Microbiome stool collection .......................................................................................... 21 
4.3.3 
Blood type determination .............................................................................................. 22 
4.3.4 
Clinical examination ...................................................................................................... 22 
4.3.5 
Adverse events assessment ............................................................................................ 22 
4.3.6 
Assessment of efficacy after treatment .......................................................................... 23 
4.3.7 
Pharmacokinetic studies ................................................................................................ 23 
4.4 
Measure to minimize bias ...................................................................................................... 24 
4.5 
Study duration and duration of subject participation ............................................................. 24 
4.6 
Schedule of visits ................................................................................................................... 25 
5. 
Selection of the trial subjects ......................................................................................................... 25 
5.1 
Recruitment ........................................................................................................................... 25 
5.2 
Inclusion criteria .................................................................................................................... 25 
5.3 
Exclusion criteria ................................................................................................................... 26 
5.4 
Criteria for discontinuation of trial ........................................................................................ 26 
5.5 
Treatment of participants ....................................................................................................... 26 
5.6 
Concomitant therapy ............................................................................................................. 27 
6. 
Safety assessments ........................................................................................................................ 28 
6.1 
Adverse event definitions ...................................................................................................... 28 
6.1.1 
Severity grading............................................................................................................. 28 
6.1.2 
Relatedness .................................................................................................................... 29 
6.1.3 
Expectedness ................................................................................................................. 29 

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6.1.4 
Serious adverse events ................................................................................................... 29 
6.1.5 
Suspected unexpected serious adverse reactions ........................................................... 30 
6.2 
Methods of recording and assessing adverse events ............................................................. 30 
6.3 
Reporting of serious adverse events ...................................................................................... 31 
6.4 
Safety reporting to Health Authorities and Ethics Committees ............................................ 31 
7. 
Data management and data quality control ................................................................................... 32 
7.1 
Source data ............................................................................................................................ 32 
7.2 
Data collection and documentation ....................................................................................... 33 
7.3 
Ethical, legal and security issues ........................................................................................... 33 
7.4 
Data storage and preservation ............................................................................................... 34 
7.5 
Study documents: translations – reference language ............................................................. 34 
8. 
Statistics......................................................................................................................................... 34 
8.1 
Definition of primary endpoint .............................................................................................. 34 
8.2 
Justification of number of trial subjects ................................................................................ 34 
8.3 
Description of statistical methods ......................................................................................... 35 
9. 
Duties of the investigator............................................................................................................... 36 
9.1 
Investigator’s confirmation ................................................................................................... 36 
9.2 
Damage coverage .................................................................................................................. 36 
9.3 
Project management .............................................................................................................. 36 
10. 
Ethical considerations ................................................................................................................ 37 
10.1 
Independent Ethics Committee (IEC) ................................................................................... 37 
10.2 
Evaluation of the risk-benefit ratio ........................................................................................ 37 
10.3 
Subject information and consent ........................................................................................... 37 
10.4 
Subjects requiring particular protection ................................................................................ 38 
11. 
Quality control and quality assurance ....................................................................................... 38 
11.1 
Monitoring and auditing ........................................................................................................ 38 
11.2 
Data and safety monitoring board (WHO) / data monitoring committee (EU/FDA) ............ 38 
12. 
Funding ...................................................................................................................................... 39 
13. 
Dissemination of results and publication .................................................................................. 39 
14. 
References ................................................................................................................................. 40 

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III. 
Abbreviations 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
AIRP 
Autorité Ivoirienne de Régulation Pharmaceutique 
ALAT 
Alanine Amino Transferase 
ASAT 
Aspartate Amino Transferase 
BMGF 
Bill & Melinda Gates Foundation 
CI 
Confidence interval 
CNESVS 
Comité Nationale d’Éthique des Sciences de la Vie et de la Santé 
CR 
Cure rate 
CRF 
Case report form 
CSRS 
Centre Suisse de Recherches Scientifiques en Côte d’Ivoire 
HIV 
Human immunodeficiency virus 
EKNZ 
Ethikkommission Nordwest- und Zentralschweiz 
EML 
Essential Medicines List 
EPG 
Eggs per gram 
ERR 
Egg reduction rate 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
Hb 
Hemoglobin 
ICF 
Informed consent form 
ICH 
International 
council 
for 
harmonization 
of 
technical 
requirements 
for 
pharmaceuticals for human use 
IEC 
Independent ethics committee 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry 
MDA 
Mass drug administration 
MDGH 
Medicines Development for Global Health 
NLME 
Nonlinear mixed-effects 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 

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PI 
Principal investigator 
PK 
Pharmacokinetics 
RCT 
Randomized controlled trial 
RDT 
Rapid Diagnostic Test 
SAE 
Serious adverse event 
STH 
Soil-transmitted helminth 
SUSAR 
Suspected unexpected serious adverse reaction 
Swiss TPH 
Swiss Tropical and Public Health Institute 
WHO 
World Health Organization 

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IV. 
Synopsis 
 
Sponsor/Sponsor-
Investigator 
Prof. Dr. Jennifer Keiser 
Study Title 
Efficacy and safety of combination moxidectin and albendazole, 
ivermectin and albendazole and albendazole alone in adolescents and 
adults infected with Trichuris trichiura: a randomized controlled trial 
Short title 
Efficacy and safety of MOX/ALB and IVM/ALB vs. ALB alone 
Study acronym 
MAC CI RCT 
Protocol Number, Date 
and Version 
1, 06 May 2021, v2.0 
Trial registration 
Registered on https://www.clinicaltrials.gov/ (NCT04726969) 
Clinical phase 
Phase 3 trial 
Sample size 
282 participants 
Indication 
Trichuris trichiura infection (eggs in stool) 
Investigational Product 
and Reference Treatment 
Moxidectin/albendazole and ivermectin/albendazole combination 
Reference: albendazole 
Study Rationale 
To provide evidence on the efficacy and safety of co-administered 
moxidectin and albendazole compared to albendazole monotherapy in 
adolescents and adults aged 12-60 years against infection with 
T. trichiura. Additionally, to substantiate evidence on the efficacy and 
safety of co-administered ivermectin and albendazole compared to 
albendazole monotherapy against T. trichiura in the same age group. 
 
 

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Study Objectives 
Our primary objective is to demonstrate superiority of 
a) Arm A: moxidectin (8 mg) / albendazole (400 mg) combination, 
compared to 
b) Arm B: albendazole (400 mg) 
in terms of cure rate (CR) against T. trichiura infections in adolescents 
and adults aged 12-60 years assessed at 14-21 days post-treatment by 
Kato-Katz microscopy. 
The secondary objectives of the trial are: 
a) 
to 
determine 
the 
egg 
reduction 
rates 
(ERRs) 
of 
moxidectin/albendazole combination therapy compared to 
albendazole monotherapy against T. trichiura 
b) 
to determine the CRs and ERRs in T. trichiura-infected 
participants given combined ivermectin (200 µg/kg) and 
albendazole (400 mg) compared to those given albendazole 
monotherapy 
c) 
to determine the CRs and ERRs of the study drugs against Ascaris 
lumbricoides and hookworm in  co-infected participants  
d) 
to evaluate the safety and tolerability of the treatment 
e) 
to characterize population pharmacokinetics (popPK) and drug-
drug interactions of the study drugs albendazole and ivermectin in 
combination with albendazole in T. trichiura infected individuals 
(aged 12 to 20 years) 
f) 
to assess the effect of the gut microbiota on pharmacokinetics 
parameters and treatment outcome (CRs and ERRs) 
g) 
to assess drug-specific off-target effects of anthelmintic treatment 
on gut microbial communities in post-treatment samples 
h) 
to assess the pharmacogenomics of ivermectin and albendazole 
using whole genome sequencing 
The exploratory objective of this trial is to assess the association 
between T. trichiura infection intensity and blood type. 
Study design 
Parallel randomized controlled superiority trial 
Study product / 
intervention 
Administration of a single oral dose of moxidectin (8 mg) / albendazole 
(400 mg) or a single dose of ivermectin (200 µg/kg) / albendazole (400 
mg) 

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Comparator(s) 
Albendazole (400 mg) 
Key inclusion / Exclusion 
criteria 
Inclusion: 
 
Individuals aged 12-60 years 
 
having given written informed consent signed by either the 
participant him/herself (18-60 years) or by caregivers for minors 
(12-17 years); and written assent by minors 
 
agreeing to comply with study procedures, including provision of 
two stool samples at screening and at follow-up assessment (14-
21 days after treatment) 
 
having at least two out of four Kato-Katz slides positive for 
T. trichiura and a minimum count of 48 eggs per gram (EPG) of 
stool 
 
able and willing to be examined by a study physician before 
treatment 
Exclusion: 
 
Presence or signs of major systemic illness 
 
Known or suspected infection with Loa loa 
 
History of severe acute disease or unmanaged, severe chronic 
disease (i.e., condition is not as therapeutically controlled as 
necessary) 
 
Abnormal liver and kidney function assessed by multiple 
biochemical blood-based analyses 
 
Recent use of anthelmintic drugs (in the 4 weeks before treatment) 
 
In case of pregnancy, lactation and/or planned pregnancy within 
the next 3 months 
 
Known allergy to study medication (i.e. albendazole, ivermectin 
or moxidectin) 
 
Prescribed or taking medication with known contraindications 
and drug interactions with the study medication 
 
Participation in other clinical trials during the study period 
Primary Endpoints 
 
T. trichiura 
infection 
status 
of 
participants 
given 
moxidectin/albendazole compared to albendazole alone 14-21 
days post-treatment assessed by Kato-Katz 

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Secondary Endpoints 
 
T. trichiura 
infection 
intensity 
of 
participants 
given 
moxidectin/albendazole compared to albendazole alone 14-21 
days post-treatment assessed by Kato-Katz 
 
T. trichiura infection status and intensity of participants given 
ivermectin/albendazole compared to albendazole alone assessed 
at 14-21 days post-treatment by Kato-Katz 
 
A. lumbricoides and hookworm infection status and intensity of 
co-infected participants given one of the study drugs assessed at 
14-21 days post-treatment by Kato-Katz 
 
Adverse events 
 
Characterization of popPK parameters of albendazole and 
evaluation of possible drug-drug interactions between ivermectin 
and albendazole and possibly PK/PD parameters of the treatment 
combinations in T. trichiura infected adolescents (aged 12-20 
years) 
 
Taxonomic and functional profiling of gut microbial communities 
using 
compositional 
(high 
throughput 
sequencing) 
and 
quantitative (qPCR) techniques 
 
Characterization of the pharmacogenomics of ivermectin and 
albendazole in PK participants 
Exploratory Endpoints 
 
Association between T. trichiura infection and blood type 
Interim Analyses 
None 
Study Duration 
4 months 
Schedule 
05/2021 of first-participant in (planned) 
08/2021 of last-participant out (planned) 
Study centres 
Dabou and Jacqueville districts, Côte d’Ivoire 
Measurements & 
procedures 
Two stool samples will be collected, if possible, on two consecutive 
days. The medical history of the participants will be assessed with a 
standardized questionnaire, in addition to a clinical examination carried 
out by the study physician before treatment. 
All participants will be interviewed before treatment and after 3 and 24 
hours (active surveillance) and retrospectively again at 14-21 days for 

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the occurrence of adverse events (AEs). Any potential AEs happening 
between 24 hours and the respective follow-up time points will be 
monitored passively and medical intervention provided if necessary. 
The efficacy of the treatment will be determined at 14-21 days post-
treatment by collecting another two stool samples. 
All stool samples will be examined with duplicate Kato-Katz thick 
smears for T. trichiura, A. lumbricoides, and hookworm. For 
microbiome analyses, T. trichiura positive samples as well as 100 STH 
negative controls (in up to 2 stool samples each at screening and 14-21 
days after treatment) will be analyzed. For this purpose, 1-2 g of freshly 
collected samples will be stored in glycerol and immediately frozen at 
the field laboratory in Côte d’Ivoire until a frozen shipment to Swiss 
TPH in Switzerland is arranged for subsequent molecular and 
microbiological analyses. 
Each participant will be asked to provide a finger-prick blood sample for 
blood type determination and hemoglobin measurement at baseline. A 
venous blood sample (approximately 4 ml) will be taken from each 
participant at baseline to assess biochemical parameters and blood cell 
counts. At the same time, anthropometric measurements (i.e. height, and 
weight) will be taken for all participants. On the day of treatment, 
participants will be asked to provide a finger-prick blood sample for a 
malaria test before treatment is administered. In addition, all female 
participants will be asked to provide a urine sample to determine 
pregnancy. 
To determine popPK, possibly PKPD and drug-drug interaction 
parameters of the study drugs albendazole and ivermectin in 
combination with albendazole, a subsample of 14 willing study 
participants (aged 12-20 years) in the two treatment arms 
(ivermectin/albendazole and albendazole alone) will be asked to provide 
a maximum of 8 micro blood samples per participant using finger pricks 
at defined time points between 0 and 24 hours. 
Statistical Analyses 
An available case analysis according to the intention to treat principles 
will be performed, including all subjects with primary endpoint data. 
Additionally, a per-protocol analysis will be conducted. CRs will be 
calculated as the percentage of egg-positive subjects at screening who 
become egg-negative after treatment, assessed at 14-21 days with 

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quadruple Kato Katz assays. Differences in CRs (between treatment 
arms) will be analyzed using logistic regression. 
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 with 5,000 replicates will be 
used to estimate 95% confidence intervals (CIs) for ERRs and 
differences between ERRs. Adverse events will be compiled into 
frequency tables and compared between treatment groups using 
descriptive summary statistics. 
To determine popPK, PK/PD and drug-drug interaction parameters, 
nonlinear mixed-effects (NLME) modeling will be used. 
The association between blood type and infection intensity will be 
analyzed using logistic regression. Microbial communities will be 
analyzed for within sample (alpha)-diversity (observed taxa, Shannon 
diversity, phylogenetic diversity, Berger-Parker dominance); between 
sample (beta)-diversity (Bray-Curtis dissimilarity, weighted and 
unweighted UniFrac distance), sample community composition 
(presence/absence and relative abundance of key taxa, most abundant 
taxon) and aggregate community composition (prevalence and relative 
abundance of key taxa, core microbiota). 
GCP statement 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, ICH-GCP E6 (R2) as well as all 
national legal and regulatory requirements. 
Key explanation for the 
inclusion of children 
This study will involve adolescents of at least 12 years of age, since an 
infection with T. trichiura occurs most often in children who are 
therefore the main target group of deworming campaigns. Younger 
children will not be included as moxidectin is registered only for 
children ≥ 12 years. 
Recruitment procedure 
The trial will be conducted in Dabou and Jacqueville districts, Côte 
d’Ivoire. 
It will take place in areas with moderate to high T. trichiura endemicity 
(communities with a prevalence ≥ 10%) identified from earlier studies 
and/or based on experience of the local collaborating team. 

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Coverage of damages 
Winterthur, Police Nr. 4746321; L’Africaine des Assurances Côte 
d’Ivoire, Police Nr. 2020-12-8218320 
Storage of data and 
samples for future 
research aims 
After the study has been completed, all samples will be destroyed. Case 
report forms and electronic source data will be kept for a minimum of 
20 years. 
Conflict of interest in 
relation to the investigated 
drugs 
We declare no conflict of interest in relation to the investigated drugs. 

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2. Background information 
Albendazole and mebendazole are the most widely used drugs for preventive chemotherapy campaigns 
against soil-transmitted helminth (STH) infections. Albendazole is characterized by high cure rates 
(CRs) against infections with Ascaris lumbricoides (96%) and moderate CRs against hookworm 
infections (80%). Despite the use of albendazole as part of mass drug administration (MDA) campaigns 
in endemic settings, lower efficacy of albendazole is observed against Trichuris trichiura infections (CR 
31%) [1, 2]. 
Therapies combining two or more drugs are widely advocated in different therapeutic areas such as 
tuberculosis, malaria, HIV/AIDS or cancer. The underlying rationale for multifactorial pharmacological 
treatment varies with the disease and includes the protection against the selection of drug-resistance, 
and hence, a prolongation of the life-span of effective and available drugs, and to increase and broaden 
the efficacy over drugs being administered in monotherapy [3]. 
To help prioritize candidate STH combinations, the Bill & Melinda Gates Foundation (BMGF) defined 
different levels of investment risk. In more detail, the prioritization includes four tiers and takes into 
account (i) the current efficacy and safety data of existing anthelmintic drugs; (ii) the financial and time 
investment required to generate the necessary evidence to change WHO treatment guidelines; and (iii) 
the potential for transformational change. The ivermectin/albendazole combination was identified as a 
first-tier priority. Moxidectin/albendazole was classified as second tier priority (since at this stage the 
drug was not yet approved). 
In 2017, ivermectin in combination with albendazole for treatment of STH was added on the Essential 
Medicines List (EML) paving the way to further evaluate efficacy of this combination among school-
aged children and communities in a range of epidemiological settings [4]. While evidence of superiority 
of combination ivermectin/albendazole compared to single standard treatments is growing [5, 6], 
efficacy of this combination can vary across settings (unpublished data). 
Moxidectin, a macrocyclic lactone, has been an FDA-approved treatment for onchocerciasis and has 
shown promising efficacy when administering 8 mg in combination with albendazole (CR: 62.5%; ERR: 
97.4%) against T. trichiura infections in adolescents [7]. A review of available data suggests that the 
high fat solubility, long half-life, intrinsic potency and high safety margin of moxidectin could allow 
this drug to be used at sufficiently high doses to safely remove ivermectin-resistant parasites. However, 
there is a need to explore whether moxidectin could reveal a benefit in the treatment of STH infections 
in settings where efficacy of ivermectin is low [8]. In this trial, we aim to evaluate if moxidectin in 
combination with albendazole is an efficacious treatment against T. trichiura in Côte d’Ivoire. 
Furthermore, this trial aims to substantiate the evidence of combined ivermectin/albendazole, since 
recent trial data suggests no major improvement against trichuriasis (observed CR of 13%). 
The pharmacokinetic/-dynamic (PK/PD) characterization of a drug is essential to understand the 
response of the human body to a drug and vice versa, especially in populations that physiologically 

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differ from healthy adults. Physiological characteristics like mal- or undernutrition due to intestinal 
worms, such as T. trichiura, can potentially affect the PK of a drug [9, 10]. Age, sex, body weight but 
also the presence of certain enzymes in different populations are important contributors to the 
pharmacokinetic profile of a drug. Additionally, pharmacokinetic interaction may occur upon co-
administration of different drugs. 
A trial currently being conducted by our group will characterize popPK and evaluate PK/PD parameters 
of albendazole in adults, pre- and school-aged children infected with T. trichiura. Our study will be the 
first one to provide PK information on albendazole in adolescents in this indication. Even more our 
study will provide essential information on the interaction between ivermectin and albendazole and thus 
guide optimal drug dosing in T. trichiura-infected individuals in Côte d’Ivoire. Moreover, ivermectin 
and albendazole are substrates for P-gp and CYP3A4, and the bioavailability of drugs can likely be 
influenced by polymorphisms in both P-gp and CYP3A4. However, extremely limited investigation on 
the pharmacogenomics of ivermectin have been performed, mainly only in Ghanaian volunteers infected 
with onchocerciasis treated with ivermectin. No pharmacogenomic differences were found to explain 
differences between treatment responders and non-responders, but a pharmacokinetic evaluation was 
not performed and the sample size was extremely limited [11]. 
Gut microbes have been shown to metabolize a wide range of orally given drugs [12]. Drug-microbe 
interactions are multifaceted resulting in increased or decreased drug potency as well as modified 
toxicity of the initial compound [13]. However, their metabolic potential and effect on treatment 
outcome is not systematically studied, especially their role during first-pass metabolism of xenobiotics. 
We have generated preliminary data showing the role of the microbiome in treatment efficacy of 
anthelminthic drugs, including praziquantel and ivermectin (unpublished data) [14]. This study will be 
the first to assess the role of the gut microbiome in moxidectin-based treatment and will enable us to 
validate our preliminary observations for ivermectin-based treatment. These observations will be used 
to assess the potential of new therapeutic opportunities based on the modulation of microbial 
communities in combination with anthelminthic drugs, to ultimately improve the general efficacy of 
these important drugs. 
 
3. Trial objective and purpose 
We designed a superiority trial to show that co-administered moxidectin and albendazole is superior 
compared to albendazole monotherapy in individuals aged 12-60 years in the Dabou and Jacqueville 
districts of Côte d’Ivoire. Moxidectin might be advantageous in terms of the drug’s longer half-life and 
in areas with possible emerging ivermectin resistance [15, 16]. This study will provide further insights 
on the potential value of moxidectin/albendazole. Our data will pave the way for possible large scale, 
multi country follow-up studies. Additionally, to substantiate evidence on the efficacy and safety of co-
administered ivermectin and albendazole against T. trichiura, we include this treatment option as a third 

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arm in our trial. As recommended for new combination therapies, we simultaneously assess superiority 
of the drug combinations compared to standard-of-care monotherapy. 
The primary objective is to demonstrate that co-administered moxidectin (8 mg) / albendazole (400 
mg) is superior to albendazole (400 mg) in terms of CRs against T. trichiura infections assessed by 
Kato-Katz at 14-21 days post-treatment in individuals aged 12-60 years. 
The secondary objectives of the trial are: 
a) to determine the egg reduction rates (ERRs) of moxidectin/albendazole combination therapy 
compared to albendazole monotherapy against T. trichiura 
b) to determine the CRs and ERRs T. trichiura-infected participants given combined ivermectin 
(200 µg/kg) and albendazole (400 mg) compared to those given albendazole monotherapy 
c) to determine the CRs and ERRs of the study drugs (i.e. albendazole alone, albendazole-
ivermectin, albendazole-moxidectin) against Ascaris lumbricoides and hookworm in co-
infected participants 
d) to evaluate the safety and tolerability of the treatment 
e) to characterize popPK and drug-drug interactions of study drugs albendazole and ivermectin in 
combination with albendazole in T. trichiura infected adolescents (aged 12-20 years) 
f) to assess the effect of the gut microbiota on pharmacokinetics parameters and treatment outcome 
(CRs and ERRs) 
g) to assess drug-specific off-target effects of anthelmintic treatment on gut microbial communities 
in post-treatment samples 
h) to assess the pharmacogenomics of ivermectin and albendazole using whole genome sequencing 
to determine associations between pharmacogenetic variants with pharmacokinetic or 
pharmacodynamic parameters 
The exploratory objectives of this trial is to assess the association between T. trichiura infection 
intensity and blood type. 
 
4. Methodology 
4.1 
Primary and secondary endpoint 
Primary endpoint: T. trichiura infection status of participants given moxidectin/albendazole compared 
to albendazole alone 14-21 days post-treatment assessed by Kato-Katz. 
Secondary endpoints: 
 
T. trichiura intensity of infection of participants given moxidectin/albendazole compared to 
albendazole alone 14-21 days post-treatment assessed by Kato-Katz. 
 
T. trichiura infection status and intensity of participants given ivermectin/albendazole compared to 
albendazole alone assessed at 14-21 days post-treatment by Kato-Katz. 

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 
A. lumbricoides and hookworm infection status and intensity of co-infected participants assessed at 
14-21 days post-treatment by Kato-Katz. 
 
Tolerability of treatment (adverse events (AEs)) assessed at 3 and 24 hour post-treatment. 
 
Population PK parameters and possible drug-drug interactions between ivermectin/albendazole 
between 0 and 24 hours post-treatment. 
 
Gut microbial profiles at screening will be correlated with drug pharmacokinetics parameters and 
treatment outcomes, and off-target effects of treatment will be measured on microbial communities 
from stool samples collected at 14-21 days post-treatment. 
 
Taxonomic relative abundances of gut bacterial communities will be analysed with high-throughput 
sequencing. Absolute abundances of specific taxa will be measured using taxon-specific qPCR. 
Changes in relative and absolute abundances will be measured before and at 14-21 days after 
treatment. 
 
For the description of genetic variation in the metabolism of ivermectin and albendazole whole 
genome sequencing will be performed on blood samples collected at baseline from PK participants 
to determine associations between pharmacogenetic variants with pharmacokinetic or 
pharmacodynamic parameters. 
Exploratory endpoints: Association between T. trichiura infection intensity and participants' blood 
type. 
4.2 
Type of trial 
Parallel randomized controlled superiority trial. 
4.3 
Trial design 
A randomized-controlled trial will be conducted with three treatment arms to be followed-up 14-21 days 
after treatment (Error! Reference source not found.). This trial will be conducted in the Dabou and 
Jacqueville districts of Côte d’Ivoire. This area was selected, because communities with high endemicity 
were identified as part of a previous trial on T. trichiura in 2019 [17]. 
The study includes one baseline (day -7 to -1) and one follow-up assessment at 14-21 days after 
treatment. The study is designed as a parallel two-arm trial with 188 participants aged 12-60 years 
randomized to either moxidectin (8 mg) and albendazole (400 mg) or albendazole (400 mg) alone. 
Additionally, approximately 94 individuals aged 12-60 years will be given the combination of 
ivermectin (200 µg/kg) and albendazole (400 mg) at treatment (day 0) and followed-up at 14-21 days 
after treatment, resulting in an overall allocation ratio of 1:1:1. 

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Figure 1. Trial design and timeline. 
4.3.1 
Diagnosis 
At screening, all participants will be asked to provide two stool samples. From each stool specimen, 
duplicate Kato-Katz thick smears (41.7 mg each) [18] will be prepared and read under a microscope for 
eggs of T. trichiura, A. lumbricoides and hookworm by experienced technicians. For quality control of 
A. lumbricoides and T. trichiura egg counts, 10% of slides will be re-read by another laboratory 
technician. Results are considered correct if the following tolerance margin is not exceeded: (i) No 
difference in presence/absence of 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). In case discrepancies 
above the tolerance margin are noted in one or more slides, the respective 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. All microscopically analyzed quadruplicate Kato-Katz thick smears will be 
destroyed after passing the quality control. The same diagnostic approach will be applied at 14-21 days 
after treatment. 
4.3.2 
Microbiome stool collection 
For microbiome analyses, T. trichiura positive samples as well as 100 STH negative controls (in up to 
2 stool samples each at baseline and 14-21 days after treatment) will be analyzed. For this purpose, 1-2 
g of freshly collected samples will be suspended in 15 mL of sterile phosphate buffer supplemented with 
0.1% L-cysteine (PBSc) in a sterile 50 mL falcon tube. The tubes will be left for 5 minutes to let 
insoluble particles settle. 1 mL aliquots (up to 2 aliquots) of the supernatant will be transferred to sterile 
cryogenic vials, supplemented with 1 mL of 40% glycerol solution, and subsequently frozen (at -20ºC) 
until shipment to Swiss TPH in Switzerland is arranged for subsequent molecular and microbiological 

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analyses. For the microbiome analysis additional data on height and weight of participants will be 
collected. 
4.3.3 
Blood type determination 
For various infectious diseases the association between blood type and susceptibility to infection as well 
as infection intensity has been studied [19, 20]. However, there is very limited evidence on this 
relationship in STH infections, particularly in T. trichiura [21]. To investigate the potential association 
between blood type and T. trichiura infection intensity all enrolled participants will be asked to provide 
a finger-prick blood sample at baseline. Blood type will be determined performing an ABO agglutination 
test (e.g., using DiaClon/BioRad ID-cards or commercial antisera A, B and D). 
4.3.4 
Clinical examination 
A clinical examination of the study participants assessing general health, anthropometric parameters 
including height and weight as well as temperature using a non-contact infrared forehead thermometer 
(Braun No touch – NTF3000; Braun, Kronberg, Germany) will precede the treatment. Each participant 
will be asked to provide a finger-prick sample to measure hemoglobin (Hb) levels, which will be 
detected using a HemoCue analyzer (Hb 301 system, Angelholm, Sweden), and to determine blood type 
(see section 4.3.3). A venous blood sample (approximately 4 ml) will be taken at baseline to assess 
biochemical parameters, such as urea, creatinine, bilirubin, azotemia, Alanine Amino Transferase 
(ALAT), Aspartate Amino Transferase (ASAT), as well as blood cell counts (e.g. hematocrit, 
erythrocytes and platelets). Results from baseline biochemical analysis may be reported back to 
participants during the trial period as seen fit. To avoid accidental treatment of pregnant girls/women all 
female participants will be asked to provide a urine sample to be subjected to a pregnancy RDT during 
clinical examination and the day of treatment administration. Before treatment is administered, each 
participant will be asked to provide a finger-prick blood sample for a rapid diagnostic test (RDT) for 
Plasmodium spp. infection. All trial participants will further be asked about existing clinical symptoms 
before drug administration using a standardized questionnaire. 
4.3.5 
Adverse events assessment 
Participants will be monitored at the site for 3 hours after treatment administration to observe any 
possible acute AEs and reassessment will be done at 24h post-treatment. Additionally, interviews will 
be conducted to determine the emergence of clinical symptoms such as headache, abdominal pain, 
itching, nausea, vomiting and diarrhea directly before treatment within the scope of baseline assessment. 
At 3 and 24 hours after treatment and retrospectively at days 14 – 21, participants will again be 
interviewed for the assessment of AEs. Symptoms arising within the timespan of 24 hours after treatment 
and the respective follow-up time points will be monitored passively by teachers or local health workers 
who will report incidences to the study team. Any symptoms will be recorded in the designated case 
report form (CRF) and immediate action will be undertaken if indicated. 

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4.3.6 
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 using duplicate Kato-Katz thick 
smears. Participants will be considered cured if no T. trichiura eggs are found in the follow-up stool 
samples. Eggs per gram 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 infection will be treated 
with the currently best recommended treatment of repeated doses of mebendazole (100 mg twice daily 
over 3 days). 
4.3.7 
Pharmacokinetic studies 
The pharmacokinetic and exposure-response correlation study will be performed in a maximum of 14 
adolescents (aged 12-20 years) in the two treatment arms receiving either ivermectin/albendazole or 
albendazole. The absorption of all study drugs is known to be better after consumption of a high-fat 
meal, therefore PK participants will receive a local high-fat breakfast before treatment [22]. Since PK 
population parameters of all study drugs are available [23], a sparse sampling approach can be applied 
to describe the PK profiles of the individual drugs upon administration as well as a potential interference 
between ivermectin and albendazole upon co-administration. Within a sparse sampling approach, 
instead of describing the PK profile for each participant separately, samples are allocated to different 
time points and/or individuals within the same treatment. Statistical inferences are performed to 
characterize the population-based PK profile of a specific treatment arm. This approach allows for a 
reduced number of samplings per treatment arm and renders a PK characterization well tolerable. To 
this end, a small drop of blood from the fingertip will be taken for a maximum of 8 finger pricks per 
participant. In total only 14 participants (7 per treatment arm) will undergo PK. The exact time points 
will cover a timespan of 0 to 24 hours after treatment and will have to be adapted according to a PK 
model of ivermectin and albendazole currently developed based on data gathered during recent trials 
involving these study drugs [24, 25]. Capillary blood (≤ 60 µL, i.e. 10 µL for albendazole, and a drop 
of blood (~ 60 µL) for ivermectin) will be collected by puncture with a finger prick. Two microsamples 
(duplicates) will be taken with one finger prick. Each time, the drop of blood (10 – 60 µL) will be 
directly transferred on Mitra® sticks (albendazole) or dried-blood spot cards (ivermectin) [26]. The dried 
sticks and filter paper will be transported to Swiss TPH, Basel, and stored at room temperature until 
analysis (< 2 months post-treatment). The quantification of the study drugs will be performed using the 
validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method as described 
elsewhere [23, 26]. Drug concentrations will be calculated by interpolation from a calibration curve with 
a lower limit of quantification of 1-5 ng/ml. 7% of the sample duplicates will be analyzed for quality 
control, and the measured concentrations will be used to determine between-run and overall precision 
and accuracy of the analysis. 

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From the 14 PK participants whole genome sequencing will be used to determine associations between 
pharmacogenetic variants with pharmacokinetic or pharmacodynamic parameters. One blood sample (1 
ml) for pharmacogenomics will be aliquoted from the venous blood sample collected at enrolment (as 
described above (4.3.4 clinical examination). Whole blood (1.5 ml) will be dispensed into an EDTA 
coated tube, inverted six times to mix anticoagulant thoroughly, and transferred by pipette to a cryovial 
and frozen. Samples will be analyzed at the University of Helsinki in Finland. 
4.4 
Measure to minimize bias 
Study participants eligible for treatment will be randomly assigned to one of the three treatment arms 
using a computer-generated stratified randomization code. The random allocation sequence with block 
sizes that will be a multiple of 3 and stratified by 2 levels of infection intensity at screening (light: 1-
999 EPG, and moderate plus heavy: ≥ 1000 EPG T. trichiura infections) will be provided by a 
statistician. This way, all treatment arms will have a similar proportion of participants with light 
infection intensity. Allocation concealment will be warranted using sequential, opaque, sealed 
envelopes. In the case of accidental unblinding or necessary code breaks, the sponsor will be 
immediately notified (within 24 hours) and data will be analyzed as set forth in section 8.3. Treatment 
arm A and B will be double blinded (i.e. study participants and the trial team/researchers conducting the 
treatment and assessing the outcomes will be blinded) using tablets and appearance-matched placebos 
in bottles relabeled with the respective arm (i.e. A or B) by investigators not involved in efficacy 
assessment of the trial. Treatment arm C (receiving ivermectin/albendazole) will be an open, unblinded 
group. 
4.5 
Study duration and duration of subject participation 
The trial will last four months, and screening is scheduled to start three months prior to treatment. The 
follow-up assessment will take place between 14-21 days after treatment and will last approximately 
three weeks. Thus, the maximum time for subject participation will be four months. Schedules of visits 
are summarized below. 
 
 

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4.6 
Schedule of visits 
Table 1. Schedule of visits of during study. 
 
Screening 
Baseline 
Treatment/Safety 
 
Follow up 
Day -90 to -8 
Day -7 to -1 
Day 0 
Day 14 to 21 
0h 
Randomization and treatment 
3h 
24h 
Informed consent 
X 
 
 
 
 
 
Diagnosis (stool examination) 
XX1 
 
 
 
 
XX1 
Microbiome assessment 
X 
 
 
 
 
X 
Medical history 
 
X 
 
 
 
 
Clinical examination 
 
X 
 
 
 
 
Venous blood assessment 
 
X 
 
 
 
 
Hemoglobin measurement 
 
X 
 
 
 
 
Blood typing 
 
X 
 
 
 
 
Pregnancy testing 
 
X 
X 
 
 
 
Malaria RDT 
 
 
X 
 
 
 
PK (microsampling) 
 
 
X 
X 
X 
 
Capturing AEs 
 
 
 
X (active) 
X (active) 
X 
Capturing SAE 
 
 
 
X (active) 
X (active) 
X 
1: For screening and follow-up assessment two stool samples will be collected and analyzed on two consecutive days. 
5. Selection of the trial subjects 
5.1 
Recruitment 
The trial will be carried out in adolescents and adults aged 12-60 years in the Dabou and Jacqueville 
districts of Côte d’Ivoire. The trial will be implemented as community-based study in communities with 
endemicity of T. trichiura infection above 10% identified during a previous trial. Guardians/caregivers 
of potential participants aged <18 years and adult participants will be invited to participate in an 
information session. The research team will explain the purpose and procedures of the study, as well as 
potential benefits and risks of participation. Attendees will be encouraged to ask questions which will 
be discussed in an open setting. 
Caregivers interested in having their child/children of 12-17 years of age participate in the study or 
adults aged 18-60 years willing to participate will be invited to complete the process of informed consent 
by signing the informed consent form (ICF). In addition, written assent will be obtained from underage 
participants. Participants having a signed ICF will be assessed for eligibility during screening 
procedures. 
5.2 
Inclusion criteria 
1. 
Aged between 12 and 60 years. 

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2. 
Written informed consent signed by either participant him/herself (18-60 years of age) or by 
parents/caregivers for underage adolescents (aged 12-17 years); and written assent by underage 
participant. 
3. 
Agree to comply with study procedures, including provision of two stool samples at the beginning 
(screening) and at follow-up assessment 14-21 days after treatment. 
4. 
Having at least two slides of the quadruple Kato-Katz thick smears positive for T. trichiura and 
infection intensities of at least 48 EPG. 
5. 
Willing to be examined by a study physician prior to treatment. 
5.3 
Exclusion criteria 
1. 
Presence or signs of major systemic illnesses, e.g. body temperature ≥ 38°C, severe anemia (below 
80g/l Hb according to WHO [27]) upon initial clinical assessment. 
2. 
Known or suspected infection with Loa loa. 
3. 
History of severe acute or unmanaged severe chronic disease (i.e., condition is not as 
therapeutically controlled as necessary). 
4. 
Abnormal liver function assessed by multiple biochemical blood-based analyses 
5. 
Recent use of anthelmintic drugs (in the 4 weeks before treatment). 
6. 
Pregnancy, lactating, and/or planning to become pregnant within the next 3 months. 
7. 
Known allergy to study medications (i.e., albendazole, ivermectin or moxidectin). 
8. 
Prescribed or taking medication with known contraindication to or interaction with study drugs. 
9. 
Participating in other clinical trials during the study period. 
5.4 
Criteria for discontinuation of trial 
A participant can be discontinued from the study for the following reasons: 
1. 
Withdrawal 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 participants will not be replaced. If, for any reason, a subject is discontinued from the 
study before the end of treatment evaluations, the AE assessment will still be conducted. Data obtained 
prior to the withdrawal will be included in the analysis to ensure the validity of the trial. Data of 
withdrawn participants are fully anonymized once analysis is complete. 
5.5 
Treatment of participants 
After randomization, all eligible participants will be treated with the respective single or combination 
treatment regimen according to their assigned treatment arm at day 0. Albendazole will be the product 
of Glaxo Smith Kline (Zentel®) and a single tablet of 400 mg will be administered. Moxidectin tablets 
and matching placebo tablets (in terms of appearance) will be obtained from Medicines Development 

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for Global Health (MDGH), Australia, and four tablets of 2 mg will be administered. Ivermectin tablets 
(3 mg) will be obtained from Merck (Stromectol®), and administered at a dose of 200 µg/kg based on 
the recorded body weight of each participant. 
The tablets will be handed out from 4 drug containers (moxidectin, ivermectin, placebo and albendazole) 
according to the randomization list. Each person will receive either: 
(i) 
A single tablet of albendazole plus four tablets of moxidectin 
(ii) 
A single tablet of albendazole plus four tablets of placebo 
(iii) 
A single tablet of albendazole plus 200 µg/kg of ivermectin 
All drugs will be administered in the presence of the PI and/or co-PI, and ingestion confirmed. This will 
be recorded with the time and date of dosing. Participants will be asked to limit the use of any drugs 
other than those prescribed by the study medical team for the duration of the study as described in section 
5.6. 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. 
The PI or the co-PIs are responsible for drug accountability at the study site. Maintaining drug 
accountability includes careful and systematic study drug storage, handling, dispensing, and 
documentation of administration. Prior to administration, drugs will be stored at room temperature and 
protected from light and exposure to moisture in a secure area with limited access at the study site. 
A study physician will do capillary blood sampling (finger pricking) for the population PK assessment 
for a maximum of 14 study participants (maximum of 7 adolescents in each of two treatment arms 
involved in PK) in a quiet location in the community.  
To avoid interference of potential on-going control programs against helminthiases with the infection 
status of the trial participants, communication with local stakeholders will be established to ascertain 
that trial participants will not undergo MDA treatment. Missed-out rounds of planned MDA against 
STH will be substituted with a free single-dose treatment (albendazole 400 mg) against STH infection 
at the study endpoint (after the follow-up assessment) offered by the study team to all community 
members not participating in the trial in communities screened. 
5.6 
Concomitant therapy 
All medications taken one month before and during the study period until the last stool examination at 
the day 14-21 follow-up assessment 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: 

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- No other active drugs against helminths are permitted during the trial. Participants receiving active 
anthelminthic concomitant medication during the trial will not be discontinued; however, a case-specific 
assessment will be done at the point of data-analysis. 
 
6. Safety assessments 
6.1 
Adverse event definitions 
The term “adverse event” is defined as follows: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment. 
An AE could therefore 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 unfavorable 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 considered as baseline medical conditions. For the 
purpose of this trial, disease progression and relapse will be considered as failure of prescribed treatment 
or failure of treatment administration, not as an Adverse Event. 
The observation time for adverse events starts when the treatment is initiated until the end of the study. 
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 physician or nurse of the trial as mild, moderate, 
severe or life threatening according to the following definitions: 
 
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. 

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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 event 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 co-administration of 
ivermectin/albendazole or moxidectin/albendazole reported in the literature or on the drug package 
leaflets and listed in the consent form. 
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. 
6.1.4 
Serious adverse events 
According to the ICH “Clinical Safety Data Management: Definitions and standards for expedited 
Reporting E2A” [28], 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 inpatient 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 (SAEs) are reported from treatment until the end of the study. 
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 SAE that occurs after the study period and its possible relatedness to the study 
treatment or study participation will also be assessed by investigators as described in section 6.1.2. 
6.1.5 
Suspected unexpected serious adverse 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 
Few adverse events have been reported following albendazole, ivermectin or moxidectin administration 
in STH-infected individuals. The most common adverse events were abdominal cramps, headache, 
fatigue, nausea, diarrhea, fever and vertigo [7, 15, 29-32]. 
The observation time for AE starts when the treatment is initiated. Subjects will be observed for at least 
3 hours following treatment for any acute AE and reassessment will be done at 24h post-treatment. If 
there is any abnormal finding, the local study physician will perform a full clinical examination and 
findings will be recorded. An emergency kit will be available on site to treat any medical conditions that 
warrant urgent medical intervention. Participants will also be interviewed at 3h and 24h actively as well 
as retrospectively 14 -21 days after treatment about the occurrence of AEs. Any potential AEs happening 
between 24 hours and the follow-up time point (14-21 days) will be monitored passively and managed 
with the help of the locally based medical team (including specifically trained community health 
workers, nurses and medical doctors). Medical intervention will be provided if necessary. 
Information on all AEs (incidence, intensity, seriousness and causality) will be entered immediately in 
the source document, and also in the appropriate AE module of the case report form. For all AEs, 
sufficient information will be pursued and/or obtained so as to permit i) an adequate determination of 
the outcome of the event (i.e. whether the event should be classified as a SAE); and; ii) an assessment 
of the casual relationship between the AE and the study treatments. Intensity of AE will be judged by 
the study physician, following guidelines by the European Medicine Agency (Note for Guidance on 
Clinical Safety Data Management). 
All SAEs, unexpected adverse drug reactions or SUSARs must be reported as described in Section 6.3. 

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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-PIs: 
Prof. Dr. Jennifer Keiser (Sponsor-investigator) 
Swiss Tropical and Public Health Institute 
Socinstrasse 57, 4051 Basel, Switzerland 
Tel.: +41 61 284 82 18 
Fax: +41 61 284 81 05 
E-mail: jennifer.keiser@swisstph.ch 
 
Dr. Jean T. Coulibaly (Co-PI) 
Université Félix Houphouët-Boigny 
23 BP 915 Abidjan 23, Côte d’Ivoire 
Tel.: +225 0500 8223 / +225 0209 1401 
E-mail: couljeanvae@yahoo.fr 
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 SAE reporting will be included in the trial-specific SAE 
form. Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
medications). 
All pregnancies in enrolled participants will be reported to the sponsor-investigator within 48 hours of 
becoming aware of the pregnancy. In the event of pregnancy in a treated participant, she should be 
monitored until the conclusion of pregnancy. The outcome of the pregnancy and any complications must 
be reported to the sponsor-investigator within 48 hours. 
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 
‘Ethikkommission Nordwest- und Zentralschweiz (EKNZ)’ in Switzerland, the ‘Comité Nationale 
d’Éthique des Sciences de la Vie et de la Santé (CNESVS)’ and the ‘Autorité Ivoirienne de Régulation 
Pharmaceutique (AIRP)’ in Côte d’Ivoire according to national rules. Fatal or life-threatening SAEs or 
SUSARs will be reported within 24 hours followed by a complete report within 7 additional calendar 

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days. Other SAEs and SUSARs that are not fatal or life-threatening will be filed as soon as possible but 
no later than 14 days after first knowledge by the sponsor. 
 
7. Data management and data quality control 
The investigators are responsible for an adequate data quality. Prior to the initiation of the study, a short 
investigator’s meeting will be held between investigators of Swiss TPH and CSRS. This meeting will 
include a detailed discussion of the protocol, performance of study procedures (standard operating 
procedures from previous studies available on site), CRF completion, specimen collection and 
diagnostic methods. 
Information about study subjects will be kept confidential and managed accordingly. Screened 
participants will be listed in a confidential “subject screening log” and attributed a unique study number. 
Enrolled participants will be listed in a confidential “subject enrolment log”; this document will 
constitute the only source to decode the pseudonymized data and will only be accessible to the 
investigators. CRF data will be double-entered and compared using Beyond Compare 4 (Scooter 
Software Inc., Madison, Wisconsin). Any discrepancies will be reviewed against the hard copies of the 
CRF and corrected accordingly. Electronic data files will be stored on secured network drives with 
restricted access for study personnel only. Data analysis will be conducted with pseudonymized data 
and reporting of findings will be fully anonymized. 
Essential infrastructure such as a locked room for safe storage of hardcopy data will be made available. 
7.1 
Source data 
Source data are comprised of clinical findings and observations as well as laboratory data maintained 
and compiled at the study site. Source data are contained in source documents and are allowed to be 
accessed by local authorities. Source data will be directly entered in the following documents: 
1. CRF: Primary data collection instrument for the study. It holds records of all clinical and 
physical examination data, treatment information and AEs. For every subject enrolled in the 
clinical trial, a corresponding CRF exists. All data requested on the CRF must be recorded, and 
investigators will review and approve each CRF for completion. 
2. Census: secondary data collected from previously completed census in communities. Holds 
name, age and sex of each potential participant. 
3. Laboratory parasitology sheets: Record of the STH egg counts at all sample collection time 
points. 
4. PK: Time records of PK samplings for 14 willing participants. 
5. Laboratory blood and stool analyses: Record of the results of microbiome and/or blood 
parameters at all sample collection time points. 

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7.2 
Data collection and documentation 
Data collected and produced within this trial will fall into one of the following categories: 
a) Egg counts of T. trichiura, Hookworm (Necator americanus and Ancylostoma duodenale, no 
differentiation between the two species will be made) and A. lumbricoides derived from standard 
Kato-Katz microscopy performed at screening as well as at 14-21 days post-treatment. 
b) Anthropometric and clinical characteristics of the trial participants collected using the study’s 
CRF such as weight, height, blood pressure, temperature, pregnancy status (for female subjects), 
overall health status and any abnormal medical condition or chronic disease. 
c) Finger prick and venous blood parameters including malaria infection status, hemoglobin, blood 
type, complete blood count and liver function parameters. 
d) Taxonomic and functional profiles will be generated from stool samples using high-throughput 
sequencing and quantitative polymerase chain reaction. Independently of the employed 
technique, sample content will be anonymized by removing host related material prior to 
analysis, e.g. by filtering out host-related sequencing reads. 
e) PK time recording of each sample per person. 
f) Measured concentrations analyzed from micro blood samples and subsequently derived PK 
parameters. 
All data categories will be recorded paper-based and with the option directly into tablets using 
CommCare (Dimagi, Inc., Cambridge, MA) or a comparable data-entry software except category e) data 
that will be captured by software only. For all data except a), the software entries will represent the 
primary data source. For data category a), data from laboratory parasitology sheets will be entered into 
CommCare or into a Microsoft Office program (Excel or Access) for data management. Data compiled 
using the software will be directly saved on the personal, password-protected laptop of one of the Co-
PIs and uploaded to a server hosted at Swiss TPH, Basel. In paper-based data collection, all missing data 
must be explained. All entries will be printed in black ink. All corrections must be noted with the initials 
of the respective team member and dated. Data in categories a) and b) will be merged into a masterfile 
and saved in .xlsx, .mdb and/or .csv. Data in all other categories will be saved as .mdb, .csv, .xlsx, .txt 
and/or .pdf files. Hard copies of the data such as parasitological sheets and CRFs will remain at CSRS. 
Digital copies along with single databases and compiled masterfiles will be transferred to the Swiss 
TPH, Basel. Data will then be analyzed as described in section 8. 
7.3 
Ethical, legal and security issues 
Screened participants will be listed in a confidential “subject screening log” and attributed a unique 
study ID. In case of enrolment, participants will be listed in a confidential “subject enrolment log” 
utilizing the same study IDs. The codes will be linked with the participant’s identity on a separate file 
(subject identification list), filed in a secured place at CSRS and will only be accessible to investigators. 
Personal data will be coded for data analysis. No names will be published at any time, and published 

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reports will not allow for identification of single subjects. Confidentiality will be ensured throughout 
the entire research project. All databases will be password secured. None of the investigators declare to 
have any conflicts of interest. 
7.4 
Data storage and preservation 
All samples will be destroyed after completion of the study. Paper-based and electronic source data and 
related material will be preserved for a minimum of 20 years to enable understanding of the study 
procedures, which allows the work to be assessed retrospectively and repeated if necessary. The study 
site will retain a copy of the documents to ensure that local collaborators can provide access to the source 
documents to a monitor, auditor, or regulatory agency. Electronic source documents will be stored on a 
flash drive and kept at the study site (CSRS, Abidjan, Côte d’Ivoire). The primary data storage and 
backup will be in the Swiss TPH shared server and secondary data storage will be on personal, password-
protected laptops of Jennifer Keiser, Eveline Hürlimann and Jean T. Coulibaly, and on SWITCHdrive 
(a cloud storage supported by University of Basel). Electronic data files and archiving conditions will 
be made strictly confidential by password protection. 
7.5 
Study documents: translations – reference language 
- 
The protocol master document will be in English and French, all further language versions are 
translated thereof. 
- 
The ICF master document will be in English and French, all further language versions are 
translated thereof. 
 
8. Statistics 
8.1 
Definition of primary endpoint 
T. trichiura infection status 14-21 days post-treatment assessed by Kato-Katz is the primary endpoint in 
our study. 
8.2 
Justification of number of trial subjects 
The primary analysis of this trial aims to assess whether combined moxidectin and albendazole is more 
efficacious against T. trichiura infection compared to standard of care therapy (albendazole 
monotherapy). We estimate a true CR of 10% for albendazole monotherapy and 30% for combination 
moxidectin/albendazole against T. trichiura. We estimate that enrolling 85 participants per arm will be 
sufficient to identify a statistically significant difference with 90% power using a two-sided 5% 
significance level. Additionally, 85 individuals will be included for the ivermectin/albendazole 
treatment arm to re-evaluate the findings from a previous study with a surprisingly low CR of only 13%. 
This sample size would allow us to detect the smallest clinically important difference (as defined by our 

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study panel) of 15%-points with a power of about 75%. To account for a loss to follow-up of 10%, we 
anticipate to recruit 94 per arm = 282 participants in total. 
The suggested sample size of a maximum eight PK samples from 14 willing adolescents (7 per 
concerned study arm) is sufficiently high to determine the population PK parameters and determine 
drug-drug interactions with a sparse sampling scheme. 
8.3 
Description of statistical methods 
The primary analysis will be performed according to the intention-to-treat principles using the available 
case population, which includes all participants with any primary end point data. Subsequently, a per-
protocol analysis will be performed. CRs will be calculated as the percentage of egg-positive participants 
at screening who become egg-negative after treatment. Differences among CRs will be assessed by using 
unadjusted logistic regressions. 
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
 
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. 
Previously established nonlinear mixed-effects (NLME) models will be used to compare and determine 
pharmacokinetic parameters [33]. Concentrations are measured with a validated LC-MS/MS method 
[23, 26]. Using NLME, the key population PK parameters will be calculated based on which an effect 
on the drug-drug interaction will be determined: 
 
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. Total drug 
exposure (AUC) and t1/2 will be calculated with the NLME modeling software Monolix 2018R2 (Lixoft, 
Antony, France) using compartmental analysis. The elimination half-life will be estimated by the 
equation: t1/2 = ln2/, where  (the elimination rate constant) will be determined by performing a 
regression of the natural logarithm of the concentration values during the elimination period. Primary 
PK parameters including absorption rate (ka), volume of distribution (V), and clearance (CL) will be 
estimated utilizing NLME modeling. 

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The exact design of the sparse sampling scheme will depend on the results of current PK trials of our 
group. 
For the analysis of association between blood type and infection severity, frequency distributions and 
descriptive summary statistics of the data will be presented by blood type. Crude effect estimates will 
be presented and adjusted effect estimates will be calculated using uni- and multivariate logistic 
regression. 
 
9. Duties of the investigator 
9.1 
Investigator’s confirmation 
This trial will be conducted in accordance with the protocol, International Conference on Harmonisation 
Good Clinical Practice E6 (R2) (ICH-GCP) and the current version of the Helsinki Declaration. 
All protocol modifications must be documented in writing. A protocol amendment can be initiated by 
either the 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 participants, 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) and a 
participant liability insurance has been issued in Côte d’Ivoire (L’Africaine des Assurance, Police Nr. 
2020-12-8218320). 
9.3 
Project management 
The trial team will include the PI (Prof. Jennifer Keiser), two Co-PIs (Dr. Eveline Hürlimann and Dr. 
Jean T. Coulibaly), two Co-investigators (Dr. Pierre H. H. Schneeberger and Dr. Daniela Hofmann), a 
trial statistician (Dr. Jan Hattendorf) and PhD student, as well as three local physicians whereof one is 
the local PI (Dr. Yves Koutouan N’Gbesso) and several laboratory technicians. Prof. Jennifer Keiser, 
Dr. Eveline Hürlimann, Dr. Jean T. Coulibaly, the two Co-investigators and the PhD student 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. 
Eveline Hürlimann, Dr. Jean T. Coulibaly and the PhD student are responsible for supervision of the 
lab- and field technicians, staff management, recruitment monitoring, supply of the material, contact to 

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the local authorities and participating communities. Dr. Yves Koutouan N’Gbesso will be responsible 
for patient recruitment, medical aspects of the trial and enrolment of patients into the trial. 
Infrastructure as required for the study needs will be installed as necessary before study launch. 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 and 
the ethical committees of Switzerland and Côte d’Ivoire. The study will be undertaken in accordance 
with the Declaration of Helsinki and GCP. 
10.2 
Evaluation of the risk-benefit ratio 
Albendazole, ivermectin, and moxidectin are well-known drugs and have little and mainly mild adverse 
events as described to date (headache, abdominal pain etc.). Albendazole and ivermectin are widely used 
drugs in mass treatment programs against filariasis and moxidectin is an FDA-approved drug against 
onchocerciasis. All community members enrolled in the study will benefit from a clinical examination 
and a treatment against STHs. All participating subjects remaining positive for T. trichiura will be 
treated with mebendazole 600 mg (to be taken as 6 repeated doses of 100 mg within 3 days), which is 
considered the most efficacious treatment in settings with potential ivermectin resistance. Participants 
still showing co-infection with hookworm or A. lumbricoides at follow-up assessment will be provided 
the current standard treatment of albendazole (400 mg). 
10.3 
Subject information and consent 
All parents or caregivers of eligible adolescents and all participants ≥18 years will be asked to sign a 
written informed consent form. In case the person is illiterate, an impartial witness that can read and 
write has to sign the consent and the illiterate participant has to give a thumb print. Parents or caregivers 
and adult participants will have sufficient time for reflection of their child’s or their own participation, 
respectively. Additionally, adolescent children (aged 12-17 years) will be briefed verbally, and written 
assent will be sought in form of their name written down or if illiterate by providing a thumb print. 

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Information sessions in the respective communities will be conducted to explain to caregivers and 
potential participants the purpose and procedures of the study. In addition, individual information 
sessions will take place when visiting potential participants or their parents/caregivers to obtain the 
written informed consent. Informed consent forms are translated into French and additionally orally 
explained in local language (i.e. Abiji, Adjoukrou and Dida) of the participant if necessary to ensure 
comprehension. 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. 
10.4 
Subjects requiring particular protection 
Our study will include adolescents, since T. trichiura infection occurs often in children and adolescents; 
hence this age group is at high risk of infection. Pharmacokinetic/-dynamic analyses in T. trichiura-
infected adolescents treated with ivermectin/albendazole or albendazole alone have not been conducted 
to date in this population. The same is true for superiority studies between co-administration of 
moxidectin/albendazole and albendazole monotherapy. Our trial will produce more evidence to support 
the search for a safe and effective treatment of STH infections in adolescents and the whole community. 
 
11. Quality control and quality assurance 
11.1 
Monitoring and auditing 
We will work with a locally based external 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 significant deviation. 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. 
11.2 
Data and safety monitoring board (WHO) / data monitoring committee (EU/FDA) 
In our study, we work with well-known drugs in a small sample size and using a single dose treatment. 
Nevertheless, the project advisors, Dr André Offiana Touré, parasitologist at the Institut Pasteur de Côte 
d'Ivoire and Prof Dr Piero Olliaro, infectious disease physician and professor of infectious diseases 
associated with poverty at Oxford University, United Kingdom, will serve as independent data and 
safety monitoring board, they will be informed regularly and the findings discussed. This means they 
have the responsibility to convene, evaluate the study data and give their advice regarding the 

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continuation or stopping of the study before the treatment, at the end of the study and in case of an 
important safety event. 
 
12. Funding 
Funding for this trial is provided by BMGF (Grant # OPP1153928). This funding source had no role in 
the design of this study and will not have any role during its execution, analyses, interpretation of the 
data, or decision to submit results. 
 
13. Dissemination of results and publication 
The final results of this study will be published in a scientific journal and presented at scientific 
conferences. BMGF 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 AIRP. After 
publication, study results will be made available to study participants.

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