Efficacy, Safety and Acceptability of Ascending Doses of Ivermectin in Combination With Albendazole for Trichuris Trichiura Infections in Preschool-aged Children: a Single-blind Randomised Controlled Dose-ranging Trial
Phase: PHASE2
Conditions: Trichuriasis, Ascariasis, Hookworm Infections
Sponsor: Jennifer Keiser

Efficacy, safety and acceptability of ascending doses of ivermectin 
in combination with albendazole for Trichuris trichiura infections in 
preschool-aged children: a single-blind randomised controlled dose-
ranging trial 
 
NCT Number: NCT06184399 
 
Document date: 08 May 2024 

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Efficacy, safety and acceptability of ascending doses of ivermectin in 
combination with albendazole for Trichuris trichiura infections in preschool-
aged children: a single-blind randomised controlled dose-ranging trial 
Document Version 
1 
Document Date 
08 May 2024 
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 
Swiss National Science 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), Allschwil, 
Switzerland 
Unit head 
Principal 
Investigator 
MSc 
Said Mohammed 
Ali 
Public Health 
Laboratory Ivo de 
Carneri (PHL-IdC) 
Foundation, Pemba, 
Tanzania 
CEO 
Co-PI 
BSc 
Fauz Abdi 
Public Health 
Laboratory Ivo de 
Carneri (PHL-IdC) 
Foundation, Pemba, 
Tanzania 
In-charge Lab 
services 
Lab lead 
Dr. 
Ibrahim Said 
Mohammed 
Ministry of Health, 
Pemba, Tanzania 
Project leader, 
physician 
Study physician 
MSc 
Viviane Sprecher 
Swiss TPH, 
Allschwil, 
Switzerland 
Doctoral student 
Co-PI, 
Study pharmacist 
MSc 
Annina Schnoz 
Swiss TPH, 
Allschwil, 
Switzerland 
Doctoral student 
Co-PI 
Dr. 
Jan Hattendorf 
Swiss TPH, 
Allschwil, 
Switzerland 
Project leader 
Statistician 

iverped_protocol_v1.2_20240508
II.
Signatures
Principal investigator 
Signature & 
Date 
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, Kreuzstrasse 2 
CH-4123 Allschwil, Switzerland 
Phone 
+41 61 284 82 18
Statistician 
Signature & 
Date 
Name 
Jan Hattendorf 
Title 
Dr. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Epidemiology and Public Health 
Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 
CH-4123 Allschwil, Switzerland 
Phone 
+41 61 284 81 93
I have read this protocol and agree that it contains all necessary details for carrying out this trial. I will 
conduct the trial as outlined herein and will complete the trial within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me 
who assist in the conduct of this trial. I will discuss this material with them to ensure they are fully 
informed regarding the drug and the conduct of the trial. 
I will use only the informed consent forms approved by the Sponsor or its representative and will fulfil 
all responsibilities for submitting pertinent information to the Independent Ethics Committees 
responsible for this trial. 
I agree that the Sponsor or its representatives shall have access to any source documents from which 
Case Report Form information may have been generated. 
Page 3 of 38
08-May-2024 | 11:37:25 CET
08-May-2024 | 13:40:16 CET

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Co-Principal investigator 
Signature & 
Date 
Name 
Said Mohammed Ali 
Title 
MSc 
Institution 
Public Health Laboratory Ivo de Carneri 
Address 
P.O. Box 122 Wawi, Chake Chake, 
Pemba, Tanzania 
Phone 
+255 24 245 20 03
Study physician 
Signature & 
Date 
Name 
Ibrahim Said Mohammed 
Title 
Dr. 
Institution 
Ministry of Health Pemba 
Address 
P.O. Box 122 Wawi, Chake Chake,
Pemba, Tanzania 
Phone 
+255 77 253 05 31
Co-Principal investigator, Study pharmacist
Signature & 
Date 
08-May-2024 | 14:23:03 CET
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, Kreuzstrasse 2 
CH-4123 Allschwil, Switzerland 
Phone 
+41 61 284 92 44
Co-Principal investigator 
Signature & 
Date 
08-May-2024 | 14:05:31 CET
Name 
Annina Schnoz 
Title 
MSc 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Kreuzstrasse 2 
CH-4123 Allschwil, Switzerland 
Phone 
+41 61 284 92 86

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Table of contents 
1.
General information ........................................................................................................................ 2
2.
Background information ................................................................................................................ 15
3.
Trial objective and purpose ........................................................................................................... 16
4.
Methodology ................................................................................................................................. 17
4.1
Primary and secondary endpoint ........................................................................................... 17
4.2
Trial design ............................................................................................................................ 17
4.3
Procedures ............................................................................................................................. 18
4.3.1
Diagnosis ....................................................................................................................... 18
4.3.2
FECPAKG2 ................................................................................................................... 19
4.3.3
Clinical examination ...................................................................................................... 19
4.3.4
Treatment of participants ............................................................................................... 19
4.3.5
Pharmacokinetic analysis .............................................................................................. 20
4.3.6
Assessment of acceptability .......................................................................................... 21
4.3.7
Safety assessment .......................................................................................................... 21
4.3.8
Efficacy assessment ....................................................................................................... 21
4.4
Measure to minimise bias ...................................................................................................... 22
4.5
Study duration and duration of participation ......................................................................... 22
5.
Selection of trial participants ......................................................................................................... 22
5.1
Recruitment ........................................................................................................................... 23
5.2
Inclusion criteria .................................................................................................................... 23
5.3
Exclusion criteria ................................................................................................................... 23
5.4
Criteria for discontinuation of trial ........................................................................................ 23
5.5
Concomitant medication ........................................................................................................ 24
6.
Safety assessments ........................................................................................................................ 24
6.1
Adverse event definitions ...................................................................................................... 24
6.1.1
Severity grading............................................................................................................. 25
6.1.2
Relatedness .................................................................................................................... 25
6.1.3
Expectedness ................................................................................................................. 25
6.1.4
Serious adverse events ................................................................................................... 26

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6.1.5 
Suspected unexpected serious adverse reactions ........................................................... 26 
6.2 
Methods of recording and assessing adverse events ............................................................. 26 
6.3 
Reporting of serious adverse events ...................................................................................... 27 
6.4 
Safety reporting to Health Authorities, Ethics Committees and other third parties .............. 28 
6.5 
Rescue medication strategy ................................................................................................... 28 
7. 
Data management and data quality control ................................................................................... 28 
7.1 
Source data ............................................................................................................................ 28 
7.2 
Data collection and documentation ....................................................................................... 29 
7.3 
Ethical, legal and security issues ........................................................................................... 29 
7.4 
Data storage and preservation ............................................................................................... 30 
7.5 
Study documents: translations – reference language ............................................................. 30 
8. 
Statistics......................................................................................................................................... 30 
8.1 
Definition of primary endpoint .............................................................................................. 30 
8.2 
Justification of number of trial participants ........................................................................... 30 
8.3 
Description of statistical methods ......................................................................................... 31 
9. 
Duties of the investigator............................................................................................................... 32 
9.1 
Investigator’s confirmation ................................................................................................... 32 
9.2 
Damage coverage .................................................................................................................. 32 
9.3 
Project management .............................................................................................................. 33 
10. 
Ethical considerations ................................................................................................................ 33 
10.1 
Independent Ethics Committee (IEC) ................................................................................... 33 
10.2 
Evaluation of the risk-benefit ratio ........................................................................................ 33 
10.3 
Participant information and consent ...................................................................................... 34 
10.4 
Participants requiring particular protection ........................................................................... 34 
11. 
Quality control and quality assurance ....................................................................................... 34 
11.1 
Monitoring and auditing ........................................................................................................ 34 
11.2 
Data and safety monitoring board (WHO) / data monitoring committee (EU/FDA) ............ 34 
12. 
Funding ...................................................................................................................................... 35 
13. 
Dissemination of results and publication .................................................................................. 35 
14. 
References ................................................................................................................................. 36 
15. 
Appendix ................................................................................................................................... 38 

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15.1 
Visual Analogue Scales for palatability ................................................................................ 38 

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III. 
Abbreviations 
AE 
Adverse event 
CI 
Confidence interval 
CR 
Cure rate 
CRF 
Case report form 
EKNZ 
Ethikkommission Nordwest- und Zentralschweiz 
EPG 
Eggs per gram 
ERR 
Egg reduction rate 
EU 
European Union 
FDA 
Food & Drug Administration 
GCP 
Good clinical practice 
Hb 
Haemoglobin 
ICF 
Informed consent form 
ICH 
International 
council 
for 
harmonization 
of 
technical 
requirements 
for 
pharmaceuticals for human use 
IEC 
Independent ethics committee 
MDA 
Mass drug administration 
NLME 
nonlinear mixed-effects 
PC 
Preventive chemotherapy 
PHL-IdC 
Public Health Laboratory Ivo de Carneri 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PSAC 
Preschool-aged children 
SAE 
Serious adverse event 
SNSF 
Swiss National Science Foundation 
STH 
Soil-transmitted helminths 
SUSAR 
Suspected unexpected serious adverse reaction 
Swiss TPH 
Swiss Tropical and Public Health Institute 
VAS 
Visual analogue scale 
WHO 
World Health Organization 

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IV. 
Synopsis 
 
Sponsor/Sponsor-
Investigator 
Prof. Dr. Jennifer Keiser 
Study title 
Efficacy, safety and acceptability of ascending doses of ivermectin in 
combination with albendazole for Trichuris trichiura infections in 
preschool-aged children: a single-blind randomised controlled dose-
ranging trial 
Short title 
Ivermectin-albendazole combination for Trichuris trichiura–infected 
children 
Study acronym 
Iverped 
Protocol version and date 
v1, 08 May 2024 
Trial registration 
Registered on https://www.clinicaltrials.gov/ (NCT06184399) 
Clinical phase 
Phase 2 trial 
Sample size 
210 participants 
Indication 
Trichuris trichiura infection (eggs in stool) 
Investigational and 
reference treatment 
Ivermectin orodispersible mini-tablets (ODTs) co-administered with 
albendazole 
Reference: albendazole; ivermectin standard tablets co-administered 
with albendazole 
Study rationale 
To provide evidence on the optimal dose of co-administered ivermectin 
and albendazole in terms of efficacy, safety and acceptability in 
preschool-aged children (PSAC; aged 2-5 years) infected with T. 
trichiura. Additionally, to compare the pharmacokinetics of the newly 
developed ODTs and the standard ivermectin tablets in this age group. 
 
 

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Study objectives 
Our primary objective is to determine the ivermectin dose-response 
relationship in terms of cure rate (CR) in PSAC (2-5 years) infected with 
T. trichiura, assessed at 14-21 days post-treatment by quadruplicate 
Kato-Katz microscopy. 
The secondary objectives of the trial are: 
a) to determine the T. trichiura egg reduction rates (ERRs) of 
treatments; 
b) to determine the CRs and ERRs of treatments against Ascaris 
lumbricoides and hookworm co-infection; 
c) to evaluate the safety and tolerability of the treatments; 
d) to characterize population pharmacokinetics (PK) of ivermectin 
ODTs compared to standard tablets in T. trichiura infected 
individuals; 
e) to assess the acceptability of the treatments. 
The exploratory objective of this trial is to assess the diagnostic 
performance of FECPAKG2. 
Study design 
Parallel randomised controlled dose-ranging trial 
Study product / 
intervention 
Administration of a single oral dose of ivermectin ODT (100-400 µg/kg) 
and albendazole (400 mg) 
Comparator(s) 
Albendazole (400 mg); ivermectin standard tablets (200 µg/kg) and 
albendazole (400 mg) 
Key inclusion / Exclusion 
criteria 
Inclusion: 
 
Individuals aged 2-5 years (24-71 months; confirmed by birth 
certificate or similar document); 
 
having 
given 
written 
informed 
consent 
signed 
by 
parents/caregivers; 
 
being able and willing to provide two stool samples at baseline 
and at follow-up assessment (14-21 days); 
 
having at least two out of four Kato-Katz slides positive for 
T. trichiura at baseline; 
 
being able and willing to be examined by a study physician 
before and after treatment. 
Exclusion: 

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 
presence or signs of major systemic illness, e.g. fever (temporal 
body temperature of >38.0°C), severe anaemia (haemoglobin 
level of <70 g/l); 
 
history of severe acute disease or unmanaged, severe chronic 
disease (i.e., condition is not as therapeutically controlled as 
necessary); 
 
use of anthelminthic drugs during study period; 
 
known allergy to study medication (i.e., ivermectin or 
albendazole); 
 
being prescribed or taking concomitantly medication with 
known contraindications or drug interactions with the study 
medication; 
 
concurrent participation in other clinical trials. 
Primary endpoints 
 
T. trichiura infection status of participants at 14-21 days post-
treatment assessed by quadruplicate Kato-Katz 
Secondary endpoints 
 
T. trichiura infection intensity of participants at 14-21 days post-
treatment assessed by quadruplicate Kato-Katz 
 
A. lumbricoides and hookworm infection status and intensity of 
co-infected participants at 14-21 days post-treatment assessed 
by quadruplicate Kato-Katz 
 
Adverse events (AEs) 
 
Population PK parameters of ivermectin ODTs and standard 
tablets in T. trichiura infected PSAC 
 
Acceptability (including palatability) 
Exploratory endpoints 
 
Diagnostic characteristics of FECPAKG2 (infection intensity, 
sensitivity, and specificity) compared to Kato-Katz 
Interim analyses 
None 
Study duration 
3 months 
Schedule 
05/2024: of first participant in (planned) 
07/2024: of last participant out (planned) 
Study centres 
T. trichiura endemic villages, Wete district, Pemba Island, Tanzania 

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Measurements & 
procedures 
For the initial diagnosis and efficacy assessment at 14-21 days post-
treatment, two stool samples will be collected from each participant on 
two consecutive days. All stool samples will be examined for presence 
of T. trichiura, A. lumbricoides, and hookworm eggs with duplicate 
Kato-Katz thick smears assessed via bright-field microscopy. The 
medical history of the participants will be assessed with a standardised 
questionnaire, in addition to a clinical examination carried out by the 
study physician before treatment. Parents/caregivers will be interviewed 
before treatment and at three and 24 hours and 14-21 days post-treatment 
for the occurrence of AEs. Any potential AEs happening between 3 
hours and the respective follow-up time points will be monitored by 
local healthcare workers and medical intervention provided if necessary. 
Each participant will be asked to provide a finger-prick blood sample for 
haemoglobin 
measurement 
at 
baseline. 
At 
the 
same 
time, 
anthropometric measurements (i.e. height, and weight) will be taken for 
all participants. 
To determine PK parameters of ivermectin ODTs and standard tablets, 
a subsample of 12 study participants per relevant treatment arm 
(ivermectin ODT 200 µg/kg and ivermectin tablet 200 µg/kg) will be 
asked to provide a maximum of 5 micro blood samples per participant 
using finger pricks at defined time points between 1 hour and 24 hours. 
To determine the acceptability of ivermectin ODTs compared to 
standard tablets, the palatability of each formulation will be rated by 
children aged 4-5 years using a 100 mm visual analogue scale (VAS). 
Additionally, participants will complete a short questionnaire right after 
treatment administration. 
Statistical analyses 
An available case analysis (full analysis set according to the intention to 
treat principles) will be performed, including all participants with 
primary endpoint data. Additionally, 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. 
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 calculate 95% confidence intervals (CIs) for ERRs. 

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Using the DoseFinding package of the statistical software environment 
R, Emax models will be implemented to predict the dose-response curves 
based on CRs and ERRs. 
AEs will be compiled into frequency tables and compared between 
treatment groups using descriptive summary statistics. 
With regard to population PK parameters, Cmax and tmax will be 
observed values, AUC and t1/2 will be calculated using nonlinear mixed-
effects (NLME) modelling with the WinNonlin software package. In 
addition, exploratory pharmacometric PK and exposure-response 
analyses may be performed with the Monolix or NONMEM software 
package. 
The VAS score for the palatability will be summarised using descriptive 
statistics according to formulation. 
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 children aged 2-5 years, since an infection with 
T. trichiura occurs often in children. The main goal of the study is to 
evaluate for the first time the efficacy and safety of a newly developed 
child-friendly formulation of ivermectin in this age group. This will 
allow that preschool aged children can also be included in deworming 
campaigns with ivermectin-albendazole combination.  
Recruitment procedure 
The trial will be conducted on Pemba Island, Tanzania. It will take place 
in areas with moderate to high T. trichiura endemicity (communities 
with a prevalence of ≥20%) identified from earlier studies and/or based 
on experience of the local collaborating team. 
Coverage of damages 
Winterthur Insurance, Policy No. 4746321; 
Pemba: National Insurance Cooperation of Tanzania LTD, Policy No. 
IMIS/GL/P/25/1/2024/771418 
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 
15 years. 

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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 
Trichuriasis is a parasitic disease caused by nematodes belonging to the group of soil-transmitted 
helminths (STH). It is estimated that around 400 million people harbour infections with Trichuris 
trichiura globally [1]. As it is the case for all STH infections, trichuriasis is mainly endemic in 
developing countries in tropical and subtropical regions, with highest burden among rural communities 
due to its link to poor sanitation [2]. 
Infection with T. trichiura occurs when ingesting embryonated eggs via soil-contaminated hands, 
drinking water or food. Having reached the small intestine, the eggs hatch realising the larvae. The 
larvae migrate directly into the cecum where they develop into adult worms and begin to oviposit. Eggs 
are excreted into the soil via the faeces, thereby closing the life cycle [3]. 
Acute symptoms of trichuriasis are generally mild or not apparent in infected individuals living in 
endemic areas [2, 4]. The main disease burden results from chronic infection and repeated re-infection, 
in which symptoms related to the location of adult worms such as abdominal pain may develop. Long-
term infection compromises the life of people by hampering their physical and mental development, 
limiting their work performance and overall quality of life [4]. 
The recent World Health Organization (WHO) road map for neglected tropical diseases targets STH 
infections for near to global elimination as a public health problem by 2030 [5]. One important 
intervention to achieve this is preventive chemotherapy (PC) [5-7]. The aim of PC is to reduce worm 
burden and hence morbidity in endemic populations by regular large-scale administration of 
anthelminthic drugs to high-risk groups, e.g. preschool-aged and school-aged children [8, 9]. The 
frequency of such mass drug administration (MDA) depends on the local infection prevalence [8, 9]. 
At present, the benzimidazoles albendazole and mebendazole are the most widely used drugs for PC 
campaigns against STH infections [7, 10]. These drugs are characterized by high cure rates (CRs) against 
infections with Ascaris lumbricoides (>95%) and moderate CRs against hookworm infections (80%). 
However, at single oral doses suitable for MDA, these drugs have demonstrated unsatisfactory efficacy 
against T. trichiura infections [11, 12]. 
Therapies combining two or more drugs are widely advocated in different therapeutic areas. The 
advantages of multifactorial pharmacological treatment include the increase and broadening of efficacy 
over drugs being administered in monotherapy and the protection against the selection of drug 
resistance, and hence, a prolongation of the life-span of effective and available drugs [13-15]. In 2017, 
ivermectin in combination with albendazole for treatment of STH was added to the Essential Medicines 
List (EML), paving the way to further evaluate the efficacy of this combination treatment among 
children and communities in a range of epidemiological settings [16]. While evidence on the superiority 
of ivermectin-albendazole combination compared to single standard treatments against STH infections, 
including trichuriasis, in school-aged children, adolescents and adults is growing, efficacy of this 
combination has not yet been assessed in the high-risk population of preschool-aged children (PSAC) 

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[17, 18]. An important reason for this knowledge gap is that oral ivermectin is not licensed for treatment 
of individuals with a bodyweight of <15 kg (corresponding to children aged less than ~5 years). 
Nevertheless, within the past two decades the safety data on individuals weighing <15 kg increased 
substantially and there are many efforts to develop oral ivermectin for small children suffering from 
scabies [19]. 
Another major drawback in the applicability of oral ivermectin in PSAC is the lack of a formulation 
suitable for administration to small children who may not be able to swallow the standard ivermectin 
tablets. Tablets offered to young children in a crushed or suspended form are prone to imprecise dosing 
and come with reduced palatability, and thereby a higher chance to be expelled out of the mouth by the 
child. Currently, several new orodispersible tablet (ODT) formulations, which are suitable for the hot 
and humid tropical conditions found in most countries in need, are being developed. 
There is a need to explore whether these new ivermectin ODT formulations could reveal a benefit in the 
treatment of STH infections in PSAC. Based on the data of a study investigating the optimal ivermectin 
dose in PSAC infected with T. trichiura in Côte d’Ivoire, it was suggested to administer higher doses 
than the standard dose in adults (200 µg/kg) to reach equivalent bioavailability [20, 21]. In this trial, we 
aim to determine the optimal dose of ivermectin, as a newly developed orodispersible tablet formulation, 
in combination with albendazole in terms of efficacy and safety in treating T. trichiura infections in 
PSAC on Pemba Island, Tanzania. Furthermore, we re-assess pharmacokinetic (PK) parameters of 
ivermectin ODTs compared to standard ivermectin tablets. The PK 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 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 [22, 23]. Age, sex, 
bodyweight but also the presence of certain enzymes in different populations are important contributors 
to the PK profile of a drug. Our study will be the first one to provide PK information on a new ivermectin 
ODT in PSAC with trichuriasis and thus guide optimal drug dosing in this high-risk population. Finally, 
acceptability (including palatability) of a drug is important to ensure compliance and effectiveness of 
treatment. Therefore, this study includes the assessment of drug acceptability applying visual analogue 
scales (VAS). 
 
3. Trial objective and purpose 
We designed a dose-ranging trial to identify the most appropriate dose of ivermectin in terms of efficacy 
and safety in treating trichuriasis in individuals aged 2-5 years on Pemba Island, Tanzania. This study 
will provide further insights on the pharmacokinetics and acceptability of a novel orodispersible 
formulation as compared to the standard tablets. Our data will pave the way for possible phase 3 follow-
up studies and support the development of ivermectin for children aged <6 years and its implementation 
in control programs. 

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The primary objective is to determine the ivermectin dose-response relationship in terms of CR in T. 
trichiura-infected children aged 2-5 years, assessed at 14-21 days post-treatment by quadruplicate Kato-
Katz microscopy. 
The secondary objectives of the trial are: 
a) to determine the T. trichiura egg reduction rates (ERRs) of treatments; 
b) to determine the CRs and ERRs of treatments against Ascaris lumbricoides and hookworm co-
infection; 
c) to evaluate the safety and tolerability of the treatments. 
d) to characterize population PK of ivermectin ODTs compared to standard tablets in T. trichiura 
infected individuals; 
e) to assess the acceptability of the treatments. 
The exploratory objective of this trial is to assess the diagnostic performance of FECPAKG2. 
 
4. Methodology 
4.1 
Primary and secondary endpoint 
Primary endpoint: T. trichiura infection status of participants at 14-21 days post-treatment assessed 
by quadruplicate Kato-Katz. 
Secondary endpoints: 
 
T. trichiura infection intensity of participants at 14-21 days post-treatment assessed by 
quadruplicate Kato-Katz; 
 
A. lumbricoides and hookworm infection status and intensity of co-infected participants at 14-21 
days post-treatment assessed by quadruplicate Kato-Katz; 
 
Tolerability of treatments (adverse events (AEs) at three and 24 hours and 14-21 days post-
treatment; 
 
Population PK parameters of ivermectin ODTs and standard tablets in T. trichiura infected PSAC; 
 
Acceptability (including palatability). 
Exploratory endpoints: Diagnostic characteristics of FECPAKG2 (infection intensity, sensitivity, and 
specificity) compared to Kato-Katz. 
4.2 
Trial design 
A parallel randomised controlled dose-ranging trial will be conducted with six treatment arms (Figure 
1). The study includes a baseline screening (day -60 to -1) and clinical baseline assessment (day 0) 
before treatment and post-treatment assessments for, pharmacokinetics (day 0 to 1), safety (day 0, 1 and 
14 to 21) and efficacy (day 14 to 21). It is designed as a dose-ranging trial with 210 participants aged 2-
5 years randomised to ivermectin ODT placebo and albendazole (400 mg), ascending doses of 
ivermectin ODT (100 µg/kg, 200 µg/kg, 300 µg/kg, or 400 µg/kg, respectively) and albendazole (400 

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mg), or the standard ivermectin tablets (200 µg/kg) and albendazole (400 mg), with an allocation ratio 
of 1:1:1:1:1:1 (i.e., 35:35:35:35:35:35). This trial will be conducted in communities in the Wete district 
on Pemba Island with high endemicity as identified in previous studies on T. trichiura. 
 
 
Figure 1. Trial design and timeline. 
4.3 
Procedures 
4.3.1 
Diagnosis 
At baseline, all participants will be asked to provide two stool samples. From each stool specimen, 
duplicate Kato-Katz thick smears (41.7 mg each) [24] will be prepared and read under a microscope for 
eggs of T. trichiura, A. lumbricoides and hookworm by experienced technicians. Eggs per gram (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. For quality control of T. trichiura and A. lumbricoides 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 T. trichiura 
and A. lumbricoides (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 analysed 
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 (see section 4.3.8). 

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4.3.2 
FECPAKG2 
Research on new diagnostic tools is necessary, since the currently recommended Kato-Katz technique 
has a low sensitivity for low STH infections and slides with hookworm eggs cannot be re-examined [25-
27]. Once moving towards transmission control and STH elimination, an increased sensitivity of the 
diagnostic method of choice is crucial [28]. Preferably, a diagnostic method that could potentially 
replace Kato-Katz would be sensitive, specific, fast, simple, cost-effective and re-analysis could be 
conducted at any time. 
The aim of this exploratory objective within this this trial is the comparison of infection intensity, 
sensitivity, and specificity of the Kato-Katz technique with the novel diagnostic tool FECPAKG2 
(Techion). FECPAKG2 is an online, remote location, parasite diagnostic system used in veterinary 
medicine [29]. An image of the Kato-Katz slide is captured, stored offline on a computer, and can be 
uploaded onto a cloud once connected to the internet. Subsequently, specialists around the world can 
analyse the image at any time. Techion’s image capture devices are robust, reliable, versatile and cost 
effective [30]. Baseline quadruplicate Kato-Katz thick smears will be used to take images by 
FECPAKG2 after the slides have been read by technicians under the microscope. 
4.3.3 
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 blood sample to measure haemoglobin (Hb) levels, which will 
be detected using a HemoCue analyzer (Hb 301 system, Angelholm, Sweden). In case of abnormal 
values, results from baseline clinical examination may be reported back to parents/caregivers during the 
trial period. Parents/caregivers of trial participants will be asked about existing clinical symptoms before 
drug administration using a standardised questionnaire. 
4.3.4 
Treatment of participants 
All eligible participants will be treated with the respective treatment regimen according to their treatment 
arm assigned by randomisation at day 0. Ivermectin tablets (ODT and standard tablets) will be obtained 
from Liconsa, and an individual number of tablets according to bodyweight and dose will be 
administered. Albendazole will be the product of GSK (Zentel®) and a single tablet of 400 mg will be 
administered. Placebo tablets will be purchased from Zentiva Pharma GmbH, Germany. 
The tablets will be handed out from four drug containers (placebo, ivermectin ODT, ivermectin standard 
tablets, and albendazole). According to the randomisation list, each person will receive either: 
 
(i) 
Placebo (number corresponding to 200 µg per kg bodyweight) plus a single tablet of albendazole 
(ii) 
100 µg ivermectin ODT per kg bodyweight plus a single tablet of albendazole 
(iii) 
200 µg ivermectin ODT per kg bodyweight plus a single tablet of albendazole 

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(iv) 
300 µg ivermectin ODT per kg bodyweight plus a single tablet of albendazole 
(v) 
400 µg ivermectin ODT per kg bodyweight plus a single tablet of albendazole 
(vi) 
200 µg ivermectin standard tablets per kg bodyweight plus a single tablet of albendazole 
 
All drugs will be administered in the presence of the Principal Investigator (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 5.5. After ingestion of the medication, the participants will be observed 
for three hours to ensure retention of the drug. Vomiting within one hour post-dosing will require re-
dosing. The participants will not be allowed more than one repeated dose. No re-administration will be 
needed for participants 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. 
 
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 infections will be substituted with a free single-dose treatment (albendazole 400 mg) against STH 
infection after the follow-up assessment, offered by the study team to all community members not 
participating in the trial in communities screened. 
4.3.5 
Pharmacokinetic analysis 
The PK and exposure-response correlation study will be performed in 24 participants in the two 
treatment arms receiving either ivermectin ODT 200 µg/kg or ivermectin standard tablets 200 µg/kg (12 
per selected treatment arm). Since PK population parameters of ivermectin are available, a sparse 
sampling approach can be applied to describe the PK profile [31]. 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 5 finger pricks per 
participant. The exact time points are 1h, 2h, 4h, 6h, and 24h, covering the relevant time span identified 
previously [31, 32]. Capillary blood (~60 µl) will be collected by puncture with a finger prick. Two 
micro-samples (duplicates) will be taken with one finger prick. Each time, the drop of blood (60 µl) will 
be directly transferred on dried-blood spot cards. The dried cards will be transported to Swiss TPH and 
stored at room temperature until analysis (< 2 months post-treatment). The quantification of the study 

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drugs will be performed using the validated liquid chromatography tandem mass spectrometry (LC-
MS/MS) method as described elsewhere [32]. 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 analysed for quality control, and the measured concentrations will be used to determine between-
run and overall precision and accuracy of the analysis. 
4.3.6 
Assessment of acceptability 
To better understand the acceptability of ivermectin ODT compared to standard ivermectin tablets in 
PSAC, the palatability of each formulation (ODT and standard tablets crushed and swallowed with 
water) will be rated by children aged 4-5 years using a 100 mm VAS incorporating a 5-point pictorial 
hedonic scale (Figure 2) [33]. This rating will take place within 5 minutes after receiving the treatment. 
Additionally, participants will complete a short questionnaire directly after treatment administration and 
the interviewers will observe the participants during medication administration and record any 
discomfort or difficulties in taking the medication. 
 
Figure 2. 100 mm hedonic visual analogue scale [33]. 
4.3.7 
Safety assessment 
Participants will be monitored at the site (i.e. health centre) for three hours after treatment administration 
to observe any possible acute AEs (continuous observation) and reassessment will be done at 24 hours 
post-treatment (follow-up visit). Additionally, interviews will be conducted with parents/caregivers to 
determine the emergence of clinical symptoms such as headache, abdominal pain, itching, nausea, 
vomiting and diarrhoea directly before treatment within the scope of baseline assessment. At three and 
24 hours and 14-21 days after treatment parents/caregivers will again be interviewed for the assessment 
of AEs. Symptoms arising within three hours after treatment and the follow-up time points will be 
monitored by parents/caregivers or local healthcare 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. 
4.3.8 
Efficacy assessment 
The efficacy of the treatment will be determined at 14-21 days post-treatment by collecting another two 
stool samples, which will be microscopically examined for T. trichiura, A. lumbricoides and hookworm 
eggs using quadruplicate Kato-Katz thick smears (two slides per sample). Quality control will be 
performed as described for the initial diagnosis (see section 4.3.1). All microscopically analysed 
quadruplicate Kato-Katz thick smears will be destroyed after passing the quality control. 

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Participants will be considered cured for an infection if no corresponding eggs are found in the follow-
up stool samples. At the end of the study, all participants remaining positive for T. trichiura or any co-
infection will be treated with the currently best recommended treatment. 
4.4 
Measure to minimise bias 
Study participants eligible for treatment will be randomly assigned to one of the six treatment arms using 
a computer-generated stratified randomisation code. The random allocation sequence with a block size 
of 6 stratified by two levels of age category (24-47 months and 48-71 months) and two levels of baseline 
T. trichiura infection intensity (light: 1-999 EPG, and moderate or heavy: ≥1000 EPG) will be provided 
by a statistician. Allocation concealment will be warranted using opaque, sealed envelopes containing 
the randomisation lists. All treatment arms will be single-blinded (i.e. study participants will be blinded) 
using appearance and texture matching placebos. Only the study pharmacist administering the treatment 
will be aware of treatment allocation; all trial team members assessing the outcomes will remain 
uninformed. In the case of accidental unblinding or necessary code breaks, the sponsor will be 
immediately notified (within 24 hours) and data will be analysed as set forth in section 8.3. 
4.5 
Study duration and duration of participation 
The trial will last three months. Baseline screening is scheduled to start two months prior to treatment 
and follow-up stool sample collection will take place at 14-21 days after treatment, lasting 
approximately two weeks. Thus, the maximum time for participation will be three months. Schedules 
of visits are summarised in Table 1. 
 
Table 1. Schedule of study visits. 
 
Screening 
Baseline/Treatment/Safety 
Follow up 
Day -60 to -1 
Day 0 
Day 14 to 21 
 
 
0h 
Randomisation and treatment 
1h 
2h 
3h 
4h 
6h 
24h 
Informed consent 
X 
 
 
 
 
 
 
 
 
Diagnosis (stool examination) 
X 
 
 
 
 
 
 
 
X 
Medical history 
 
X 
 
 
 
 
 
 
 
Clinical examination 
 
X 
 
 
 
 
 
 
 
Haemoglobin measurement 
 
X 
 
 
 
 
 
 
 
PK (microsampling) 
 
 
X 
X 
 
X 
X 
X 
 
Capturing AEs and SAEs 
 
 
 
 
X 
 
 
X 
X 
 
5. Selection of trial participants 

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5.1 
Recruitment 
The trial will be carried out in children aged 2-5 years in the Wete district, Pemba Island, Tanzania. The 
trial will be implemented as community-based study in communities with endemicity of T. trichiura 
infection above 20% identified during previous trials. Parents/caregivers of potential 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 participate in the study will be invited to complete the 
informed consenting process by signing the informed consent form (ICF). Participants having a signed 
ICF will be assessed for eligibility during screening procedures. 
5.2 
Inclusion criteria 
1. 
Aged between 2 and 5 years (24-71 months; confirmed by birth certificate or similar document). 
2. 
Written informed consent signed by parents/caregivers. 
3. 
Agree to comply with study procedures, including provision of two stool samples at the beginning 
(baseline) and at follow-up assessment 14-21 days after treatment. 
4. 
At least two slides of the quadruplicate Kato-Katz thick smears positive for T. trichiura. 
5. 
Willing to be examined by a study physician prior to treatment. 
5.3 
Exclusion criteria 
1. 
Presence or signs of major systemic illness, e.g. fever (temporal body temperature ≥ 38°C) or severe 
anaemia (Hb level <70 g/l according to WHO [34]) upon initial clinical assessment. 
2. 
History of severe acute disease or unmanaged, severe chronic disease (i.e., condition is not as 
therapeutically controlled as necessary). 
3. 
Use of anthelminthic drugs during study period. 
4. 
Known allergy to study medication (i.e. ivermectin, albendazole). 
5. 
Being prescribed or taking concomitantly medication with known contraindication or drug 
interactions with the study medication. 
6. 
Concurrent participation in other clinical trials. 
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 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 participant is discontinued from the 
study before the end of treatment evaluations, the AE assessment will still be conducted. Data obtained 

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prior to the withdrawal will be included in the analysis to ensure the validity of the trial. Data of 
withdrawn participants are fully anonymised once analysis is complete. 
5.5 
Concomitant medication 
All medications taken between one month before treatment and the follow-up assessment at 14-21 days 
post-treatment 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 participants in case of fever, antiemetics to 
prevent nausea and vomiting and/or antibiotics to prevent or treat bacterial superinfection. 
Medication(s)/treatment(s) NOT permitted during the trial: 
- No other active drugs against helminths are permitted during the trial. 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” (AE) is defined as follows: 
Any untoward medical occurrence in a patient or clinical investigation participant 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 unfavourable and unintended signs, symptoms or disease temporally associated with the use of 
a medicinal product, whether or not considered related to the condition under study and the study 
product. 
b. Any abnormality detected during physical examination. 
The medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial will not be defined as AEs, 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 AE. 
The observation time for AEs 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 

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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 participant is aware of the event or symptom, but the event or symptom is 
easily tolerated. 
2 
Moderate: the participant experiences sufficient discomfort to interfere with or 
reduce his or her usual level of activity. 
3 
Severe: significant impairment of functioning: the participant is unable to carry out 
his or her usual activities. 
4 
Life-threatening or disabling 
5 
Death related to AEs 
 
6.1.2 
Relatedness 
Relatedness will be assessed as defined below based on the temporal relationship between the AE and 
the treatment, known side effects of treatment, medical history, concomitant medication, course of the 
underlying disease and trial procedures. 
Possibly related: an AE, which can medically (pharmacologically/clinically) be attributed to the study 
treatment. 
Unrelated: an AE, which is not reasonably related to the study treatment. A reasonable alternative 
explanation must be available. 
An AE that is determined to be related to the administration of a study product is referred to as an 
“adverse drug reaction”. 
6.1.3 
Expectedness 
Expected adverse drug reaction: Any AE possibly related to the administration of ivermectin, 
albendazole or ivermectin-albendazole combination reported in the literature or on the drug package 
leaflets, if available, and listed in the consent form. 
Unexpected adverse drug reaction: Any AE possibly related to the study drug administration, the nature, 
frequency, specificity or severity of which is unanticipated and not consistent with the available risk 
information described for these drugs. 

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6.1.4 
Serious adverse events 
According to the ICH “Clinical Safety Data Management: Definitions and standards for expedited 
Reporting E2A” [35], a serious adverse event (SAE) 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 participant 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; 
5. creates a congenital anomaly or birth defect (not relevant for this study); 
6. is an important medical event, based upon appropriate medical judgement, that may 
jeopardize the participant or may require medical or surgical intervention to prevent one 
of the other outcomes defining serious. 
 
A “severe” AE does not necessarily meet the criteria for a “serious” AE. SAEs are reported from 
treatment until the end of the study. 
SAEs 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 SAE. 
6.2 
Methods of recording and assessing adverse events 
Few AEs have been reported following ivermectin, albendazole, or ivermectin-albendazole co-
administration in STH infected individuals. The most common AEs were abdominal cramps, headache, 
fatigue, nausea, diarrhoea, fever, and vertigo. Such symptoms can, however, also result from the 
infection itself. Such side effects may be more frequent and/or serious in patients with a heavy worm 
burden. 
The observation time for AEs starts when the treatment is initiated. Participants will be observed for at 
least three hours following treatment for any acute AE and reassessment will be done at 24 hours and 
14-21 days 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 

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at three and 24 hours as well as at 14-21 days after treatment about the occurrence of AEs. Any potential 
AEs happening between three hours post-treatment and the further follow-up time points (24 hours and 
14-21 days) will be monitored 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 appropriate AE module of the CRF. 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 Medicines 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. 
6.3 
Reporting of serious adverse events 
Any study-related unanticipated problem posing risk of harm to participants or others (including all 
unexpected adverse drug reactions), and any type of SAE will be immediately (within a maximum of 
24 hours after becoming aware of the event) notified to the study sponsor-investigator and Co-PIs: 
Prof. Dr. Jennifer Keiser (Sponsor-Investigator/PI) 
Swiss Tropical and Public Health Institute 
Kreuzstrasse 2, 4123 Allschwil, Switzerland 
Tel.: +41 61 284 82 18 
Fax: +41 61 284 81 05 
E-mail: jennifer.keiser@swisstph.ch 
 
Mr. Said Mohammed Ali (Co-PI) 
Public Health Laboratory Ivo de Carneri 
P.O. Box 122 Wawi, Chake Chake, Pemba, Tanzania 
Tel.: +255 24 245 20 03 
E-mail: saidmali2003@yahoo.com 
Within the following 48 hours, the local co-investigator must provide further information on the SAE 
or the unanticipated problem in the form of a written narrative to the study sponsor-investigator. This 
should include a copy of a completed SAE form, and any other diagnostic information that will assist 
the understanding of the event. In exceptional circumstances, a SAE may be reported by telephone. In 
these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, addresses and 
telephone for SAE reporting will be included in the trial-specific SAE form. Relevant pages from the 
CRF may be provided in parallel (e.g., medical history, concomitant medications). 

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6.4 
Safety reporting to Health Authorities, Ethics Committees and other third parties 
The sponsor-investigator will send appropriate safety notifications to Health Authorities in accordance 
with applicable laws and regulations. Additionally, this information will be provided to the responsible 
ethics committees in Switzerland and Zanzibar 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 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-investigator. SAEs involving 
ivermectin ODTs will be reported to the manufacturer. 
6.5 
Rescue medication strategy 
In case an adverse event requires medical intervention, this will be performed by the study physician 
and in accordance with local medical guidelines. Given the most common adverse events (headache, 
abdominal pain, itching, nausea, vomiting and diarrhoea), analgesics and antipyretics (e.g. paracetamol) 
are allowed to be given to participants in case of pain or fever, antiemetics (e.g. dimenhydrinate) to 
prevent nausea and vomiting and/or antibiotics to prevent or treat bacterial superinfection. In addition, 
electrolyte replacement solution in case of severe vomiting and diarrhoea, immunosuppressants (e.g. 
dexamethasone) in case of allergies or immune system over-reaction (e.g. due to a high amount of worms 
being expulsed) or an adsorptive antidote (e.g. activated charcoal) may be administered. 
At the end of the study, all participants remaining positive for T. trichiura or any co-infection will be 
treated with the currently best recommended treatment. 
 
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 PHL-IdC. 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. 
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 hardcopy 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 participant 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: Holds name, age and sex of each potential participant. 

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3. Laboratory parasitology sheets: Record of the T. trichiura, A. lumbricoides and hookworm egg 
counts at all sample collection time points. 
4. PK: Time records of PK sample collection. 
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, A. lumbricoides and hookworm derived from quadruplicate Kato-
Katz microscopy performed at baseline 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, overall health status and any abnormal 
medical condition or chronic disease. 
c) Finger prick blood samples for haemoglobin measurement and PK analysis. 
d) Collection date and time of each PK sample. 
e) Measured concentrations analysed from finger prick blood samples and subsequently derived 
PK parameters. 
All data categories will be recorded paper-based (primary data source), e.g. on the CRF, and double-
entered into the electronic data collection software REDCap (Vanderbilt University, US) using tablets. 
In this case, the paper-based data will represent the primary data source. All entries will be printed in 
blue ink and all corrections must be documented with date and initials of the respective team member. 
Double-entered data will be compared using the REDCap internal ‘Data Comparison Tool’ and any 
discrepancies will be reviewed against the hardcopies of the CRF and corrected accordingly. All data 
files in REDCap will be merged into a master file and saved as .xlsx and/or .csv file. Data analysis will 
be conducted with pseudonymised data and reporting of findings will be fully anonymised. 
7.3 
Ethical, legal and security issues 
Information about study participants will be kept confidential and managed accordingly. Screened 
participants will be listed in a confidential “participant screening log” and attributed a unique participant 
ID (PID). In case of enrolment, participants will be listed in a confidential “participant enrolment log” 
utilizing the same PID. The PID will be linked with the participant’s identity on a separate file 
(participant identification list), filed in a secured place at PHL-IdC. This document will constitute the 
only source to decode the pseudonymised data and will only be accessible to investigators. Personal data 
will be coded for data analysis. No names will be published at any time, and published reports will not 
allow for identification of single participants. 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. 

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7.4 
Data storage and preservation 
All samples containing biological material will be destroyed after completion of the study. Paper-based 
and electronic source data and related material will be preserved for a minimum of 15 years to enable 
understanding of the study procedures, which allows the work to be assessed retrospectively and 
repeated if necessary. The study site (PHL-IdC) will retain the original hardcopy source documents such 
as CRFs to ensure that local collaborators can provide access to these documents to a monitor, auditor, 
or regulatory agency. Essential infrastructure such as a locked room for safe storage of hardcopy data 
will be made available. Electronic copies of source documents will be transferred to Swiss TPH, 
Allschwil, Switzerland, for storage on secured network drives with restricted access for study personnel 
only. The primary storage of electronic data will be within REDCap on the Swiss TPH shared server 
and strictly confidential by password protection. The entire REDCap project (including all data) will be 
backed up regularly, e.g. weekly. Secondary data storage will be on personal, password-protected 
laptops of the PI and Co-PIs, and on a flash drive kept by Co-PIs at the study site. 
7.5 
Study documents: translations – reference language 
- 
The protocol master document will be in English, all further language versions (e.g. Kiswahili) 
are translated thereof. 
- 
The ICF master document will be in English, all further language versions (e.g. Kiswahili) are 
translated thereof. 
- 
The CRF master document will be in English, all further language versions (e.g. Kiswahili) 
are translated thereof. 
 
8. Statistics 
8.1 
Definition of primary endpoint 
T. trichiura infection status 14-21 days post-treatment assessed by quadruplicate Kato-Katz is the 
primary endpoint in our study. 
8.2 
Justification of number of trial participants 
The main aim of this study is to elucidate the nature of the dose-response relationship. A series of 
simulations was carried out to determine the required sample size. We assumed different sets of true 
CRs ranging from very optimistic (10%, 45%, 54%, 58% and 60%) to very pessimistic (15%, 30%, 
33%, 34% and 35%) for 0, 100, 200, 300 and 400 µg/kg, respectively. Assuming a loss to follow-up of 
10%, we estimated that enrolling 35 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 %-points in the relevant dose range from 100 µg/kg to 400 µg/kg. Additionally, 35 individuals will 
be included for the standard tablet arm. In total, we anticipate to recruit 210 participants. 

iverped_protocol_v1.2_20240508 
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The suggested sample size of a maximum 5 PK samples from 24 participants (12 per concerned study 
arm) is sufficiently high to determine the population PK parameters with a sparse sampling scheme. 
8.3 
Description of statistical methods 
The primary analysis will use the full analysis set (available case population) according to the intention-
to-treat principles defined as all randomised participants who provide any follow-up data. Only 
randomised participants not providing follow-up data as well as participants who were negative at 
baseline and erroneously randomised will be excluded from the analysis. In addition, a per-protocol 
analysis will be conducted. Eligibility for analysis sets will be determined before unblinding. 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. Geometric and arithmetic mean egg counts will be calculated 
for the different treatment arms before and after treatment to assess the corresponding ERRs (see 
formula). 
𝐸𝑅𝑅=  1 − 
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝 + 1) −1
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 1)      −1
 
Bootstrap resampling method with 5,000 replicates will be used to calculate 95% confidence intervals 
(CIs) for ERR point estimates. Using the DoseFinding package of the statistical software environment 
R, hyperbolic Emax models will be implemented to predict the curves of the dose-response in terms of 
CRs and ERRs. 
Previous similar trials have shown that the proportion of participants lost to follow-up is usually far 
below 10%, therefore, no imputation of missing data will be performed. Infection status and egg counts 
of participants with incomplete data at follow-up (i.e. only one stool sample available at follow-up) will 
be estimated based on the available data. This means a participant is considered infected if any sample 
is positive and EPGs will be calculated as mean egg count of the available sample multiplied by 12. 
The safety analysis set will include all treated participants. AEs will be evaluated descriptively focusing 
on the proportion of participants reporting symptoms before and after treatment in each arm. 
Previously established nonlinear mixed-effects (NLME) models will be used to compare and determine 
PK parameters [21]. Concentrations are measured with a validated LC-MS/MS method [32]. Using 
NLME, the following key PK parameters will be calculated: 
 
Cmax 
maximal plasma concentration 
 
tmax 
time to reach Cmax 

iverped_protocol_v1.2_20240508 
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 
AUC area under the curve, from 0 to 24 h 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 WinNonlin software package 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 modelling. In 
addition, exploratory pharmacometric PK and exposure-response analyses may be performed with the 
Monolix or NONMEM software package. 
 
The VAS score for the palatability will be summarised using descriptive statistics according to 
formulation (ivermectin ODT, and ivermectin standard tablets crushed and swallowed with water). Each 
of the arms receiving the new formulation (arm A, B, C, D and E) will be tested against the current 
formulation (Arm F). 
 
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.[36, 37] 
All protocol modifications must be documented in writing. A protocol amendment can be initiated by 
either the Sponsor-Investigator/PI or any Co-PI. The Investigator will provide the reasons for the 
proposed amendment in writing and will discuss with the Sponsor-Investigator/PI and Co-PIs. Any 
protocol amendment must be approved and signed by the Sponsor-Investigator/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 Insurance, Policy No. 4746321) 
and a participant liability insurance has been issued in Pemba, Tanzania (National Insurance 
Cooperation of Tanzania LTD, Policy No. IMIS/GL/P/25/1/2024/771418). 

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9.3 
Project management 
The trial team will include the PI (Prof. Jennifer Keiser), three Co-PIs (Said Mohammed Ali, Viviane 
Sprecher, Annina Schnoz), a study physician (Dr. Ibrahim Said Mohammed), a study pharmacist 
(Viviane Sprecher), and a statistician (Dr. Jan Hattendorf), as well as a local medical team and several 
laboratory technicians. The PI and Co-PIs 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. The Co-PIs are responsible for supervision of the 
lab and field technicians, staff management, participant recruitment and enrolment monitoring, supply 
of the material, contact to the local authorities and participating communities. 
The study site (PHL-IdC) has more than 20 years of research experience with a special focus on 
neglected tropical diseases, including trichuriasis, and owns well-established diagnostic laboratories in 
parasitology and other infectious disease fields, run by trained and experienced technicians. 
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. No changes should be 
made without the agreement of the PI and the Co-PIs, except when necessary to eliminate an apparent 
immediate hazard or danger to a study participant. All investigators will work according to the protocol 
and GCP. All investigators 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 Co-PI. All entries have to be made clearly readable with a 
pen. All investigators 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 Swiss TPH and the 
ethical committees of Switzerland and Zanzibar. The study will be undertaken in accordance with the 
Declaration of Helsinki and ICH-GCP. 
10.2 
Evaluation of the risk-benefit ratio 
Ivermectin and albendazole are well-known drugs and have little and mainly mild AEs as described to 
date (headache, abdominal pain etc.). Both drugs are approved for and widely used in mass treatment 
programs against nematode infections. Albendazole is approved in children aged ≥1 year and ivermectin 
has been tested for trichuriasis in PSAC.[20] All PSAC enrolled in the study will benefit from a clinical 
examination and a treatment against STH infections. All participants remaining positive for T. trichiura 
or any co-infection will be treated with the currently best recommended treatment. 

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10.3 
Participant information and consent 
All parents or caregivers of eligible participants will be asked to sign a written informed consent form. 
In case the parent/caregiver is illiterate, an impartial witness that can read and write has to sign the 
consent and the illiterate person has to give a thumb print. Parents or caregivers will have sufficient time 
for reflection of their child’s participation. 
Information sessions in the respective communities will be conducted to explain to caregivers and 
potential participants the purpose and procedures of the study. Informed consent forms are orally 
explained in local language of the parents/caregivers 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 
Participants requiring particular protection 
Our study will include PSAC, since this population group is at high risk of T. trichiura infection. Our 
trial will produce more evidence for the use of ivermectin for trichuriasis in children and the whole 
community. 
Throughout the entire study, from the preparation phase to the dissemination of results, community 
representatives (e.g. health centre staff) will be consulted to ensure any concerns regarding the study 
can be tackled in an anonymous and timely manner and the study addresses the community’s needs as 
far as possible. 
 
11. Quality control and quality assurance 
11.1 
Monitoring and auditing 
We will work with a locally based external monitor. The monitor will conduct site visits to the 
investigational facilities with the purpose of monitoring the study. Details will be described in a separate 
monitoring plan. The investigators will grant access to study documentation, laboratory facilities, 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 
preventive 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 investigators agree to allow inspectors from regulatory 
agencies to review records and 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 Said Abdallah Jongo, physician and senior clinical research 
scientist at the Ifakara Health Institute (IHI) in Bagamoyo, Tanzania, and Prof Dr Piero Olliaro, 

iverped_protocol_v1.2_20240508 
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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 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 the Swiss National Science Foundation (SNSF). 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 for publication. 
 
13. Dissemination of results and publication 
The final results of this study will be published in a peer-reviewed scientific journal and presented at 
scientific conferences. SNSF 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 findings may be shared with local health 
authorities prior to publication. After publication, study results will be made available to study 
participants.

iverped_protocol_v1.2_20240508 
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14. References 
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helminths: systematic review and network meta-analysis. BMJ, 2017. 358: p. j4307. 
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Clarke, N.E., et al., Efficacy of Anthelminthic Drugs and Drug Combinations Against Soil-
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Palmeirim, M.S., et al., Efficacy and safety of co-administered ivermectin plus albendazole for 
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18. 
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21. 
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Children and Adults. Clin Pharmacol Ther, 2019. 106(3): p. 661-667. 
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Geary, T.G., et al., Unresolved issues in anthelmintic pharmacology for helminthiases of 
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15. Appendix 
15.1 
Visual Analogue Scales for palatability 
 
1. 
Did the drug have a taste? 
No taste 
 
Very strong 
taste 
|__|__|.|__| cm 
2. 
Was the drug bitter? 
Not bitter 
 
Very bitter 
|__|__|.|__| cm 
3. 
Was the drug sweet? 
Not sweet 
 
Very sweet 
|__|__|.|__| cm 
4. 
Did you like the taste of the drug? 
 
 
 
 
Very 
unpleasant 
  
 
 
 
 
 
 
Very 
pleasant 
|__|__|.|__| cm