Clinical trial NCT03527732
Conditions: Trichuriasis
Sponsor: Jennifer Keiser
Start date: 2018-09-09; Completion date: 2020-07-15
Enrollment: 1673 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a double-blind randomized clinical trial conducted with two settings in Africa and one in Asia, namely Côte d'Ivoire, Pemba (Zanzibar, Tanzania) and Lao PDR. This study aims at providing evidence on the efficacy and safety of co-administered albendazole and ivermectin versus albendazole monotherapy (standard of care) against whipworm (T. trichiura) infections in children and adults (6-60 years).

The efficacy of the treatment and potential extended effects on follow-up prevalence will be determined 14-21 days, 6 months and 12 months post-treatment by collecting another two stool samples. The cure rate will be calculated as the percentage of egg-positive subjects at baseline who become egg-negative after treatment.

Detailed description:
This study is a double-blind randomized clinical trial which aims at providing evidence on the efficacy and safety of co-administered albendazole and ivermectin versus albendazole monotherapy (standard of care) against T. trichiura infections in children and adults (6-60 years) in different transmission settings and geographies. Embedded in this trial a smaller dose-finding (DF) study with the goal to investigate efficacy, safety and pharmacokinetic parameters of ascending doses of ivermectin ((i) 200 µg/kg, (ii) 400 µg/kg, and (iii) 600 µg/kg) co-administered with albendazole (400 mg) in school-aged children infected with T. trichiura will take place.

The primary objective of the trial is to comparatively assess the efficacy in terms of cure rate against T. trichiura infections among school-aged children and adults from three different epidemiological settings and monitored over a 12-month period of albendazole/ivermectin combination therapy and albendazole monotherapy. A DF study will be implemented in the trial with the objective to understand the dose-dependent efficacy and pharmacokinetic profile of the co-administration of albendazole and ivermectin in school-aged children (6-12 years) with the following four oral treatment regimens: i) albendazole (400 mg) /ivermectin (200 µg/kg) combination, ii) albendazole (400 mg) /ivermectin (400 µg/kg) combination, iii) albendazole (400 mg) /ivermectin (600 µg/kg) combination, and iv) placebo.

The secondary objectives of the trial are to evaluate the safety and tolerability of the treatment regimens, compare the ERRs of the treatment regimens (combination vs. monotherapy and ascending doses of the combination) against T. trichiura, determine the CRs and ERRs of the drugs in study participants (6-60 years) infected with hookworm, A lumbricoides and S stercoralis, investigate potential extended effects on follow-up helminth prevalences (6 and 12 months post-treatment) of the two standard-dose treatment regimens (as assessed among participants with cleared infection on days 21 and 180), compare CRs based on infection status determined by novel polymerase chain reaction (PCR)-based and standard microscopic diagnosis, assess potential differences in susceptibility to the treatment regimen between the three hookworm species, Necator americanus, Ancylostoma duodenale and A. ceylanicum, as classified through the novel PCR-based diagnosis, characterize T. trichiura strains from different epidemiological settings through genotyping, evaluate potential benefits from deworming on morbidity (clinically evaluated and self-rated from questionnaire interviews) and nutritional indicators, and determine an exposure (including length of time that the drug concentration is above the minimal inhibitory concentration (MIC), Cmax, area under the curve (AUC))-response correlation of ivermectin and albendazole in school-aged children.

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

Randomization of participants into the two treatment arms will be stratified according to intensity of infection. All participants will be interviewed before treatment, 3 and 24 hours and 3 weeks after treatment about the occurrence of adverse events. Children aged 6-16 years will additionally be asked to rate their own physical functioning by replying to a pre-tested questionnaire at baseline and 6 and 12 months after treatment. The efficacy of the treatment and potential extended effects on follow-up prevalence will be determined 14-21 days, 6 months and 12 months post-treatment by collecting another two stool samples. Subjective treatment satisfaction will be assessed 3 hours, 3 weeks and 6 months after treatment to investigate relationship with treatment compliance and observed efficacy in reducing egg output and morbidity.

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

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

Arms: arm 1: 400 mg albendazole single tablet (Zentel®) and 200µg/kg using 3mg tablets of placebo at day 0 administered orally arm 2: 400 mg albendazole single tablet (Zentel®) and 200µg/kg using 3mg tablets of ivermectin (Stromectol®) at day 0 administered orally
Interventions: intervention 1: Albendazole intervention 2: Albendazole and Ivermectin
Intervention descriptions: intervention 1: Monotherapy of albendazole (400 mg) intervention 2: Combination therapy of albendazole (400 mg) and ivermectin (200 µg/kg)

Protocol documents:
Prot_SAP_000.pdf: 
Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 1 of 176 
 
 
 
 
Efficacy and Safety of Ivermectin and Albendazole Co-
administration in School-aged Children and Adults Infected 
with Trichuris Trichiura: a Multi-country Randomized 
Controlled Trial 
 
Trial registration number: NCT 03527732 
 
Study protocols and SAP 
 
 
 
 
 
 
 
 
 
 
 
Document date 24 November 2021


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 2 of 176 
 
 
 
I. 
Table of content 
1.    Supplement overview …………………………………………………...………………………... 3 
2.    Protocol versions and history of protocol changes ……………………...………………………... 4 
3. 
Original protocol approved by the Swiss Ethics committee (EKNZ) …...………………………... 5 
4. 
Trial protocol Pemba Island: …………………………………………...………………………... 47 
5.    Trial protocol Cote d’Ivoire: …………………………………………...………………………… 84 
6.    Trial protocol Laos: ……………………………………………………………………………  127 
7.    Statistical Analysis Plan (SAP) ………………………………………………………………… 163 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 3 of 176 
 
 
 
1. Supplement overview 
 
This supplement contains the following items: 
 
1) An overview on protocol versions and history of protocol changes 
2) Original protocol approved by the ethical committee of northwestern Switzerland (EKNZ) 05.05.2018. 
This protocol is the most comprehensive version and includes procedures for all three study countries. 
3) Final protocol Pemba  
4) Final protocol Côte d’Ivoire 
5) Final protocol Laos 
6) Statistical analysis plan (original statistical plan= final statistical analysis plan) 
In every study country (i.e. Côte d’Ivoire, Laos and Pemba Island/Tanzania) country-specific protocols were 
submitted in different language versions (French in Côte d’Ivoire, Lao in Laos and English in Pemba Island). The 
final country versions differ from this version with respect to the following points: 
Variations of country-specific protocols compared to this protocol: 
- Côte d’Ivoire: The dose-finding sub study was removed from the protocol including all related objectives and 
procedures. The collection of stool sub samples for microbiome analysis was added to the protocol. Diagnosis of 
Strongyloides stercoralis was never considered for this country. 
- Laos: The dose-finding sub study was never part of the protocol including all related objectives and procedures. 
Rapid testing for Wuchereria bancrofti was never considered for this country. The collection of stool sub samples 
for microbiome analysis and reporting of medical findings (blood parameter evaluation) back to participants was 
added to the protocol. We emphasized in the protocol that refusal to provide venous blood was not an exclusion 
criterion. Age in girls for pregnancy testing was raised from 10 to 12 years and older. 
- Pemba Island: The dose-finding sub study was never part of the protocol including all related objectives and 
procedures. Venous blood sampling, rapid testing for Plasmodium spp. and diagnosis of S. stercoralis infections 
were never considered for this country. The collection of stool sub samples for microbiome analysis was added to 
the protocol.


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 4 of 176 
 
 
 
2. Protocol versions and history of protocol changes 
Country 
Protocol version date 
Date of (re-) submission/Name of IEC 
Date accepted by IEC 
Date of submission/Name of 
author authority 
Date accepted author 
authority 
Pemba/Tanzania 
13.02.2018 21.02.2018/ZAMREC 
23.05.2018 
Laos (1st submission) 
18.06.2018 27.07.2018/NECHR 
Laos (re-submission after comments) 
19.09.2018 19.09.2018/NECHR 
23.10.2018 
Côte d'Ivoire (1st submission) 
12.04.2018 20.04.2018/CNESVS 
03.07.2018 accepted / 10.09.2018 
suspended 
13.07.2018/DPML 
09.08.2018 trial suspended 
Côte d'Ivoire (re-submission after 
comments and suspension by DPML) 
22.11.2018 07.01.2019/CNESVS 
24.01.2019 06.02.2019/DPML 
22.03.2019 
Switzerland 
12.06.2018 13.06.2018/EKNZ 
05.07.2018 
Abbreviations:  IEC,  Independent Ethics Committee; EKNZ, Ethikkomission Nordwest- und Zentralschweiz ; CNESVS, Comité National d’Ethique des Sciences de la Vie et de 
la Santé; DPML, Direction de la Pharmacie, du Médicament et des Laboratoires ; NECHR, National Ethics Committee  for Health Research;  ZAMREC,  Zanzibar Medical Research 
and Ethics committee 
 
Change 
Timepoint of change 
Country/Protocol version including change 
Change in procedures 
Additional secondary outcome: optimal 
timepoint for efficacy assessment (daily 
stool sampling) 
12.06.2018 
Switzerland (EKNZ accepted version/12.06.2018), Laos (resubmitted 
and accepted version/19.09.2018), Côte d’Ivoire (resubmitted and 
DPML accepted version/22.11.2018) 
A subsample of 30 participants in each treatment arm (total 60 
participants) will be asked to provide a daily stool sample for a period of 
up to 4 weeks to monitor dynamics of T. trichiura egg output for 
subsequent determination of the optimal timing for drug efficacy 
assessment. 
Precision secondary outcome: To 
characterize T. trichiura strains from 
different epidemiological settings and 
investigate potential resistance markers 
using a deep sequencing analysis 
12.06.2018 
Switzerland (EKNZ accepted version/12.06.2018), Laos (resubmitted 
and accepted version/19.09.2018), Côte d’Ivoire (resubmitted and 
DPML accepted version/22.11.2018) 
No changes in sampling procedure, but samples may be shipped to 
additional labs specialized in deep sequencing and resistance marker 
analysis. 
Further elaborated description of data 
management and data quality control plan 13.06.2018 
Switzerland (EKNZ accepted version/12.06.2018), Laos (resubmitted 
and accepted version/19.09.2018), CI (resubmitted and DPML 
accepted version/22.11.2018) 
updated material transfer agreement and SOPs 
additional secondary outcome: 
microbiome assessment 
19.09.2018 
Laos (resubmitted and accepted version/19.09.2018), Côte d’Ivoire 
(resubmitted and DPML accepted version/22.11.2018) 
An additional aliquot of 1.5-2 g from each stool specimen will be frozen, 
shipped to and analyzed in Switzerland. 
Precision exclusion/inclusion criteria: 
below age 6 and 15 kg body weight 
19.09.2018 
Laos (resubmitted and accepted version/19.09.2018), Côte d’Ivoire 
(resubmitted and DPML accepted version/22.11.2018) 
Additional check for weight below 15kg on treatment days 
Split of Côte d'Ivoire study protocol into 
two separate protocols: i) multi-country 
trial comparable to Pemba and Laos, ii) 
dose-finding study for ascending doses of 
IVM (200, 400 and 600 µg/kg) with 
single ALB (400mg) vs. Placebo 
22.11.2018 
Côte d’Ivoire (resubmitted and DPML accepted version/22.11.2018) 
The IVM-ALB vs. ALB efficacy trial in 6-60 year olds was separately 
resubmitted to ethical committee of Côte d'Ivoire and DPML and received 
respective approvals on the 24.01.2019 and 22.03.2019. The second 
submission including the dose-finding trial of ascending doses of 
ivermectin with albendazole (400mg) was suspended by DPML (decision 
from 22.03.2019) until today. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 5 of 176 
 
 
 
3. Original protocol approved by the Swiss Ethics committee (EKNZ) 
 
Efficacy and safety of ivermectin and albendazole co-administration in school-aged children and adults 
infected with Trichuris trichiura: a multi-country randomized controlled trial 
 
 
Protocol Number 
1 
Version Number 
1.01 
Document Date 
12.06.2018 
Sponsor Contact 
Prof. Dr. Jennifer Keiser,  
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@unibas.ch 
Principle Investigator 
Prof. Dr. Jennifer Keiser,  
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@unibas.ch 
Funding Agency 
Bill and Melinda Gates Foundation 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 6 of 176 
 
 
 
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 
Postdoc 
Co-PI 
Dr. 
Jessica Schulz 
Swiss TPH 
Postdoc 
Co-PI 
Dr.  
Jean Coulibaly 
Swiss TPH / Université 
Félix Hophouët-Boigny 
(UFHB), Abidjan, Côte 
d‘Ivoire 
Group leader 
Co-PI 
Dr. 
Yves N'Gbesso 
Departement 
d'Agboville, Centre de 
Santé Urbain d'Azaguié, 
Azaguié 
Medical 
doctor 
Study physician 
Dr. 
Jan Hattendorf 
 
Swiss TPH  
 
Project leader 
Statistician 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 7 of 176 
 
 
 
II. 
Signatures  
 
Statistician 
Signature 
 
 
 
 
 
Date of Signature  
12.06.2018 
Name  
Jan Hattendorf 
Title 
Dr.  
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 284-8193 
 
Principal investigator 
Signature 
 
 
 
 
 
Date of Signature  
12.06.2018 
Name  
Jennifer Keiser 
Title 
Prof. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 284-8218 
 
I have read this protocol and agree that it contains all necessary details for carrying out this trial. I will conduct 
the trial as outlined herein and will complete the trial within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist 
in the conduct of this trial. I will discuss this material with them to ensure they are fully informed regarding the 
drug and the conduct of the trial. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 8 of 176 
 
 
 
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. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 9 of 176 
 
 
 
Co-Principal investigator 
Signature 
 
 
 
Date of Signature  
12.06.2018 
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 
Phone 
+41 61 284 87 04 
 
Co-Principal investigator 
Signature 
 
 
 
 
 
Date of Signature  
12.06.2018 
Name  
Jessica Schulz 
Title 
Dr. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 207 15 06 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 10 of 176 
 
 
 
Co-Principal investigator 
Signature 
 
 
 
Date of Signature  
12.06.2018 
Name  
Jean Coulibaly 
Title 
Dr. 
Institution 
Swiss Tropical and Public Health Institute/Université Félix Houphouët-Boigny 
Address 
23 BP 915 Abidjan 23 
Phone 
+225 0500 8223/+225 0209 1401 
 
 
Study physician 
Signature 
 
 
Date de Signature  
12.06.2018 
Nom 
Yves Koutouan N'Gbesso 
Title 
Dr. 
Institution 
Departement d'Agboville, Centre de Santé Urbain d'Azaguié, Azaguié 
Address 
 
Phone 
+225 07442207/ +225 02729236  
 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 11 of 176 
 
 
 
Table of contents 
 
1. 
General information ........................................................................................................................................6 
2. 
Background information................................................................................................................................20 
3. 
Trial objective and purpose ...........................................................................................................................21 
4. 
Methodology .................................................................................................................................................23 
4.1 
Primary and secondary endpoint...........................................................................................................23 
4.2 
Type of trial ..........................................................................................................................................23 
4.3 
Trial design ...........................................................................................................................................23 
4.3.1 
Baseline survey and screening .....................................................................................................23 
4.3.2 
Assessment of efficacy and other benefits after treatment ...........................................................26 
4.3.3 
Pharmacokinetic studies...............................................................................................................27 
4.4 
Measure to minimize bias .....................................................................................................................27 
4.5 
Study duration and duration of subject participation ............................................................................28 
4.6 
Schedule of visits ..................................................................................................................................28 
5. 
Selection of the trial subjects .........................................................................................................................30 
5.1 
Recruitment ..........................................................................................................................................30 
5.2 
Inclusion criteria ...................................................................................................................................31 
5.3 
Exclusion criteria ..................................................................................................................................31 
5.4 
Criteria for discontinuation of trial .......................................................................................................31 
5.5 
Treatment of subjects............................................................................................................................31 
5.6 
Concomitant therapy.............................................................................................................................32 
6. 
Safety assessments ........................................................................................................................................32 
6.1 
Adverse event definitions .....................................................................................................................33 
6.1.1 
Severity grading ...........................................................................................................................33 
6.1.2 
Relatedness ..................................................................................................................................33 
6.1.3 
Expectedness ................................................................................................................................34 
6.1.4 
Serious adverse events .................................................................................................................34 
6.1.5 
Suspected unexpected serious adverse reactions .........................................................................34 
6.2 
Methods of recording and assessing adverse events .............................................................................34 
6.3 
Reporting of serious adverse events .....................................................................................................35 
6.4 
Safety reporting to Health Authorities and Ethics Committees ............................................................36 
7. 
Statistics ........................................................................................................................................................36 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 12 of 176 
 
 
 
7.1 
Definition of primary endpoint .............................................................................................................36 
7.2 
Justification of number of trial subjects ................................................................................................36 
7.3 
Description of statistical methods .........................................................................................................37 
7.4 
Description of data management and data quality control ....................................................................38 
8. 
Duties of the investigator ..............................................................................................................................39 
8.1 
Investigator’s confirmation ...................................................................................................................39 
8.2 
Damage coverage .................................................................................................................................39 
8.3 
Project management .............................................................................................................................40 
9. 
Ethical considerations....................................................................................................................................40 
9.1 
Independent ethics committee ..............................................................................................................40 
9.2 
Evaluation of the risk-benefit ratio .......................................................................................................40 
9.3 
Subject information and consent...........................................................................................................40 
9.4 
Subject confidentiality ..........................................................................................................................41 
9.5 
Subjects requiring particular protection ................................................................................................41 
9.6 
Other aspects.........................................................................................................................................41 
10. 
Quality control and quality assurance .......................................................................................................41 
10.1 
Monitoring and auditing .......................................................................................................................41 
10.2 
Access to data, handling of data and samples (data protection), archiving (place, duration) and 
destruction .........................................................................................................................................................42 
10.3 
Data entered directly in the CRF – definition of source data ................................................................42 
10.4 
Data and safety monitoring board / data monitoring committee...........................................................42 
10.5 
Study Documents: Translations - Reference language .........................................................................43 
11. 
Dissemination of results and publication ..................................................................................................43 
12. 
References .................................................................................................................................................44 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 13 of 176 
 
 
 
III. 
Abbreviations 
AE 
Adverse event 
AUC 
Area under the curve 
CI 
Confidence interval 
CNER 
Comité Nationale d’Ethique de la Recherche 
CR 
Cure rate 
CRF 
Case report form 
CSRS 
Centre Suisse de Recherches Scientifiques en Côte d’Ivoire 
DF 
Dose-finding 
DPML 
Direction de la Pharmacie, du Médicament et des Laboratoires 
EKNZ 
Ethikkomission Nordwest- und Zentralschweiz 
EML 
Essential medicine list 
EPG 
Eggs per gram 
ERR 
Egg reduction rate 
GCP 
Good clinical practice 
GEE 
Generalized estimating equation 
Hb 
Hemoglobin 
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 
MIC 
Minimal inhibitory concentration 
MUAC 
Mid-upper arm circumference 
PC 
Preventive chemotherapy 
PCR 
Polymerase chain reaction 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/pharmacodynamic 
RDT 
Rapid diagnostic test 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
STH 
Soil-transmitted helminth 
Swiss TPH 
Swiss Tropical and Public Health Institute 
SUSAR 
Suspected unexpected serious adverse reaction 
WHO 
World Health Organization 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 14 of 176 
 
 
 
IV. 
Synopsis 
 
Sponsor/Sponsor-
Investigator 
Prof. Dr. Jennifer Keiser 
Study Title 
Efficacy and safety of ivermectin and albendazole co-administration in school-
aged children and adults infected with Trichuris trichiura: a multi-country 
randomized controlled trial 
Short title 
Efficacy and safety of IVM/ALB co-administration 
Protocol Number, Date and 
Version 
1, 12.06.2018, v1.01 
Trial registration 
Has been registered on ClinicalTrials.gov (reference: NCT 03527732) 
Clinical phase 
Phase 3 trial 
Sample size 
1960 (600 participants in each of 3 settings for the parallel group trial 
including 160 participants for the dose-finding (DF) study) 
Indication 
Trichuris trichiura infection (eggs in stool) 
Investigational Product and 
Reference Treatment 
Ivermectin and albendazole 
Study Rationale 
To provide evidence on  
a) potentially enhanced efficacy by combining the standard drug albendazole 
with ivermectin in school-aged children and adults against infection with T. 
trichiura. 
b) effective doses of ivermectin in combination with albendazole in school-
aged children against infection with T. trichiura. 
Study Objectives 
To compare the efficacy and safety of: 
(a) standard doses of co-administered ivermectin (200 µg/kg) and albendazole 
(400 mg) compared to albendazole (400 mg) monotherapy in community 
members aged 6-60 years and (b) ascending doses of ivermectin ((i) 200 
µg/kg, (ii) 400 µg/kg, and (iii) 600 µg/kg) co-administered with albendazole 
(400 mg) in school-aged children (6-12 years) infected with T. trichiura and to 
measure ivermectin and albendazole disposition in children using a 
microsampling device. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 15 of 176 
 
 
 
 
Our primary objective is to comparatively assess the efficacy in terms of cure 
rates (CRs) against T. trichiura infections among school-aged children and 
adults of the following oral treatment regimens: 
a) in a parallel group trial: 
Albendazole (400 mg)/ivermectin (200 µg/kg) combination  
Albendazole (400 mg) monotherapy 
b) in the DF study (school-aged children only): 
Albendazole (400 mg)/ivermectin (200 µg/kg) combination 
Albendazole (400 mg)/ivermectin (400 µg/kg) combination  
Albendazole (400 mg)/ivermectin (600 µg/kg) combination  
Placebo 
 
The secondary objectives of the trial are: 
a) To evaluate the safety and tolerability of the treatment regimens  
b) To compare the egg reduction rate (ERR) of the treatment regimens 
(combination vs. monotherapy and ascending doses of the 
combination) against T. trichiura 
c) To determine the CRs and ERRs of the drugs in study participants (6-
60 years) infected with hookworm, Ascaris lumbricoides and 
Strongyloides stercoralis 
d) To investigate potential extended effects on follow-up helminth 
prevalences (6 and 12 months post-treatment) of the two standard-dose 
treatment regimens (as assessed among participants with cleared 
infection on days 21 and 180) 
e) To compare CRs based on infection status determined by novel 
polymerase chain reaction (PCR)-based and standard microscopic 
diagnosis 
f) 
To assess potential differences in susceptibility to the treatment 
regimen between the hookworm species, Necator americanus, 
Ancylostoma duodenale and A. ceylanicum, as classified through the 
novel PCR-based diagnosis 
g) To characterize T. trichiura strains from different epidemiological 
settings and investigate potential resistance markers using a deep 
sequencing analysis 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 16 of 176 
 
 
 
h) To determine optimal timing for measuring anthelmintic efficacy in 
T. trichiura infection 
i) 
To evaluate potential benefits from deworming on morbidity 
indicators and nutritional parameters 
j) 
To determine an exposure (including length of time that the drug 
concentration is above the minimal inhibitory concentration (MIC), 
Cmax, area under the curve (AUC))-response correlation of ivermectin 
and albendazole in school-aged children 
Study design 
Double blind, randomized controlled trial 
Study product / intervention Administration of a single oral dose of  ivermectin + albendazole 
Comparator(s) 
main trial: albendazole (400 mg) monotherapy, DF study: placebo 
Key inclusion / Exclusion 
criteria 
Inclusion:  School-aged children and adults (6-60 years) infected with 
T. trichiura with at least two slides of the quadruple Kato-Katz thick smears 
positive and infection intensities of at least 100 eggs per gram of stool (EPG), 
agreeing to comply with study procedures, including provision of two stool 
samples at the beginning (baseline) and on three follow-up assessments 
(approximately 3 weeks, 6 months, and 12 months later), written informed 
consent signed by parents and/or caregivers for children/adolescents; and 
written assent by child/adolescent (aged 6-20 years). 
Exclusion: No written informed consent by individual/parents and/or 
caregiver, any clinically relevant abnormality (including severe anemia or 
clinical malaria) or history of acute or severe chronic disease (e.g. cancer, 
diabetes, chronic heart, liver or renal disease), recent use of anthelminthic 
drug (past 4 weeks), attending other clinical trials during study, negative 
diagnostic or low egg count (less than 100 EPG or less than 2 out of 4 slides 
positive) result for T. trichiura, known allergy to study medication, pregnancy 
or lactating in the 1st week after birth, taking medication with known 
interaction on study drugs. 
Primary Endpoints 
T. trichiura infection status assessed by Kato-Katz 14-21 days after treatment 
Secondary Endpoints 
 
ERR against T. trichiura  
 
CRs and ERRs against A. lumbricoides, hookworm and S. stercoralis 
 
Adverse events 
 
Infection status assessed by PCR 
 
Pharmacokinetic parameters for ivermectin and albendazole in school-
aged children 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 17 of 176 
 
 
 
Exploratory Endpoints 
 
Molecular characterization and resistance markers of T. trichiura 
 
Optimal timing for drug efficacy assessment in T. trichiura infection 
 
Nutritional status 
 
Morbidity indicators 
Interim Analyses 
None 
Study Duration 
14 months  
Schedule 
06/2018 of first-participant in (planned) 
08/2019 of last-participant out (planned) 
Study centers 
Multinational study with trial sites in Côte d’Ivoire, Lao PDR and Pemba 
Island (Tanzania) 
Measurements & procedures Two stool samples (each of a minimum of 15 grams) will be collected if 
possible on two consecutive days or otherwise within a maximum of 5 days. 
The medical history of the participants will be assessed with a standardized 
questionnaire, in addition to a clinical examination carried out by the study 
physician before treatment.  
All participants will be interviewed before treatment, 3 and 24 hours and 3 
weeks after treatment about the occurrence of adverse events. Children aged 
6-16 years will additionally be asked to rate their own physical functioning by 
replying to a pre-tested questionnaire at baseline and 6 and 12 months after 
treatment. The efficacy of the treatment and potential extended effects on 
follow-up prevalence will be determined 14-21 days, 6 months and 12 months 
post-treatment by collecting another two stool samples. Subjective treatment 
satisfaction will be assessed 3 hours, 3 weeks and 6 months after treatment to 
investigate relationship with treatment compliance and observed efficacy in 
reducing egg output and morbidity. 
All stool samples will be examined with duplicated Kato-Katz thick smears 
for T. trichiura, A. lumbricoides and hookworm. S. stercoralis infections will 
be identified using the Baermann technique and recorded qualitatively as 
larvae-positive or negative. For subsequent PCR-analysis a portion of 1.5-2 g 
of stool from each specimen will be preserved in 70% ethanol and shipped to a 
reference laboratory at Swiss TPH in Switzerland. At baseline and in the first 
follow-up (3 weeks post treatment) an additional portion of stool (1.5-2 g) 
from a subsample of 10 participants identified with heavy intensity infections 
in each case and study setting will be preserved in 95% ethanol, shipped to the 
same reference laboratory and subjected to deep sequencing for 
characterization of T. trichiura strains and investigation of potential resistance 
markers. Fecal occult blood and calprotectin in stool as markers for gut 
morbidity and inflammation will be detected using a rapid diagnostic test and 
an immunoassay, respectively. A subsample of 30 participants will be asked to 
provide a daily stool sample for a period of up to 4 weeks to monitor dynamics 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 18 of 176 
 
 
 
of T. trichiura egg output for subsequent determination of the optimal timing 
for drug efficacy assessment. Individuals found T. trichiura positive 6 months 
after baseline will receive a second round of treatment according to their 
group scheme.  
Each participant will be asked to provide a finger-prick blood sample for 
hemoglobin measurement, a rapid diagnostic test (RDT) for Plasmodium spp. 
and where applicable a biplex RDT for lymphatic filariasis/onchocerciasis at 
baseline and 6 and 12 months after treatment. At the same time points 
anthropometric measurements (i.e. height, weight, mid-upper arm 
circumference (MUAC) and skinfold thickness) will be taken for all 
participants. In addition, a venous blood sample (~8 ml) will be taken from 
each participant to assess biochemical blood parameters as proxies for vital 
organ functioning (e.g. complete blood count, urea, creatinine, transaminases 
etc.) and nutritional indicators for micro- (i.e. (pro-) vitamins, inflammation 
markers, and iron/ferritin) and macronutrient (i.e. albumin) deficiencies at 
baseline, day 21, day 180 and day 360. 
To all participating households, a questionnaire will be administered assessing 
information on socioeconomic characteristics and access to sanitation, water 
facilities, and hygiene behavior. 
For the assessment of pharmacokinetic parameters within the DF study the 
participating school-aged children (6-12 years) will be sampled using finger 
pricking for microsampling at 0, 1, 2, 3, 4, 5, 6, 7, 9, 24, 48 hours post-dosing. 
Statistical Analyses 
An available case analysis will be performed, including all subjects with 
primary end point data. Supplementary, a per-protocol analysis will be 
conducted. CRs will be calculated as the percentage of egg-positive subjects at 
baseline who become egg-negative after treatment. Differences among CRs 
(between treatment arms and between diagnostic approaches) will be analysed 
by using crude and adjusted logistic regression modeling (adjustment for age, 
sex and weight).  
Geometric and arithmetic mean egg counts will be calculated for the different 
treatment arms before and after treatment to assess the corresponding ERRs. 
Bootstrap resampling method with 5,000 replicates will be used to calculate 
95% confidence intervals (CIs) for differences in ERRs.  
Further secondary outcomes – as nutritional and morbidity indicators - will be 
analysed using logistic and linear regression as appropriate. To compare 
individual’s changes in nutrition/morbidity categories as an effect from 
treatment McNemar’s test will be applied. The analysis after 6 and 12 month 
of follow-up will be complemented by generalized estimating equation (GEE) 
models with independent correlation structure and empirical estimators to 
account for missing data. 
Nonlinear mixed-effects modeling will be used to determine pharmacokinetic 
parameters. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 19 of 176 
 
 
 
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 school-aged children, since an infection with 
T. trichiura occurs most often in children and they are further the main target 
group of deworming campaigns. 
Recruitment procedure 
The parallel group trial will be conducted as a multi-country study with two 
settings in Africa and one in Asia recruiting each 600 community members: 
 
West African setting: Côte d’Ivoire 
 
East African setting: Pemba (Zanzibar, Tanzania)  
 
Asian setting: Lao PDR 
 
The DF study will be embedded in the trial and implies the recruitment of an 
additional 160 school-aged children (6-12 years) to be able to include 40 
children per arm in Côte d’Ivoire. 
 
The studies will be conducted in areas with moderate to high T. trichiura 
endemicity (communities with a prevalence ≥ 25%) identified from earlier 
studies and/or based of experience of the local collaborating teams. They will 
be implemented as community-based studies in order to recruit participants 
from a broad age range (6-60 years). Ideally, entire communities with a 
population size of < 1000 inhabitants will be included in the study for pre-
screening and identification of T. trichiura cases to avoid potential selection 
bias of households. To identify all potentially eligible households of the 
respective communities and its composition in terms of age groups a 
preceding population census will be conducted. 
Coverage of damages 
Winterthur Police Nr. 4746321, BERACA Côte d’Ivoire, No: to be issued 
Storage of data and samples 
for future research aims 
After the study has been completed all samples will be destroyed and case 
report forms will be kept for a minimum of 15 years (chapter 10). 
 
Conflict of interest in 
relation to the investigated 
drugs 
We declare no conflict of interest in relation to the investigated drugs. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 20 of 176 
 
 
 
2. 
Background information 
Albendazole and mebendazole are the most widely used drugs for preventive chemotherapy (PC) campaigns 
against soil-transmitted helminth (STH) infections. Albendazole is characterized by high cure rates (CRs) and 
egg reduction rates (ERRs) against infections with Ascaris lumbricoides (95.7% and 98.5%) and hookworm 
infections (79.5 and 89.6%). Lower efficacy is observed against Trichuris trichiura infections (CR 30.7%, and 
ERR of 49.9%) [1].  
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 mono-therapy [2].   
A recent review and meta-analysis found that ivermectin co-administered with albendazole is highly efficacious 
for the treatment of T. trichiura and is comparatively more efficacious than albendazole alone (Figure 1) [3]. 
Efficacy of ivermectin and albendazole against A. lumbricoides and hookworm are comparable and in some 
cases more efficacious than albendazole alone. Summarized efficacy measures of albendazole, mebendazole, and 
ivermectin against trichuriasis from a recent review [1] and earlier trials [4, 5]  are shown in Table 1. 
 
 
Figure 1. Forest plot displaying the results of a random-effects meta-analysis of the effect of the co-
administration of albendazole-ivermectin on the number of patients infected with T. trichiura compared to 
albendazole alone.  
 
Table 1. Average CRs and ERRs of albendazole and mebendazole for T. trichiura from a recent review [1] as 
well as findings from studies investigating ivermectin [4, 5] 
Drug 
CR (%) 
95% CI 
ERR (%) 
95% CI 
Albendazole 
30.7 
(21.0, 42.5) 
49.9 
(39.0, 60.6) 
Mebendazole 
42.1 
(25.9, 60.2) 
66.0  
(54.6, 77.3) 
Ivermectin 
11-35 
NA 
43-98 
NA 
NA, not applicable 
 
The individual studies included in the review are summarized in Table 2. All four studies are randomized 
controlled trials and used the standard dose of 200 µg/kg ivermectin and 400 mg albendazole [4, 6-8]. Against 
infections with T. trichiura, CRs ranging from 27.5-81.1%, ERR based on geometric mean ranging from 91.3-
99.7%, and ERR based on arithmetic mean ranging from 85.6-97.5% were observed. CRs for T. trichiura 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 21 of 176 
 
 
 
observed in Asian settings were higher than in African settings. One reason for this finding may be differences in 
the study design and quality (e.g. in terms of diagnostic approach used). Another possible reason recently 
highlighted is genetic diversity of T. trichiura strains and variation in susceptibility to anthelmintics and/or drug 
resistance [9-11]. Interestingly, the higher efficacy of ivermectin in combination with albendazole translated – at 
least in some settings – into lower prevalences even after one year [4, 12]. The efficacy of albendazole-
ivermectin against A. lumbricoides was excellent (CRs >78% and ERRs >99.5%), while moderate CRs (50-
66.7%) and high ERRs (>95.4%) were observed against hookworm. 
 
Table 2. Known efficacy of co-administered ALB-IVMa against T. trichiura: 
Study 
Setting 
Cure rate in % 
(nneg/n) 
Eggs per gram 
 (pre/post) 
Egg reduction rate 
in % 
Ismail et al. 1999 
Sri Lanka 
81.1% (43/53) 
1544.0/78.7 (unkwn) 
94.9% (unkwn) 
Belizario et al. 2003 
Philippines 
65.1% (97/149) 
4948.1/122.5 (ar) 
550.0/1.9 (geo) 
97.5% (ar)  
99.7% (geo) 
Knopp et al. 2010 
Tanzania 
(Pemba) 
37.9% (53/140) 
127/11 (geo) 
91.3% (geo) 
Speich et al. 2015 
Tanzania 
(Pemba) 
27.5% (30/109) 
1059/153 (ar) 
489/27 (geo) 
85.6% (ar) 
94.5% (geo) 
All studies 
 
49.4% (223/451) 
 
 
aConsidered doses: albendazole=400 mg, ivermectin=200 µg/kg 
ar=arithmetic mean, geo=geometric mean, unkwn=unknown mean 
 
The WHO Expert Committee met from March 27-31, 2017 and, based on review of a dossier suggesting 
inclusion of ivermectin as an anthelmintic in the Essential Medicines List, made the following recommendation:  
“…adding ivermectin on the Essential Medicines List under the section intestinal anthelminthic for use against 
Strongyloides stercoralis and STH. It may be used in combination with albendazole for treatment of soil-
transmitted helminthiasis.” 
This important milestone paves the way for further, standardized trials to evaluate the efficacy of this 
combination among school-aged children in a range of epidemiological settings. In addition, the combination 
should be evaluated among adults, as there is growing interest in broadening deworming to include adults in 
order to move from morbidity control toward interruption of transmission [13, 14].  
In the proposed work, three trials are planned across a range of transmission settings, including Côte d'Ivoire, 
Lao PDR, and Pemba (Tanzania). Follow-up will be conducted at 1, 6, and 12 months to inform treatment 
frequency. Results from these trials will inform decisions on how the combination could be introduced into 
existing mass drug administration (MDA) programs and therefore provide a valuable adjunct tool for 
interrupting STH transmission.  
3. 
Trial objective and purpose 
The overall goal of the study is to assess the efficacy and safety of co-administered albendazole and ivermectin 
versus albendazole monotherapy (standard of care) against T. trichiura infections in children and adults (6-60 
years) in different transmission settings and geographies. Embedded in this trial a smaller dose-finding (DF) 
study with the goal to investigate efficacy, safety and pharmacokinetic parameters of ascending doses of 
ivermectin ((i) 200 µg/kg, (ii) 400 µg/kg, and (iii) 600 µg/kg) co-administered with albendazole (400 mg) in 
school-aged children infected with T. trichiura will take place. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 22 of 176 
 
 
 
We hypothesize that albendazole-ivermectin has a higher efficacy against T. trichiura infections than 
albendazole alone, and hence, the efficacy against all three STH species (A. lumbricoides, T. trichiura, and 
hookworm) and Strongyloides stercoralis will be increased. 
The primary objective of the trial is to comparatively assess the efficacy in terms of CR against T. trichiura 
infections among school-aged children and adults from three different epidemiological settings and monitored 
over a 12-month period of the following two oral treatment regimens: 
• 
Albendazole/ivermectin combination 
• 
Albendazole monotherapy 
 
A DF study will be implemented in the trial with the objective to understand the dose-dependent efficacy and 
pharmacokinetic profile of the co-administration of albendazole and ivermectin in school-aged children (6‒12 
years) with the following four oral treatment regimens: 
• 
Albendazole (400 mg) /ivermectin (200 µg/kg) combination 
• 
Albendazole (400 mg) /ivermectin (400 µg/kg) combination 
• 
Albendazole (400 mg) /ivermectin (600 µg/kg) combination 
• 
Placebo 
 
The secondary objectives of the trial are: 
a) To evaluate the safety and tolerability of the treatment regimens  
b) To compare the ERRs of the treatment regimens (combination vs. monotherapy and ascending doses of 
the combination) against T. trichiura 
c) To determine the CRs and ERRs of the drugs in study participants (6-60 years) infected with hookworm, 
A. lumbricoides and S. stercoralis 
d) To investigate potential extended effects on follow-up helminth prevalences (6 and 12 months post-
treatment) of the two standard-dose treatment regimens (as assessed among participants with cleared 
infection on days 21 and 180) 
e) To compare CRs based on infection status determined by novel polymerase chain reaction (PCR)-based 
and standard microscopic diagnosis 
f) 
To assess potential differences in susceptibility to the treatment regimen between the three hookworm 
species, Necator americanus, Ancylostoma duodenale and A. ceylanicum, as classified through the novel 
PCR-based diagnosis 
g) To characterize T. trichiura strains from different epidemiological settings and investigate potential 
resistance markers using a deep sequencing analysis 
h) To determine optimal timing for measuring anthelmintic efficacy in T. trichiura infection 
i) 
To evaluate potential benefits from deworming on morbidity (clinically evaluated and self-rated from 
questionnaire interviews) and nutritional indicators  


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 23 of 176 
 
 
 
j) 
To determine an exposure (including length of time that the drug concentration is above the minimal 
inhibitory concentration (MIC), Cmax, area under the curve (AUC))-response correlation of ivermectin 
and albendazole in school-aged children 
 
4. 
Methodology 
4.1 
Primary and secondary endpoint 
T. trichiura infection status assessed by Kato-Katz 14-21 days after treatment will be the primary endpoint and 
the main outcome for efficacy be expressed as cure rate (CR) (i.e. conversion from being egg positive pre-
treatment to egg negative post-treatment) and egg reduction rate (ERR) (secondary end point). Secondary 
endpoints include further infection status with A. lumbricoides, hookworm and S. stercoralis and related efficacy 
measures, adverse events, infection status assessed by PCR and key pharmacokinetic parameters in school-aged 
children. In addition, optimal timing for drug efficacy assessment in T. trichiura infection will be determined, 
T. trichiura strains will be described and potential resistance markers evaluated using deep sequencing and 
potential benefits on nutritional and morbidity indicators from treatment assessed (exploratory end points). 
 
4.2 
Type of trial 
Double blind randomized controlled trial. 
 
4.3 
Trial design 
4.3.1 
Baseline survey and screening 
Parallel group multi-country study 
A randomized-controlled trial will be conducted with two treatment arms to be followed-up over a 12 months 
period with an intermediate re-treatment of participants found re-infected after 6 months (Figure ). This parallel 
group trial will be conducted as a multi-country study; thus, in each setting a separate trial according to the 
design described below will be set up, to provide a better basis for the subsequent generalization of its findings. 
This arises from the possibility of recruiting the subjects from a wider population and of administering the 
medication in a broader range of clinical settings, thus presenting an experimental situation that is more typical 
of future use. The study includes one baseline and three follow-up assessments at 3 weeks (day 21), 6 months 
(day 180), and 12 months (day 360). 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 24 of 176 
 
 
 
 
Figure 2. Design and timeline of the randomized-controlled trial to be implemented in each of three settings. 
 
The study is designed as a two-armed trial including one arm with a single drug administration (arm A; 
albendazole) and one arm with combined treatment through co-administration of separate tablets (arm B; 
albendazole and ivermectin).  
The trial will be conducted as a multi-country study with two settings in Africa and one in Asia, namely Côte 
d’Ivoire, Pemba (Zanzibar, Tanzania) and Lao PDR. 
At baseline, all participants will be asked to provide two stool samples of at least 15 grams each (within a 
maximum of 5 days). From every stool specimen, duplicate Kato-Katz thick smears (41.7 mg each) [15] will be 
prepared and read under a microscope for eggs of T. trichiura, A. lumbricoides and hookworm by experienced 
technicians. A small amount of feces (~10 mg and 60 μg, respectively) will further be tested on fecal occult 
blood and calprotectin as proxies for gut morbidity and inflammation using a rapid diagnostic test an 
immunoassay, respectively [16]. Additionally, a portion of 1.5-2 g of stool from each specimen will be preserved 
in 70% ethanol and shipped to a reference laboratory at the Swiss Tropical and Public Health Institute (Swiss 
TPH, Basel, Switzerland) for PCR analysis [17]. While discrimination of hookworm species via morphological 
comparison during microscopy of Kato-Katz slides is not feasible [18], PCR will allow to accurately determining 
efficacy and for further classification of hookworm infection into the three species N. americanus, A. duodenale 
and A. ceylanicum. The remains of each stool sample (ideally 10 to 20 g) will be processed by the Baermann 
technique for identification of S. stercoralis infections and be recorded qualitatively as larvae-positive or 
negative. At baseline and in the first follow-up (3 weeks post treatment) an additional portion of the second stool 
sample (1.5-2 g) from a subsample of 10 participants identified with heavy intensity infections in each case (as 
assed on the first sample) will be preserved in 95% ethanol, shipped to the same reference laboratory at Swiss 
TPH in Switzerland and subjected to deep sequencing for characterization of T. trichiura strains and 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 25 of 176 
 
 
 
investigation of potential resistance markers [19]. A subsample of 30 participants will be asked to provide a daily 
stool sample for a period of up to 4 weeks to monitor dynamics of T. trichiura egg output for subsequent 
determination of the optimal timing for drug efficacy assessment as has been done for other STH species earlier 
[20]. 
A subsequent independent quality control of sample results (approximately 10%) will be conducted. Results are 
considered correct if the following tolerance margin is not exceeded: (i) No difference in presence/absence of 
hookworm, A. lumbricoides and T. trichiura, (ii) egg counts are +/-10 eggs for counts ≤100 eggs or +/-20% for 
counts >100 eggs (for each species separately) [21]. In case discrepancies above the tolerance margin are noted 
in one or more slides, all slides are re-read by the local technicians. The new results are discussed, so that in case 
of discordant results, slides can be re-evaluated to reach consensus. Infection intensity expressed as the 
arithmetic and geometric mean egg count per gram of stool (EPG) will be calculated for each treatment arm. All 
microscopically analyzed quadruplicate Kato-Katz thick smears will be destroyed within one day (after passing 
the quality control). The same sampling procedure and diagnostic approach will be applied at days 21, 180 and 
360 post-treatment. 
Patients with filariasis showed significantly higher numbers of adverse events (AE) for treatment with 
ivermectin in combination with albendazole in earlier studies [22-24]. A rapid diagnostic test (RDT; i.e. SD 
BIOLINE Oncho/LF IgG4 biplex test) to detect antigens in the blood will therefore be used to identify potential 
co-infection with Wuchereria bancrofti and Onchocerca volvulus at baseline, 6 and 12 months post-treatment 
(before a potential re-treatment). AEs after treating filariasis were mostly mild [3]; the approach of capturing 
AEs will thus not change but the result of the RDT be used to explain potential differences in AE reporting 
between filariasis negative and positive participants. 
A clinical examination of the study participants assessing general health, anthropometric parameters including 
height, weight, mid-upper arm circumference (MUAC) and skinfold thickness (i.e. triceps and subscapular 
skinfolds) as well as tympanic temperature using an ear thermometer will precede the treatment and will be 
repeated on two follow-up assessments (days 180 and 360) to evaluate potential benefits from deworming. Each 
participant will be asked to provide a finger-prick blood sample for a RDT for Plasmodium spp. infection and to 
evaluate hemoglobin (Hb) levels using a HemoCue analyzer (Hemocue Hb 301 system; Angelholm, Sweden) 
following the same (re-)assessment schedule. To assess potential improvement on nutritional indicators for 
micro- (i.e. (pro-) vitamins, inflammation markers, and iron/ferritin) and macronutrient (i.e. albumin) 
deficiencies and dynamics of biochemical blood parameters as a proxy for functioning of vital organs a venous 
blood sample (approximately 8 ml) will be taken at baseline, day 21, day 180 and 360. The biochemical 
parameters to be assessed include urea, creatinine, bilirubin, azotemia, Alanine Amino Transferase (ALAT), 
Aspartate Amino Transferase (ASAT) as well as blood cell counts (e.g. hematocrit, erythrocytes and platelets). 
To avoid accidental treatment of pregnant girls/women all female participants (≥ 10 years) will be asked to 
provide a urine sample of at least 10 ml to be subjected to a pregnancy RDT on day 0 and day 180. 
All trial participants will further be asked about existing clinical symptoms before drug administration. 
Additionally, they will be asked to provide subjective short-term (e.g. convenience of treatment) and long-term 
(e.g. effectiveness in reducing symptoms) treatment satisfaction embedded in the re-assessment questionnaires. 
As a measure of patient-rated physical functioning and wellbeing all children (6-16 years) will be administered a 
questionnaire before, 6 and 12 months after treatment, based and adapted from tools already validated in school-
aged children from rural settings in Côte d’Ivoire [25] and pre-tested in a comparable school-aged population not 
otherwise involved in this trial. To adjust for known influencing factors with regard to reinfection and morbidity 
[26, 27] in the subsequent analysis and to identify risk factors for residual infections [28] a household-based 
questionnaire will be administered to one adult member of each participating household, assessing information 
on socioeconomic characteristics, access to sanitation and water facilities as well as hygiene behavior.  
DF study with school-aged children 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 26 of 176 
 
 
 
Embedded in the parallel group trial a randomized-controlled DF study assessing ascending doses of ivermectin 
co-administered with a single dose of albendazole will be implemented. The study is designed as a four-armed 
trial including ascending doses of ivermectin co-administered with the standard dose of albendazole (arm 1‒3) 
and one placebo arm serving as a comparator (arm 4) (Figure ). 160 school-aged children infected with T. 
trichiura will be randomly assigned to arm 1‒4. Baseline and screening procedures are identical to the parallel 
group study. Children in arm 1-3 will be micro sampled on different time points between treatment day 0 and 
day 2 (at 0, 1, 2, 3, 4, 5, 6, 7, 9, 24, 48 hours post-dosing) in order to obtain pharmacokinetic data while children 
in arm 4 will provide finger-prick blood samples at day 0 only for RDT assessments. 
 
Figure 3. Efficacy, safety and pharmacokinetics of ivermectin-albendazole co-administration: dose-finding study 
flow. 
 
4.3.2 
Assessment of efficacy and other benefits after treatment 
Parallel group multi-country and DF study 
The efficacy of the treatment will be determined 21 days post-treatment by collecting another two stool samples 
which will be microscopically examined for T. trichiura using duplicate Kato-Katz thick smears and potential 
co-infection with S. stercoralis applying the Baermann technique. Participants will be considered T. trichiura 
cured if no eggs have been found in the stool. EPG will be assessed by adding up the egg counts from the 
quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic 
mean egg counts will be calculated for the different treatment arms before and after treatment to assess the 
corresponding ERRs. The stool samples collected 21 days post-treatment for efficacy assessment will further be 
re-tested with the same rapid diagnostic test and immunoassay used at baseline to determine fecal occult blood 
and calprotectin levels. Frequencies of subjects found positive with either of the two markers and by intensity 
category for calprotectin will be calculated by treatment arm. 
At the end of the study (i.e. for exclusive DF study participants 1 month post-treatment, for trial participants 12 
months post-treatment) all participants remaining positive for T. trichiura, other soil-transmitted helminths or 
filariasis will be treated with albendazole-ivermectin, the currently best approved and recommended treatment 
against T. trichiura [29]. 
Parallel group multi-country study 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 27 of 176 
 
 
 
Potential extended effects on follow-up helminth prevalences will be assessed using the same methodological 
approach as used for the efficacy assessment and will be based on stool samples collected 6 and 12 months post-
treatment. Likewise fecal occult blood and calprotectin will be re-determined on the same stool samples. 
To assess eventual reduction in morbidity and improvement in nutritional indicators all trial participants will be 
asked to provide another finger-prick at the 6 and 12 month follow-up for Hb measurement and rapid diagnostic 
testing (i.e. malaria and filariasis) and once more a venous blood sample for micronutrient/blood parameter 
evaluation at all three follow-up time points, respectively. Anthropometric measurement including height, 
weight, MUAC and skinfold thickness will be repeated on the same occasion. Children (6-16 years) will be 
asked to re-assess their own physical functioning in repeated questionnaire interviews during these two last 
follow-ups. Long-term satisfaction with the treatment will be asked 6 months post-treatment. Mean values for 
continuous outcomes and frequencies for binary/categorical outcomes will be calculated for each treatment arm 
and follow-up time point and compared using descriptive and repeated measurement analysis as detailed in 
section 7.3. 
4.3.3 
Pharmacokinetic studies 
DF study 
The micro-sampling device dried blood spot (DBS) is a more robust, ethical and patient-friendly technique 
compared to venous blood sampling to evaluate the pharmacokinetic profile of a drug. In order to use DBS in a 
clinical trial, it first needs to be evaluated that the analysis of venous and capillary blood yields same drug 
concentrations. Therefore, plasma and DBS samples were previously collected in two independent clinical trials 
in rural Côte d'Ivoire with adult volunteers who received either the standard dose of albendazole (400 mg) or the 
standard dose of ivermectin (200 µg/kg). Methods to extract and quantify ivermectin in the different matrixes 
have been validated and applied to the samples of the adult volunteers. Results show consistent correlation of 
plasma and DBS samples so that DBS can be reliably used.  
The micro-sampling device DBS will be used as a tool to evaluate the pharmacokinetic (PK) parameters of 
albendazole and ivermectin in the DF study of their co-administration in school-aged children. In more detail, 
capillary blood (± 0.1 ml) will be collected by middle or ring finger tip puncture using a finger pricker (e.g. 
Accu-chek Softclix Pro®, Roche). Sampling will be conducted at 0, 1, 2, 3, 4, 5, 6, 7, 9, 24, 48 hours post-
dosing. A few drops of blood will be transferred at each time point on DBS filter paper (Whatman) and dried for 
approximately 1 hour. The DBS cards will be transported to Basel and stored at -80° C until analysis. 
Albendazole and its metabolites will be quantified using a validated liquid chromatography tandem mass 
spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration 
curve with a foreseen limit of quantification of approximately 3 ng/ml. Quality control samples will be included 
in the study and its measured concentrations used to determine between-run and overall precision and accuracy 
of the analysis.  
 
4.4 
Measure to minimize bias 
For each study (i.e. parallel group trial and DF study) independently study participants eligible for treatment will 
be randomly assigned to one of the treatment arms using a computer-generated stratified block randomization 
code. The random allocation sequence with varying random blocks of four or eight and stratified by 2 levels of 
baseline infection intensity (light: <1000 EPG, and moderate plus heavy: ≥ 1000 EPG T. trichiura infections) 
will be provided by a statistician. The treatment arms will have an equal number of participants with light 
infection intensity, although the number of light versus moderate/heavy infections are not expected to be equal in 
each arm, depending on the distribution of infection intensity in the recruited cohort. The parallel group trial will 
be double blinded (i.e. study participants and the trial team/researchers conducting the treatment and assessing 
the outcomes will be blinded) using repacked tablets including appearance-matched placebos while the DF study 
will be single blinded (i.e. all outcome assessors except the investigators who provide the treatment and the study 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 28 of 176 
 
 
 
participants who get either active or placebo tablets matching in appearance will be blinded) due to the nature of 
this study (i.e. including ascending doses). 
 
4.5 
Study duration and duration of subject participation 
The trial will last fourteen months. The screening for the baseline will start three weeks prior to the treatment. 
Follow-up screening will take place 14-21 days, 180 days and 360 days post-treatment and last each time for 
about three weeks. Schedules of visits are summarized below. 
 
4.6 
Schedule of visits 
Parallel group multi-country study  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 29 of 176 
 
 
 
Table 3. Schedule of visits of parallel group study. 
 
Screenin
g 
Baseline/Treatment/Safety 
Follow up 
 
-21 to -1 
days 
Hours 
Days 
 
0 
Randomization and treatment 
3 
24 
21 
180 
185 
360 
Diagnosis (stool 
examination) 
X 
 
 
 
X 
X 
Selective re-treatment 
X 
Gut morbidity (stool 
RDTs) 
X 
 
 
 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Clinical examination 
 
X 
 
 
 
X 
X 
Pregnancy testing 
 
X 
 
 
 
X 
 
Hemoglobin measurement 
 
X 
 
 
 
X 
X 
Plasmodium co-infection 
 
X 
 
 
 
X 
X 
Filaria co-infection 
 
X 
 
 
 
X 
X 
Venous blood examination 
 
X 
 
 
X 
X 
X 
Physical functioning 
 
X 
 
 
 
X 
X 
Capturing AEs 
 
 
X 
X 
X 
 
 
Capturing SAE 
 
 
X 
X 
X 
 
 
Treatment satisfaction 
 
 
 
X 
 
X 
X 
 
 
 
DF study 
The general outline of the DF study is similar to the parallel group multi-country study with the following 
adaption: Follow-up will be performed 21 days after treatment only and micro-blood sampling will be performed 
0‒48 hours post treatment.  
 
 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 30 of 176 
 
 
 
Table 4. Schedule of visits of dose-finding study.  
 
Screening 
 
Follow up 
 
-21 to -1 days 
Hours 
21 days 
 
0 
Randomization and treatment 
1-9 
24 
48 
Diagnosis (stool 
examination) 
X 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
Clinical examination 
 
X 
 
 
 
 
Rapid diagnostic tests 
 
X 
 
 
 
 
PK sampling 
 
X 
X 
X 
X 
 
Capturing AEs 
 
 
X (3h) 
X 
 
X 
Capturing SAE 
 
 
X (3h) 
X 
 
X 
 
5. 
Selection of the trial subjects 
5.1 
Recruitment 
The study will be carried out in community members aged 6‒60 years in areas with moderate to high T. trichiura 
endemicity (communities with a prevalence ≥ 25%) identified from earlier studies and/or based on experience of 
the local collaborating teams. The trial will be implemented as community-based study in order to recruit 
participants from a broad age range (6‒60 years). Ideally, entire communities with a population size of < 1000 
inhabitants will be included in the study for pre-screening and identification of T. trichiura cases to avoid 
potential selection bias of households. To identify all potentially eligible households of the respective 
communities and its composition in terms of age groups a preceding population census will be conducted. 
All adult community members, including parents/caregivers of minor participants, will be invited to participate 
in an information meeting to explain the purpose and procedures of the study, including potential benefits and 
risks. Parents/caregivers/potential participants will be encouraged to ask questions in an open discussion forum. 
During this session, they will be informed of preventive actions they can take to help protect their children from 
acquiring T. trichiura and other STH infections in the future (e.g. adequate food, preparation and defecation 
behavior). 
Those parents/caregivers and their children who are interested in the study will be invited to complete the 
process of informed consent. See section 9.3 for details on obtaining informed consent. Only those participants 
who have written informed consent will be assessed for study eligibility criteria during screening procedures. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 31 of 176 
 
 
 
5.2 
Inclusion criteria 
1. Written informed consent signed by either the participant him/herself (≥21 years of age) or by parents 
and/or caregivers for children/adolescents; and written assent by child/adolescent (aged 6‒20 years). 
2. Agree to comply with study procedures, including provision of two stool samples at the beginning 
(baseline) and on three follow-up assessments (approximately 3 weeks, 6 months, and 12 months later). 
3. Aged ≥6 to 60 years for parallel group trial and ≥6 to 12 years for DF study. 
4. At least two slides of the quadruple Kato-Katz thick smears positive for T. trichiura and infection 
intensities of at least 100 EPG. 
 
5.3 
Exclusion criteria 
1. No written informed consent by individual/parents and/or caregiver.  
2. Presence of major systemic illnesses, e.g. severe anemia (below 80 g/l Hb according to WHO [30]), 
clinical malaria as assessed by a medical doctor (positive Plasmodium RDT and ≥38 °C ear temperature), 
upon initial clinical assessment. 
3. History of acute or severe chronic disease (e.g. cancer, diabetes, chronic heart, liver or renal disease). 
4. Recent use of anthelmintic drug (within past 4 weeks). 
5. Attending other clinical trials during the study. 
6. Negative or low egg count (less than 100 EPG or less than 2 out of 4 slides positive) diagnostic result for 
T. trichiura eggs in the stool. 
7. Known allergy to study medications (i.e. albendazole and ivermectin). 
8. Pregnancy or lactating in the 1st week after birth (according to WHO guidelines within LF control 
programs [31]). 
9. Currently taking medication with known interaction (e.g. for albendazole: cimetidine, praziquantel and 
dexamethasone; for ivermectin: warfarin). 
 
5.4 
Criteria for discontinuation of trial 
A subject can be discontinued from the study for the following reasons: 
1. 
Withdraws from the study (this can happen anytime as participation is voluntary and there are no further 
obligations once a participant withdraws). 
2. 
At the discretion of the Principal Investigator (PI) or co-PI, if the participant is not compliant to the 
requirements of the protocol. 
Discontinued subjects will not be replaced. If, for any reason, a subject is discontinued from the study before the 
end of treatment evaluations, the safety procedures planned (AEs monitoring) will be conducted. 
 
5.5 
Treatment of subjects 
Parallel group multi-country and DF study 
All T. trichiura-infected, consenting, and participating community members will be treated with the respective 
single or combination treatment regimen at day 0. 400 mg albendazole will be the product of Glaxo Smith Kline 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 32 of 176 
 
 
 
(Zentel®) and a single tablet administered. 3 mg tablets of ivermectin (Stromectol®) will be obtained from 
Merck, France, the weight recorded for each participant and the correct dose evaluated and administered. 
Matching ivermectin placebo tablets (in terms of appearance) will be produced and a certificate of manufacture 
and analysis be provided by the University of Basel. The tablets for the main trial, which is double-blinded, will 
be repacked into neutral separate plastic bags each containing one albendazole tablet and the maximum number 
of ivermectin tablets with regard to weight and dose or the corresponding number of placebo tablets. The 
ivermectin tablets for the dose-finding study will be kept in the original package until treatment day. Since 
albendazole and ivermectin are known to be better absorbed in humans after a high-fat meal was consumed, 
participants will receive a local high-fat breakfast (sandwich with e.g. oily sardines) prior to treatment [32, 33]. 
All drugs will be administered in the presence of the investigator(s), and ingestion confirmed. This will be 
recorded with the time and date of closing. Subjects will be asked not to take any drugs other than those 
prescribed by the study medical team. After ingestion of the medication, the subjects will be observed for 3 
hours to ensure retention of the drug. Vomiting within 1-hour post-dosing will require re-dosing. The subjects 
will not be allowed more than one repeated dose. No re-administration will be needed for subjects vomiting after 
one hour. The Principal Investigator is responsible for drug accountability at the study site. Maintaining drug 
accountability includes careful and systematic study drug storage, handling, dispensing and documentation of 
administration. 
Antimalarial treatment (i.e., artemisinin-based combination therapy) will be provided to participants found with 
clinical malaria (i.e. positive Plasmodium RDT and ≥38 °C ear temperature) or severely anemic in combination 
with a positive RDT result. Iron supplementation will be offered to severely anemic individuals with a negative 
RDT result. 
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 helminthiases in study 
participants will be substituted with a free single-dose treatment (i.e. albendazole 400 mg + ivermectin 200 
µg/kg) against STH, S. stercoralis as well as Filaria infection at the study endpoint (after the day 360 follow-up 
assessment) offered by the study team. At each follow-up time point, participants will be interviewed whether 
they had taken any anthelmintic treatment (e.g. self-purchased, obtained from clinics etc). 
 
5.6 
Concomitant therapy 
All medications taken one month before and during the study period until the last stool examination must be 
recorded with indication, dose regimen, date and time of administration. 
Medication(s)/treatment(s) permitted during the trial: 
- Analgesics and antipyretics are allowed to be given to the subjects in case of fever, antiemetics to prevent 
nausea and vomiting and/or antibiotics to prevent or treat bacterial superinfection. 
Medication(s)/treatment(s) NOT permitted during the trial:  
- No other active drugs against helminths are permitted during the trial. 
- No drugs with known interactions with the study medication are permitted during the trial. 
 
6. 
Safety assessments 
Few AEs have been reported following ivermectin-albendazole co-administration in STH-infected individuals. 
The most common AEs were abdominal cramps, headache, fatigue, nausea, diarrhea, fever and vertigo [7, 8, 34]. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 33 of 176 
 
 
 
The safety profile of co-administered ivermectin and albendazole will be assessed through the recording, 
reporting and analysis of baseline medical conditions, AEs and a physical, clinical and biochemical 
examinations. 
 
6.1 
Adverse event definitions 
The term “adverse event” could include any of the following events which develop or increase in severity during 
the course of the study, after administration of the study product: 
a) 
Any 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 AEs but be considered baseline medical conditions. For the purpose of this trial, disease 
progression and relapse will be considered as treatment failure, not as an AE.  
The observation time for AEs starts when the treatment is initiated until day 21 (3 weeks after last drug 
administration).  
These data will be recorded on the appropriate case report form (CRF) sections, regardless of whether they are 
thought to be associated with the study or the drug under investigation. Associated with the use of the drug 
means that there is a reasonable possibility that the event may have been caused by the drug (see also relatedness 
definitions below). 
6.1.1 
Severity grading 
Adverse signs or symptoms will be graded by the Investigator as mild, moderate, severe or life threatening 
according to the following definitions:  
Grade 
Definition 
1 
Mild: the subject is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
2 
Moderate: the subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity. 
3 
Severe: significant impairment of functioning: the subject is unable to carry out his or her 
usual activities. 
4 
Life threatening or disabling  
5 
Death related to adverse events 
 
6.1.2 
Relatedness 
Relatedness will be assessed as defined below based on the temporal relationship between the AE and the 
treatment, known side effects of treatment, medical history, concomitant medication, course of the underlying 
disease and trial procedures. 
Possibly related: an AE which can medically (pharmacologically/clinically) be attributed to the study treatment. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 34 of 176 
 
 
 
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 co-administration of ivermectin-albendazole 
reported in the literature or on the drug package leaflets and listed in the consent form. 
Unexpected adverse drug reaction: Any AE possibly related to the study product administration, the nature, 
frequency, specificity or severity of which is unanticipated and not consistent with the available risk information 
described for these drugs.  
6.1.4 
Serious adverse events 
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 subject was, in the view of the Investigator, at immediate risk 
of death from the reaction as it occurred, i.e. it does not include a reaction that, had it occurred 
in a more serious form, might have caused death; 
3. results in persistent or significant disability/incapacity, i.e. the event causes a substantial 
disruption of a person’s ability to conduct normal life functions; 
4. requires in patient hospitalization or prolongation of existing hospitalization; 
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” AE does not necessarily meet the criteria for a “serious” AE. SAEs are reported from consent to 3 
weeks post-treatment (Day 21).  
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 SAEs.  
 
6.2 
Methods of recording and assessing adverse events 
Subjects will be kept for observation for at least 3 hours following treatment for any acute AEs. If there is any 
abnormal finding, the local study physician will perform a full clinical, physical and biochemical examination 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 35 of 176 
 
 
 
and findings will be recorded. An emergency kit will be available on site to treat any medical conditions that 
warrant urgent medical intervention. In addition patients will also be interviewed 3 and 24 hours and again 3 
weeks after treatment about the occurrence of AEs (see chapter 4.6). 
Information on all AEs (onset, duration, intensity, seriousness and causality) will be immediately entered in the 
appropriate AE module of the CRF that serves as source document. For all AEs, sufficient information will be 
pursued and/or obtained so as to permit i) an adequate determination of the seriousness of the event (i.e. whether 
the event should be classified as a SAE); ii) an assessment of the casual relationship between the AE and the 
study treatments and iii) an assessment of intensity of AEs will be judged by the study physician. 
All SAEs or SUSARs must be reported as described in Section 6.3. 
 
6.3 
Reporting of serious adverse events 
Any study-related unanticipated problem posing risk of harm to subjects or others (including all unexpected 
adverse drug reactions), and any type of SAE will be immediately (within a maximum of 24 hours after 
becoming aware of the event) notified to the study sponsor-investigator and co-PIs: 
Prof. Dr. Jennifer Keiser (Sponsor-investigator) 
Swiss Tropical and Public Health Institute 
Socinstrasse 57, 4051 Basel, Switzerland 
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
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 SAE or the unanticipated problem in the form of a written narrative. This should include a 
copy of a completed SAE form, and any other diagnostic information that will assist the understanding of the 
event. In exceptional circumstances, a SAE may be reported by telephone. In these cases, a written report must 
be sent immediately thereafter by fax or e-mail. Names, addresses and telephone for SAE reporting will be 
included in the trial-specific SAE form. Relevant pages from the CRF may be provided in parallel (e.g. medical 
history, concomitant medications).  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 36 of 176 
 
 
 
6.4 
Safety reporting to Health Authorities and Ethics Committees 
The sponsor-investigator will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. Additionally, this information will be provided to ‘Ethikkomission Nordwest- 
und Zentralschweiz’ (EKNZ, Switzerland), the ethics committee and the ‘Direction de la Pharmacie, du 
Médicament et des Laboratoires (DPML)’ in Côte d’Ivoire according to national rules. Fatal or life-threatening 
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. 
 
7. 
Statistics 
7.1 
Definition of primary endpoint 
CR of co-administered ivermectin-albendazole against T. trichiura is the primary endpoint in our study. Since 
treatment success is influenced by infection intensity, stratified block randomization will be used (baseline 
infection intensity: light infections and moderate/heavy infections) to ensure balanced treatment groups in terms 
of infection intensity. 
 
7.2 
Justification of number of trial subjects  
Parallel group multi-country study 
Based on available summarized efficacy measures from a recent review [1] and the published literature, we 
assume that the CR of albendazole against T. trichiura is 30% compared to 50% in the albendazole-ivermectin 
treatment regimen. To detect a difference with 90% power at a two-sided 5% significance level, we require 121 
participants per study arm and 143 to account for potential loss to follow-up of 15%. We further assume the 
same treatment efficacy in the mid-term treatment and a 6-months reinfection risk of 10%. Consequently we 
expect a proportion of negative patients after 12 months of 44% in the albendazole arm and of 65% in the 
albendazole-ivermectin arm resulting in a required sample size of 111 participants per arm. To account for a loss 
to follow-up of 30% after 6 months and 40% at final assessment (12 months) we aim to recruit 300 participants 
in each treatment group (600 in total) in each country.  
Subgroup analysis will be conducted stratifying the study population by age category (school-aged and adults). 
For the subgroup analysis we will pool the data from all 3 countries to ensure sufficient statistical power. 
DF study 
Since the existence of a drug effect is well known, the main aim of the study is the elucidation of the nature of 
the dose–response relationship. Modeling approaches showed that with 40 children enrolled in each of the 4 
study arms (placebo, 200 µg/kg, 400 µg/kg, and 600 µg/kg co-administered with albendazole (400 mg)) the dose 
response prediction model had a median precision (one half length of the 95%-confidence intervals) of 10% 
assuming associated cure rates of 2.5%, 50%, 60% and 70% taking into account a loss to follow up of 10%. The 
suggested sample size is also in line with the recommendations from Klingenberg et al. 2009 [36]. This sample 
size is sufficiently high to determine the key PK parameters as well as pharmacokinetic/pharmacodynamic 
(PK/PD) relationships taking into account that PK variability is high.  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 37 of 176 
 
 
 
7.3 
Description of statistical methods 
The primary available case analysis will include all participants with primary end point data. In addition, an 
intention-to-treat analysis will be conducted considering all participants with missing endpoint data as treatment 
failure or all as treatment success to ensure that the results are not sensitive to potential loss to follow-up bias. CRs 
will be calculated as the percentage of egg-positive (larvae- positive for S. stercoralis) participants at baseline who 
become egg-negative (larvae-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. For S. stercoralis 
infection no further quantification of larvae in stool will be done. The ERR of STH infection will be calculated as: 
𝐸𝑅𝑅=  1 − 
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝 + 1) −1
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 1)      −1  
In the primary model we estimate the difference among CRs by using unadjusted logistic regressions. In a 
subsequent analysis an adjusted logistic regression (adjustment for age, sex and weight) will be performed.  
Geometric mean egg counts will be calculated for the different treatment arms before and after treatment to assess 
the corresponding ERRs. Bootstrap resampling method with 5,000 replicates will be used to calculate 95% 
confidence intervals (CIs) for ERRs and the difference between the ERRs. 
Results from the stool RDT for fecal occult blood will be categorized as negative, trace and positive. For 
calprotectin, individuals with levels exceeding 50 μg/g will be considered as positive and concentrations be 
classified into low (51–149 μg/g), medium (150–299 μg/g) and high (≥300 μg/g) intensity [16]. 
Anthropometric measurements such as height and weight of school-aged children will be translated into weight-
for-age, height-for-age and weight-for-height related z-scores using readily available Stata macros calculating 
growth indicators for children 5-19 years [37]. Body mass index and indicators for muscle and fat tissue such as 
MUAC and skinfold thickness will serve as additional indicators of nutritional status for adults and will further be 
classified using a percentiles approach to compare within populations [38]. 
Questionnaires on physical functioning and treatment satisfaction will be evaluated by creating summary scores 
by summing up and transforming the single question scores according to the following formula: [(actual raw score-
lowest possible raw score)/(possible raw score range)]*100 [25]. 
Nutritional and morbidity indicators will be analysed using logistic and linear regression as appropriate. To 
compare individual’s changes in nutrition/morbidity categories as an effect from treatment McNemar’s test will 
be applied. The analysis after 6 and 12 month of follow-up will be complemented by generalized estimating 
equation (GEE) models with independent correlation structure and empirical estimators to account for missing 
data. 
AEs will be evaluated descriptively as the difference of proportion reporting AEs before and after treatment. 
On the basis of the LC-MS/MS measurements, the following PK parameters for plasma will be calculated:  
Cmax 
maximal plasma concentration 
tmax 
time to reach Cmax 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 38 of 176 
 
 
 
AUC 
area under the curve, from 0 to 24h and 0 to infinity 
T1/2 
elimination half-life 
T and AUC above minimal inhibitory concentration (MIC) 
Cmax and Tmax will be observed values derived from the plasma concentration time profile. AUC and T1/2 will 
calculated with the software WinNonlin (Version 5.2, Pharsight Corporation, USA) using compartmental 
analysis. The elimination half-life will be estimated by the equation: T1/2 = ln2/, where  will be determined by 
performing a regression of the natural logarithm of the concentration values during the elimination period.  
Further PK analysis will be undertaken fitting a structural compartmental PK model with the software 
NONMEM 7 [39] via nonlinear mixed effects modeling (allowing for both between patient variation and random 
effects). This model will describe the plasma drug levels in time, allowing one to investigate variation between 
patients in drug levels. In addition, PK/PD analysis will be undertaken via NONMEM to investigate the drivers 
of cure and/or burden reduction and potentially any covariates with drug levels. 
 
7.4 
Description of 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 with the investigators and their study coordinators and a member from Swiss 
TPH. This meeting will include a detailed discussion of the protocol, performance of study procedures (standard 
operating procedures (SOPs) from previous studies available on site), CRF completion, and specimen collection 
and diagnostic methods.  
The data produced from this research project will fall into the following categories:  
 
1. Eggs counts of T. trichiura, A. lumbricoides and hookworm and infection status with S. stercoralis based 
on participants’ stool samples analyzed using the Kato-Katz and Baermann technique, respectively,  
before (baseline) and at 3 time points after treatment (follow-ups after 3 weeks, 6 and 12 months). 
Presence of fecal occult blood and elevated calprotectin levels will be evaluated and recorded applying 
RDTs on the same stool samples and assessment time points. 
2. Personal information such as name, age, gender and household composition of trial participants. 
3. Anthropometric and clinical characteristics of the trial participants collected using the study’s CRF such 
as weight, height, skinfold thickness, blood pressure, temperature, hemoglobin level, infection status with 
Plasmodium spp. and filariasis, any abnormal medical condition or chronic disease as well as pregnancy 
in female participants 10 years and above. 
4. Number and type of AEs registered in the CRF actively probed for 3 and 24 hours after treatment. The 
same data will be collected during the collection of the first sample at the 3-week follow-up. 
5. Scales for participant-rated treatment satisfaction and self-rated physical functioning in school-aged 
children captured on different time points (i.e. 3 weeks and 6 months and baseline, 6 and 12 months after 
treatment, respectively) and recorded on the CRF. 
6. Concentration levels of blood and biochemical parameters together with indicators for micronutrient 
status before (baseline) and at 3 time points after treatment (follow-ups after 3 weeks, 6 and 12 months).  
7. Household-level data on socioeconomic characteristics, presence and use of water and sanitation as well 
as hygiene-related attitudes and practices. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 39 of 176 
 
 
 
All data on parasitology and questionnaires about AEs, self-reported clinical signs and symptoms, physical 
functioning, and treatment satisfaction will be paper-captured and subsequently doubled entered (data entry 
SOP) into ACCESS data entry masks by two independent persons. For quality assurance error, range and 
consistency checks will be programmed for the ACCESS data entry masks and all double-entered data be cross-
checked using the Data Compare utility of EpiInfo. Any discrepancies will be corrected by consulting the hard 
copy.  
Data in category 1 to 6 will be double-entered using an EpiInfo mask and saved in .mdb, .xlsx, .dta, and .csv. 
Data in category 7 will be directly entered while collecting into tablets using Open Data Kit (free electronic data 
collection software) and uploaded to a server hosted at Swiss TPH. All categories will be merged into a single 
master file saved in .dta, .xlsx and .csv. Data will then be analysed as described in section 7.3. Hard copies of the 
data collected within the trial country such as parasitological, stool RDT, blood parameter sheets and CRFs will 
remain at Centre Suisse de Recherches Scientifiques en Côte d’Ivoire (CSRS). Digital copies along with the 
databases will be transferred to the Swiss TPH after a Material Transfer Agreement has been signed by both the 
Swiss TPH and CSRS. All data is expected to not exceed 5GB. 
Invited and screened patients will be listed in a confidential “subject identification list and screening log”. 
Enrolled patients will be listed in a confidential “subject enrolment log” and attributed a unique study number; 
this document will constitute the only source to decode the pseudonymised data and will only be accessible to 
the local principal investigator. All study-specific data will only contain this unique identifier instead of any 
names. Electronic data files will be stored on secured network drives with restricted access for study personnel 
only. Data analysis will be conducted with pseudonymised data and reporting of findings will be fully 
anonymised. All databases will be password secured. 
Essential infrastructure such as lockable cabinets for safe storage of hardcopy data will be made available. 
Network drives with restricted access for authorized personnel only and appropriate analysis software are 
available.  
 
8. 
Duties of the investigator  
8.1 
Investigator’s confirmation 
This trial will be conducted in accordance with the protocol, International Conference on Harmonization Good 
Clinical Practice E6 (R2) (ICH-GCP) and the current version of the Helsinki Declaration. 
All protocol modifications must be documented in writing. A protocol amendment can be initiated by either the 
Sponsor/PI or any Investigator. The Investigator will provide the reasons for the proposed amendment in writing 
and will discuss with the Sponsor/PI and Co-PIs. Any protocol amendment must be approved and signed by the 
Sponsor/PI and must be submitted to the appropriate Independent Ethics Committee (IEC) for information and 
approval, in accordance with local requirements, and to regulatory agencies if required. Approval by IEC must 
be received before any changes can be implemented, except for changes necessary to eliminate an immediate 
hazard to trial subjects, or when the change involves only logistical or administrative aspects of the trial, e.g. 
change of telephone number(s). 
 
8.2 
Damage coverage 
A general liability insurance of the Swiss TPH is in place (Winterthur Police Nr. 4746321) and patient liability 
insurances will be issued in the respective trial countries. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 40 of 176 
 
 
 
8.3 
Project management 
The trial team will include the PI (Prof. Jennifer Keiser), three Co-PIs (Dr. Eveline Hürlimann, Dr. Jessica 
Schulz, and Dr. Jean Coulibaly), a trial statistician (Dr. Jan Hattendorf), as well as a local physician (Dr. Yves 
Koutouan N'Gbesso), nurses and laboratory technicians. Prof. Jennifer Keiser, Dr. Eveline Hürlimann, Dr. 
Jessica Schulz and a 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. Jean Coulibaly and the PhD student will monitor all field activities at the 
study site. Dr. Yves Koutouan N'Gbesso, will be responsible for patient recruitment, medical aspects of the trial 
and enrolment of patients in the trial. 
The investigator team is responsible for ensuring that the protocol is strictly followed. The investigator should 
not make any changes without the agreement of the Principal Investigator and the Co-Investigators, except when 
necessary to eliminate an apparent immediate hazard or danger to a study participant. The investigator will work 
according to the protocol and GCP. The investigator may take any steps judged necessary to protect the safety of 
the participants, whether specified in the protocol or not. Any such steps must be documented. During the 
treatment the records are maintained by the responsible medical doctor. All entries have to be made clearly 
readable with a pen. The investigator must be thoroughly familiar with the properties, effects and safety of the 
investigational pharmaceutical product.  
 
9. 
Ethical considerations 
9.1 
Independent ethics committee 
The study will be submitted for approval by the institutional research commission of the Swiss TPH and the 
ethics committees of Switzerland (EKNZ: Ethical Commission of northwest/central Switzerland) and Côte 
d’Ivoire (CNER: Comité Nationale d’Ethique de la Recherche) and the Ivorian medicines regulatory authority 
(DPML: Direction de la Pharmacie, du Médicament et des Laboratoires). The study will be undertaken in 
accordance with the Declaration of Helsinki and GCP. 
 
9.2 
Evaluation of the risk-benefit ratio 
Ivermectin in combination with albendazole are well-known, widely used drugs in mass treatment programs 
against filariasis, and have little and mainly mild AEs (headache, abdominal pain etc.). 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 ivermectin (200 μg/kg)-albendazole (400 mg) 
considering higher efficacy compared to the existing standard treatment (albendazole monotherapy) and recent 
inclusion as recommended treatment scheme on the Essentials Medicines List [29]. 
 
9.3 
Subject information and consent 
Community meetings allowing for open exchange will be organized in every study locality where a prescreening 
for identification of positive cases is to be conducted. The purpose and procedures, the benefits and risks of the 
study will be explained in order to make sure that all community members are at the same level in terms of 
information. All parents or caregivers of eligible children and all adult participants (≥21 years) will be 
individually informed about benefits and risk associated to the trial. They will have sufficient time for reflection 
of their child’s or their own participation, respectively. They will then be asked to sign a written informed 
consent sheet. In case the person is illiterate, an impartial witness that can read and write has to sign the consent 
and the illiterate participant to give a thumb print. In addition to a written informed consent form signed by their 
parent or caregiver, minor participants (aged 6-20 years) will also be briefed verbally and written assent sought 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 41 of 176 
 
 
 
in form of their name written down or if illiterate by providing a thumb print. Even if the minor participant gives 
written assent, the parent/caregiver has to sign the consent. 
Information sheets are printed in French but will additionally be verbally translated into local languages (i.e. 
Abbé, Attié, Dioula, Moré) during community meetings. To all participants and parents/caregivers a signed copy 
of the informed consent form will be given. Participation is voluntary and all participants have the right to 
withdraw from the study at any given point in time with no further obligations. Participation itself will not be 
awarded with compensation. 
 
9.4 
Subject confidentiality 
The obtained data will be handled strictly confidentially. Only members of the study team will have access to the 
data. Personal data will be coded for data analysis. The codes will be filled with the participant’s identity on a 
separate file (subject identification list and screening log) and stored in a secured place at the local institutions 
(i.e. Côte d’Ivoire: CSRS, Lao PDR: National Institute of Public Health, and Pemba: Public Health Laboratory 
Ivo de Carneri) and will only be accessible to investigators. No names will be published at any time, and 
published reports will not allow for identification of single subjects. Confidentiality and anonymity will be 
ensured throughout the entire research project. The investigators have all been trained in GCP. None of the 
investigators declare to have any conflicts of interest. 
 
9.5 
Subjects requiring particular protection 
This study will include school-aged children, since T. trichiura infection occurs often in children; hence this age 
group is at high risk of infection and is therefore the major target group in MDA campaigns. Pharmacokinetic 
and DF studies in this population, however, have to our knowledge so far only been done or are underway by the 
research team itself for the investigated medicine products (i.e. ivermectin and albendazole). Since PK 
parameters vary between children and adults these studies cannot be obtained by carrying out the trial on adults. 
Our trial will produce more evidence to support the search for a safe and effective treatment scheme against STH 
infections in children and whole communities. 
 
9.6 
Other aspects 
Within the DF study one study arm will include school-aged children treated with placebo. However, this group 
will be treated with a single dose of co-administered albendazole (400 mg) and ivermectin (200μg/kg), as 
meanwhile listed on the EML of WHO to treat STH infection [29], at the first follow-up (already 3‒4 weeks 
later). Considering all security measures (clinical, physical and biochemical exams) set up for inclusion of trial 
participants, any person showing an unfavorable medical condition will not be included in the trial. Hence, we 
believe that a 3-weeks delay in treatment should not cause any medical concern for the participants of the 
placebo arm. Of note, populations at risk are in general treated only in yearly intervals to reduce morbidity from 
chronic infections within MDA campaigns of national control programs. 
 
10. Quality control and quality assurance 
10.1 
Monitoring and auditing 
We will work with locally based monitors. These 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 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 42 of 176 
 
 
 
observations and findings will be documented and communicated to appropriate study personnel and 
management. A corrective and preventative action plan will be requested and documented in response to any 
audit observations. No sponsor initiated audits are foreseen, but audits and inspections may be conducted by the 
local regulatory authorities or ethics committees. The Investigator agrees to allow inspectors from regulatory 
agencies to review records and is encouraged to assist the inspectors in their duties, if requested. 
 
10.2 
Access to data, handling of data and samples (data protection), archiving (place, duration) and 
destruction 
Information about study subjects will be kept confidential and managed accordingly. A paper CRF will be 
completed for each subject enrolled into the clinical study. The investigators will review, and approve each 
completed CRF. The study CRF is the primary data collection instrument for the study. All data requested on the 
CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank because the 
procedure was not done or the question was not asked “N/D” will be entered. If the item is not applicable to the 
individual case “N/A” will be written. All entries will be printed in black ink. All corrections must be initialed 
and dated.  
The results of the research study will be published, but subjects’ names or identities will not be revealed. 
Records will remain confidential. To maintain confidentiality, the Sponsor-Investigator will keep records in 
locked cabinets and the results of tests will be coded to prevent association with participant’s names. Data 
entered into the ACCESS data entry mask will be accessible only by authorized personnel directly involved with 
the study and will be encoded. Subject-specific information may be provided to other appropriate medical 
personnel only with the subject’s permission for adults or the parent/caregiver’s permission for minors. 
After the study has been completed all samples will be destroyed and research data and related material will be 
kept for a minimum of 15 years to enable understanding of what was done, how and why, which allow the work 
to be assessed retrospectively and repeated if necessary. Storage and backup will be in three places: personal 
laptops of Jennifer Keiser, Eveline Hürlimann, Jessica Schulz, Chandni Patel and Jean Coulibaly, Swiss TPH 
shared server and SWITCHdrive (a cloud storage supported by University of Basel). Archiving conditions will 
be made strictly confidential by password protection. 
 
10.3 
Data entered directly in the CRF – definition of source data 
Source Data are the clinical findings and observations, laboratory data maintained at the study site. Source data 
are contained in source documents. Local authorities are allowed to access the source data. Data will be entered 
directly onto the CRFs. The CRF is considered as a source document. All CRFs will be kept for at least 15 years. 
The study site will retain the original of the CRF to ensure that local collaborators can provide access to the 
source documents to a monitor, auditor, or regulatory agency while a copy of the CRF will be taken to Swiss 
TPH. 
 
10.4 
Data and safety monitoring board / data monitoring committee  
In our study no data and safety monitoring board will be established, since we work with well-known drugs in a 
limited number of participants and using a single dose treatment. This study is anticipated to be no greater than 
minimal risk to participants. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 43 of 176 
 
 
 
10.5 
Study Documents: Translations - Reference language 
- Protocol: Master document in English, all further language versions are translations thereof. 
- CRF: Master document in English, all further language versions are translations thereof. 
- ICF: Master document in English, all further language versions are translations thereof. 
 
11. Dissemination of results and publication 
The final results of this study will be published in a scientific journal and presented at scientific conferences. The 
Bill & Melinda Gates Foundation 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 study report will be shared with the local ethics committees and the national 
regulatory authorities. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 44 of 176 
 
 
 
12. References 
1. 
Moser W, Schindler C, Keiser J: Efficacy of recommended drugs against soil transmitted helminths: 
systematic review and network meta-analysis. BMJ 2017, 358:j4307. 
2. 
Hughes D, Andersson DI: Evolutionary consequences of drug resistance: shared principles across 
diverse targets and organisms. Nat Rev Genet 2015, 16(8):459-471. 
3. 
Palmeirim MS, Hürlimann E, Knopp S, Speich B, Belizario V, Jr., Joseph SA, Vaillant M, Olliaro P, 
Keiser J: Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-
transmitted helminths: A systematic review, meta-analysis and individual patient data analysis. 
PLoS Negl Trop Dis 2018, 12(4):e0006458. 
4. 
Belizario VY, Amarillo ME, de Leon WU, de los Reyes AE, Bugayong MG, Macatangay BJ: A 
comparison of the efficacy of single doses of albendazole, ivermectin, and diethylcarbamazine alone 
or in combinations against Ascaris and Trichuris spp. Bull World Health Organ 2003, 81(1):35-42. 
5. 
Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C: A comparative trial of a single-
dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and 
other soil-transmitted helminth infections in children. Am J Trop Med Hyg 1996, 55(5):477-481. 
6. 
Ismail MM, Jayakody RL: Efficacy of albendazole and its combinations with ivermectin or 
diethylcarbamazine (DEC) in the treatment of Trichuris trichiura infections in Sri Lanka. Ann Trop 
Med Parasitol 1999, 93(5):501-504. 
7. 
Knopp S, Mohammed KA, Speich B, Hattendorf J, Khamis IS, Khamis AN, Stothard JR, Rollinson D, 
Marti H, Utzinger J: Albendazole and mebendazole administered alone or in combination with 
ivermectin against Trichuris trichiura: a randomized controlled trial. Clin Infect Dis 2010, 
51(12):1420-1428. 
8. 
Speich B, Ali SM, Ame SM, Bogoch, II, Alles R, Huwyler J, Albonico M, Hattendorf J, Utzinger J, 
Keiser J: Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, 
albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and 
concomitant soil-transmitted helminth infections: a four-arm, randomised controlled trial. Lancet 
Infect Dis 2015, 15(3):277-284. 
9. 
Betson M, Søe MJ, Nejsum P: Human trichuriasis: whipworm genetics, phylogeny, transmission and 
future research directions. Current Tropical Medicine Reports 2015, 2(4):209-217. 
10. 
Ghai RR, Simons ND, Chapman CA, Omeja PA, Davies TJ, Ting N, Goldberg TL: Hidden population 
structure and cross-species transmission of whipworms (Trichuris sp.) in humans and non-human 
primates in Uganda. PLoS Negl Trop Dis 2014, 8(10):e3256. 
11. 
Hawash MB, Betson M, Al-Jubury A, Ketzis J, LeeWillingham A, Bertelsen MF, Cooper PJ, Littlewood 
DT, Zhu XQ, Nejsum P: Whipworms in humans and pigs: origins and demography. Parasit Vectors 
2016, 9:37. 
12. 
Speich B, Moser W, Ali SM, Ame SM, Albonico M, Hattendorf J, Keiser J: Efficacy and reinfection 
with 
soil-transmitted 
helminths 
18-weeks 
post-treatment 
with 
albendazole-ivermectin, 
albendazole-mebendazole, albendazole-oxantel pamoate and mebendazole. Parasit Vectors 2016, 
9:123. 
13. 
Anderson R, Farrell S, Turner H, Walson J, Donnelly CA, Truscott J: Assessing the interruption of the 
transmission of human helminths with mass drug administration alone: optimizing the design of 
cluster randomized trials. Parasit Vectors 2017, 10(1):93. 
14. 
Lo NC, Addiss DG, Hotez PJ, King CH, Stothard JR, Evans DS, Colley DG, Lin W, Coulibaly JT, 
Bustinduy AL, Raso G, Bendavid E, Bogoch, II, Fenwick A, Savioli L, Molyneux D, Utzinger J, Andrews 
JR: A call to strengthen the global strategy against schistosomiasis and soil-transmitted 
helminthiasis: the time is now. Lancet Infect Dis 2017, 17(2):e64-e69. 
15. 
Katz N, Chaves A, Pellegrino J: A simple device for quantitative stool thick-smear technique in 
Schistosomiasis mansoni. Rev Inst Med Trop São Paulo 1972, 14(6):397-400. 
16. 
Bustinduy AL, Sousa-Figueiredo JC, Adriko M, Betson M, Fenwick A, Kabatereine N, Stothard JR: 
Fecal occult blood and fecal calprotectin as point-of-care markers of intestinal morbidity in 
Ugandan children with Schistosoma mansoni infection. PLoS Negl Trop Dis 2013, 7(11):e2542. 
17. 
Kaisar MMM, Brienen EAT, Djuardi Y, Sartono E, Yazdanbakhsh M, Verweij JJ, Supali T, van Lieshout 
L: Improved diagnosis of Trichuris trichiura by using a bead-beating procedure on ethanol 
preserved stool samples prior to DNA isolation and the performance of multiplex real-time PCR 
for intestinal parasites. Parasitology 2017, 144(7):965-974. 
18. 
Becker SL, Vogt J, Knopp S, Panning M, Warhurst DC, Polman K, Marti H, von Muller L, Yansouni CP, 
Jacobs J, Bottieau E, Sacko M, Rijal S, Meyanti F, Miles MA, Boelaert M, Lutumba P, van Lieshout L, 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 45 of 176 
 
 
 
N'Goran EK, Chappuis F, Utzinger J: Persistent digestive disorders in the tropics: causative infectious 
pathogens and reference diagnostic tests. BMC Infect Dis 2013, 13:37. 
19. 
Avramenko RW, Redman EM, Lewis R, Bichuette MA, Palmeira BM, Yazwinski TA, Gilleard JS: The 
use of nemabiome metabarcoding to explore gastro-intestinal nematode species diversity and 
anthelmintic treatment effectiveness in beef calves. Int J Parasitol 2017, 47(13):893-902. 
20. 
Scherrer AU, Sjoberg MK, Allangba A, Traore M, Lohourignon LK, Tschannen AB, N'Goran EK, 
Utzinger J: Sequential analysis of helminth egg output in human stool samples following albendazole 
and praziquantel administration. Acta Trop 2009, 109(3):226-231. 
21. 
Speich B, Ali SM, Ame SM, Albonico M, Utzinger J, Keiser J: Quality control in the diagnosis of 
Trichuris trichiura and Ascaris lumbricoides using the Kato-Katz technique: experience from three 
randomised controlled trials. Parasit Vectors 2015, 8:82. 
22. 
Dunyo SK, Nkrumah FK, Simonsen PE: A randomized double-blind placebo-controlled field trial of 
ivermectin and albendazole alone and in combination for the treatment of lymphatic filariasis in 
Ghana. Trans R Soc Trop Med Hyg 2000, 94(2):205-211. 
23. 
Awadzi K, Edwards G, Duke BO, Opoku NO, Attah SK, Addy ET, Ardrey AE, Quartey BT: The co-
administration of ivermectin and albendazole--safety, pharmacokinetics and efficacy against 
Onchocerca volvulus. Ann Trop Med Parasitol 2003, 97(2):165-178. 
24. 
Simonsen PE, Magesa SM, Dunyo SK, Malecela-Lazaro MN, Michael E: The effect of single dose 
ivermectin alone or in combination with albendazole on Wuchereria bancrofti infection in primary 
school children in Tanzania. Trans R Soc Trop Med Hyg 2004, 98(8):462-472. 
25. 
Fürst T, Müller I, Coulibaly JT, Yao AK, Utzinger J, N'Goran EK: Questionnaire-based approach to 
assess schoolchildren's physical fitness and its potential role in exploring the putative impact of 
helminth and Plasmodium spp. infections in Côte d'Ivoire. Parasit Vectors 2011, 4:116. 
26. 
Campbell SJ, Nery SV, McCarthy JS, Gray DJ, Soares Magalhaes RJ, Clements AC: A critical appraisal 
of control strategies for soil-transmitted helminths. Trends Parasitol 2016, 32(2):97-107. 
27. 
Strunz EC, Addiss DG, Stocks ME, Ogden S, Utzinger J, Freeman MC: Water, sanitation, hygiene, and 
soil-transmitted helminth infection: a systematic review and meta-analysis. PLoS Med 2014, 
11(3):e1001620. 
28. 
Kepha S, Mwandawiro CS, Anderson RM, Pullan RL, Nuwaha F, Cano J, Njenga SM, Odiere MR, Allen 
E, Brooker SJ, Nikolay B: Impact of single annual treatment and four-monthly treatment for 
hookworm and Ascaris lumbricoides, and factors associated with residual infection among Kenyan 
school children. Infect Dis Poverty 2017, 6(1):30. 
29. 
WHO: The selection and use of essential medicines: report of the WHO Expert Committee, 2017 
(including the 20th WHO model list of essential medicines and the 6th WHO model list of essential 
medicines for children). WHO technical report series, vol. no. 1006. Geneva: World Health 
Organization; 2017. 
30. 
WHO: Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. 
Vitamin and Mineral Nutrition Information System. Geneva: World Health Organization; 2011: 
(WHO/NMH/NHD/MNM/11.11). 
31. 
WHO: Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs 
in control interventions: a manual for health professionals and programme managers. Geneva: 
World Health Organization; 2006: 62. 
32. 
Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, 
Lasseter KC: Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in 
healthy adult subjects. J Clin Pharmacol 2002, 42(10):1122-1133. 
33. 
Pawluk SA, Roels CA, Wilby KJ, Ensom MH: A review of pharmacokinetic drug-drug interactions 
with the anthelmintic medications albendazole and mebendazole. Clin Pharmacokinet 2015, 
54(4):371-383. 
34. 
Ndyomugyenyi R, Kabatereine N, Olsen A, Magnussen P: Efficacy of ivermectin and albendazole 
alone and in combination for treatment of soil-transmitted helminths in pregnancy and adverse 
events: a randomized open label controlled intervention trial in Masindi district, western Uganda. 
Am J Trop Med Hyg 2008, 79(6):856-863. 
35. 
ICH Expert Working Group: ICH harmonised tripartite guideline. Clinical safety data management: 
definitions and standards for expedited reporting E2A. International conference on harmonisation of 
technical requirements for registration of pharmaceuticals for human use; 1994. 
36. 
Klingenberg B: Proof of concept and dose estimation with binary responses under model 
uncertainty. Stat Med 2009, 28(2):274-292. 
37. 
Duggan MB: Anthropometry as a tool for measuring malnutrition: impact of the new WHO growth 
standards and reference. Ann Trop Paediatr 2010, 30(1):1-17. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 46 of 176 
 
 
 
38. 
Wang Y, Chen H: Use of Percentiles and Z-Scores in Anthropometry. In: Handbook of Anthropometry. 
Edited by Preedy V. New York: Springer; 2012: 29-48. 
39. 
Beal S, Sheiner LB, Boeckmann A, Bauer RJ: NONMEM User's Guides (1989-2009). Ellicott City, 
MD, USA: Icon Development Solutions; 2009. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 47 of 176 
 
 
 
 
4. Trial protocol Pemba Island:  
 
Efficacy and safety of ivermectin and albendazole co-administration in school-aged children and adults 
infected with Trichuris trichiura: a multi-country randomized controlled trial 
 
 
Protocol Number 
1 
Version Number 
1.01 
Document Date 
13.02.2018 
Sponsor Contact 
Prof. Dr. Jennifer Keiser,  
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@unibas.ch 
Principle Investigator 
Prof. Dr. Jennifer Keiser,  
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@unibas.ch 
Funding Agency 
Bill and Melinda Gates Foundation 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 48 of 176 
 
 
 
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 
Postdoc 
Co-PI 
MSc 
Shaali Ame 
Public Health Laboratory 
– IdC  
Head 
laboratory 
Services 
Co-PI 
MSc 
Said Mohammed 
Ali 
Public Health Laboratory 
- Ivo de Carneri (PHL-
IdC), Chake-Chake, 
Pemba (Tanzania) 
CEO 
Co-PI 
Dr. 
Jan Hattendorf 
 
Swiss TPH  
 
Group leader 
Statistician 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 49 of 176 
 
 
 
II. 
Signatures  
 
Statistician 
Signature 
 
 
 
 
 
Date of Signature  
13.02.2018 
Name  
Jan Hattendorf 
Title 
Dr.  
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 284-8193 
 
Principal investigator 
Signature 
 
 
 
 
 
Date of Signature  
13.02.2018 
Name  
Jennifer Keiser 
Title 
Prof. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 284-8218 
 
I have read this protocol and agree that it contains all necessary details for carrying out this trial. I will conduct 
the trial as outlined herein and will complete the trial within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist 
in the conduct of this trial. I will discuss this material with them to ensure they are fully informed regarding the 
drug and the conduct of the trial. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 50 of 176 
 
 
 
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. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 51 of 176 
 
 
 
Co-Principal investigator 
Signature 
 
 
 
Date of Signature  
13.02.2018 
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 
Phone 
+41 61 284 87 04 
 
 
 
Co-Principal investigator 
Signature 
 
 
 
 
Date of Signature  
13.02.2018 
Name  
Said Ali 
Title 
MSc  
Institution 
Public Health Laboratory Ivo de Carneri 
Address 
Public Health Laboratory Ivo de Carneri 
P.O. Box 122 Wawi, Chake Chake 
Pemba, Zanzibar (Tanzania) 
Phone 
+255 24 245-2003 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 52 of 176 
 
 
 
Co- Principal investigator 
 
Signature 
 
 
 
Date of Signature  
13.02.2018 
Name  
Shaali Ame 
Title 
MSc  
Institution 
Public Health Laboratory Ivo de Carneri 
Address 
Public Health Laboratory Ivo de Carneri 
P.O. Box 122 Wawi, Chake Chake 
Pemba, Zanzibar (Tanzania) 
Phone 
+255 24 245-2003 
 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 53 of 176 
 
 
 
Table of contents 
 
1. 
General information ......................................................................................................................................48 
2. 
Background information................................................................................................................................61 
3. 
Trial objective and purpose ...........................................................................................................................62 
4. 
Methodology .................................................................................................................................................63 
4.1 
Primary and secondary endpoint...........................................................................................................63 
4.2 
Type of trial ..........................................................................................................................................63 
4.3 
Trial design ...........................................................................................................................................64 
4.3.1 
Baseline survey and screening .....................................................................................................64 
4.3.2 
Assessment of efficacy after treatment ........................................................................................65 
4.4 
Measure to minimize bias .....................................................................................................................66 
4.5 
Study duration and duration of subject participation ............................................................................66 
4.6 
Schedule of visits ..................................................................................................................................66 
5. 
Selection of the trial subjects .........................................................................................................................67 
5.1 
Recruitment ..........................................................................................................................................67 
5.2 
Inclusion criteria ...................................................................................................................................68 
5.3 
Exclusion criteria ..................................................................................................................................68 
5.4 
Criteria for discontinuation of trial .......................................................................................................68 
5.5 
Treatment of subjects............................................................................................................................68 
5.6 
Concomitant therapy.............................................................................................................................69 
6. 
Safety assessments ........................................................................................................................................69 
6.1 
Adverse event definitions .....................................................................................................................69 
6.1.1 
Severity grading ...........................................................................................................................70 
6.1.2 
Relatedness ..................................................................................................................................70 
6.1.3 
Expectedness ................................................................................................................................71 
6.1.4 
Serious adverse events .................................................................................................................71 
6.1.5 
Suspected unexpected serious adverse reactions .........................................................................71 
6.2 
Methods of recording and assessing adverse events .............................................................................71 
6.3 
Reporting of serious adverse events .....................................................................................................72 
6.4 
Safety reporting to Health Authorities and Ethics Committees ............................................................73 
7. 
Statistics ........................................................................................................................................................73 
7.1 
Definition of primary endpoint .............................................................................................................73 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 54 of 176 
 
 
 
7.2 
Justification of number of trial subjects ................................................................................................73 
7.3 
Description of statistical methods .........................................................................................................73 
7.4 
Description of data management ..........................................................................................................74 
8. 
Duties of the investigator ..............................................................................................................................74 
8.1 
Investigator’s confirmation ...................................................................................................................75 
8.2 
Damage coverage .................................................................................................................................75 
8.3 
Project management .............................................................................................................................75 
9. 
Ethical considerations....................................................................................................................................75 
9.1 
Independent Ethics Committee (IEC) ...................................................................................................75 
9.2 
Evaluation of the risk-benefit ratio .......................................................................................................75 
9.3 
Subject information and consent...........................................................................................................76 
9.4 
Subject confidentiality ..........................................................................................................................76 
9.5 
Subjects requiring particular protection ................................................................................................76 
9.6 
Other aspects.........................................................................................................................................76 
10. 
Quality control and quality assurance .......................................................................................................76 
10.1 
Monitoring and auditing .......................................................................................................................76 
10.2 
Access to data, handling of data and samples (data protection), archiving (place, duration) and 
destruction .........................................................................................................................................................77 
10.3 
Data entered directly in the CRF – definition of source data ................................................................77 
10.4 
Data and safety monitoring board (WHO)/ data monitoring committee (EU/FDA).............................77 
10.5 
Study Documents: Translations - Reference language .........................................................................77 
11. 
Dissemination of results and publication ..................................................................................................77 
12. 
References .................................................................................................................................................79 
13. 
Appendix...................................................................................................................................................81 
13.1 
Household-based questionnaire ............................................................................................................81 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 55 of 176 
 
 
 
III. 
Abbreviations 
AE 
Adverse event 
CI 
Confidence interval 
CR 
Cure rate 
CRF 
Case report form 
EKNZ 
Ethikkomission Nordwest- und Zentralschweiz 
EML 
Essential medicine list 
EPG 
Eggs per gram 
ERR 
Egg reduction rate 
GCP 
Good clinical practice 
Hb 
Hemoglobin 
ICH 
International council for harmonization of technical requirements for pharmaceuticals for 
human use 
IEC 
Independent ethics committee 
MDA 
Mass drug administration 
MUAC 
Mid-upper arm circumference 
PC 
Preventive chemotherapy 
PCR 
Polymerase chain reaction 
PI 
Principal investigator 
RDT 
Rapid diagnostic test 
SAE 
Serious adverse event 
STH 
Soil-transmitted helminth 
SUSAR 
Suspected unexpected serious adverse reaction 
WHO 
World Health Organization 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 56 of 176 
 
 
 
IV. 
Synopsis 
 
Sponsor/Sponsor-
Investigator 
Prof. Dr. Jennifer Keiser 
Study Title 
Efficacy and safety of ivermectin and albendazole co-administration in school-
aged children and adults infected with Trichuris trichiura: a multi-country 
randomized controlled trial 
Short title 
Efficacy and safety of IVM/ALB co-administration 
Protocol Number, Date and 
Version 
1, 13.02.2018, v1.01 
Trial registration 
Will be registered on (http://www.controlled-trials.com/) 
Clinical phase 
Phase 3 trial 
Sample size 
1800 (600 participants in each of 3 settings)  
Indication 
Trichuris trichiura infection (eggs in stool) 
Investigational Product and 
Reference Treatment 
Ivermectin and albendazole 
Study Rationale 
To provide evidence on potentially enhanced efficacy by combining the 
standard drug albendazole with ivermectin in school-aged children and adults 
against infection with T. trichiura. 
 
Study Objectives 
To compare the efficacy and safety of standard doses of co-administered 
ivermectin (200 µg/kg) and albendazole (400 mg) compared to albendazole 
(400 mg) alone in community members aged 6-60 years. 
  
Our primary objective is to comparatively assess the efficacy in terms of cure 
rates (CRs) against T. trichiura infections among school-aged children and 
adults of the following oral treatment regimens: 
 
Albendazole (400 mg)/ivermectin (200 µg/kg) combination  
 
Albendazole (400 mg) alone 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 57 of 176 
 
 
 
 
The secondary objectives of the trial are: 
 
a) To evaluate the safety and tolerability of the two treatment regimens  
b) To evaluate the egg reduction rate (ERR) of the two treatment 
regimens against T. trichiura 
c) To determine the CRs and ERRs of the drugs in study participants (6-
60 years) infected with hookworm, Ascaris lumbricoides and 
Strongyloides stercoralis 
d) To investigate potential extended effects on follow-up helminth 
prevalences (6 and 12 months post-treatment) of the two treatment 
regimens (as assessed among participants with cleared infection on 
days 21 and 180) 
e) To compare CRs based on egg counts retrieved from novel PCR-based 
and standard microscopic diagnosis 
f) 
To assess potential differences in susceptibility to the two treatment 
regimen between the hookworm species, Necator americanus, 
Ancylostoma duodenale and A. ceylanicum, as classified through the 
novel PCR-based diagnosis 
g) To characterize Trichuris strains from different epidemiological 
settings  
h) To evaluate potential benefits from deworming on morbidity 
indicators (e.g. anemia, occult fecal blood, calprotectin, growth 
standards, self-reported physical functioning)  
Study design 
Double blind, randomized controlled trial  
Study product / intervention Administration of a single oral dose of  ivermectin + albendazole 
Comparator(s) 
albendazole (400 mg) alone 
Key inclusion / Exclusion 
criteria 
Inclusion:  School-aged children or adults (6-60 years) infected with 
T. trichiura with at least two slides of the quadruple Kato-Katz thick smears 
positive and infection intensities of at least 100 eggs per gram of stool (EPG), 
able and willing to be examined by a study physician at the beginning of the 
study and to provide two stool samples at baseline and on the three follow-up 
assessments (approximately 3 weeks, 6 months, and 12 months later), absence 
of major systemic illnesses or history of chronic disease, written informed 
consent signed by parents and/or caregivers for minors; and oral assent by 
school-aged children, no known allergy to study medication, no recent 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 58 of 176 
 
 
 
anthelminthic treatment (past 4 weeks) and for girls/women of fertile age: not 
being pregnant or lactating in the 1st week after birth. 
Exclusion: No written informed consent, any abnormal medical conditions or 
history of acute or severe chronic disease, recent use of anthelminthic drug 
(past 4 weeks), negative diagnostic or low egg count (less than 100 EPG or 
less than 2 out of 4 slides positive) result for T. trichiura, pregnancy or 
lactating in the 1st week after birth. 
Primary Endpoints 
CR on T. trichiura 
Secondary Endpoints 
 
ERR against T. trichiura  
 
CRs and ERRs against A. lumbricoides, hookworm and S. stercoralis 
 
Safety 
 
Diagnostic performance 
 
Molecular characterization of Trichuris spp. 
 
Changes in morbidity  
Exploratory Endpoints 
None  
Interim Analyses 
None 
Study Duration 
14 months total; up to 12 months per participant 
Schedule 
06/2018 of first-participant in (planned) 
08/2019 of last-participant out (planned) 
Study centres 
Multinational study with trial sites in Côte d’Ivoire, Lao PDR and Pemba 
Island (Tanzania) 
Measurements & procedures Two stool samples will be collected if possible on two consecutive days or 
otherwise within a maximum of 5 days. The medical history of the participants 
will be assessed with a standardized questionnaire, in addition to a clinical 
examination carried out by the study physician before treatment.  
All participants will also be interviewed before treatment, 3 and 24 hours and 
3 weeks after treatment about the occurrence of adverse events. Children (6-16 
years) will additionally be asked to rate their own physical functioning by 
replying to a pre-tested questionnaire at baseline and 6 and 12 months after 
treatment. The efficacy of the treatment and potential extended effects on 
follow-up prevalence will be determined 14-21 days, 6 months and 12 months 
post-treatment by collecting another two stool samples. Subjective treatment 
satisfaction will be assessed 3 hours, 3 weeks and 6 months after treatment to 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 59 of 176 
 
 
 
investigate relationship with treatment compliance and observed efficacy in 
reducing egg output and morbidity. 
All stool samples will be examined with duplicated Kato-Katz thick smears 
for T. trichiura, A. lumbricoides and hookworm. S. stercoralis infections will 
be identified using the Baermann technique. For subsequent PCR-analysis a 
portion of 1.5-2 g of stool from each specimen will be preserved in 70% 
ethanol and shipped to a reference laboratory. From a subsample of 10 
children with heavy intensity infections in each study setting an additional 
portion of stool (1.5-2 g) will be preserved in 95% ethanol, shipped to a 
reference laboratory and subjected to whole genome sequencing for 
characterization of Trichuris strains. Fecal occult blood and calprotectin in 
stool as markers for gut morbidity and inflammation will be detected using a 
rapid diagnostic test and an immunoassay, respectively. Individuals found 
positive 6 months after baseline will receive a second round of treatment 
according to their group scheme.  
Each participant will be asked to provide a finger-prick blood sample for 
hemoglobin measurement and co-infection with Wuchereria bancrofti at 
baseline and 6 and 12 months after treatment. At the same time points 
anthropometric measurements (i.e. height, weight, mid-upper arm 
circumference (MUAC) and skinfold thickness) will be taken for all 
participants. To all participating households, a questionnaire will be 
administered assessing information on socioeconomic characteristics and 
access to sanitation, water facilities, and hygiene behavior. 
Statistical Analyses 
An available case analysis will be performed, including all subjects with 
primary end point data. Supplementary, a per-protocol analysis will be 
conducted. CRs will be calculated as the percentage of egg-positive subjects at 
baseline who become egg-negative after treatment. Differences among CRs 
(between treatment arms and between diagnostic approaches) will be analysed 
by using crude and adjusted logistic regression modelling (adjustment for age, 
sex, community, weight and height).  
Geometric and arithmetic mean egg counts will be calculated for the different 
treatment arms before and after treatment to assess the corresponding ERRs. 
Bootstrap resampling method with 5,000 replicates will be used to calculate 
95% confidence intervals (CIs) for ERRs. Morbidity indicators (continuous 
measurements) will be compared in a first step within and between groups 
using independent and paired t-test statistics while chi-square testing will be 
performed for binary/categorical outcomes (e.g. anemia, blood in stool). To 
compare individual’s changes in morbidity categories as an effect from 
treatment McNemar’s test will be applied. In a second step, adjusted repeated 
measures linear and logistic regressions using generalized estimating equation 
(GEE) models will be performed to assess development of morbidity 
indicators within each individual and related factors be investigated.  
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. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 60 of 176 
 
 
 
Key explanation for the 
inclusion of children 
This study will involve school-aged children, since an infection with 
T. trichiura occurs most often in children and they are further the main target 
group of deworming campaigns. 
Recruitment procedure 
The longitudinal trial will be conducted as a multi-country study with two 
settings in Africa and one in Asia recruiting each 600 community members: 
 
West African setting: Côte d’Ivoire 
 
East African setting: Pemba (Zanzibar, Tanzania)  
 
Asian setting: Lao PDR 
 
The studies will be conducted in areas with moderate to high T. trichiura 
infection intensities (communities with a prevalence ≥ 25%) identified from 
earlier studies and/or based of experience of the local collaborating teams. 
They will be implemented as community-based studies in order to recruit 
participants from a broad age range (6-60 years). Ideally, entire communities 
with a population size of < 1000 inhabitants will be included in the study for 
pre-screening and identification of T. trichiura cases to avoid potential 
selection bias of households. 
Coverage of damages 
Winterthur Police Nr. 4746321, National Insurance Corporation of Tanzania 
(to be issued) 
Storage of data and samples 
for future research aims 
After the study has been completed all samples will be destroyed and case 
report forms will be kept for a minimum of 15 years (chapter 10). 
 
Conflict of interest in 
relation to the investigated 
drugs 
We declare no conflict of interest in relation to the investigated drugs. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 61 of 176 
 
 
 
2. 
Background information 
Albendazole and mebendazole are the most widely used drugs for preventive chemotherapy (PC) campaigns 
against soil-transmitted helminth (STH) infections. Albendazole is characterized by high cure rates (CRs) and 
egg reduction rates (ERRs) against infections with Ascaris lumbricoides (95.6% and 98.5%) and hookworm 
infections (79.4 and 89.6%). Lower efficacy is observed against Trichuris trichiura infections (CR 31.5%, and 
ERR of 49.8%) [1].  
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 mono-therapy [2].   
A recent review and meta-analysis found that ivermectin co-administered with albendazole is highly efficacious 
for the treatment of T. trichiura and is comparatively more efficacious than albendazole alone (Figure 1) [3]. 
Efficacy of ivermectin and albendazole against A. lumbricoides and hookworm are comparable and in some 
cases more efficacious than albendazole alone. Summarized efficacy measures of albendazole, mebendazole, and 
ivermectin against trichuriasis from a recent review [1] and earlier trials [4, 5]  are shown in Table 1. 
 
 
Figure 1. Forest plot displaying the results of a random-effects meta-analysis of the effect of the co-
administration of albendazole-ivermectin on the number of patients infected with T. trichiura compared to 
albendazole alone.  
 
Table 1. Average CRs and ERRs of albendazole and mebendazole for T. trichiura from a recent review [6] as 
well as findings from studies investigating ivermectin [4, 5] 
Drug 
CR (%) 
95% CI 
ERR (%) 
95% CI 
Albendazole 
30.7 
(21.0, 42.5) 
49.9 
(39.0, 60.6) 
Mebendazole 
42.1 
(25.9, 60.2) 
66.0  
(54.6, 77.3) 
Ivermectin 
11-35 
NA 
43-98 
NA 
 
 
The individual studies included in the review are summarized in Table 2. All four studies are randomized 
controlled trials and used the standard dose of 200 µg/kg ivermectin and 400 mg albendazole [4, 7-9]. Against 
infections with T. trichiura, CRs ranging from 27.5-81.1%, ERR based on geometric mean ranging from 91.3-
99.7%, and ERR based on arithmetic mean ranging from 85.6-97.5% were observed. CRs for T. trichiura 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 62 of 176 
 
 
 
observed in Asian settings were higher than in African settings. One reason for this finding may be differences in 
the study design and quality (e.g., in terms of diagnostic approach used). Another possible reason recently 
highlighted is genetic diversity of T. trichiura strains and variation in susceptibility to anthelmintics and/or drug 
resistance [10-12]. Interestingly, the higher efficacy of ivermectin in combination with albendazole translated – 
at least in some settings – into lower prevalences even after one year [4, 13]. The efficacy of albendazole-
ivermectin against A. lumbricoides was excellent (CRs >78% and ERRs >99.5%), while moderate CRs (50-
66.7%) and high ERRs (>95.4%) were observed against hookworm. 
 
Table 2. Known efficacy of co-administered ALB-IVMѱ against T. trichiura: 
Study 
Setting 
Cure rate in % 
(nneg/n) 
Eggs per gram 
(pre/post) 
Egg reduction rate 
in % 
Ismail et al. 1999 
Sri Lanka 
81.1% (43/53) 
1544.0/78.7 (unkwn) 
94.9% (unkwn) 
Belizario et al. 2003 
Philippines 
65.1% (97/149) 
4948.1/122.5 (ar) 
550.0/1.9 (geo) 
97.5% (ar)  
99.7% (geo) 
Knopp et al. 2010 
Tanzania 
(Pemba) 
37.9% (53/140) 
127/11 (geo) 
91.3% (geo) 
Speich et al. 2015 
Tanzania 
(Pemba) 
27.5% (30/109) 
1059/153 (ar) 
489/27 (geo) 
85.6% (ar) 
94.5% (geo) 
All studies 
 
49.4% (223/451) 
 
 
ѱConsidered doses: albendazole=400 mg, ivermectin=200 µg/kg 
ar=arithmetic mean, geo=geometric mean, unkwn=unknown mean 
 
 
The WHO Expert Committee met from March 27-31, 2017 and, based on review of the dossier, made the 
following recommendation:  
 
“…adding ivermectin on the Essential Medicines List under the section intestinal anthelminthic for use against 
Strongyloides stercoralis and STH. It may be used in combination with albendazole for treatment of soil-
transmitted helminthiasis.” 
 
This important milestone paves the way for further, standardized trials to evaluate the efficacy of this 
combination among school-aged children in a range of epidemiological settings. In addition, the combination 
should be evaluated among adults, as there is growing interest in broadening deworming to include adults in 
order to move from morbidity control toward interruption of transmission [14, 15].  
In the proposed work, three trials are planned across a range of transmission settings, including Côte d'Ivoire, 
Lao PDR, and Pemba (Tanzania). Follow-up will be conducted at 1, 6, and 12 months to inform treatment 
frequency. Results from these trials will inform decisions on how the combination could be introduced into 
existing MDA programs and therefore provide a valuable adjunct tool for interrupting STH transmission.  
3. 
Trial objective and purpose 
The overall goal of the study is to assess the efficacy and safety of co-administered albendazole and ivermectin 
versus albendazole alone (standard of care) against T. trichiura infections in children and adults (6-60 years) in 
different transmission settings and geographies.  


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 63 of 176 
 
 
 
 
We hypothesize that albendazole-ivermectin has a higher efficacy against T. trichiura infections than 
albendazole alone, and hence, the efficacy against all three commonly STH species (A. lumbricoides, 
T. trichiura, and hookworm) and Strongyloides stercoralis will be increased. 
The primary objective of the trial is to comparatively assess the efficacy in terms of CR against T. trichiura 
infections among school-aged children and adults from three different epidemiological settings and monitored 
over a 12-month period of the following two oral treatment regimens: 
• 
Albendazole/ivermectin combination 
• 
Albendazole alone 
 
The secondary objectives of the trial are: 
a) To evaluate the safety and tolerability of the treatment regimens  
b) To evaluate the ERR of the treatment regimens against T. trichiura 
c) To determine the CRs and ERRs of the drugs in study participants (6-60 years) infected with hookworm, 
Ascaris lumbricoides and Strongyloides stercoralis 
d) To investigate potential extended effects on follow-up helminth prevalences (6 and 12 months post-
treatment) of the two treatment regimens (as assessed among participants with cleared infection on days 
21 and 180) 
e) To compare CRs based on egg counts retrieved from novel PCR-based and standard microscopic 
diagnosis 
f) 
To assess potential differences in susceptibility to the two treatment regimen between the two hookworm 
species, Necator americanus,  Ancylostoma duodenale and A. ceylanicum, as classified through the novel 
PCR-based diagnosis 
g) To characterize Trichuris strains from different epidemiological settings through genotyping 
h) To evaluate potential benefits from deworming on morbidity indicators (clinically evaluated and self-
rated from questionnaire interviews) 
4. 
Methodology 
4.1 
Primary and secondary endpoint 
CR (primary end point, i.e. conversion from being egg positive pre-treatment to egg negative post-treatment) and 
ERR (secondary end point). In addition, diagnostic performance using different tools will be evaluated, Trichuris 
strains described using molecular characterization and safety and potential benefits on morbidity indicators from 
treatment assessed (secondary end points). 
4.2 
Type of trial 
Double blind randomized controlled trial. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 64 of 176 
 
 
 
4.3 
Trial design 
4.3.1 
Baseline survey and screening 
A randomized-controlled trial will be conducted with two treatment arms to be followed-up over a 12 months 
period with an intermediate re-treatment of participants found re-infected after 6 months (Figure ). This trial will 
be conducted as a multi-country study; thus, in each setting a separate trial according to the design described 
below will be set up, to provide a better basis for the subsequent generalization of its findings. This arises from 
the possibility of recruiting the subjects from a wider population and of administering the medication in a 
broader range of clinical settings, thus presenting an experimental situation that is more typical of future use. The 
study includes one baseline and three follow-up assessments at 3 weeks (day 21), 6 months (day 180), and 12 
months (day 360). 
 
 
Figure 1. Design and timeline of the randomized-controlled trial to be implemented in each of three settings. 
 
The study is designed as a two-armed trial including one arm with a single drug administration (arm A; 
albendazole) and one arm with combined treatment through co-administration of separate tablets (arm B; 
albendazole and ivermectin).  
The trial will be conducted as a multi-country study with two settings in Africa and one in Asia, namely Côte 
d’Ivoire, Pemba (Zanzibar, Tanzania) and Lao PDR. 
At baseline, all participants will be asked to provide two stool samples (within a maximum of 5 days). From each 
stool specimen, duplicate Kato-Katz thick smears (41.7 mg each) [16] will be prepared and read under a 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 65 of 176 
 
 
 
microscope for eggs of T. trichiura, A. lumbricoides and hookworm by experienced technicians and a subsequent 
independent quality control of sample results (approximately 10%) will be conducted. Results are considered 
correct if the following tolerance margin is not exceeded: (i) No difference in presence/absence of hookworm, A. 
lumbricoides and T. trichiura, (ii) egg counts are +/-10 eggs for counts ≤100 eggs or +/-20% for counts >100 
eggs (for each species separately) [17]. In case discrepancies above the tolerance margin are noted in one or 
more slides, all slides are re-read by the local technicians. The new results are discussed, so that in case of 
discordant results, slides can be re-evaluated to reach consensus. Infection intensity expressed as the arithmetic 
and geometric mean egg count per gram of stool (EPG) will be calculated for each treatment arm. All 
microscopically analyzed quadruplicate Kato-Katz thick smears will be destroyed within one day (after passing 
the quality control). S. stercoralis infections will be identified using the Baermann technique. Additionally, a 
portion of 1.5-2 g of stool from each specimen will be preserved in 70% ethanol and shipped to a reference 
laboratory for polymerase chain reaction (PCR) analysis [18]. PCR will allow to accurately determining efficacy 
and for further classification of hookworm infection into the three species N. americanus, A. duodenale and 
A. ceylanicum. From a subsample of 10 children with heavy intensity infections an additional portion of stool 
(1.5-2 g) will be preserved in 95% ethanol, shipped to a reference laboratory and subjected to whole genome 
sequencing for characterization of Trichuris strains. Each collected stool sample will further be tested on fecal 
occult blood and calprotectin as proxies for gut morbidity and inflammation using a rapid diagnostic test and an 
immunoassay, respectively [19]. The same sampling procedure and diagnostic approach will be applied at days 
21, 180 and 360 post-treatment. 
Patients with filarial disease showed significantly higher numbers of adverse events (AEs) for treatment with 
ivermectin in combination with albendazole in earlier studies [20-22]. A rapid diagnostic test (RDT; i.e., SD 
BIOLINE Oncho/LF IgG4 biplex test) to detect antigens in the blood will therefore be used to identify potential 
co-infection with Wuchereria bancrofti. 
A clinical examination of the study participants assessing general health, anthropometric parameters including 
height, weight, mid-upper arm circumference (MUAC) and triceps skinfold thickness as well as tympanic 
temperature using an ear thermometer will precede the treatment and will be repeated on two follow-up 
assessments (days 180 and 360) to evaluate potential benefits from deworming. Each participant will be asked to 
provide a finger-prick blood sample to evaluate hemoglobin (Hb) levels using a HemoCue analyzer (Hemocue 
Hb 301 system; Angelholm, Sweden) following the same (re-)assessment schedule. To avoid accidental 
treatment of pregnant girls/women all female participants (≥ 10 years) will be asked to provide a urine sample to 
be subjected to a pregnancy RDT on day 0 and day 180. 
All trial participants will further be asked about existing clinical symptoms before drug administration. 
Additionally, they will be asked to provide subjective short-term (e.g. convenience of treatment) and long-term 
(e.g. effectiveness in reducing symptoms) treatment satisfaction embedded in the re-assessment questionnaires. 
As a measure of patient-rated physical functioning and wellbeing all children (6-16 years) will be administered a 
questionnaire before, 6 and 12 months after treatment, based and adapted from tools already validated in school-
aged children from rural settings in Côte d’Ivoire [23]. Before application this tool will be adapted to local 
conditions of Pemba and pre-tested in a comparable school-aged population not otherwise involved in this trial. 
To adjust for known influencing factors with regard to reinfection and morbidity [24, 25] in the subsequent 
analysis and to identify risk factors for residual infections [26] a household-based questionnaire will be 
administered to one adult member of each participating household, assessing information on socioeconomic 
characteristics, access to sanitation and water facilities as well as hygiene behavior.  
4.3.2 
Assessment of efficacy after treatment 
The efficacy of the treatment will be determined 21 days post-treatment by collecting another two stool samples 
which will be microscopically examined for T. trichiura using duplicate Kato-Katz thick smears and potential 
co-infection with S. stercoralis applying the Baermann technique. Participants will be considered T. trichiura 
cured if no eggs have been found in the stool. EPG will be assessed by adding up the egg counts from the 
quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic 
mean egg counts will be calculated for the different treatment arms before and after treatment to assess the 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 66 of 176 
 
 
 
corresponding ERRs. The stool samples collected 21 days post-treatment for efficacy assessment will further be 
re-tested with the same rapid diagnostic test and immunoassay used at baseline to determine fecal occult blood 
and calprotectin levels. Frequencies of subjects found positive with either of the two markers and by intensity 
category for calprotectin will be calculated by treatment arm. 
At the end of the study (approximately 12 months post-treatment) all participants remaining positive for T. 
trichiura and other soil-transmitted helminths will be treated with albendazole-ivermectin, the currently best 
recommended treatment against T. trichiura. 
Potential extended effects on follow-up helminth prevalences will be assessed using the same methodological 
approach as used for the efficacy assessment and will be based on stool samples collected 6 and 12 months post-
treatment. Likewise fecal occult blood and calprotectin will be re-determined on the same stool samples. 
To assess eventual reduction in morbidity indicators all trial participants will be asked to provide another finger-
prick blood sample at the 6 and 12 month follow-up for Hb measurement. Anthropometric measurement 
including height, weight, MUAC and triceps skinfold thickness will be repeated on the same occasion. Children 
(6-16 years) will be asked to re-assess their own physical functioning in repeated questionnaire interviews during 
these two last follow-ups. Long-term satisfaction with the treatment will be asked 6 months past-treatment. Mean 
values for continuous outcomes and frequencies for binary/categorical outcomes will be calculated for each 
treatment arm and follow-up time point and compared using descriptive and repeated measurement analysis as 
detailed in section 7.3. 
4.4 
Measure to minimize bias 
Study participants eligible for treatment will be randomly assigned to one of the two treatment arms using a 
computer-generated stratified block randomization code. The random allocation sequence with varying random 
blocks of four or eight and stratified by 2 levels of baseline infection intensity (light: <1000 EPG, and moderate 
plus heavy: ≥ 1000 EPG T. trichiura infections) will be provided by a statistician. The treatment arms will have 
an equal number of participants with light infection intensity, although the number of light versus 
moderate/heavy infections are not expected to be equal in each arm, depending on the distribution of infection 
intensity in the recruited cohort. The study will be double blinded. 
4.5 
Study duration and duration of subject participation 
The trial will last fourteen months. The screening for the baseline will start three weeks prior to the treatment. 
Follow-up screening will take place 14-21 days, 180 days and 360 days post-treatment and last each time for 
about three weeks. Schedules of visits are summarized below. 
4.6 
Schedule of visits 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 67 of 176 
 
 
 
Table 1. Schedule of visits of longitudinal study. 
 
Screenin
g 
Baseline/Treatment/Safety 
Follow up 
 
-21 to -1 
days 
Hours 
Days 
 
0 
Randomization and treatment 
3 
24 
21 
180 
185 
360 
Diagnosis (stool 
examination) 
X 
 
 
 
X 
X 
Selective re-treatment 
X 
Gut morbidity (stool 
RDTs) 
X 
 
 
 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Clinical examination 
 
X 
 
 
 
X 
X 
Pregnancy testing 
 
X 
 
 
 
X 
 
Hemoglobin measurement 
 
X 
 
 
 
X 
X 
W. bancrofti co-infection 
 
X 
 
 
 
X 
X 
Physical functioning 
 
X 
 
 
 
X 
X 
Capturing AEs 
 
 
X 
X 
X 
 
 
Capturing SAE 
 
 
X 
X 
X 
 
 
Treatment satisfaction 
 
 
 
X 
 
X 
X 
 
 
 
5. 
Selection of the trial subjects 
5.1 
Recruitment 
The study will be carried out in community members aged 6‒60 years in areas with moderate to high T. trichiura 
infection intensities (communities with a prevalence ≥ 25%) identified from earlier studies and/or based of 
experience of the local collaborating teams. The trial will be implemented as community-based study in order to 
recruit participants from a broad age range (6‒60 years). Ideally, entire communities with a population size of < 
1000 inhabitants will be included in the study for pre-screening and identification of T. trichiura cases to avoid 
potential selection bias of households. Another option might be to run the trial at schools and invite school-aged 
children and one adult for each child of the same household. 
All adult community members, including parents/caregivers of minor participants, will be invited to participate 
in an information meeting to explain the purpose and procedures of the study, including potential benefits and 
risks. Parents/caregivers/potential participants will be encouraged to ask questions in an open discussion forum. 
During this session, they will be informed of preventive actions they can take to help protect their children from 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 68 of 176 
 
 
 
acquiring T. trichiura and other STH infections in the future (e.g., adequate food preparation and defecation 
behavior). 
Those parents/caregivers and their children who are interested in the study will be invited to complete the 
process of informed consent. See section 9.3 for details on obtaining informed consent. Only those participants 
who have written informed consent will be assessed for study eligibility criteria during screening procedures. 
5.2 
Inclusion criteria 
1. Written informed consent signed by either the participant him/herself (≥18 years of age) or by parents 
and/or caregivers for children; and oral assent by child (aged 6‒17 years). 
2. Agree to comply with study procedures, including provision of two stool samples at the beginning 
(baseline) and on three follow-up assessments (approximately 3 weeks, 6 months, and 12 months later). 
3. Aged ≥6 to 60 years. 
4. At least two slides of the quadruple Kato-Katz thick smears positive for T. trichiura and infection 
intensities of at least 100 eggs per gram of stool (EPG).  
5.3 
Exclusion criteria 
1. No written informed consent by individual/parents and/or caregiver.  
2. Presence of major systemic illnesses, e.g., severe anaemia (below 80 g/l Hb according to WHO)[27], as 
assessed by a medical doctor, upon initial clinical assessment. 
3. History of acute or severe chronic disease (e.g. cancer, diabetes, chronic heart, liver or renal disease). 
4. Recent use of anthelmintic drug (within past 4 weeks). 
5. Attending other clinical trials during the study. 
6. Negative or low egg count (less than 100 EPG or less than 2 out of 4 slides positive) diagnostic result for 
T. trichiura eggs in the stool. 
7. Pregnancy or lactating in the 1st week after birth (according to WHO guidelines within LF control 
programs [28]). 
8. Known allergy to study medications (i.e. albendazole and ivermectin). 
5.4 
Criteria for discontinuation of trial 
A subject can be discontinued from the study for the following reasons: 
1. 
Withdraws from the study (this can happen anytime as participation is voluntary and there are no further 
obligations once a participant withdraws). 
2. 
At the discretion of the Principal Investigator (PI) or co-PI, if the participant is not compliant to the 
requirements of the protocol. 
Discontinued subjects will not be replaced. If, for any reason, a subject is discontinued from the study before the 
end of treatment evaluations, the safety procedures planned (adverse events monitoring) will be conducted. 
5.5 
Treatment of subjects 
All T. trichiura-infected, consenting, and participating community members will be treated with the respective 
single or combination treatment regimen at day 0. 400 mg albendazole will be the product of Glaxo Smith Kline 
(Zentel®) and a single tablet administered. 3 mg tablets of ivermectin will be obtained from Merck 
(Stromectol®). The weight will be recorded for each participant and the correct dose evaluated and administered. 
Matching ivermectin placebo tablets will be produced by the University of Basel, Switzerland. To ensure double-


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 69 of 176 
 
 
 
blinding the tablets will be repacked into neutral separate plastic bags each containing one albendazole tablet and 
the maximum number of ivermectin tablets with regard to weight and dose or the corresponding number of 
placebo tablets. Since albendazole and ivermectin are known to be better absorbed in humans after a high-fat 
meal was consumed, participants will receive a local high-fat breakfast (sandwich with e.g. oily sardines) prior to 
treatment [29, 30]. 
All drugs will be administered in the presence of the investigator(s), and ingestion confirmed. This will be 
recorded with the time and date of closing. Subjects will be asked not to take any drugs other than those 
prescribed by the study medical team. After ingestion of the medication, the subjects will be observed for 3 
hours to ensure retention of the drug. Vomiting within 1-hour post-dosing will require re-dosing. The subjects 
will not be allowed more than one repeated dose. No re-administration will be needed for subjects vomiting after 
one hour. The Principal Investigator is responsible for drug accountability at the study site. Maintaining drug 
accountability includes careful and systematic study drug storage, handling, dispensing and documentation of 
administration. 
 
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 in the participating study 
communities be substituted with a free community-wide single-dose treatment (i.e., albendazole 400 mg + 
ivermectin 200 µg/kg) against STH as well as S. stercoralis infection at the study endpoint (after the day 360 
follow-up assessment) offered by the study team. At each follow-up time point, participants will be interviewed 
whether they had taken anthelmintic treatment (e.g. self-purchased, obtained from clinics etc). Participants found 
to be severely anemic at any of the three assessment time points (baseline, 6 and 12 months post-treatment) will 
be referred to the next hospital/clinic. 
5.6 
Concomitant therapy 
All medications taken one month before and during the study period until the last stool examination must be 
recorded with indication, dose regimen, date and time of administration. 
 
Medication(s)/treatment(s) permitted during the trial: 
- Analgesics and antipyretics are allowed to be given to the subjects in case of fever, antiemetics to prevent 
nausea and vomiting and/or antibiotics to prevent or treat bacterial superinfection. 
 
Medication(s)/treatment(s) NOT permitted during the trial:  
- No other active drugs against helminths are permitted during the trial. 
6. 
Safety assessments 
Few AEs have been reported following ivermectin-albendazole co-administration in STH-infected individuals. 
The most common AEs were abdominal cramps, headache, fatigue, nausea, diarrhea, fever and vertigo [8, 9, 31]. 
The safety profile of co-administered ivermectin and albendazole will be assessed through the recording, 
reporting and analysis of baseline medical conditions, AEs and a physical and clinical examination. 
6.1 
Adverse event definitions 
The term “adverse event” could include any of the following events which develop or increase in severity during 
the course of the study, after administration of the study product: 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 70 of 176 
 
 
 
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 AEs but as be considered baseline medical conditions. For the purpose of this trial, disease 
progression and relapse will be considered as treatment failure, not as an AE.  
 
The observation time for AEs starts when the treatment is initiated until day 21 (3 weeks after last drug 
administration).  
 
These data will be recorded on the appropriate CRF sections, regardless of whether they are thought to be 
associated with the study or the drug under investigation. Associated with the use of the drug means that there is 
a reasonable possibility that the event may have been caused by the drug (see also relatedness definitions below). 
6.1.1 
Severity grading 
Adverse signs or symptoms will be graded by the Investigator as mild, moderate, severe or life threatening 
according to the following definitions:  
 
Grade 
Definition 
1 
Mild: the subject is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
2 
Moderate: the subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity. 
3 
Severe: significant impairment of functioning: the subject is unable to carry out his or her 
usual activities. 
4 
Life threatening or disabling  
5 
Death related to adverse events 
6.1.2 
Relatedness 
Relatedness will be assessed as defined below based on the temporal relationship between the AE and the 
treatment, known side effects of treatment, medical history, concomitant medication, course of the underlying 
disease and trial procedures. 
Possibly related: an AE which can medically (pharmacologically/clinically) be attributed to the study treatment. 
Unrelated: an 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.” 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 71 of 176 
 
 
 
6.1.3 
Expectedness 
Expected adverse drug reaction: Any AE possibly related to the co-administration of ivermectin-albendazole 
reported in the literature or on the drug package leaflets and listed in the consent form.  
Unexpected adverse drug reaction: Any AE possibly related to the study product administration, the nature, 
frequency, specificity or severity of which is unanticipated and not consistent with the available risk information 
described for these drugs.  
6.1.4 
Serious adverse events 
According to the ICH “Clinical Safety Data Management: Definitions and standards for expedited Reporting 
E2A” [32], 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 subject was, in the view of the Investigator, at immediate risk 
of death from the reaction as it occurred, i.e. it does not include a reaction that, had it occurred 
in a more serious form, might have caused death; 
3. results in persistent or significant disability/incapacity, i.e. the event causes a substantial 
disruption of a person’s ability to conduct normal life functions; 
4. requires in patient hospitalization or prolongation of existing hospitalization; 
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” AE does not necessarily meet the criteria for a “serious” AE. Serious AEs are reported from consent 
to 24 hours post-treatment (Day 2).  
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 SAEs.  
6.2 
Methods of recording and assessing adverse events 
Subjects will be kept for observation for at least 3 hours following treatment for any acute AEs. If there is any 
abnormal finding, the local study physician will perform a full clinical and physical examination and findings 
will be recorded. An emergency kit will be available on site to treat any medical conditions that warrant urgent 
medical intervention. In addition patients will also be interviewed 3 and 24 hours and again 3 weeks after 
treatment about the occurrence of AEs (see chapter 4.6). 
Information on all AEs (onset, duration, intensity, seriousness and causality) will be immediately entered in the 
appropriate AE module of the case report form (CRF) that serves as source document. For all AEs, sufficient 
information will be pursued and/or obtained so as to permit i) an adequate determination of the seriousness of the 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 72 of 176 
 
 
 
event (i.e. whether the event should be classified as a SAE); ii) an assessment of the casual relationship between 
the AE and the study treatments and iii) an assessment of intensity of AEs will be judged by the study physician. 
 
All SAEs or SUSARs must be reported as described in Section 6.3. 
6.3 
Reporting of serious adverse events 
Any study-related unanticipated problem posing risk of harm to subjects or others (including all unexpected 
adverse drug reactions), and any type of SAE will be immediately (within a maximum of 24 hours after 
becoming aware of the event) notified to the study sponsor-investigator and co-PIs: 
 
 
Prof. Dr. Jennifer Keiser (Sponsor-investigator) 
Swiss Tropical and Public Health Institute 
Socinstrasse 57, 4051 Basel, Switzerland 
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@swisstph.ch 
 
 
 
Mr. Said Ali (Co-PI) 
Public Health Laboratory Ivo de Carneri 
P.O. Box 122 Wawi, Chake Chake 
Pemba, Zanzibar (Tanzania) 
Tel.: +255 24 245-23 
Fax: +255 24 245-2003 
Mobile: +255 77 741-6867 
Email: saidmali2003@yahoo.com 
 
 
Within the following 48 hours, the local co-investigator must provide to study sponsor-investigator further 
information on the SAE or the unanticipated problem in the form of a written narrative. This should include a 
copy of a completed SAE form, and any other diagnostic information that will assist the understanding of the 
event. In exceptional circumstances, a SAE may be reported by telephone. In these cases, a written report must 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 73 of 176 
 
 
 
be sent immediately thereafter by fax or e-mail. Names, addresses and telephone for SAE reporting will be 
included in the trial-specific SAE form. Relevant pages from the CRF may be provided in parallel (e.g., medical 
history, concomitant medications).  
6.4 
Safety reporting to Health Authorities and Ethics Committees 
The sponsor-investigator will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. Additionally, this information will be provided to ‘Ethikkomission Nordwest- 
und Zentralschweiz’ (EKNZ, Switzerland), and the ‘Zanzibar Medical Research and Ethical Committee’ 
(ZAMREC, Tanzania) in 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. 
7. 
Statistics 
7.1 
Definition of primary endpoint 
Cure rate of co-administered ivermectin-albendazole against T. trichiura is the primary endpoint in our study. 
Since this might be influenced by infection intensity, treatment groups will be equally balanced in terms of 
infection intensity by 2 levels of baseline infection intensity (light infections and moderate/heavy infections).  
7.2 
Justification of number of trial subjects  
Based on available summarized efficacy measures from a recent review [1] and the published literature, we 
assume that the CR of albendazole against T. trichiura is 30% compared to 50% in the albendazole-ivermectin 
treatment regimen. To detect a difference with 90% power at a two-sided 5% significance level, we require 121 
participants per study arm and 143 to account for potential loss to follow-up of 15%. We further assume the 
same treatment efficacy in the mid-term treatment and a 6-months reinfection risk of 10%. Consequently we 
expect a proportion of negative patients after 12 months of 44% in the albendazole arm and of 65% in the 
albendazole-ivermectin arm resulting in a required sample size of 111 participants per arm. To account for a loss 
to follow-up of 30% after 6 months and 40% at final assessment (12 months) we aim to recruit 300 participants 
in each group (600 in total). This number is largely sufficient to further show differences in efficacy in 
subgroups such as school-aged versus adult study populations without losing statistical power as long as 
individuals get recruited in similar proportions to these two groups. 
7.3 
Description of statistical methods 
The primary available case analysis will include all participants with primary end point data. In addition, an 
intention-to-treat analysis will be conducted considering all participants with missing endpoint data as treatment 
failure or all as treatment success to ensure that the results are not sensitive to potential loss to follow-up bias. CRs 
will be calculated as the percentage of egg-positive children at baseline who become egg-negative after treatment. 
EPG will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying 
this number by a factor of six. The ERR will be calculated as: 
 
𝐸𝑅𝑅=  1 − 
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝 + 1) −1
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 1)      −1  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 74 of 176 
 
 
 
In the primary model we estimate the difference among CRs by using unadjusted logistic regressions. In a 
subsequent analysis an adjusted logistic regression (adjustment for age, sex, community, weight and height) will 
be performed.  
Geometric mean egg counts will be calculated for the different treatment arms before and after treatment to assess 
the corresponding ERRs. Bootstrap resampling method with 5,000 replicates will be used to calculate 95% 
confidence intervals (CIs) for ERRs and the difference between the ERRs. 
Results from the stool RDT for fecal occult blood will be categorized as negative, trace and positive. For 
calprotectin, individuals with levels exceeding 50 μg/g will be considered as positive and concentrations be 
classified into low (51–149 μg/g), medium (150–299 μg/g) and high (≥300 μg/g) intensity [19]. 
Anthropometric measurements such as height, weight will be translated into weight- and height-related z-scores 
using readily available Stata macros calculating growth indicators for children 5-19 years [33]. Body mass index 
and indicators for muscle and fat tissue such as MUAC and triceps skinfold thickness will serve as indicators for 
all ages and further be classified using a percentiles approach to compare within populations [34]. 
Questionnaires on physical functioning and treatment satisfaction will be evaluated by creating summary scores 
by summing up and transforming the single question scores according to the following formula: [(actual raw score-
lowest possible raw score)/(possible raw score range)]*100 [23]. 
Morbidity indicators with continuous values (e.g. anthropometric, Hb, mean physical functioning scores) will be 
compared in a first step within and between groups using independent and paired t-test statistics while chi-square 
testing will be performed for binary/categorical outcomes (e.g. anemia, malnutrition categories, fecal 
calprotectin intensity, blood in stool). To compare individual’s changes in malnutrition categories as an effect 
from treatment McNemar’s test will be applied. In a second step, adjusted repeated measures linear and logistic 
regressions using generalized estimating equation (GEE) models will be performed to assess development of 
morbidity indicators and related factors be investigated. 
AEs will be evaluated descriptively as the difference of proportion reporting AEs before and after treatment. 
7.4 
Description of data management 
The investigators are responsible for an adequate data quality. Prior to the initiation of the study, a short 
investigator’s meeting will be held with the investigators and their study coordinators and a member from Swiss 
TPH. This meeting will include a detailed discussion of the protocol, performance of study procedures (SOPs 
from previous studies available on site), CRF completion, and specimen collection and diagnostic methods.  
Screened patients will be listed in a confidential “subject screening log”. Enrolled patients will be listed in a 
confidential “subject enrolment log” and attributed a unique study number; this document will constitute the only 
source to decode the pseudonymised data and will only be accessible to the local principal investigator. All data 
that have been hand-entered in the database will be verified by a double-key entry procedure in a validated 
electronic data base system and error, range and consistency checks will be programmed. Any discrepancies will 
be reviewed against the hard copy CRF and corrected. Electronic data files will be stored on secured network 
drives with restricted access for study personnel only. Data analysis will be conducted with pseudonymised data 
and reporting of findings will be fully anonymised.  
Essential infrastructure such as lockable cabinets for safe storage of hardcopy data will be made available. 
Network drives with restricted access for authorized personnel only and appropriate analysis software are 
available.  
8. 
Duties of the investigator  


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 75 of 176 
 
 
 
8.1 
Investigator’s confirmation 
This trial will be conducted in accordance with the protocol, International Conference on Harmonisation Good 
Clinical Practice E6 (R2) (ICH-GCP) and the current version of the Helsinki Declaration. 
All protocol modifications must be documented in writing. A protocol amendment can be initiated by either the 
Sponsor/PI or any Investigator. The Investigator will provide the reasons for the proposed amendment in writing 
and will discuss with the Sponsor/PI and Co-PIs. Any protocol amendment must be approved and signed by the 
Sponsor/PI and must be submitted to the appropriate Independent Ethics Committee (IEC) for information and 
approval, in accordance with local requirements, and to regulatory agencies if required. Approval by IEC must 
be received before any changes can be implemented, except for changes necessary to eliminate an immediate 
hazard to trial subjects, or when the change involves only logistical or administrative aspects of the trial, e.g. 
change of telephone number(s). 
8.2 
Damage coverage 
A general liability insurance of the Swiss TPH is in place (Winterthur Police Nr. 4746321) and patient liability 
insurances will be issued in Pemba (Tanzania). 
8.3 
Project management 
The trial team will include the PI (Prof. Jennifer Keiser), three Co-PIs (Dr. Eveline Hürlimann, Mr. Shaali Ame 
and Mr. Said Ali), a PhD student, a trial statistician (Dr. Jan Hattendorf), as well as two local physicians and 
laboratory technicians. Prof. Jennifer Keiser, Dr. Eveline Hürlimann, Mr. Shaali Ame and a 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. Mr. Shaali Ame is 
responsible for supervision of the lab- and field technicians, staff management, recruitment monitoring, supply 
of the material, contact to the local authorities and participating schools. Dr. Eveline Hürlimann is responsible 
for oversight of the study in the three continents.  
The investigator team is responsible for ensuring that the protocol is strictly followed. The investigator should 
not make any changes without the agreement of the Principal Investigator and the Co-Investigators, except when 
necessary to eliminate an apparent immediate hazard or danger to a study participant. The investigator will work 
according to the protocol and GCP. The investigator may take any steps judged necessary to protect the safety of 
the participants, whether specified in the protocol or not. Any such steps must be documented. During the 
treatment the records are maintained by the responsible medical doctor. All entries have to be made clearly 
readable with a pen. The investigator must be thoroughly familiar with the properties, effects and safety of the 
investigational pharmaceutical product. 
9. 
Ethical considerations 
9.1 
Independent Ethics Committee (IEC) 
The study will be submitted for approval by the institutional research commission of the Swiss TPH and the 
ethical committees of Switzerland (EKNZ) and Zanzibar (ZAMREC). The study will be undertaken in 
accordance with the Declaration of Helsinki and good clinical practice (GCP). 
9.2 
Evaluation of the risk-benefit ratio 
Ivermectin in combination with albendazole are well-known, widely used drugs in mass treatment programs 
against filariasis, and have little and mainly mild AEs (headache, abdominal pain etc.). 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 ivermectin (200 μg/kg)-albendazole (400 mg) 
considering higher efficacy compared to the existing standard treatment (albendazole alone) and recent inclusion 
as recommended treatment scheme on the Essentials Medicines List [35]. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 76 of 176 
 
 
 
9.3 
Subject information and consent 
All parents or caregivers of eligible children and all adult participants ≥18 years) will be asked to sign a written 
informed consent sheet. In case the person is illiterate, an impartial witness that can read and write has to sign 
the consent and the illiterate participant to give a thumb print. Parents or caregivers and adult participants will 
have sufficient time for reflection of their child’s or their own participation, respectively.  
Community meetings will be conducted to explain to caregivers and potential participants the purpose and 
procedures of the study. Parents or caregivers attending this meeting will receive a small provision to cover their 
costs for transportation (~US$ 2). One of the parents/caregiver of an eligible individual will be asked to sign a 
written informed consent form (translated into the local language, i.e. Kiswahili) after having had sufficient time 
for reflection of their child’s participation. Children (aged 6-17 years) will be briefed verbally and asked orally 
for assent. Even if the participant gives oral assent, the parent/caregiver has to sign the consent. 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. 
9.4 
Subject confidentiality 
The obtained data will be handled strictly confidentially. Only members of the study team will have access to the 
data. Personal data will be coded for data analysis. The codes will be filled with the participant’s identity on a 
separate file (subject identification list) and stored in a secured place at the local institutions (i.e., Côte d’Ivoire: 
UFR Biosciences - Université Félix Hophouët-Boigny, Lao PDR: National Institute of Public Health, and 
Pemba: Public Health Laboratory Ivo de Carneri) and will only be accessible to investigators. No names will be 
published at any time, and published reports will not allow for identification of single subjects. Confidentiality 
and anonymity will be ensured throughout the entire research project. 
The investigators have all been trained in GCP. None of the investigators declare to have any conflicts of 
interest. 
9.5 
Subjects requiring particular protection 
This study will include school-aged children, since T. trichiura infection occurs often in children; hence this age 
group is at high risk of infection and is therefore the major target group in MDA campaigns. Our trial will 
produce more evidence to support the search for a safe and effective treatment of STH infections in children and 
whole communities. 
9.6 
Other aspects 
Patients are in general treated only in yearly intervals to reduce morbidity from chronic infections. A treatment 
delay of 3-4 weeks is not expected to cause any problem. 
 
10. Quality control and quality assurance 
10.1 
Monitoring and auditing 
We will work with locally based monitors. These will conduct site visits to the investigational facilities for the 
purpose of monitoring the study. Details will be described in a separate monitoring plan. The investigator will 
permit them access to study documentation and the clinical supplies dispensing and storage area. Monitoring 
observations and findings will be documented and communicated to appropriate study personnel and 
management. A corrective and preventative action plan will be requested and documented in response to any 
audit observations. No sponsor initiated audits are foreseen, but audits and inspections may be conducted by the 
local regulatory authorities or ethics committees. The Investigator agrees to allow inspectors from regulatory 
agencies to review records and is encouraged to assist the inspectors in their duties, if requested. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 77 of 176 
 
 
 
10.2 
Access to data, handling of data and samples (data protection), archiving (place, duration) and 
destruction 
Information about study subjects will be kept confidential and managed accordingly. A CRF will be completed 
for each subject enrolled into the clinical study. The investigators will review, and approve each completed CRF. 
The study CRF is the primary data collection instrument for the study. All data requested on the CRF must be 
recorded. All missing data must be explained. If a space on the CRF is left blank because the procedure was not 
done or the question was not asked “N/D” will be entered. If the item is not applicable to the individual case 
“N/A” will be written. All entries will be printed in black ink. All corrections must be initialed and dated.  
All data on parasitology and questionnaires about AEs and self-reported clinical signs and symptoms will be 
doubled entered into a database by two independent persons and cross-checked. Discrepancies between data 
entries will be corrected by consulting the hard copy.  
The collected data together with the hard copy CRFs, ICFs and other study documents will be stored at server of 
the Public Health Laboratory in Pemba and are encrypted with Secure Sockets Layer  
The results of the research study will be published, but subjects’ names or identities will not be revealed. 
Records will remain confidential. To maintain confidentiality, the Sponsor-Investigator will keep records in 
locked cabinets and the results of tests will be coded to prevent association with participant’s names. Data 
entered into the ACCESS data entry mask will be accessible only by authorized personnel directly involved with 
the study and will be encoded. Subject-specific information may be provided to other appropriate medical 
personnel only with the subject’s permission. 
After the study has been completed all samples will be destroyed and research data and related material will be 
kept for a minimum of 15 years to enable understanding of what was done, how and why, which allow the work 
to be assessed retrospectively and repeated if necessary. 
10.3 
Data entered directly in the CRF – definition of source data 
Source Data are the clinical findings and observations, laboratory data maintained at the study site. Source data 
are contained in source documents. Local authorities are allowed to access the source data. Data will be entered 
directly onto the CRFs. The CRF is considered as a source document. All CRFs will be kept for at least 15 years. 
The study site will retain a copy of the CRF to ensure that local collaborators can provide access to the source 
documents to a monitor, auditor, or regulatory agency. 
10.4 
Data and safety monitoring board (WHO)/ data monitoring committee (EU/FDA) 
In our study no data and safety monitoring board will be established, since we work with well-known drugs in a 
small sample size and using a single dose treatment. This study is anticipated to be no greater than minimal risk 
to participants. 
10.5 
Study Documents: Translations - Reference language 
- Protocol: Master document in English, all further language versions are translations thereof. 
- CRF: Master document in English, all further language versions are translations thereof. 
- ICF: Master document in English, all further language versions are translations thereof. 
 
11. Dissemination of results and publication 
The final results of this study will be published in a scientific journal and presented at scientific conferences. The 
Bill & Melinda Gates Foundation will be acknowledged as study funder. All results from this investigation are 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 78 of 176 
 
 
 
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 ZAMREC. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 79 of 176 
 
 
 
 
12. References 
1. 
Moser W, Schindler C, Keiser J: Efficacy of recommended drugs against soil transmitted helminths: 
systematic review and network meta-analysis. BMJ 2017, 358:j4307. 
2. 
Hughes D, Andersson DI: Evolutionary consequences of drug resistance: shared principles across 
diverse targets and organisms. Nat Rev Genet 2015, 16(8):459-471. 
3. 
Palmeirim M, Hürlimann E, Joseph SA, Vaillant M, Olliaro P, Keiser J: Efficacy and safety of co-
administered ivermectin plus albendazole for treating soil-transmitted helminths: a systematic 
review meta-analysis and individual patient data analysis. PLoS Negl Trop Dis 2018((under review)). 
4. 
Belizario VY, Amarillo ME, de Leon WU, de los Reyes AE, Bugayong MG, Macatangay BJ: A 
comparison of the efficacy of single doses of albendazole, ivermectin, and diethylcarbamazine alone 
or in combinations against Ascaris and Trichuris spp. Bull World Health Organ 2003, 81(1):35-42. 
5. 
Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C: A comparative trial of a single-
dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and 
other soil-transmitted helminth infections in children. Am J Trop Med Hyg 1996, 55(5):477-481. 
6. 
Moser W, Schindler C, Keiser J: Efficacy of drugs used in preventive chemotherapy against soil-
transmitted helminths: systematic review and meta-analysis. BMJ 2017, (under review). 
7. 
Ismail MM, Jayakody RL: Efficacy of albendazole and its combinations with ivermectin or 
diethylcarbamazine (DEC) in the treatment of Trichuris trichiura infections in Sri Lanka. Ann Trop 
Med Parasitol 1999, 93(5):501-504. 
8. 
Knopp S, Mohammed KA, Speich B, Hattendorf J, Khamis IS, Khamis AN, Stothard JR, Rollinson D, 
Marti H, Utzinger J: Albendazole and mebendazole administered alone or in combination with 
ivermectin against Trichuris trichiura: a randomized controlled trial. Clin Infect Dis 2010, 
51(12):1420-1428. 
9. 
Speich B, Ali SM, Ame SM, Bogoch, II, Alles R, Huwyler J, Albonico M, Hattendorf J, Utzinger J, 
Keiser J: Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, 
albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and 
concomitant soil-transmitted helminth infections: a four-arm, randomised controlled trial. Lancet 
Infect Dis 2015, 15(3):277-284. 
10. 
Betson M, Søe MJ, Nejsum P: Human trichuriasis: whipworm genetics, phylogeny, transmission and 
future research directions. Current Tropical Medicine Reports 2015, 2(4):209-217. 
11. 
Ghai RR, Simons ND, Chapman CA, Omeja PA, Davies TJ, Ting N, Goldberg TL: Hidden population 
structure and cross-species transmission of whipworms (Trichuris sp.) in humans and non-human 
primates in Uganda. PLoS Negl Trop Dis 2014, 8(10):e3256. 
12. 
Hawash MB, Betson M, Al-Jubury A, Ketzis J, LeeWillingham A, Bertelsen MF, Cooper PJ, Littlewood 
DT, Zhu XQ, Nejsum P: Whipworms in humans and pigs: origins and demography. Parasit Vectors 
2016, 9:37. 
13. 
Speich B, Moser W, Ali SM, Ame SM, Albonico M, Hattendorf J, Keiser J: Efficacy and reinfection 
with 
soil-transmitted 
helminths 
18-weeks 
post-treatment 
with 
albendazole-ivermectin, 
albendazole-mebendazole, albendazole-oxantel pamoate and mebendazole. Parasit Vectors 2016, 
9:123. 
14. 
Anderson R, Farrell S, Turner H, Walson J, Donnelly CA, Truscott J: Assessing the interruption of the 
transmission of human helminths with mass drug administration alone: optimizing the design of 
cluster randomized trials. Parasit Vectors 2017, 10(1):93. 
15. 
Lo NC, Addiss DG, Hotez PJ, King CH, Stothard JR, Evans DS, Colley DG, Lin W, Coulibaly JT, 
Bustinduy AL, Raso G, Bendavid E, Bogoch, II, Fenwick A, Savioli L, Molyneux D, Utzinger J, Andrews 
JR: A call to strengthen the global strategy against schistosomiasis and soil-transmitted 
helminthiasis: the time is now. Lancet Infect Dis 2017, 17(2):e64-e69. 
16. 
Katz N, Chaves A, Pellegrino J: A simple device for quantitative stool thick-smear technique in 
Schistosomiasis mansoni. Rev Inst Med Trop São Paulo 1972, 14(6):397-400. 
17. 
Speich B, Ali SM, Ame SM, Albonico M, Utzinger J, Keiser J: Quality control in the diagnosis of 
Trichuris trichiura and Ascaris lumbricoides using the Kato-Katz technique: experience from three 
randomised controlled trials. Parasit Vectors 2015, 8:82. 
18. 
Mejia R, Vicuna Y, Broncano N, Sandoval C, Vaca M, Chico M, Cooper PJ, Nutman TB: A novel, multi-
parallel, real-time polymerase chain reaction approach for eight gastrointestinal parasites provides 
improved diagnostic capabilities to resource-limited at-risk populations. Am J Trop Med Hyg 2013, 
88(6):1041-1047. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 80 of 176 
 
 
 
19. 
Bustinduy AL, Sousa-Figueiredo JC, Adriko M, Betson M, Fenwick A, Kabatereine N, Stothard JR: 
Fecal occult blood and fecal calprotectin as point-of-care markers of intestinal morbidity in 
Ugandan children with Schistosoma mansoni infection. PLoS Negl Trop Dis 2013, 7(11):e2542. 
20. 
Dunyo SK, Nkrumah FK, Simonsen PE: A randomized double-blind placebo-controlled field trial of 
ivermectin and albendazole alone and in combination for the treatment of lymphatic filariasis in 
Ghana. Trans R Soc Trop Med Hyg 2000, 94(2):205-211. 
21. 
Awadzi K, Edwards G, Duke BO, Opoku NO, Attah SK, Addy ET, Ardrey AE, Quartey BT: The co-
administration of ivermectin and albendazole--safety, pharmacokinetics and efficacy against 
Onchocerca volvulus. Ann Trop Med Parasitol 2003, 97(2):165-178. 
22. 
Simonsen PE, Magesa SM, Dunyo SK, Malecela-Lazaro MN, Michael E: The effect of single dose 
ivermectin alone or in combination with albendazole on Wuchereria bancrofti infection in primary 
school children in Tanzania. Trans R Soc Trop Med Hyg 2004, 98(8):462-472. 
23. 
Fürst T, Müller I, Coulibaly JT, Yao AK, Utzinger J, N'Goran EK: Questionnaire-based approach to 
assess schoolchildren's physical fitness and its potential role in exploring the putative impact of 
helminth and Plasmodium spp. infections in Côte d'Ivoire. Parasit Vectors 2011, 4:116. 
24. 
Campbell SJ, Nery SV, McCarthy JS, Gray DJ, Soares Magalhaes RJ, Clements AC: A Critical 
Appraisal of Control Strategies for Soil-Transmitted Helminths. Trends Parasitol 2016, 32(2):97-
107. 
25. 
Strunz EC, Addiss DG, Stocks ME, Ogden S, Utzinger J, Freeman MC: Water, sanitation, hygiene, and 
soil-transmitted helminth infection: a systematic review and meta-analysis. PLoS Med 2014, 
11(3):e1001620. 
26. 
Kepha S, Mwandawiro CS, Anderson RM, Pullan RL, Nuwaha F, Cano J, Njenga SM, Odiere MR, Allen 
E, Brooker SJ, Nikolay B: Impact of single annual treatment and four-monthly treatment for 
hookworm and Ascaris lumbricoides, and factors associated with residual infection among Kenyan 
school children. Infect Dis Poverty 2017, 6(1):30. 
27. 
WHO: Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. 
Vitamin and Mineral Nutrition Information System. Geneva: World Health Organization; 2011: 
(WHO/NMH/NHD/MNM/11.11). 
28. 
WHO: Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs 
in control interventions: a manual for health professionals and programme managers. Geneva: 
World Health Organization; 2006: 62. 
29. 
Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, 
Lasseter KC: Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in 
healthy adult subjects. J Clin Pharmacol 2002, 42(10):1122-1133. 
30. 
Pawluk SA, Roels CA, Wilby KJ, Ensom MH: A review of pharmacokinetic drug-drug interactions 
with the anthelmintic medications albendazole and mebendazole. Clin Pharmacokinet 2015, 
54(4):371-383. 
31. 
Ndyomugyenyi R, Kabatereine N, Olsen A, Magnussen P: Efficacy of ivermectin and albendazole 
alone and in combination for treatment of soil-transmitted helminths in pregnancy and adverse 
events: a randomized open label controlled intervention trial in Masindi district, western Uganda. 
Am J Trop Med Hyg 2008, 79(6):856-863. 
32. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: ICH Harmonised Tripartite Guideline. Clinical Safety Data 
Management: definition and standards for expedited reporting E2A. 1994. 
33. 
Duggan MB: Anthropometry as a tool for measuring malnutrition: impact of the new WHO growth 
standards and reference. Ann Trop Paediatr 2010, 30(1):1-17. 
34. 
Wang Y, Chen H: Use of Percentiles and Z-Scores in Anthropometry. In: Handbook of Anthropometry. 
Edited by Preedy V. New York: Springer; 2012: 29-48. 
35. 
WHO: The selection and use of essential medicines: report of the 21st WHO Expert Committee. 
WHO Technical Report Series. Geneva: World Health Organization; 2017. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 81 of 176 
 
 
 
13. Appendix 
13.1 
Household-based questionnaire 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 82 of 176 
 
 
 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 83 of 176 
 
 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 84 of 176 
 
 
 
5. Trial protocol Cote d’Ivoire:  
 
Efficacy and safety of ivermectin and albendazole co-administration in school-aged children and adults 
infected with Trichuris trichiura: a multi-country randomized controlled trial 
 
 
Protocol Number 
1 
Version Number 
1.01 
Document Date 
12.06.2018 
Sponsor Contact 
Prof. Dr. Jennifer Keiser,  
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@unibas.ch 
Principle Investigator 
Prof. Dr. Jennifer Keiser,  
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@unibas.ch 
Funding Agency 
Bill and Melinda Gates Foundation 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 85 of 176 
 
 
 
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 
Postdoc 
Co-PI 
Dr. 
Jessica Schulz 
Swiss TPH 
Postdoc 
Co-PI 
Dr.  
Jean Coulibaly 
Swiss TPH / Université 
Félix Hophouët-Boigny 
(UFHB), Abidjan, Côte 
d‘Ivoire 
Group leader 
Co-PI 
Dr. 
Yves N'Gbesso 
Departement 
d'Agboville, Centre de 
Santé Urbain d'Azaguié, 
Azaguié 
Medical 
doctor 
Study physician 
Dr. 
Jan Hattendorf 
 
Swiss TPH  
 
Project leader 
Statistician 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 86 of 176 
 
 
 
II. 
Signatures  
 
Statistician 
Signature 
 
 
 
 
 
Date of Signature  
12.06.2018 
Name  
Jan Hattendorf 
Title 
Dr.  
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 284-8193 
 
Principal investigator 
Signature 
 
 
 
 
 
Date of Signature  
12.06.2018 
Name  
Jennifer Keiser 
Title 
Prof. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 284-8218 
 
I have read this protocol and agree that it contains all necessary details for carrying out this trial. I will conduct 
the trial as outlined herein and will complete the trial within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist 
in the conduct of this trial. I will discuss this material with them to ensure they are fully informed regarding the 
drug and the conduct of the trial. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 87 of 176 
 
 
 
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. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 88 of 176 
 
 
 
Co-Principal investigator 
Signature 
 
 
 
Date of Signature  
12.06.2018 
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 
Phone 
+41 61 284 87 04 
 
Co-Principal investigator 
Signature 
 
 
 
 
 
Date of Signature  
12.06.2018 
Name  
Jessica Schulz 
Title 
Dr. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 207 15 06 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 89 of 176 
 
 
 
Co-Principal investigator 
Signature 
 
 
 
Date of Signature  
12.06.2018 
Name  
Jean Coulibaly 
Title 
Dr. 
Institution 
Swiss Tropical and Public Health Institute/Université Félix Houphouët-Boigny 
Address 
23 BP 915 Abidjan 23 
Phone 
+225 0500 8223/+225 0209 1401 
 
 
Study physician 
Signature 
 
 
Date de Signature  
12.06.2018 
Nom 
Yves Koutouan N'Gbesso 
Title 
Dr. 
Institution 
Departement d'Agboville, Centre de Santé Urbain d'Azaguié, Azaguié 
Address 
 
Phone 
+225 07442207/ +225 02729236  
 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 90 of 176 
 
 
 
Table of contents 
 
1. 
General information ......................................................................................................................................85 
2. 
Background information................................................................................................................................99 
3. 
Trial objective and purpose .........................................................................................................................101 
4. 
Methodology ...............................................................................................................................................103 
4.1 
Primary and secondary endpoint.........................................................................................................103 
4.2 
Type of trial ........................................................................................................................................103 
4.3 
Trial design .........................................................................................................................................103 
4.3.1 
Baseline survey and screening ...................................................................................................103 
4.3.2 
Assessment of efficacy and other benefits after treatment .........................................................106 
4.3.3 
Pharmacokinetic studies.............................................................................................................107 
4.4 
Measure to minimize bias ...................................................................................................................107 
4.5 
Study duration and duration of subject participation ..........................................................................108 
4.6 
Schedule of visits ................................................................................................................................108 
5. 
Selection of the trial subjects .......................................................................................................................110 
5.1 
Recruitment ........................................................................................................................................110 
5.2 
Inclusion criteria .................................................................................................................................110 
5.3 
Exclusion criteria ................................................................................................................................111 
5.4 
Criteria for discontinuation of trial .....................................................................................................111 
5.5 
Treatment of subjects..........................................................................................................................111 
5.6 
Concomitant therapy...........................................................................................................................112 
6. 
Safety assessments ......................................................................................................................................112 
6.1 
Adverse event definitions ...................................................................................................................113 
6.1.1 
Severity grading .........................................................................................................................113 
6.1.2 
Relatedness ................................................................................................................................113 
6.1.3 
Expectedness ..............................................................................................................................114 
6.1.4 
Serious adverse events ...............................................................................................................114 
6.1.5 
Suspected unexpected serious adverse reactions .......................................................................114 
6.2 
Methods of recording and assessing adverse events ...........................................................................114 
6.3 
Reporting of serious adverse events ...................................................................................................115 
6.4 
Safety reporting to Health Authorities and Ethics Committees ..........................................................116 
7. 
Statistics ......................................................................................................................................................116 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 91 of 176 
 
 
 
7.1 
Definition of primary endpoint ...........................................................................................................116 
7.2 
Justification of number of trial subjects ..............................................................................................116 
7.3 
Description of statistical methods .......................................................................................................117 
7.4 
Description of data management and data quality control ..................................................................118 
8. 
Duties of the investigator ............................................................................................................................119 
8.1 
Investigator’s confirmation .................................................................................................................119 
8.2 
Damage coverage ...............................................................................................................................119 
8.3 
Project management ...........................................................................................................................120 
9. 
Ethical considerations..................................................................................................................................120 
9.1 
Independent ethics committee ............................................................................................................120 
9.2 
Evaluation of the risk-benefit ratio .....................................................................................................120 
9.3 
Subject information and consent.........................................................................................................120 
9.4 
Subject confidentiality ........................................................................................................................121 
9.5 
Subjects requiring particular protection ..............................................................................................121 
9.6 
Other aspects.......................................................................................................................................121 
10. 
Quality control and quality assurance .....................................................................................................121 
10.1 
Monitoring and auditing .....................................................................................................................121 
10.2 
Access to data, handling of data and samples (data protection), archiving (place, duration) and 
destruction .......................................................................................................................................................122 
10.3 
Data entered directly in the CRF – definition of source data ..............................................................122 
10.4 
Data and safety monitoring board / data monitoring committee.........................................................122 
10.5 
Study Documents: Translations - Reference language .......................................................................123 
11. 
Dissemination of results and publication ................................................................................................123 
12. 
References ...............................................................................................................................................124 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 92 of 176 
 
 
 
III. 
Abbreviations 
AE 
Adverse event 
AUC 
Area under the curve 
CI 
Confidence interval 
CNER 
Comité Nationale d’Ethique de la Recherche 
CR 
Cure rate 
CRF 
Case report form 
CSRS 
Centre Suisse de Recherches Scientifiques en Côte d’Ivoire 
DF 
Dose-finding 
DPML 
Direction de la Pharmacie, du Médicament et des Laboratoires 
EKNZ 
Ethikkomission Nordwest- und Zentralschweiz 
EML 
Essential medicine list 
EPG 
Eggs per gram 
ERR 
Egg reduction rate 
GCP 
Good clinical practice 
GEE 
Generalized estimating equation 
Hb 
Hemoglobin 
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 
MIC 
Minimal inhibitory concentration 
MUAC 
Mid-upper arm circumference 
PC 
Preventive chemotherapy 
PCR 
Polymerase chain reaction 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/pharmacodynamic 
RDT 
Rapid diagnostic test 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
STH 
Soil-transmitted helminth 
Swiss TPH 
Swiss Tropical and Public Health Institute 
SUSAR 
Suspected unexpected serious adverse reaction 
WHO 
World Health Organization 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 93 of 176 
 
 
 
IV. 
Synopsis 
 
Sponsor/Sponsor-
Investigator 
Prof. Dr. Jennifer Keiser 
Study Title 
Efficacy and safety of ivermectin and albendazole co-administration in school-
aged children and adults infected with Trichuris trichiura: a multi-country 
randomized controlled trial 
Short title 
Efficacy and safety of IVM/ALB co-administration 
Protocol Number, Date and 
Version 
1, 12.06.2018, v1.01 
Trial registration 
Has been registered on ClinicalTrials.gov (reference: NCT 03527732) 
Clinical phase 
Phase 3 trial 
Sample size 
1960 (600 participants in each of 3 settings for the parallel group trial 
including 160 participants for the dose-finding (DF) study) 
Indication 
Trichuris trichiura infection (eggs in stool) 
Investigational Product and 
Reference Treatment 
Ivermectin and albendazole 
Study Rationale 
To provide evidence on  
a) potentially enhanced efficacy by combining the standard drug albendazole 
with ivermectin in school-aged children and adults against infection with T. 
trichiura. 
b) effective doses of ivermectin in combination with albendazole in school-
aged children against infection with T. trichiura. 
Study Objectives 
To compare the efficacy and safety of: 
(a) standard doses of co-administered ivermectin (200 µg/kg) and albendazole 
(400 mg) compared to albendazole (400 mg) monotherapy in community 
members aged 6-60 years and (b) ascending doses of ivermectin ((i) 200 
µg/kg, (ii) 400 µg/kg, and (iii) 600 µg/kg) co-administered with albendazole 
(400 mg) in school-aged children (6-12 years) infected with T. trichiura and to 
measure ivermectin and albendazole disposition in children using a 
microsampling device. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 94 of 176 
 
 
 
 
Our primary objective is to comparatively assess the efficacy in terms of cure 
rates (CRs) against T. trichiura infections among school-aged children and 
adults of the following oral treatment regimens: 
a) in a parallel group trial: 
Albendazole (400 mg)/ivermectin (200 µg/kg) combination  
Albendazole (400 mg) monotherapy 
b) in the DF study (school-aged children only): 
Albendazole (400 mg)/ivermectin (200 µg/kg) combination 
Albendazole (400 mg)/ivermectin (400 µg/kg) combination  
Albendazole (400 mg)/ivermectin (600 µg/kg) combination  
Placebo 
 
The secondary objectives of the trial are: 
a) To evaluate the safety and tolerability of the treatment regimens  
b) To compare the egg reduction rate (ERR) of the treatment regimens 
(combination vs. monotherapy and ascending doses of the 
combination) against T. trichiura 
c) To determine the CRs and ERRs of the drugs in study participants (6-
60 years) infected with hookworm, Ascaris lumbricoides and 
Strongyloides stercoralis 
d) To investigate potential extended effects on follow-up helminth 
prevalences (6 and 12 months post-treatment) of the two standard-dose 
treatment regimens (as assessed among participants with cleared 
infection on days 21 and 180) 
e) To compare CRs based on infection status determined by novel 
polymerase chain reaction (PCR)-based and standard microscopic 
diagnosis 
f) 
To assess potential differences in susceptibility to the treatment 
regimen between the hookworm species, Necator americanus, 
Ancylostoma duodenale and A. ceylanicum, as classified through the 
novel PCR-based diagnosis 
g) To characterize T. trichiura strains from different epidemiological 
settings and investigate potential resistance markers using a deep 
sequencing analysis 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 95 of 176 
 
 
 
h) To determine optimal timing for measuring anthelmintic efficacy in 
T. trichiura infection 
i) 
To evaluate potential benefits from deworming on morbidity 
indicators and nutritional parameters 
j) 
To determine an exposure (including length of time that the drug 
concentration is above the minimal inhibitory concentration (MIC), 
Cmax, area under the curve (AUC))-response correlation of ivermectin 
and albendazole in school-aged children 
Study design 
Double blind, randomized controlled trial 
Study product / intervention Administration of a single oral dose of  ivermectin + albendazole 
Comparator(s) 
main trial: albendazole (400 mg) monotherapy, DF study: placebo 
Key inclusion / Exclusion 
criteria 
Inclusion:  School-aged children and adults (6-60 years) infected with 
T. trichiura with at least two slides of the quadruple Kato-Katz thick smears 
positive and infection intensities of at least 100 eggs per gram of stool (EPG), 
agreeing to comply with study procedures, including provision of two stool 
samples at the beginning (baseline) and on three follow-up assessments 
(approximately 3 weeks, 6 months, and 12 months later), written informed 
consent signed by parents and/or caregivers for children/adolescents; and 
written assent by child/adolescent (aged 6-20 years). 
Exclusion: No written informed consent by individual/parents and/or 
caregiver, any clinically relevant abnormality (including severe anemia or 
clinical malaria) or history of acute or severe chronic disease (e.g. cancer, 
diabetes, chronic heart, liver or renal disease), recent use of anthelminthic 
drug (past 4 weeks), attending other clinical trials during study, negative 
diagnostic or low egg count (less than 100 EPG or less than 2 out of 4 slides 
positive) result for T. trichiura, known allergy to study medication, pregnancy 
or lactating in the 1st week after birth, taking medication with known 
interaction on study drugs. 
Primary Endpoints 
T. trichiura infection status assessed by Kato-Katz 14-21 days after treatment 
Secondary Endpoints 
 
ERR against T. trichiura  
 
CRs and ERRs against A. lumbricoides, hookworm and S. stercoralis 
 
Adverse events 
 
Infection status assessed by PCR 
 
Pharmacokinetic parameters for ivermectin and albendazole in school-
aged children 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 96 of 176 
 
 
 
Exploratory Endpoints 
 
Molecular characterization and resistance markers of T. trichiura 
 
Optimal timing for drug efficacy assessment in T. trichiura infection 
 
Nutritional status 
 
Morbidity indicators 
Interim Analyses 
None 
Study Duration 
14 months  
Schedule 
06/2018 of first-participant in (planned) 
08/2019 of last-participant out (planned) 
Study centers 
Multinational study with trial sites in Côte d’Ivoire, Lao PDR and Pemba 
Island (Tanzania) 
Measurements & procedures Two stool samples (each of a minimum of 15 grams) will be collected if 
possible on two consecutive days or otherwise within a maximum of 5 days. 
The medical history of the participants will be assessed with a standardized 
questionnaire, in addition to a clinical examination carried out by the study 
physician before treatment.  
All participants will be interviewed before treatment, 3 and 24 hours and 3 
weeks after treatment about the occurrence of adverse events. Children aged 
6-16 years will additionally be asked to rate their own physical functioning by 
replying to a pre-tested questionnaire at baseline and 6 and 12 months after 
treatment. The efficacy of the treatment and potential extended effects on 
follow-up prevalence will be determined 14-21 days, 6 months and 12 months 
post-treatment by collecting another two stool samples. Subjective treatment 
satisfaction will be assessed 3 hours, 3 weeks and 6 months after treatment to 
investigate relationship with treatment compliance and observed efficacy in 
reducing egg output and morbidity. 
All stool samples will be examined with duplicated Kato-Katz thick smears 
for T. trichiura, A. lumbricoides and hookworm. S. stercoralis infections will 
be identified using the Baermann technique and recorded qualitatively as 
larvae-positive or negative. For subsequent PCR-analysis a portion of 1.5-2 g 
of stool from each specimen will be preserved in 70% ethanol and shipped to a 
reference laboratory at Swiss TPH in Switzerland. At baseline and in the first 
follow-up (3 weeks post treatment) an additional portion of stool (1.5-2 g) 
from a subsample of 10 participants identified with heavy intensity infections 
in each case and study setting will be preserved in 95% ethanol, shipped to the 
same reference laboratory and subjected to deep sequencing for 
characterization of T. trichiura strains and investigation of potential resistance 
markers. Fecal occult blood and calprotectin in stool as markers for gut 
morbidity and inflammation will be detected using a rapid diagnostic test and 
an immunoassay, respectively. A subsample of 30 participants will be asked to 
provide a daily stool sample for a period of up to 4 weeks to monitor dynamics 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 97 of 176 
 
 
 
of T. trichiura egg output for subsequent determination of the optimal timing 
for drug efficacy assessment. Individuals found T. trichiura positive 6 months 
after baseline will receive a second round of treatment according to their 
group scheme.  
Each participant will be asked to provide a finger-prick blood sample for 
hemoglobin measurement, a rapid diagnostic test (RDT) for Plasmodium spp. 
and where applicable a biplex RDT for lymphatic filariasis/onchocerciasis at 
baseline and 6 and 12 months after treatment. At the same time points 
anthropometric measurements (i.e. height, weight, mid-upper arm 
circumference (MUAC) and skinfold thickness) will be taken for all 
participants. In addition, a venous blood sample (~8 ml) will be taken from 
each participant to assess biochemical blood parameters as proxies for vital 
organ functioning (e.g. complete blood count, urea, creatinine, transaminases 
etc.) and nutritional indicators for micro- (i.e. (pro-) vitamins, inflammation 
markers, and iron/ferritin) and macronutrient (i.e. albumin) deficiencies at 
baseline, day 21, day 180 and day 360. 
To all participating households, a questionnaire will be administered assessing 
information on socioeconomic characteristics and access to sanitation, water 
facilities, and hygiene behavior. 
For the assessment of pharmacokinetic parameters within the DF study the 
participating school-aged children (6-12 years) will be sampled using finger 
pricking for microsampling at 0, 1, 2, 3, 4, 5, 6, 7, 9, 24, 48 hours post-dosing. 
Statistical Analyses 
An available case analysis will be performed, including all subjects with 
primary end point data. Supplementary, a per-protocol analysis will be 
conducted. CRs will be calculated as the percentage of egg-positive subjects at 
baseline who become egg-negative after treatment. Differences among CRs 
(between treatment arms and between diagnostic approaches) will be analysed 
by using crude and adjusted logistic regression modeling (adjustment for age, 
sex and weight).  
Geometric and arithmetic mean egg counts will be calculated for the different 
treatment arms before and after treatment to assess the corresponding ERRs. 
Bootstrap resampling method with 5,000 replicates will be used to calculate 
95% confidence intervals (CIs) for differences in ERRs.  
Further secondary outcomes – as nutritional and morbidity indicators - will be 
analysed using logistic and linear regression as appropriate. To compare 
individual’s changes in nutrition/morbidity categories as an effect from 
treatment McNemar’s test will be applied. The analysis after 6 and 12 month 
of follow-up will be complemented by generalized estimating equation (GEE) 
models with independent correlation structure and empirical estimators to 
account for missing data. 
Nonlinear mixed-effects modeling will be used to determine pharmacokinetic 
parameters. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 98 of 176 
 
 
 
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 school-aged children, since an infection with 
T. trichiura occurs most often in children and they are further the main target 
group of deworming campaigns. 
Recruitment procedure 
The parallel group trial will be conducted as a multi-country study with two 
settings in Africa and one in Asia recruiting each 600 community members: 
 
West African setting: Côte d’Ivoire 
 
East African setting: Pemba (Zanzibar, Tanzania)  
 
Asian setting: Lao PDR 
 
The DF study will be embedded in the trial and implies the recruitment of an 
additional 160 school-aged children (6-12 years) to be able to include 40 
children per arm in Côte d’Ivoire. 
 
The studies will be conducted in areas with moderate to high T. trichiura 
endemicity (communities with a prevalence ≥ 25%) identified from earlier 
studies and/or based of experience of the local collaborating teams. They will 
be implemented as community-based studies in order to recruit participants 
from a broad age range (6-60 years). Ideally, entire communities with a 
population size of < 1000 inhabitants will be included in the study for pre-
screening and identification of T. trichiura cases to avoid potential selection 
bias of households. To identify all potentially eligible households of the 
respective communities and its composition in terms of age groups a 
preceding population census will be conducted. 
Coverage of damages 
Winterthur Police Nr. 4746321, BERACA Côte d’Ivoire, No: to be issued 
Storage of data and samples 
for future research aims 
After the study has been completed all samples will be destroyed and case 
report forms will be kept for a minimum of 15 years (chapter 10). 
 
Conflict of interest in 
relation to the investigated 
drugs 
We declare no conflict of interest in relation to the investigated drugs. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 99 of 176 
 
 
 
2. 
Background information 
Albendazole and mebendazole are the most widely used drugs for preventive chemotherapy (PC) campaigns 
against soil-transmitted helminth (STH) infections. Albendazole is characterized by high cure rates (CRs) and 
egg reduction rates (ERRs) against infections with Ascaris lumbricoides (95.7% and 98.5%) and hookworm 
infections (79.5 and 89.6%). Lower efficacy is observed against Trichuris trichiura infections (CR 30.7%, and 
ERR of 49.9%) [1].  
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 mono-therapy [2].   
A recent review and meta-analysis found that ivermectin co-administered with albendazole is highly efficacious 
for the treatment of T. trichiura and is comparatively more efficacious than albendazole alone (Figure 1) [3]. 
Efficacy of ivermectin and albendazole against A. lumbricoides and hookworm are comparable and in some 
cases more efficacious than albendazole alone. Summarized efficacy measures of albendazole, mebendazole, and 
ivermectin against trichuriasis from a recent review [1] and earlier trials [4, 5]  are shown in Table 1. 
 
 
Figure 1. Forest plot displaying the results of a random-effects meta-analysis of the effect of the co-
administration of albendazole-ivermectin on the number of patients infected with T. trichiura compared to 
albendazole alone.  
 
 
 
 
 
Table 1. Average CRs and ERRs of albendazole and mebendazole for T. trichiura from a recent review [1] as 
well as findings from studies investigating ivermectin [4, 5] 
Drug 
CR (%) 
95% CI 
ERR (%) 
95% CI 
Albendazole 
30.7 
(21.0, 42.5) 
49.9 
(39.0, 60.6) 
Mebendazole 
42.1 
(25.9, 60.2) 
66.0  
(54.6, 77.3) 
Ivermectin 
11-35 
NA 
43-98 
NA 
NA, not applicable 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 100 of 176 
 
 
 
 
The individual studies included in the review are summarized in Table 2. All four studies are randomized 
controlled trials and used the standard dose of 200 µg/kg ivermectin and 400 mg albendazole [4, 6-8]. Against 
infections with T. trichiura, CRs ranging from 27.5-81.1%, ERR based on geometric mean ranging from 91.3-
99.7%, and ERR based on arithmetic mean ranging from 85.6-97.5% were observed. CRs for T. trichiura 
observed in Asian settings were higher than in African settings. One reason for this finding may be differences in 
the study design and quality (e.g. in terms of diagnostic approach used). Another possible reason recently 
highlighted is genetic diversity of T. trichiura strains and variation in susceptibility to anthelmintics and/or drug 
resistance [9-11]. Interestingly, the higher efficacy of ivermectin in combination with albendazole translated – at 
least in some settings – into lower prevalences even after one year [4, 12]. The efficacy of albendazole-
ivermectin against A. lumbricoides was excellent (CRs >78% and ERRs >99.5%), while moderate CRs (50-
66.7%) and high ERRs (>95.4%) were observed against hookworm. 
 
Table 2. Known efficacy of co-administered ALB-IVMa against T. trichiura: 
Study 
Setting 
Cure rate in % 
(nneg/n) 
Eggs per gram 
 (pre/post) 
Egg reduction rate 
in % 
Ismail et al. 1999 
Sri Lanka 
81.1% (43/53) 
1544.0/78.7 (unkwn) 
94.9% (unkwn) 
Belizario et al. 2003 
Philippines 
65.1% (97/149) 
4948.1/122.5 (ar) 
550.0/1.9 (geo) 
97.5% (ar)  
99.7% (geo) 
Knopp et al. 2010 
Tanzania 
(Pemba) 
37.9% (53/140) 
127/11 (geo) 
91.3% (geo) 
Speich et al. 2015 
Tanzania 
(Pemba) 
27.5% (30/109) 
1059/153 (ar) 
489/27 (geo) 
85.6% (ar) 
94.5% (geo) 
All studies 
 
49.4% (223/451) 
 
 
aConsidered doses: albendazole=400 mg, ivermectin=200 µg/kg 
ar=arithmetic mean, geo=geometric mean, unkwn=unknown mean 
 
 
The WHO Expert Committee met from March 27-31, 2017 and, based on review of a dossier suggesting 
inclusion of ivermectin as an anthelmintic in the Essential Medicines List, made the following recommendation:  
 
“…adding ivermectin on the Essential Medicines List under the section intestinal anthelminthic for use against 
Strongyloides stercoralis and STH. It may be used in combination with albendazole for treatment of soil-
transmitted helminthiasis.” 
 
This important milestone paves the way for further, standardized trials to evaluate the efficacy of this 
combination among school-aged children in a range of epidemiological settings. In addition, the combination 
should be evaluated among adults, as there is growing interest in broadening deworming to include adults in 
order to move from morbidity control toward interruption of transmission [13, 14].  
In the proposed work, three trials are planned across a range of transmission settings, including Côte d'Ivoire, 
Lao PDR, and Pemba (Tanzania). Follow-up will be conducted at 1, 6, and 12 months to inform treatment 
frequency. Results from these trials will inform decisions on how the combination could be introduced into 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 101 of 176 
 
 
 
existing mass drug administration (MDA) programs and therefore provide a valuable adjunct tool for 
interrupting STH transmission.  
 
3. 
Trial objective and purpose 
The overall goal of the study is to assess the efficacy and safety of co-administered albendazole and ivermectin 
versus albendazole monotherapy (standard of care) against T. trichiura infections in children and adults (6-60 
years) in different transmission settings and geographies. Embedded in this trial a smaller dose-finding (DF) 
study with the goal to investigate efficacy, safety and pharmacokinetic parameters of ascending doses of 
ivermectin ((i) 200 µg/kg, (ii) 400 µg/kg, and (iii) 600 µg/kg) co-administered with albendazole (400 mg) in 
school-aged children infected with T. trichiura will take place. 
 
We hypothesize that albendazole-ivermectin has a higher efficacy against T. trichiura infections than 
albendazole alone, and hence, the efficacy against all three STH species (A. lumbricoides, T. trichiura, and 
hookworm) and Strongyloides stercoralis will be increased. 
The primary objective of the trial is to comparatively assess the efficacy in terms of CR against T. trichiura 
infections among school-aged children and adults from three different epidemiological settings and monitored 
over a 12-month period of the following two oral treatment regimens: 
• 
Albendazole/ivermectin combination 
• 
Albendazole monotherapy 
 
A DF study will be implemented in the trial with the objective to understand the dose-dependent efficacy and 
pharmacokinetic profile of the co-administration of albendazole and ivermectin in school-aged children (6‒12 
years) with the following four oral treatment regimens: 
• 
Albendazole (400 mg) /ivermectin (200 µg/kg) combination 
• 
Albendazole (400 mg) /ivermectin (400 µg/kg) combination 
• 
Albendazole (400 mg) /ivermectin (600 µg/kg) combination 
• 
Placebo 
 
The secondary objectives of the trial are: 
a) To evaluate the safety and tolerability of the treatment regimens  
b) To compare the ERRs of the treatment regimens (combination vs. monotherapy and ascending doses of 
the combination) against T. trichiura 
c) To determine the CRs and ERRs of the drugs in study participants (6-60 years) infected with hookworm, 
A. lumbricoides and S. stercoralis 
d) To investigate potential extended effects on follow-up helminth prevalences (6 and 12 months post-
treatment) of the two standard-dose treatment regimens (as assessed among participants with cleared 
infection on days 21 and 180) 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 102 of 176 
 
 
 
e) To compare CRs based on infection status determined by novel polymerase chain reaction (PCR)-based 
and standard microscopic diagnosis 
f) 
To assess potential differences in susceptibility to the treatment regimen between the three hookworm 
species, Necator americanus, Ancylostoma duodenale and A. ceylanicum, as classified through the novel 
PCR-based diagnosis 
g) To characterize T. trichiura strains from different epidemiological settings and investigate potential 
resistance markers using a deep sequencing analysis 
h) To determine optimal timing for measuring anthelmintic efficacy in T. trichiura infection 
i) 
To evaluate potential benefits from deworming on morbidity (clinically evaluated and self-rated from 
questionnaire interviews) and nutritional indicators  
j) 
To determine an exposure (including length of time that the drug concentration is above the minimal 
inhibitory concentration (MIC), Cmax, area under the curve (AUC))-response correlation of ivermectin 
and albendazole in school-aged children 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 103 of 176 
 
 
 
4. 
Methodology 
4.1 
Primary and secondary endpoint 
T. trichiura infection status assessed by Kato-Katz 14-21 days after treatment will be the primary endpoint and 
the main outcome for efficacy be expressed as cure rate (CR) (i.e. conversion from being egg positive pre-
treatment to egg negative post-treatment) and egg reduction rate (ERR) (secondary end point). Secondary 
endpoints include further infection status with A. lumbricoides, hookworm and S. stercoralis and related efficacy 
measures, adverse events, infection status assessed by PCR and key pharmacokinetic parameters in school-aged 
children. In addition, optimal timing for drug efficacy assessment in T. trichiura infection will be determined, 
T. trichiura strains will be described and potential resistance markers evaluated using deep sequencing and 
potential benefits on nutritional and morbidity indicators from treatment assessed (exploratory end points). 
 
4.2 
Type of trial 
Double blind randomized controlled trial. 
 
4.3 
Trial design 
4.3.1 
Baseline survey and screening 
Parallel group multi-country study 
A randomized-controlled trial will be conducted with two treatment arms to be followed-up over a 12 months 
period with an intermediate re-treatment of participants found re-infected after 6 months (Figure ). This parallel 
group trial will be conducted as a multi-country study; thus, in each setting a separate trial according to the 
design described below will be set up, to provide a better basis for the subsequent generalization of its findings. 
This arises from the possibility of recruiting the subjects from a wider population and of administering the 
medication in a broader range of clinical settings, thus presenting an experimental situation that is more typical 
of future use. The study includes one baseline and three follow-up assessments at 3 weeks (day 21), 6 months 
(day 180), and 12 months (day 360). 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 104 of 176 
 
 
 
 
Figure 2. Design and timeline of the randomized-controlled trial to be implemented in each of three settings. 
 
The study is designed as a two-armed trial including one arm with a single drug administration (arm A; 
albendazole) and one arm with combined treatment through co-administration of separate tablets (arm B; 
albendazole and ivermectin).  
The trial will be conducted as a multi-country study with two settings in Africa and one in Asia, namely Côte 
d’Ivoire, Pemba (Zanzibar, Tanzania) and Lao PDR. 
At baseline, all participants will be asked to provide two stool samples of at least 15 grams each (within a 
maximum of 5 days). From every stool specimen, duplicate Kato-Katz thick smears (41.7 mg each) [15] will be 
prepared and read under a microscope for eggs of T. trichiura, A. lumbricoides and hookworm by experienced 
technicians. A small amount of feces (~10 mg and 60 μg, respectively) will further be tested on fecal occult 
blood and calprotectin as proxies for gut morbidity and inflammation using a rapid diagnostic test an 
immunoassay, respectively [16]. Additionally, a portion of 1.5-2 g of stool from each specimen will be preserved 
in 70% ethanol and shipped to a reference laboratory at the Swiss Tropical and Public Health Institute (Swiss 
TPH, Basel, Switzerland) for PCR analysis [17]. While discrimination of hookworm species via morphological 
comparison during microscopy of Kato-Katz slides is not feasible [18], PCR will allow to accurately determining 
efficacy and for further classification of hookworm infection into the three species N. americanus, A. duodenale 
and A. ceylanicum. The remains of each stool sample (ideally 10 to 20 g) will be processed by the Baermann 
technique for identification of S. stercoralis infections and be recorded qualitatively as larvae-positive or 
negative. At baseline and in the first follow-up (3 weeks post treatment) an additional portion of the second stool 
sample (1.5-2 g) from a subsample of 10 participants identified with heavy intensity infections in each case (as 
assed on the first sample) will be preserved in 95% ethanol, shipped to the same reference laboratory at Swiss 
TPH in Switzerland and subjected to deep sequencing for characterization of T. trichiura strains and 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 105 of 176 
 
 
 
investigation of potential resistance markers [19]. A subsample of 30 participants will be asked to provide a daily 
stool sample for a period of up to 4 weeks to monitor dynamics of T. trichiura egg output for subsequent 
determination of the optimal timing for drug efficacy assessment as has been done for other STH species earlier 
[20]. 
A subsequent independent quality control of sample results (approximately 10%) will be conducted. Results are 
considered correct if the following tolerance margin is not exceeded: (i) No difference in presence/absence of 
hookworm, A. lumbricoides and T. trichiura, (ii) egg counts are +/-10 eggs for counts ≤100 eggs or +/-20% for 
counts >100 eggs (for each species separately) [21]. In case discrepancies above the tolerance margin are noted 
in one or more slides, all slides are re-read by the local technicians. The new results are discussed, so that in case 
of discordant results, slides can be re-evaluated to reach consensus. Infection intensity expressed as the 
arithmetic and geometric mean egg count per gram of stool (EPG) will be calculated for each treatment arm. All 
microscopically analyzed quadruplicate Kato-Katz thick smears will be destroyed within one day (after passing 
the quality control). The same sampling procedure and diagnostic approach will be applied at days 21, 180 and 
360 post-treatment. 
Patients with filariasis showed significantly higher numbers of adverse events (AE) for treatment with 
ivermectin in combination with albendazole in earlier studies [22-24]. A rapid diagnostic test (RDT; i.e. SD 
BIOLINE Oncho/LF IgG4 biplex test) to detect antigens in the blood will therefore be used to identify potential 
co-infection with Wuchereria bancrofti and Onchocerca volvulus at baseline, 6 and 12 months post-treatment 
(before a potential re-treatment). AEs after treating filariasis were mostly mild [3]; the approach of capturing 
AEs will thus not change but the result of the RDT be used to explain potential differences in AE reporting 
between filariasis negative and positive participants. 
A clinical examination of the study participants assessing general health, anthropometric parameters including 
height, weight, mid-upper arm circumference (MUAC) and skinfold thickness (i.e. triceps and subscapular 
skinfolds) as well as tympanic temperature using an ear thermometer will precede the treatment and will be 
repeated on two follow-up assessments (days 180 and 360) to evaluate potential benefits from deworming. Each 
participant will be asked to provide a finger-prick blood sample for a RDT for Plasmodium spp. infection and to 
evaluate hemoglobin (Hb) levels using a HemoCue analyzer (Hemocue Hb 301 system; Angelholm, Sweden) 
following the same (re-)assessment schedule. To assess potential improvement on nutritional indicators for 
micro- (i.e. (pro-) vitamins, inflammation markers, and iron/ferritin) and macronutrient (i.e. albumin) 
deficiencies and dynamics of biochemical blood parameters as a proxy for functioning of vital organs a venous 
blood sample (approximately 8 ml) will be taken at baseline, day 21, day 180 and 360. The biochemical 
parameters to be assessed include urea, creatinine, bilirubin, azotemia, Alanine Amino Transferase (ALAT), 
Aspartate Amino Transferase (ASAT) as well as blood cell counts (e.g. hematocrit, erythrocytes and platelets). 
To avoid accidental treatment of pregnant girls/women all female participants (≥ 10 years) will be asked to 
provide a urine sample of at least 10 ml to be subjected to a pregnancy RDT on day 0 and day 180. 
All trial participants will further be asked about existing clinical symptoms before drug administration. 
Additionally, they will be asked to provide subjective short-term (e.g. convenience of treatment) and long-term 
(e.g. effectiveness in reducing symptoms) treatment satisfaction embedded in the re-assessment questionnaires. 
As a measure of patient-rated physical functioning and wellbeing all children (6-16 years) will be administered a 
questionnaire before, 6 and 12 months after treatment, based and adapted from tools already validated in school-
aged children from rural settings in Côte d’Ivoire [25] and pre-tested in a comparable school-aged population not 
otherwise involved in this trial. To adjust for known influencing factors with regard to reinfection and morbidity 
[26, 27] in the subsequent analysis and to identify risk factors for residual infections [28] a household-based 
questionnaire will be administered to one adult member of each participating household, assessing information 
on socioeconomic characteristics, access to sanitation and water facilities as well as hygiene behavior.  
DF study with school-aged children 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 106 of 176 
 
 
 
Embedded in the parallel group trial a randomized-controlled DF study assessing ascending doses of ivermectin 
co-administered with a single dose of albendazole will be implemented. The study is designed as a four-armed 
trial including ascending doses of ivermectin co-administered with the standard dose of albendazole (arm 1‒3) 
and one placebo arm serving as a comparator (arm 4) (Figure ). 160 school-aged children infected with T. 
trichiura will be randomly assigned to arm 1‒4. Baseline and screening procedures are identical to the parallel 
group study. Children in arm 1-3 will be micro sampled on different time points between treatment day 0 and 
day 2 (at 0, 1, 2, 3, 4, 5, 6, 7, 9, 24, 48 hours post-dosing) in order to obtain pharmacokinetic data while children 
in arm 4 will provide finger-prick blood samples at day 0 only for RDT assessments. 
 
Figure 3. Efficacy, safety and pharmacokinetics of ivermectin-albendazole co-administration: dose-finding study 
flow. 
 
4.3.2 
Assessment of efficacy and other benefits after treatment 
Parallel group multi-country and DF study 
The efficacy of the treatment will be determined 21 days post-treatment by collecting another two stool samples 
which will be microscopically examined for T. trichiura using duplicate Kato-Katz thick smears and potential 
co-infection with S. stercoralis applying the Baermann technique. Participants will be considered T. trichiura 
cured if no eggs have been found in the stool. EPG will be assessed by adding up the egg counts from the 
quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic 
mean egg counts will be calculated for the different treatment arms before and after treatment to assess the 
corresponding ERRs. The stool samples collected 21 days post-treatment for efficacy assessment will further be 
re-tested with the same rapid diagnostic test and immunoassay used at baseline to determine fecal occult blood 
and calprotectin levels. Frequencies of subjects found positive with either of the two markers and by intensity 
category for calprotectin will be calculated by treatment arm. 
At the end of the study (i.e. for exclusive DF study participants 1 month post-treatment, for trial participants 12 
months post-treatment) all participants remaining positive for T. trichiura, other soil-transmitted helminths or 
filariasis will be treated with albendazole-ivermectin, the currently best approved and recommended treatment 
against T. trichiura [29]. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 107 of 176 
 
 
 
 
Parallel group multi-country study 
Potential extended effects on follow-up helminth prevalences will be assessed using the same methodological 
approach as used for the efficacy assessment and will be based on stool samples collected 6 and 12 months post-
treatment. Likewise fecal occult blood and calprotectin will be re-determined on the same stool samples. 
To assess eventual reduction in morbidity and improvement in nutritional indicators all trial participants will be 
asked to provide another finger-prick at the 6 and 12 month follow-up for Hb measurement and rapid diagnostic 
testing (i.e. malaria and filariasis) and once more a venous blood sample for micronutrient/blood parameter 
evaluation at all three follow-up time points, respectively. Anthropometric measurement including height, 
weight, MUAC and skinfold thickness will be repeated on the same occasion. Children (6-16 years) will be 
asked to re-assess their own physical functioning in repeated questionnaire interviews during these two last 
follow-ups. Long-term satisfaction with the treatment will be asked 6 months post-treatment. Mean values for 
continuous outcomes and frequencies for binary/categorical outcomes will be calculated for each treatment arm 
and follow-up time point and compared using descriptive and repeated measurement analysis as detailed in 
section 7.3. 
4.3.3 
Pharmacokinetic studies 
DF study 
The micro-sampling device dried blood spot (DBS) is a more robust, ethical and patient-friendly technique 
compared to venous blood sampling to evaluate the pharmacokinetic profile of a drug. In order to use DBS in a 
clinical trial, it first needs to be evaluated that the analysis of venous and capillary blood yields same drug 
concentrations. Therefore, plasma and DBS samples were previously collected in two independent clinical trials 
in rural Côte d'Ivoire with adult volunteers who received either the standard dose of albendazole (400 mg) or the 
standard dose of ivermectin (200 µg/kg). Methods to extract and quantify ivermectin in the different matrixes 
have been validated and applied to the samples of the adult volunteers. Results show consistent correlation of 
plasma and DBS samples so that DBS can be reliably used.  
The micro-sampling device DBS will be used as a tool to evaluate the pharmacokinetic (PK) parameters of 
albendazole and ivermectin in the DF study of their co-administration in school-aged children. In more detail, 
capillary blood (± 0.1 ml) will be collected by middle or ring finger tip puncture using a finger pricker (e.g. 
Accu-chek Softclix Pro®, Roche). Sampling will be conducted at 0, 1, 2, 3, 4, 5, 6, 7, 9, 24, 48 hours post-
dosing. A few drops of blood will be transferred at each time point on DBS filter paper (Whatman) and dried for 
approximately 1 hour. The DBS cards will be transported to Basel and stored at -80° C until analysis. 
Albendazole and its metabolites will be quantified using a validated liquid chromatography tandem mass 
spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration 
curve with a foreseen limit of quantification of approximately 3 ng/ml. Quality control samples will be included 
in the study and its measured concentrations used to determine between-run and overall precision and accuracy 
of the analysis.  
 
4.4 
Measure to minimize bias 
For each study (i.e. parallel group trial and DF study) independently study participants eligible for treatment will 
be randomly assigned to one of the treatment arms using a computer-generated stratified block randomization 
code. The random allocation sequence with varying random blocks of four or eight and stratified by 2 levels of 
baseline infection intensity (light: <1000 EPG, and moderate plus heavy: ≥ 1000 EPG T. trichiura infections) 
will be provided by a statistician. The treatment arms will have an equal number of participants with light 
infection intensity, although the number of light versus moderate/heavy infections are not expected to be equal in 
each arm, depending on the distribution of infection intensity in the recruited cohort. The parallel group trial will 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 108 of 176 
 
 
 
be double blinded (i.e. study participants and the trial team/researchers conducting the treatment and assessing 
the outcomes will be blinded) using repacked tablets including appearance-matched placebos while the DF study 
will be single blinded (i.e. all outcome assessors except the investigators who provide the treatment and the study 
participants who get either active or placebo tablets matching in appearance will be blinded) due to the nature of 
this study (i.e. including ascending doses). 
 
4.5 
Study duration and duration of subject participation 
The trial will last fourteen months. The screening for the baseline will start three weeks prior to the treatment. 
Follow-up screening will take place 14-21 days, 180 days and 360 days post-treatment and last each time for 
about three weeks. Schedules of visits are summarized below. 
 
4.6 
Schedule of visits 
Parallel group multi-country study  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 109 of 176 
 
 
 
Table 3. Schedule of visits of parallel group study. 
 
Screenin
g 
Baseline/Treatment/Safety 
Follow up 
 
-21 to -1 
days 
Hours 
Days 
 
0 
Randomization and treatment 
3 
24 
21 
180 
185 
360 
Diagnosis (stool 
examination) 
X 
 
 
 
X 
X 
Selective re-treatment 
X 
Gut morbidity (stool 
RDTs) 
X 
 
 
 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Clinical examination 
 
X 
 
 
 
X 
X 
Pregnancy testing 
 
X 
 
 
 
X 
 
Hemoglobin measurement 
 
X 
 
 
 
X 
X 
Plasmodium co-infection 
 
X 
 
 
 
X 
X 
Filaria co-infection 
 
X 
 
 
 
X 
X 
Venous blood examination 
 
X 
 
 
X 
X 
X 
Physical functioning 
 
X 
 
 
 
X 
X 
Capturing AEs 
 
 
X 
X 
X 
 
 
Capturing SAE 
 
 
X 
X 
X 
 
 
Treatment satisfaction 
 
 
 
X 
 
X 
X 
 
 
 
DF study 
The general outline of the DF study is similar to the parallel group multi-country study with the following 
adaption: Follow-up will be performed 21 days after treatment only and micro-blood sampling will be performed 
0‒48 hours post treatment.  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 110 of 176 
 
 
 
Table 4. Schedule of visits of dose-finding study.  
 
Screening 
 
Follow up 
 
-21 to -1 days 
Hours 
21 days 
 
0 
Randomization and treatment 
1-9 
24 
48 
Diagnosis (stool 
examination) 
X 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
Clinical examination 
 
X 
 
 
 
 
Rapid diagnostic tests 
 
X 
 
 
 
 
PK sampling 
 
X 
X 
X 
X 
 
Capturing AEs 
 
 
X (3h) 
X 
 
X 
Capturing SAE 
 
 
X (3h) 
X 
 
X 
5. 
Selection of the trial subjects 
5.1 
Recruitment 
The study will be carried out in community members aged 6‒60 years in areas with moderate to high T. trichiura 
endemicity (communities with a prevalence ≥ 25%) identified from earlier studies and/or based on experience of 
the local collaborating teams. The trial will be implemented as community-based study in order to recruit 
participants from a broad age range (6‒60 years). Ideally, entire communities with a population size of < 1000 
inhabitants will be included in the study for pre-screening and identification of T. trichiura cases to avoid 
potential selection bias of households. To identify all potentially eligible households of the respective 
communities and its composition in terms of age groups a preceding population census will be conducted. 
All adult community members, including parents/caregivers of minor participants, will be invited to participate 
in an information meeting to explain the purpose and procedures of the study, including potential benefits and 
risks. Parents/caregivers/potential participants will be encouraged to ask questions in an open discussion forum. 
During this session, they will be informed of preventive actions they can take to help protect their children from 
acquiring T. trichiura and other STH infections in the future (e.g. adequate food, preparation and defecation 
behavior). 
Those parents/caregivers and their children who are interested in the study will be invited to complete the 
process of informed consent. See section 9.3 for details on obtaining informed consent. Only those participants 
who have written informed consent will be assessed for study eligibility criteria during screening procedures. 
 
5.2 
Inclusion criteria 
1. Written informed consent signed by either the participant him/herself (≥21 years of age) or by parents 
and/or caregivers for children/adolescents; and written assent by child/adolescent (aged 6‒20 years). 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 111 of 176 
 
 
 
2. Agree to comply with study procedures, including provision of two stool samples at the beginning 
(baseline) and on three follow-up assessments (approximately 3 weeks, 6 months, and 12 months later). 
3. Aged ≥6 to 60 years for parallel group trial and ≥6 to 12 years for DF study. 
4. At least two slides of the quadruple Kato-Katz thick smears positive for T. trichiura and infection 
intensities of at least 100 EPG. 
 
5.3 
Exclusion criteria 
1. No written informed consent by individual/parents and/or caregiver.  
2. Presence of major systemic illnesses, e.g. severe anemia (below 80 g/l Hb according to WHO [30]), 
clinical malaria as assessed by a medical doctor (positive Plasmodium RDT and ≥38 °C ear temperature), 
upon initial clinical assessment. 
3. History of acute or severe chronic disease (e.g. cancer, diabetes, chronic heart, liver or renal disease). 
4. Recent use of anthelmintic drug (within past 4 weeks). 
5. Attending other clinical trials during the study. 
6. Negative or low egg count (less than 100 EPG or less than 2 out of 4 slides positive) diagnostic result for 
T. trichiura eggs in the stool. 
7. Known allergy to study medications (i.e. albendazole and ivermectin). 
8. Pregnancy or lactating in the 1st week after birth (according to WHO guidelines within LF control 
programs [31]). 
9. Currently taking medication with known interaction (e.g. for albendazole: cimetidine, praziquantel and 
dexamethasone; for ivermectin: warfarin). 
 
5.4 
Criteria for discontinuation of trial 
A subject can be discontinued from the study for the following reasons: 
1. 
Withdraws from the study (this can happen anytime as participation is voluntary and there are no further 
obligations once a participant withdraws). 
2. 
At the discretion of the Principal Investigator (PI) or co-PI, if the participant is not compliant to the 
requirements of the protocol. 
Discontinued subjects will not be replaced. If, for any reason, a subject is discontinued from the study before the 
end of treatment evaluations, the safety procedures planned (AEs monitoring) will be conducted. 
 
5.5 
Treatment of subjects 
Parallel group multi-country and DF study 
All T. trichiura-infected, consenting, and participating community members will be treated with the respective 
single or combination treatment regimen at day 0. 400 mg albendazole will be the product of Glaxo Smith Kline 
(Zentel®) and a single tablet administered. 3 mg tablets of ivermectin (Stromectol®) will be obtained from 
Merck, France, the weight recorded for each participant and the correct dose evaluated and administered. 
Matching ivermectin placebo tablets (in terms of appearance) will be produced and a certificate of manufacture 
and analysis be provided by the University of Basel. The tablets for the main trial, which is double-blinded, will 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 112 of 176 
 
 
 
be repacked into neutral separate plastic bags each containing one albendazole tablet and the maximum number 
of ivermectin tablets with regard to weight and dose or the corresponding number of placebo tablets. The 
ivermectin tablets for the dose-finding study will be kept in the original package until treatment day. Since 
albendazole and ivermectin are known to be better absorbed in humans after a high-fat meal was consumed, 
participants will receive a local high-fat breakfast (sandwich with e.g. oily sardines) prior to treatment [32, 33]. 
All drugs will be administered in the presence of the investigator(s), and ingestion confirmed. This will be 
recorded with the time and date of closing. Subjects will be asked not to take any drugs other than those 
prescribed by the study medical team. After ingestion of the medication, the subjects will be observed for 3 
hours to ensure retention of the drug. Vomiting within 1-hour post-dosing will require re-dosing. The subjects 
will not be allowed more than one repeated dose. No re-administration will be needed for subjects vomiting after 
one hour. The Principal Investigator is responsible for drug accountability at the study site. Maintaining drug 
accountability includes careful and systematic study drug storage, handling, dispensing and documentation of 
administration. 
Antimalarial treatment (i.e., artemisinin-based combination therapy) will be provided to participants found with 
clinical malaria (i.e. positive Plasmodium RDT and ≥38 °C ear temperature) or severely anemic in combination 
with a positive RDT result. Iron supplementation will be offered to severely anemic individuals with a negative 
RDT result. 
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 helminthiases in study 
participants will be substituted with a free single-dose treatment (i.e. albendazole 400 mg + ivermectin 200 
µg/kg) against STH, S. stercoralis as well as Filaria infection at the study endpoint (after the day 360 follow-up 
assessment) offered by the study team. At each follow-up time point, participants will be interviewed whether 
they had taken any anthelmintic treatment (e.g. self-purchased, obtained from clinics etc). 
 
5.6 
Concomitant therapy 
All medications taken one month before and during the study period until the last stool examination must be 
recorded with indication, dose regimen, date and time of administration. 
Medication(s)/treatment(s) permitted during the trial: 
- Analgesics and antipyretics are allowed to be given to the subjects in case of fever, antiemetics to prevent 
nausea and vomiting and/or antibiotics to prevent or treat bacterial superinfection. 
Medication(s)/treatment(s) NOT permitted during the trial:  
- No other active drugs against helminths are permitted during the trial. 
- No drugs with known interactions with the study medication are permitted during the trial. 
6. 
Safety assessments 
Few AEs have been reported following ivermectin-albendazole co-administration in STH-infected individuals. 
The most common AEs were abdominal cramps, headache, fatigue, nausea, diarrhea, fever and vertigo [7, 8, 34]. 
The safety profile of co-administered ivermectin and albendazole will be assessed through the recording, 
reporting and analysis of baseline medical conditions, AEs and a physical, clinical and biochemical 
examinations. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 113 of 176 
 
 
 
6.1 
Adverse event definitions 
The term “adverse event” could include any of the following events which develop or increase in severity during 
the course of the study, after administration of the study product: 
a) 
Any 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 AEs but be considered baseline medical conditions. For the purpose of this trial, disease 
progression and relapse will be considered as treatment failure, not as an AE.  
The observation time for AEs starts when the treatment is initiated until day 21 (3 weeks after last drug 
administration).  
These data will be recorded on the appropriate case report form (CRF) sections, regardless of whether they are 
thought to be associated with the study or the drug under investigation. Associated with the use of the drug 
means that there is a reasonable possibility that the event may have been caused by the drug (see also relatedness 
definitions below). 
6.1.1 
Severity grading 
Adverse signs or symptoms will be graded by the Investigator as mild, moderate, severe or life threatening 
according to the following definitions:  
Grade 
Definition 
1 
Mild: the subject is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
2 
Moderate: the subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity. 
3 
Severe: significant impairment of functioning: the subject is unable to carry out his or her 
usual activities. 
4 
Life threatening or disabling  
5 
Death related to adverse events 
 
6.1.2 
Relatedness 
Relatedness will be assessed as defined below based on the temporal relationship between the AE and the 
treatment, known side effects of treatment, medical history, concomitant medication, course of the underlying 
disease and trial procedures. 
Possibly related: an AE which can medically (pharmacologically/clinically) be attributed to the study treatment. 
Unrelated: an AE which is not reasonably related to the study treatment. A reasonable alternative explanation 
must be available. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 114 of 176 
 
 
 
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 co-administration of ivermectin-albendazole 
reported in the literature or on the drug package leaflets and listed in the consent form. 
Unexpected adverse drug reaction: Any AE possibly related to the study product administration, the nature, 
frequency, specificity or severity of which is unanticipated and not consistent with the available risk information 
described for these drugs.  
6.1.4 
Serious adverse events 
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 subject was, in the view of the Investigator, at immediate risk 
of death from the reaction as it occurred, i.e. it does not include a reaction that, had it occurred 
in a more serious form, might have caused death; 
3. results in persistent or significant disability/incapacity, i.e. the event causes a substantial 
disruption of a person’s ability to conduct normal life functions; 
4. requires in patient hospitalization or prolongation of existing hospitalization; 
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” AE does not necessarily meet the criteria for a “serious” AE. SAEs are reported from consent to 3 
weeks post-treatment (Day 21).  
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 SAEs.  
 
6.2 
Methods of recording and assessing adverse events 
Subjects will be kept for observation for at least 3 hours following treatment for any acute AEs. If there is any 
abnormal finding, the local study physician will perform a full clinical, physical and biochemical examination 
and findings will be recorded. An emergency kit will be available on site to treat any medical conditions that 
warrant urgent medical intervention. In addition patients will also be interviewed 3 and 24 hours and again 3 
weeks after treatment about the occurrence of AEs (see chapter 4.6). 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 115 of 176 
 
 
 
Information on all AEs (onset, duration, intensity, seriousness and causality) will be immediately entered in the 
appropriate AE module of the CRF that serves as source document. For all AEs, sufficient information will be 
pursued and/or obtained so as to permit i) an adequate determination of the seriousness of the event (i.e. whether 
the event should be classified as a SAE); ii) an assessment of the casual relationship between the AE and the 
study treatments and iii) an assessment of intensity of AEs will be judged by the study physician. 
All SAEs or SUSARs must be reported as described in Section 6.3. 
 
6.3 
Reporting of serious adverse events 
Any study-related unanticipated problem posing risk of harm to subjects or others (including all unexpected 
adverse drug reactions), and any type of SAE will be immediately (within a maximum of 24 hours after 
becoming aware of the event) notified to the study sponsor-investigator and co-PIs: 
 
 
Prof. Dr. Jennifer Keiser (Sponsor-investigator) 
Swiss Tropical and Public Health Institute 
Socinstrasse 57, 4051 Basel, Switzerland 
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
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 SAE or the unanticipated problem in the form of a written narrative. This should include a 
copy of a completed SAE form, and any other diagnostic information that will assist the understanding of the 
event. In exceptional circumstances, a SAE may be reported by telephone. In these cases, a written report must 
be sent immediately thereafter by fax or e-mail. Names, addresses and telephone for SAE reporting will be 
included in the trial-specific SAE form. Relevant pages from the CRF may be provided in parallel (e.g. medical 
history, concomitant medications).  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 116 of 176 
 
 
 
6.4 
Safety reporting to Health Authorities and Ethics Committees 
The sponsor-investigator will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. Additionally, this information will be provided to ‘Ethikkomission Nordwest- 
und Zentralschweiz’ (EKNZ, Switzerland), the ethics committee and the ‘Direction de la Pharmacie, du 
Médicament et des Laboratoires (DPML)’ in Côte d’Ivoire according to national rules. Fatal or life-threatening 
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. 
7. 
Statistics 
7.1 
Definition of primary endpoint 
CR of co-administered ivermectin-albendazole against T. trichiura is the primary endpoint in our study. Since 
treatment success is influenced by infection intensity, stratified block randomization will be used (baseline 
infection intensity: light infections and moderate/heavy infections) to ensure balanced treatment groups in terms 
of infection intensity. 
 
7.2 
Justification of number of trial subjects  
Parallel group multi-country study 
Based on available summarized efficacy measures from a recent review [1] and the published literature, we 
assume that the CR of albendazole against T. trichiura is 30% compared to 50% in the albendazole-ivermectin 
treatment regimen. To detect a difference with 90% power at a two-sided 5% significance level, we require 121 
participants per study arm and 143 to account for potential loss to follow-up of 15%. We further assume the 
same treatment efficacy in the mid-term treatment and a 6-months reinfection risk of 10%. Consequently we 
expect a proportion of negative patients after 12 months of 44% in the albendazole arm and of 65% in the 
albendazole-ivermectin arm resulting in a required sample size of 111 participants per arm. To account for a loss 
to follow-up of 30% after 6 months and 40% at final assessment (12 months) we aim to recruit 300 participants 
in each treatment group (600 in total) in each country.  
Subgroup analysis will be conducted stratifying the study population by age category (school-aged and adults). 
For the subgroup analysis we will pool the data from all 3 countries to ensure sufficient statistical power. 
 
DF study 
Since the existence of a drug effect is well known, the main aim of the study is the elucidation of the nature of 
the dose–response relationship. Modeling approaches showed that with 40 children enrolled in each of the 4 
study arms (placebo, 200 µg/kg, 400 µg/kg, and 600 µg/kg co-administered with albendazole (400 mg)) the dose 
response prediction model had a median precision (one half length of the 95%-confidence intervals) of 10% 
assuming associated cure rates of 2.5%, 50%, 60% and 70% taking into account a loss to follow up of 10%. The 
suggested sample size is also in line with the recommendations from Klingenberg et al. 2009 [36]. This sample 
size is sufficiently high to determine the key PK parameters as well as pharmacokinetic/pharmacodynamic 
(PK/PD) relationships taking into account that PK variability is high.  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 117 of 176 
 
 
 
7.3 
Description of statistical methods 
The primary available case analysis will include all participants with primary end point data. In addition, an 
intention-to-treat analysis will be conducted considering all participants with missing endpoint data as treatment 
failure or all as treatment success to ensure that the results are not sensitive to potential loss to follow-up bias. CRs 
will be calculated as the percentage of egg-positive (larvae- positive for S. stercoralis) participants at baseline who 
become egg-negative (larvae-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. For S. stercoralis 
infection no further quantification of larvae in stool will be done. The ERR of STH infection will be calculated as: 
𝐸𝑅𝑅=  1 − 
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝 + 1) −1
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 1)      −1  
In the primary model we estimate the difference among CRs by using unadjusted logistic regressions. In a 
subsequent analysis an adjusted logistic regression (adjustment for age, sex and weight) will be performed.  
Geometric mean egg counts will be calculated for the different treatment arms before and after treatment to assess 
the corresponding ERRs. Bootstrap resampling method with 5,000 replicates will be used to calculate 95% 
confidence intervals (CIs) for ERRs and the difference between the ERRs. 
Results from the stool RDT for fecal occult blood will be categorized as negative, trace and positive. For 
calprotectin, individuals with levels exceeding 50 μg/g will be considered as positive and concentrations be 
classified into low (51–149 μg/g), medium (150–299 μg/g) and high (≥300 μg/g) intensity [16]. 
Anthropometric measurements such as height and weight of school-aged children will be translated into weight-
for-age, height-for-age and weight-for-height related z-scores using readily available Stata macros calculating 
growth indicators for children 5-19 years [37]. Body mass index and indicators for muscle and fat tissue such as 
MUAC and skinfold thickness will serve as additional indicators of nutritional status for adults and will further be 
classified using a percentiles approach to compare within populations [38]. 
Questionnaires on physical functioning and treatment satisfaction will be evaluated by creating summary scores 
by summing up and transforming the single question scores according to the following formula: [(actual raw score-
lowest possible raw score)/(possible raw score range)]*100 [25]. 
Nutritional and morbidity indicators will be analysed using logistic and linear regression as appropriate. To 
compare individual’s changes in nutrition/morbidity categories as an effect from treatment McNemar’s test will 
be applied. The analysis after 6 and 12 month of follow-up will be complemented by generalized estimating 
equation (GEE) models with independent correlation structure and empirical estimators to account for missing 
data. 
AEs will be evaluated descriptively as the difference of proportion reporting AEs before and after treatment. 
On the basis of the LC-MS/MS measurements, the following PK parameters for plasma will be calculated:  
Cmax 
maximal plasma concentration 
tmax 
time to reach Cmax 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 118 of 176 
 
 
 
AUC 
area under the curve, from 0 to 24h and 0 to infinity 
T1/2 
elimination half-life 
T and AUC above minimal inhibitory concentration (MIC) 
Cmax and Tmax will be observed values derived from the plasma concentration time profile. AUC and T1/2 will 
calculated with the software WinNonlin (Version 5.2, Pharsight Corporation, USA) using compartmental 
analysis. The elimination half-life will be estimated by the equation: T1/2 = ln2/, where  will be determined by 
performing a regression of the natural logarithm of the concentration values during the elimination period.  
Further PK analysis will be undertaken fitting a structural compartmental PK model with the software 
NONMEM 7 [39] via nonlinear mixed effects modeling (allowing for both between patient variation and random 
effects). This model will describe the plasma drug levels in time, allowing one to investigate variation between 
patients in drug levels. In addition, PK/PD analysis will be undertaken via NONMEM to investigate the drivers 
of cure and/or burden reduction and potentially any covariates with drug levels. 
 
7.4 
Description of 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 with the investigators and their study coordinators and a member from Swiss 
TPH. This meeting will include a detailed discussion of the protocol, performance of study procedures (standard 
operating procedures (SOPs) from previous studies available on site), CRF completion, and specimen collection 
and diagnostic methods.  
The data produced from this research project will fall into the following categories:  
 
1. Eggs counts of T. trichiura, A. lumbricoides and hookworm and infection status with S. stercoralis based 
on participants’ stool samples analyzed using the Kato-Katz and Baermann technique, respectively,  
before (baseline) and at 3 time points after treatment (follow-ups after 3 weeks, 6 and 12 months). 
Presence of fecal occult blood and elevated calprotectin levels will be evaluated and recorded applying 
RDTs on the same stool samples and assessment time points. 
2. Personal information such as name, age, gender and household composition of trial participants. 
3. Anthropometric and clinical characteristics of the trial participants collected using the study’s CRF such 
as weight, height, skinfold thickness, blood pressure, temperature, hemoglobin level, infection status with 
Plasmodium spp. and filariasis, any abnormal medical condition or chronic disease as well as pregnancy 
in female participants 10 years and above. 
4. Number and type of AEs registered in the CRF actively probed for 3 and 24 hours after treatment. The 
same data will be collected during the collection of the first sample at the 3-week follow-up. 
5. Scales for participant-rated treatment satisfaction and self-rated physical functioning in school-aged 
children captured on different time points (i.e. 3 weeks and 6 months and baseline, 6 and 12 months after 
treatment, respectively) and recorded on the CRF. 
6. Concentration levels of blood and biochemical parameters together with indicators for micronutrient 
status before (baseline) and at 3 time points after treatment (follow-ups after 3 weeks, 6 and 12 months).  
7. Household-level data on socioeconomic characteristics, presence and use of water and sanitation as well 
as hygiene-related attitudes and practices. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 119 of 176 
 
 
 
All data on parasitology and questionnaires about AEs, self-reported clinical signs and symptoms, physical 
functioning, and treatment satisfaction will be paper-captured and subsequently doubled entered (data entry 
SOP) into ACCESS data entry masks by two independent persons. For quality assurance error, range and 
consistency checks will be programmed for the ACCESS data entry masks and all double-entered data be cross-
checked using the Data Compare utility of EpiInfo. Any discrepancies will be corrected by consulting the hard 
copy.  
Data in category 1 to 6 will be double-entered using an EpiInfo mask and saved in .mdb, .xlsx, .dta, and .csv. 
Data in category 7 will be directly entered while collecting into tablets using Open Data Kit (free electronic data 
collection software) and uploaded to a server hosted at Swiss TPH. All categories will be merged into a single 
master file saved in .dta, .xlsx and .csv. Data will then be analysed as described in section 7.3. Hard copies of the 
data collected within the trial country such as parasitological, stool RDT, blood parameter sheets and CRFs will 
remain at Centre Suisse de Recherches Scientifiques en Côte d’Ivoire (CSRS). Digital copies along with the 
databases will be transferred to the Swiss TPH after a Material Transfer Agreement has been signed by both the 
Swiss TPH and CSRS. All data is expected to not exceed 5GB. 
Invited and screened patients will be listed in a confidential “subject identification list and screening log”. 
Enrolled patients will be listed in a confidential “subject enrolment log” and attributed a unique study number; 
this document will constitute the only source to decode the pseudonymised data and will only be accessible to 
the local principal investigator. All study-specific data will only contain this unique identifier instead of any 
names. Electronic data files will be stored on secured network drives with restricted access for study personnel 
only. Data analysis will be conducted with pseudonymised data and reporting of findings will be fully 
anonymised. All databases will be password secured. 
Essential infrastructure such as lockable cabinets for safe storage of hardcopy data will be made available. 
Network drives with restricted access for authorized personnel only and appropriate analysis software are 
available.  
 
8. 
Duties of the investigator  
8.1 
Investigator’s confirmation 
This trial will be conducted in accordance with the protocol, International Conference on Harmonization Good 
Clinical Practice E6 (R2) (ICH-GCP) and the current version of the Helsinki Declaration. 
All protocol modifications must be documented in writing. A protocol amendment can be initiated by either the 
Sponsor/PI or any Investigator. The Investigator will provide the reasons for the proposed amendment in writing 
and will discuss with the Sponsor/PI and Co-PIs. Any protocol amendment must be approved and signed by the 
Sponsor/PI and must be submitted to the appropriate Independent Ethics Committee (IEC) for information and 
approval, in accordance with local requirements, and to regulatory agencies if required. Approval by IEC must 
be received before any changes can be implemented, except for changes necessary to eliminate an immediate 
hazard to trial subjects, or when the change involves only logistical or administrative aspects of the trial, e.g. 
change of telephone number(s). 
 
8.2 
Damage coverage 
A general liability insurance of the Swiss TPH is in place (Winterthur Police Nr. 4746321) and patient liability 
insurances will be issued in the respective trial countries. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 120 of 176 
 
 
 
8.3 
Project management 
The trial team will include the PI (Prof. Jennifer Keiser), three Co-PIs (Dr. Eveline Hürlimann, Dr. Jessica 
Schulz, and Dr. Jean Coulibaly), a trial statistician (Dr. Jan Hattendorf), as well as a local physician (Dr. Yves 
Koutouan N'Gbesso), nurses and laboratory technicians. Prof. Jennifer Keiser, Dr. Eveline Hürlimann, Dr. 
Jessica Schulz and a 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. Jean Coulibaly and the PhD student will monitor all field activities at the 
study site. Dr. Yves Koutouan N'Gbesso, will be responsible for patient recruitment, medical aspects of the trial 
and enrolment of patients in the trial. 
The investigator team is responsible for ensuring that the protocol is strictly followed. The investigator should 
not make any changes without the agreement of the Principal Investigator and the Co-Investigators, except when 
necessary to eliminate an apparent immediate hazard or danger to a study participant. The investigator will work 
according to the protocol and GCP. The investigator may take any steps judged necessary to protect the safety of 
the participants, whether specified in the protocol or not. Any such steps must be documented. During the 
treatment the records are maintained by the responsible medical doctor. All entries have to be made clearly 
readable with a pen. The investigator must be thoroughly familiar with the properties, effects and safety of the 
investigational pharmaceutical product.  
 
9. 
Ethical considerations 
9.1 
Independent ethics committee 
The study will be submitted for approval by the institutional research commission of the Swiss TPH and the 
ethics committees of Switzerland (EKNZ: Ethical Commission of northwest/central Switzerland) and Côte 
d’Ivoire (CNER: Comité Nationale d’Ethique de la Recherche) and the Ivorian medicines regulatory authority 
(DPML: Direction de la Pharmacie, du Médicament et des Laboratoires). The study will be undertaken in 
accordance with the Declaration of Helsinki and GCP. 
 
9.2 
Evaluation of the risk-benefit ratio 
Ivermectin in combination with albendazole are well-known, widely used drugs in mass treatment programs 
against filariasis, and have little and mainly mild AEs (headache, abdominal pain etc.). 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 ivermectin (200 μg/kg)-albendazole (400 mg) 
considering higher efficacy compared to the existing standard treatment (albendazole monotherapy) and recent 
inclusion as recommended treatment scheme on the Essentials Medicines List [29]. 
 
9.3 
Subject information and consent 
Community meetings allowing for open exchange will be organized in every study locality where a prescreening 
for identification of positive cases is to be conducted. The purpose and procedures, the benefits and risks of the 
study will be explained in order to make sure that all community members are at the same level in terms of 
information. All parents or caregivers of eligible children and all adult participants (≥21 years) will be 
individually informed about benefits and risk associated to the trial. They will have sufficient time for reflection 
of their child’s or their own participation, respectively. They will then be asked to sign a written informed 
consent sheet. In case the person is illiterate, an impartial witness that can read and write has to sign the consent 
and the illiterate participant to give a thumb print. In addition to a written informed consent form signed by their 
parent or caregiver, minor participants (aged 6-20 years) will also be briefed verbally and written assent sought 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 121 of 176 
 
 
 
in form of their name written down or if illiterate by providing a thumb print. Even if the minor participant gives 
written assent, the parent/caregiver has to sign the consent. 
Information sheets are printed in French but will additionally be verbally translated into local languages (i.e. 
Abbé, Attié, Dioula, Moré) during community meetings. To all participants and parents/caregivers a signed copy 
of the informed consent form will be given. Participation is voluntary and all participants have the right to 
withdraw from the study at any given point in time with no further obligations. Participation itself will not be 
awarded with compensation. 
 
9.4 
Subject confidentiality 
The obtained data will be handled strictly confidentially. Only members of the study team will have access to the 
data. Personal data will be coded for data analysis. The codes will be filled with the participant’s identity on a 
separate file (subject identification list and screening log) and stored in a secured place at the local institutions 
(i.e. Côte d’Ivoire: CSRS, Lao PDR: National Institute of Public Health, and Pemba: Public Health Laboratory 
Ivo de Carneri) and will only be accessible to investigators. No names will be published at any time, and 
published reports will not allow for identification of single subjects. Confidentiality and anonymity will be 
ensured throughout the entire research project. The investigators have all been trained in GCP. None of the 
investigators declare to have any conflicts of interest. 
 
9.5 
Subjects requiring particular protection 
This study will include school-aged children, since T. trichiura infection occurs often in children; hence this age 
group is at high risk of infection and is therefore the major target group in MDA campaigns. Pharmacokinetic 
and DF studies in this population, however, have to our knowledge so far only been done or are underway by the 
research team itself for the investigated medicine products (i.e. ivermectin and albendazole). Since PK 
parameters vary between children and adults these studies cannot be obtained by carrying out the trial on adults. 
Our trial will produce more evidence to support the search for a safe and effective treatment scheme against STH 
infections in children and whole communities. 
 
9.6 
Other aspects 
Within the DF study one study arm will include school-aged children treated with placebo. However, this group 
will be treated with a single dose of co-administered albendazole (400 mg) and ivermectin (200μg/kg), as 
meanwhile listed on the EML of WHO to treat STH infection [29], at the first follow-up (already 3‒4 weeks 
later). Considering all security measures (clinical, physical and biochemical exams) set up for inclusion of trial 
participants, any person showing an unfavorable medical condition will not be included in the trial. Hence, we 
believe that a 3-weeks delay in treatment should not cause any medical concern for the participants of the 
placebo arm. Of note, populations at risk are in general treated only in yearly intervals to reduce morbidity from 
chronic infections within MDA campaigns of national control programs. 
 
10. Quality control and quality assurance 
10.1 
Monitoring and auditing 
We will work with locally based monitors. These 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 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 122 of 176 
 
 
 
observations and findings will be documented and communicated to appropriate study personnel and 
management. A corrective and preventative action plan will be requested and documented in response to any 
audit observations. No sponsor initiated audits are foreseen, but audits and inspections may be conducted by the 
local regulatory authorities or ethics committees. The Investigator agrees to allow inspectors from regulatory 
agencies to review records and is encouraged to assist the inspectors in their duties, if requested. 
 
10.2 
Access to data, handling of data and samples (data protection), archiving (place, duration) and 
destruction 
Information about study subjects will be kept confidential and managed accordingly. A paper CRF will be 
completed for each subject enrolled into the clinical study. The investigators will review, and approve each 
completed CRF. The study CRF is the primary data collection instrument for the study. All data requested on the 
CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank because the 
procedure was not done or the question was not asked “N/D” will be entered. If the item is not applicable to the 
individual case “N/A” will be written. All entries will be printed in black ink. All corrections must be initialed 
and dated.  
The results of the research study will be published, but subjects’ names or identities will not be revealed. 
Records will remain confidential. To maintain confidentiality, the Sponsor-Investigator will keep records in 
locked cabinets and the results of tests will be coded to prevent association with participant’s names. Data 
entered into the ACCESS data entry mask will be accessible only by authorized personnel directly involved with 
the study and will be encoded. Subject-specific information may be provided to other appropriate medical 
personnel only with the subject’s permission for adults or the parent/caregiver’s permission for minors. 
After the study has been completed all samples will be destroyed and research data and related material will be 
kept for a minimum of 15 years to enable understanding of what was done, how and why, which allow the work 
to be assessed retrospectively and repeated if necessary. Storage and backup will be in three places: personal 
laptops of Jennifer Keiser, Eveline Hürlimann, Jessica Schulz, Chandni Patel and Jean Coulibaly, Swiss TPH 
shared server and SWITCHdrive (a cloud storage supported by University of Basel). Archiving conditions will 
be made strictly confidential by password protection. 
 
10.3 
Data entered directly in the CRF – definition of source data 
Source Data are the clinical findings and observations, laboratory data maintained at the study site. Source data 
are contained in source documents. Local authorities are allowed to access the source data. Data will be entered 
directly onto the CRFs. The CRF is considered as a source document. All CRFs will be kept for at least 15 years. 
The study site will retain the original of the CRF to ensure that local collaborators can provide access to the 
source documents to a monitor, auditor, or regulatory agency while a copy of the CRF will be taken to Swiss 
TPH. 
 
10.4 
Data and safety monitoring board / data monitoring committee  
In our study no data and safety monitoring board will be established, since we work with well-known drugs in a 
limited number of participants and using a single dose treatment. This study is anticipated to be no greater than 
minimal risk to participants. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 123 of 176 
 
 
 
10.5 
Study Documents: Translations - Reference language 
- Protocol: Master document in English, all further language versions are translations thereof. 
- CRF: Master document in English, all further language versions are translations thereof. 
- ICF: Master document in English, all further language versions are translations thereof. 
 
11. Dissemination of results and publication 
The final results of this study will be published in a scientific journal and presented at scientific conferences. The 
Bill & Melinda Gates Foundation 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 study report will be shared with the local ethics committees and the national 
regulatory authorities. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 124 of 176 
 
 
 
12. References 
1. 
Moser W, Schindler C, Keiser J: Efficacy of recommended drugs against soil transmitted helminths: 
systematic review and network meta-analysis. BMJ 2017, 358:j4307. 
2. 
Hughes D, Andersson DI: Evolutionary consequences of drug resistance: shared principles across 
diverse targets and organisms. Nat Rev Genet 2015, 16(8):459-471. 
3. 
Palmeirim MS, Hürlimann E, Knopp S, Speich B, Belizario V, Jr., Joseph SA, Vaillant M, Olliaro P, 
Keiser J: Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-
transmitted helminths: A systematic review, meta-analysis and individual patient data analysis. 
PLoS Negl Trop Dis 2018, 12(4):e0006458. 
4. 
Belizario VY, Amarillo ME, de Leon WU, de los Reyes AE, Bugayong MG, Macatangay BJ: A 
comparison of the efficacy of single doses of albendazole, ivermectin, and diethylcarbamazine alone 
or in combinations against Ascaris and Trichuris spp. Bull World Health Organ 2003, 81(1):35-42. 
5. 
Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C: A comparative trial of a single-
dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and 
other soil-transmitted helminth infections in children. Am J Trop Med Hyg 1996, 55(5):477-481. 
6. 
Ismail MM, Jayakody RL: Efficacy of albendazole and its combinations with ivermectin or 
diethylcarbamazine (DEC) in the treatment of Trichuris trichiura infections in Sri Lanka. Ann Trop 
Med Parasitol 1999, 93(5):501-504. 
7. 
Knopp S, Mohammed KA, Speich B, Hattendorf J, Khamis IS, Khamis AN, Stothard JR, Rollinson D, 
Marti H, Utzinger J: Albendazole and mebendazole administered alone or in combination with 
ivermectin against Trichuris trichiura: a randomized controlled trial. Clin Infect Dis 2010, 
51(12):1420-1428. 
8. 
Speich B, Ali SM, Ame SM, Bogoch, II, Alles R, Huwyler J, Albonico M, Hattendorf J, Utzinger J, 
Keiser J: Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, 
albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and 
concomitant soil-transmitted helminth infections: a four-arm, randomised controlled trial. Lancet 
Infect Dis 2015, 15(3):277-284. 
9. 
Betson M, Søe MJ, Nejsum P: Human trichuriasis: whipworm genetics, phylogeny, transmission and 
future research directions. Current Tropical Medicine Reports 2015, 2(4):209-217. 
10. 
Ghai RR, Simons ND, Chapman CA, Omeja PA, Davies TJ, Ting N, Goldberg TL: Hidden population 
structure and cross-species transmission of whipworms (Trichuris sp.) in humans and non-human 
primates in Uganda. PLoS Negl Trop Dis 2014, 8(10):e3256. 
11. 
Hawash MB, Betson M, Al-Jubury A, Ketzis J, LeeWillingham A, Bertelsen MF, Cooper PJ, Littlewood 
DT, Zhu XQ, Nejsum P: Whipworms in humans and pigs: origins and demography. Parasit Vectors 
2016, 9:37. 
12. 
Speich B, Moser W, Ali SM, Ame SM, Albonico M, Hattendorf J, Keiser J: Efficacy and reinfection 
with 
soil-transmitted 
helminths 
18-weeks 
post-treatment 
with 
albendazole-ivermectin, 
albendazole-mebendazole, albendazole-oxantel pamoate and mebendazole. Parasit Vectors 2016, 
9:123. 
13. 
Anderson R, Farrell S, Turner H, Walson J, Donnelly CA, Truscott J: Assessing the interruption of the 
transmission of human helminths with mass drug administration alone: optimizing the design of 
cluster randomized trials. Parasit Vectors 2017, 10(1):93. 
14. 
Lo NC, Addiss DG, Hotez PJ, King CH, Stothard JR, Evans DS, Colley DG, Lin W, Coulibaly JT, 
Bustinduy AL, Raso G, Bendavid E, Bogoch, II, Fenwick A, Savioli L, Molyneux D, Utzinger J, Andrews 
JR: A call to strengthen the global strategy against schistosomiasis and soil-transmitted 
helminthiasis: the time is now. Lancet Infect Dis 2017, 17(2):e64-e69. 
15. 
Katz N, Chaves A, Pellegrino J: A simple device for quantitative stool thick-smear technique in 
Schistosomiasis mansoni. Rev Inst Med Trop São Paulo 1972, 14(6):397-400. 
16. 
Bustinduy AL, Sousa-Figueiredo JC, Adriko M, Betson M, Fenwick A, Kabatereine N, Stothard JR: 
Fecal occult blood and fecal calprotectin as point-of-care markers of intestinal morbidity in 
Ugandan children with Schistosoma mansoni infection. PLoS Negl Trop Dis 2013, 7(11):e2542. 
17. 
Kaisar MMM, Brienen EAT, Djuardi Y, Sartono E, Yazdanbakhsh M, Verweij JJ, Supali T, van Lieshout 
L: Improved diagnosis of Trichuris trichiura by using a bead-beating procedure on ethanol 
preserved stool samples prior to DNA isolation and the performance of multiplex real-time PCR 
for intestinal parasites. Parasitology 2017, 144(7):965-974. 
18. 
Becker SL, Vogt J, Knopp S, Panning M, Warhurst DC, Polman K, Marti H, von Muller L, Yansouni CP, 
Jacobs J, Bottieau E, Sacko M, Rijal S, Meyanti F, Miles MA, Boelaert M, Lutumba P, van Lieshout L, 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 125 of 176 
 
 
 
N'Goran EK, Chappuis F, Utzinger J: Persistent digestive disorders in the tropics: causative infectious 
pathogens and reference diagnostic tests. BMC Infect Dis 2013, 13:37. 
19. 
Avramenko RW, Redman EM, Lewis R, Bichuette MA, Palmeira BM, Yazwinski TA, Gilleard JS: The 
use of nemabiome metabarcoding to explore gastro-intestinal nematode species diversity and 
anthelmintic treatment effectiveness in beef calves. Int J Parasitol 2017, 47(13):893-902. 
20. 
Scherrer AU, Sjoberg MK, Allangba A, Traore M, Lohourignon LK, Tschannen AB, N'Goran EK, 
Utzinger J: Sequential analysis of helminth egg output in human stool samples following albendazole 
and praziquantel administration. Acta Trop 2009, 109(3):226-231. 
21. 
Speich B, Ali SM, Ame SM, Albonico M, Utzinger J, Keiser J: Quality control in the diagnosis of 
Trichuris trichiura and Ascaris lumbricoides using the Kato-Katz technique: experience from three 
randomised controlled trials. Parasit Vectors 2015, 8:82. 
22. 
Dunyo SK, Nkrumah FK, Simonsen PE: A randomized double-blind placebo-controlled field trial of 
ivermectin and albendazole alone and in combination for the treatment of lymphatic filariasis in 
Ghana. Trans R Soc Trop Med Hyg 2000, 94(2):205-211. 
23. 
Awadzi K, Edwards G, Duke BO, Opoku NO, Attah SK, Addy ET, Ardrey AE, Quartey BT: The co-
administration of ivermectin and albendazole--safety, pharmacokinetics and efficacy against 
Onchocerca volvulus. Ann Trop Med Parasitol 2003, 97(2):165-178. 
24. 
Simonsen PE, Magesa SM, Dunyo SK, Malecela-Lazaro MN, Michael E: The effect of single dose 
ivermectin alone or in combination with albendazole on Wuchereria bancrofti infection in primary 
school children in Tanzania. Trans R Soc Trop Med Hyg 2004, 98(8):462-472. 
25. 
Fürst T, Müller I, Coulibaly JT, Yao AK, Utzinger J, N'Goran EK: Questionnaire-based approach to 
assess schoolchildren's physical fitness and its potential role in exploring the putative impact of 
helminth and Plasmodium spp. infections in Côte d'Ivoire. Parasit Vectors 2011, 4:116. 
26. 
Campbell SJ, Nery SV, McCarthy JS, Gray DJ, Soares Magalhaes RJ, Clements AC: A critical appraisal 
of control strategies for soil-transmitted helminths. Trends Parasitol 2016, 32(2):97-107. 
27. 
Strunz EC, Addiss DG, Stocks ME, Ogden S, Utzinger J, Freeman MC: Water, sanitation, hygiene, and 
soil-transmitted helminth infection: a systematic review and meta-analysis. PLoS Med 2014, 
11(3):e1001620. 
28. 
Kepha S, Mwandawiro CS, Anderson RM, Pullan RL, Nuwaha F, Cano J, Njenga SM, Odiere MR, Allen 
E, Brooker SJ, Nikolay B: Impact of single annual treatment and four-monthly treatment for 
hookworm and Ascaris lumbricoides, and factors associated with residual infection among Kenyan 
school children. Infect Dis Poverty 2017, 6(1):30. 
29. 
WHO: The selection and use of essential medicines: report of the WHO Expert Committee, 2017 
(including the 20th WHO model list of essential medicines and the 6th WHO model list of essential 
medicines for children). WHO technical report series, vol. no. 1006. Geneva: World Health 
Organization; 2017. 
30. 
WHO: Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. 
Vitamin and Mineral Nutrition Information System. Geneva: World Health Organization; 2011: 
(WHO/NMH/NHD/MNM/11.11). 
31. 
WHO: Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs 
in control interventions: a manual for health professionals and programme managers. Geneva: 
World Health Organization; 2006: 62. 
32. 
Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, 
Lasseter KC: Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in 
healthy adult subjects. J Clin Pharmacol 2002, 42(10):1122-1133. 
33. 
Pawluk SA, Roels CA, Wilby KJ, Ensom MH: A review of pharmacokinetic drug-drug interactions 
with the anthelmintic medications albendazole and mebendazole. Clin Pharmacokinet 2015, 
54(4):371-383. 
34. 
Ndyomugyenyi R, Kabatereine N, Olsen A, Magnussen P: Efficacy of ivermectin and albendazole 
alone and in combination for treatment of soil-transmitted helminths in pregnancy and adverse 
events: a randomized open label controlled intervention trial in Masindi district, western Uganda. 
Am J Trop Med Hyg 2008, 79(6):856-863. 
35. 
ICH Expert Working Group: ICH harmonised tripartite guideline. Clinical safety data management: 
definitions and standards for expedited reporting E2A. International conference on harmonisation of 
technical requirements for registration of pharmaceuticals for human use; 1994. 
36. 
Klingenberg B: Proof of concept and dose estimation with binary responses under model 
uncertainty. Stat Med 2009, 28(2):274-292. 
37. 
Duggan MB: Anthropometry as a tool for measuring malnutrition: impact of the new WHO growth 
standards and reference. Ann Trop Paediatr 2010, 30(1):1-17. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 126 of 176 
 
 
 
38. 
Wang Y, Chen H: Use of Percentiles and Z-Scores in Anthropometry. In: Handbook of Anthropometry. 
Edited by Preedy V. New York: Springer; 2012: 29-48. 
39. 
Beal S, Sheiner LB, Boeckmann A, Bauer RJ: NONMEM User's Guides (1989-2009). Ellicott City, 
MD, USA: Icon Development Solutions; 2009. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 127 of 176 
 
 
 
6. Trial protocol Laos:  
 
Efficacy and safety of ivermectin and albendazole co-administration in school-aged children and adults 
infected with Trichuris trichiura: a multi-country randomized controlled trial 
 
 
Protocol Number 
1 
Version Number 
1.01 
Document Date 
14.06.2018 
Sponsor Contact 
Prof. Dr. Jennifer Keiser,  
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@unibas.ch 
Principle Investigator 
Prof. Dr. Jennifer Keiser,  
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@unibas.ch 
Funding Agency 
Bill and Melinda Gates Foundation 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 128 of 176 
 
 
 
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 
Postdoc 
Co-PI 
Dr. 
Somphou Sayasone 
Lao Tropical and Public 
Health Institute (Lao 
TPHI) Vientiane, Lao 
PDR 
Group leader / 
Study 
physician 
Co-PI 
Dr. 
Jan Hattendorf 
 
Swiss TPH  
 
Project leader 
Statistician 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 129 of 176 
 
 
 
II. 
Signatures  
 
Statistician 
Signature 
 
 
 
 
 
Date of Signature  
14.06.2018 
Name  
Jan Hattendorf 
Title 
Dr.  
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 284-8193 
 
Principal investigator 
Signature 
 
 
 
 
 
Date of Signature  
14.06.2018 
Name  
Jennifer Keiser 
Title 
Prof. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Socinstr. 57 
Phone 
+41 61 284-8218 
 
I have read this protocol and agree that it contains all necessary details for carrying out this trial. I will conduct 
the trial as outlined herein and will complete the trial within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist 
in the conduct of this trial. I will discuss this material with them to ensure they are fully informed regarding the 
drug and the conduct of the trial. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 130 of 176 
 
 
 
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. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 131 of 176 
 
 
 
Co-Principal investigator 
Signature 
 
 
 
Date of Signature  
14.06.2018 
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 
Phone 
+41 61 284 87 04 
 
Co-Principal investigator 
Signature 
 
Date of Signature  
14.06.2018 
Name  
Somphou Sayasone 
Title 
Dr. 
Institution 
Lao Tropical and Public Health Institute 
Address 
International Program for Health in the Tropics, Samsenthai Road, Sisattanak district, 
Phone 
+856 20 556 79 603 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 132 of 176 
 
 
 
Table of contents 
 
1. 
General information ....................................................................................................................................128 
2. 
Background information..............................................................................................................................141 
3. 
Trial objective and purpose .........................................................................................................................143 
4. 
Methodology ...............................................................................................................................................143 
4.1 
Primary and secondary endpoint.........................................................................................................144 
4.2 
Type of trial ........................................................................................................................................144 
4.3 
Trial design .........................................................................................................................................144 
4.3.1 
Baseline survey and screening .......................................................................................................144 
4.3.2 
Assessment of efficacy and other benefits after treatment .............................................................146 
4.4 
Measure to minimize bias ...................................................................................................................147 
4.5 
Study duration and duration of subject participation ..........................................................................147 
4.6 
Schedule of visits ................................................................................................................................147 
5. 
Selection of the trial subjects .......................................................................................................................148 
5.1 
Recruitment ........................................................................................................................................148 
5.2 
Inclusion criteria .................................................................................................................................149 
5.3 
Exclusion criteria ................................................................................................................................149 
5.4 
Criteria for discontinuation of trial .....................................................................................................149 
5.5 
Treatment of subjects..........................................................................................................................150 
5.6 
Concomitant therapy...........................................................................................................................150 
6. 
Safety assessments ......................................................................................................................................151 
6.1 
Adverse event definitions ...................................................................................................................151 
6.1.1 
Severity grading .............................................................................................................................151 
6.1.2 
Relatedness.....................................................................................................................................152 
6.1.3 
Expectedness ..................................................................................................................................152 
6.1.4 
Serious adverse events ...................................................................................................................152 
6.1.5 
Suspected unexpected serious adverse reactions ............................................................................153 
6.2 
Methods of recording and assessing adverse events ...........................................................................153 
6.3 
Reporting of serious adverse events ...................................................................................................153 
6.4 
Safety reporting to Health Authorities and Ethics Committees ..........................................................154 
7. 
Statistics ......................................................................................................................................................154 
7.1 
Definition of primary endpoint ...........................................................................................................154 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 133 of 176 
 
 
 
7.2 
Justification of number of trial subjects ..............................................................................................154 
7.3 
Description of statistical methods .......................................................................................................155 
7.4 
Description of data management and data quality control ..................................................................155 
8. 
Duties of the investigator ............................................................................................................................157 
8.1 
Investigator’s confirmation .................................................................................................................157 
8.2 
Damage coverage ...............................................................................................................................157 
8.3 
Project management ...........................................................................................................................157 
9. 
Ethical considerations..................................................................................................................................158 
9.1 
Independent ethics committee ............................................................................................................158 
9.2 
Evaluation of the risk-benefit ratio .....................................................................................................158 
9.3 
Subject information and consent.........................................................................................................158 
9.4 
Subject confidentiality ........................................................................................................................158 
9.5 
Subjects requiring particular protection ..............................................................................................159 
10. 
Quality control and quality assurance .....................................................................................................159 
10.1 
Monitoring and auditing .....................................................................................................................159 
10.2 
Access to data, handling of data and samples (data protection), archiving (place, duration) and 
destruction .......................................................................................................................................................159 
10.3 
Data entered directly in the CRF – definition of source data ..............................................................160 
10.4 
Data and safety monitoring board/ data monitoring committee..........................................................160 
10.5 
Study Documents: Translations - Reference language .......................................................................160 
11. 
Dissemination of results and publication ................................................................................................160 
12. 
References ...............................................................................................................................................161 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 134 of 176 
 
 
 
III. 
Abbreviations 
AE 
Adverse event 
CI 
Confidence interval 
CR 
Cure rate 
CRF 
Case report form 
EKNZ 
Ethikkomission Nordwest- und Zentralschweiz 
EML 
Essential medicine list 
EPG 
Eggs per gram 
ERR 
Egg reduction rate 
GCP 
Good clinical practice 
GEE 
Generalized estimating equation 
Hb 
Hemoglobin 
ICH 
International council for harmonization of technical requirements for pharmaceuticals for 
human use 
IEC 
Independent ethics committee 
Lao TPHI 
Lao Tropical and Public Health Institute 
MDA 
Mass drug administration 
MUAC 
Mid-upper arm circumference 
PC 
Preventive chemotherapy 
PCR 
Polymerase chain reaction 
PI 
Principal investigator 
RDT 
Rapid diagnostic test 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
STH 
Soil-transmitted helminth 
Swiss TPH 
Swiss Tropical and Public Health Institute 
SUSAR 
Suspected unexpected serious adverse reaction 
WHO 
World Health Organization 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 135 of 176 
 
 
 
IV. 
Synopsis 
 
Sponsor/Sponsor-
Investigator 
Prof. Dr. Jennifer Keiser 
Study Title 
Efficacy and safety of ivermectin and albendazole co-administration in school-
aged children and adults infected with Trichuris trichiura: a multi-country 
randomized controlled trial 
Short title 
Efficacy and safety of IVM/ALB co-administration 
Protocol Number, Date and 
Version 
1, 13.06.2018, v1.01 
Trial registration 
Has been registered on ClinicalTrials.gov (reference: NCT 03527732) 
Clinical phase 
Phase 3 trial 
Sample size 
1800 (600 participants in each of 3 settings) 
Indication 
Trichuris trichiura infection (eggs in stool) 
Investigational Product and 
Reference Treatment 
Ivermectin and albendazole 
Study Rationale 
To provide evidence on potentially enhanced efficacy by combining the 
standard drug albendazole with ivermectin in school-aged children and adults 
against infection with T. trichiura. 
Study Objectives 
To compare the efficacy and safety of standard doses of co-administered 
ivermectin (200 µg/kg) and albendazole (400 mg) compared to albendazole 
(400 mg) alone in community members aged 6-60 years.  
 
Our primary objective is to comparatively assess the efficacy in terms of cure 
rates (CRs) against T. trichiura infections among school-aged children and 
adults of the following oral treatment regimens: 
 
Albendazole (400 mg)/ivermectin (200 µg/kg) combination  
 
Albendazole (400 mg) monotherapy 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 136 of 176 
 
 
 
The secondary objectives of the trial are: 
a) To evaluate the safety and tolerability of the treatment regimens  
b) To compare the egg reduction rate (ERR) of the treatment regimens 
against T. trichiura 
c) To determine the CRs and ERRs of the drugs in study participants (6-
60 years) infected with hookworm, Ascaris lumbricoides and 
Strongyloides stercoralis 
d) To investigate potential extended effects on follow-up helminth 
prevalences (6 and 12 months post-treatment) of the two treatment 
regimens (as assessed among participants with cleared infection on 
days 21 and 180) 
e) To compare CRs based on infection status determined by novel 
polymerase chain reaction (PCR)-based and standard microscopic 
diagnosis 
f) 
To assess potential differences in susceptibility to the treatment 
regimen between the hookworm species, Necator americanus, 
Ancylostoma duodenale and A. ceylanicum, as classified through the 
novel PCR-based diagnosis 
g) To characterize T. trichiura strains from different epidemiological 
settings and investigate potential resistance markers using a deep 
sequencing analysis 
h) To determine optimal timing for measuring anthelmintic efficacy in 
T. trichiura infection 
i) 
To evaluate potential benefits from deworming on morbidity 
indicators, microbiome and nutritional parameters 
Study design 
Double blind, randomized controlled trial 
Study product / intervention Administration of a single oral dose of  ivermectin + albendazole 
Comparator(s) 
albendazole (400 mg) monotherapy 
Key inclusion / Exclusion 
criteria 
Inclusion:  School-aged children and adults (6-60 years) infected with 
T. trichiura with at least two slides of the quadruple Kato-Katz thick smears 
positive and infection intensities of at least 100 eggs per gram of stool (EPG), 
agreeing to comply with study procedures, including provision of two stool 
samples at the beginning (baseline) and on three follow-up assessments 
(approximately 3 weeks, 6 months, and 12 months later), written informed 
consent signed by parents and/or caregivers for children/adolescents; and oral 
assent by child/adolescent (6-17 years). 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 137 of 176 
 
 
 
Exclusion: No written informed consent by individual/parents and/or 
caregiver, below age of 6 years and weight of 15 kg, any clinically relevant 
abnormality (including severe anemia or clinical malaria) or history of acute 
or severe chronic disease (e.g. cancer, diabetes, chronic heart, liver or renal 
disease), recent use of anthelminthic drug (past 4 weeks), attending other 
clinical trials during study, negative diagnostic or low egg count (less than 100 
EPG or less than 2 out of 4 slides positive) result for T. trichiura, known 
allergy to study medication, pregnancy or lactating in the 1st week after birth, 
taking medication with known interaction on study drugs. 
Primary Endpoints 
T. trichiura infection status assessed by Kato-Katz 14-21 days after treatment 
Secondary Endpoints 
 
ERR against T. trichiura  
 
CRs and ERRs against A. lumbricoides, hookworm and S. stercoralis 
 
Adverse events 
 
Infection status assessed by PCR 
Exploratory Endpoints 
 
Molecular characterization and resistance markers of T. trichiura 
 
Optimal timing for drug efficacy assessment in T. trichiura infection 
 
Nutritional and microbiome status 
 
Morbidity indicators 
Interim Analyses 
None 
Study Duration 
14 months 
Schedule 
06/2018 of first-participant in (planned) 
08/2019 of last-participant out (planned) 
Study centres 
Multinational study with trial sites in Côte d’Ivoire, Lao PDR and Pemba 
Island (Tanzania) 
Measurements & procedures Two stool samples (each of a minimum of 15 grams) will be collected if 
possible on two consecutive days or otherwise within a maximum of 5 days. 
During collection of the second stool sample participants will be asked to 
provide a urine sample (minimum 10 ml) additionally. 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 also be interviewed before treatment, 3 and 24 hours and 
3 weeks after treatment about the occurrence of adverse events. Children aged 
6-16 years will additionally be asked to rate their own physical functioning by 
replying to a pre-tested questionnaire at baseline and 6 and 12 months after 
treatment. The efficacy of the treatment and potential extended effects on 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 138 of 176 
 
 
 
follow-up prevalence will be determined 14-21 days, 6 months and 12 months 
post-treatment by collecting another two stool samples. Subjective treatment 
satisfaction will be assessed 3 hours, 3 weeks and 6 months after treatment to 
investigate relationship with treatment compliance and observed efficacy in 
reducing egg output and morbidity. 
All stool samples will be examined with duplicated Kato-Katz thick smears 
for T. trichiura, A. lumbricoides and hookworm. S. stercoralis infections will 
be identified using the Baermann technique and recorded qualitatively as 
larvae-positive or negative. Complementary to stool-based diagnostics, a small 
portion of urine from each participant will be fixed, transferred to a laboratory 
at Khon Kaen University in Thailand and examined for antibodies of 
S. stercoralis using a newly developed ELISA-based assay. For subsequent 
PCR and microbiome analysis of the stool samples a portion of 1.5-2 g from 
each specimen will be frozen and preserved in 70% ethanol, respectively and 
shipped to a reference laboratory at Swiss TPH in Switzerland. At baseline 
and in the first follow-up (3 weeks post treatment) an additional portion of 
stool (1.5-2 g) from a subsample of 10 participants identified with heavy 
intensity infections in each case and study setting will be preserved in 95% 
ethanol, shipped to the same reference laboratory and subjected to deep 
sequencing for characterization of T. trichiura strains and investigation of 
potential resistance markers. Fecal occult blood and calprotectin in stool as 
markers for gut morbidity and inflammation will be detected using a rapid 
diagnostic test and an immunoassay, respectively. A subsample of 30 
participants will be asked to provide a daily stool sample for a period of up to 
4 weeks to monitor dynamics of T. trichiura egg output for subsequent 
determination of the optimal timing for drug efficacy assessment. Individuals 
found T. trichiura positive 6 months after baseline will receive a second round 
of treatment according to their group scheme.  
Each participant will be asked to provide a finger-prick blood sample for 
hemoglobin measurement and a rapid diagnostic test (RDT) for Plasmodium 
spp. at baseline and 6 and 12 months after treatment. At the same time points 
anthropometric measurements (i.e. height, weight, mid-upper arm 
circumference (MUAC) and skinfold thickness) will be taken for all 
participants. In addition, a venous blood sample (~8 ml) will be taken from 
each participant to assess biochemical blood parameters as proxies for vital 
organ functioning (e.g. complete blood count, urea, creatinine, transaminases 
etc.) measured in Laos and nutritional indicators for micro- (i.e. (pro-) 
vitamins, inflammation markers, and iron/ferritin) and macronutrient (i.e. 
albumin) deficiencies (evaluated in Switzerland) at baseline, day 21, day 180 
and day 360. 
To all participating households (to any adult household member, ideally the 
household head), a household questionnaire will be administered assessing 
information on socioeconomic characteristics and access to sanitation, water 
facilities, and hygiene behavior. 
Statistical Analyses 
An available case analysis will be performed, including all subjects with 
primary end point data. Supplementary, a per-protocol analysis will be 
conducted. CRs will be calculated as the percentage of egg-positive subjects at 
baseline who become egg-negative after treatment. Differences among CRs 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 139 of 176 
 
 
 
(between treatment arms and between diagnostic approaches) will be analysed 
by using crude and adjusted logistic regression modeling (adjustment for age, 
sex, and weight).  
Geometric and arithmetic mean egg counts will be calculated for the different 
treatment arms before and after treatment to assess the corresponding ERRs. 
Bootstrap resampling method with 5,000 replicates will be used to calculate 
95% confidence intervals (CIs) for differences in ERRs.  
Further secondary outcomes – as nutritional and morbidity indicators - will be 
analysed using logistic and linear regression as appropriate. To compare 
individual’s changes in nutrition/morbidity categories as an effect from 
treatment McNemar’s test will be applied. The analysis after 6 and 12 month 
of follow-up will be complemented by generalized estimating equation (GEE) 
models with independent correlation structure and empirical estimators to 
account for missing data. 
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 school-aged children, since an infection with 
T. trichiura occurs most often in children and they are further the main target 
group of deworming campaigns. 
Recruitment procedure 
The parallel group trial will be conducted as a multi-country study with two 
settings in Africa and one in Asia recruiting each 600 community members: 
 
West African setting: Côte d’Ivoire 
 
East African setting: Pemba (Zanzibar, Tanzania)  
 
Asian setting: Lao PDR 
 
The studies will be conducted in areas with moderate to high T. trichiura 
endemicity (communities with a prevalence ≥ 25%) identified from earlier 
studies and/or based on experience of the local collaborating teams. They will 
be implemented as community-based studies in order to recruit participants 
from a broad age range (6-60 years). Ideally, entire communities with a 
population size of < 1000 inhabitants will be included in the study for pre-
screening and identification of T. trichiura cases to avoid potential selection 
bias of households. To identify all potentially eligible households of the 
respective communities and its composition in terms of age groups a 
preceding population census will be conducted. 
Coverage of damages 
Winterthur Police Nr. 4746321, trial insurance in Lao PDR: to be issued 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 140 of 176 
 
 
 
Storage of data and samples 
for future research aims 
After the study has been completed all samples will be destroyed and case 
report forms will be kept for a minimum of 15 years (chapter 10). 
 
Conflict of interest in 
relation to the investigated 
drugs 
We declare no conflict of interest in relation to the investigated drugs. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 141 of 176 
 
 
 
2. 
Background information 
Albendazole and mebendazole are the most widely used drugs for preventive chemotherapy (PC) campaigns 
against soil-transmitted helminth (STH) infections. Albendazole is characterized by high cure rates (CRs) and 
egg reduction rates (ERRs) against infections with Ascaris lumbricoides (95.7% and 98.5%) and hookworm 
infections (79.5 and 89.6%). Lower efficacy is observed against Trichuris trichiura infections (CR 30.7%, and 
ERR of 49.9%) [1].  
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 mono-therapy [2]. 
A recent review and meta-analysis found that ivermectin co-administered with albendazole is highly efficacious 
for the treatment of T. trichiura and is comparatively more efficacious than albendazole alone (Figure 1) [3]. 
Efficacy of ivermectin and albendazole against A. lumbricoides and hookworm are comparable and in some 
cases more efficacious than albendazole alone. Summarized efficacy measures of albendazole, mebendazole, and 
ivermectin against trichuriasis from a recent review [1] and earlier trials [4, 5] are shown in Table 1. 
 
 
Figure 1. Forest plot displaying the results of a random-effects meta-analysis of the effect of the co-
administration of albendazole-ivermectin on the number of patients infected with T. trichiura compared to 
albendazole alone.  
 
 
 
 
Table 1. Average CRs and ERRs of albendazole and mebendazole for T. trichiura from a recent review [1] as 
well as findings from studies investigating ivermectin [4, 5] 
Drug 
CR (%) 
95% CI 
ERR (%) 
95% CI 
Albendazole 
30.7 
(21.0, 42.5) 
49.9 
(39.0, 60.6) 
Mebendazole 
42.1 
(25.9, 60.2) 
66.0  
(54.6, 77.3) 
Ivermectin 
11-35 
NA 
43-98 
NA 
NA, not applicable 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 142 of 176 
 
 
 
 
The individual studies included in the review are summarized in Table 2. All four studies are randomized 
controlled trials and used the standard dose of 200 µg/kg ivermectin and 400 mg albendazole [4, 6-8]. Against 
infections with T. trichiura, CRs ranging from 27.5-81.1%, ERR based on geometric mean ranging from 91.3-
99.7%, and ERR based on arithmetic mean ranging from 85.6-97.5% were observed. CRs for T. trichiura 
observed in Asian settings were higher than in African settings. One reason for this finding may be differences in 
the study design and quality (e.g. in terms of diagnostic approach used). Another possible reason recently 
highlighted is genetic diversity of T. trichiura strains and variation in susceptibility to anthelmintics and/or drug 
resistance [9-11]. Interestingly, the higher efficacy of ivermectin in combination with albendazole translated – at 
least in some settings – into lower prevalences even after one year [4, 12]. The efficacy of albendazole-
ivermectin against A. lumbricoides was excellent (CRs >78% and ERRs >99.5%), while moderate CRs (50-
66.7%) and high ERRs (>95.4%) were observed against hookworm. 
 
Table 2. Known efficacy of co-administered ALB-IVMa against T. trichiura: 
Study 
Setting 
Cure rate in % 
(nneg/n) 
Eggs per gram 
(pre/post) 
Egg reduction rate 
in % 
Ismail et al. 1999 
Sri Lanka 
81.1% (43/53) 
1544.0/78.7 (unkwn) 
94.9% (unkwn) 
Belizario et al. 2003 
Philippines 
65.1% (97/149) 
4948.1/122.5 (ar) 
550.0/1.9 (geo) 
97.5% (ar)  
99.7% (geo) 
Knopp et al. 2010 
Tanzania 
(Pemba) 
37.9% (53/140) 
127/11 (geo) 
91.3% (geo) 
Speich et al. 2015 
Tanzania 
(Pemba) 
27.5% (30/109) 
1059/153 (ar) 
489/27 (geo) 
85.6% (ar) 
94.5% (geo) 
All studies 
 
49.4% (223/451) 
 
 
aConsidered doses: albendazole=400 mg, ivermectin=200 µg/kg 
ar=arithmetic mean, geo=geometric mean, unkwn=unknown mean 
 
 
The WHO Expert Committee met from March 27-31, 2017 and, based on review of a dossier suggesting 
inclusion of ivermectin as an anthelmintic in the Essential Medicines List, made the following recommendation:  
 
“…adding ivermectin on the Essential Medicines List under the section intestinal anthelminthic for use against 
Strongyloides stercoralis and STH. It may be used in combination with albendazole for treatment of soil-
transmitted helminthiasis.” 
 
This important milestone paves the way for further, standardized trials to evaluate the efficacy of this 
combination among school-aged children in a range of epidemiological settings. In addition, the combination 
should be evaluated among adults, as there is growing interest in broadening deworming to include adults in 
order to move from morbidity control toward interruption of transmission [13, 14].  
In the proposed work, three trials are planned across a range of transmission settings, including Côte d'Ivoire, 
Lao PDR, and Pemba (Tanzania). Follow-up will be conducted at 1, 6, and 12 months to inform treatment 
frequency. Results from these trials will inform decisions on how the combination could be introduced into 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 143 of 176 
 
 
 
existing mass drug administration (MDA) programs and therefore provide a valuable adjunct tool for 
interrupting STH transmission.  
 
3. 
Trial objective and purpose 
The overall goal of the study is to assess the efficacy and safety of co-administered albendazole and ivermectin 
versus albendazole monotherapy (standard of care) against T. trichiura infections in children and adults (6-60 
years) in different transmission settings and geographies. 
 
We hypothesize that albendazole-ivermectin has a higher efficacy against T. trichiura infections than 
albendazole alone, and hence, the efficacy against all three STH species (A. lumbricoides, T. trichiura, and 
hookworm) and Strongyloides stercoralis will be increased. 
The primary objective of the trial is to comparatively assess the efficacy in terms of CR against T. trichiura 
infections among school-aged children and adults from three different epidemiological settings and monitored 
over a 12-month period of the following two oral treatment regimens: 
• 
Albendazole/ivermectin combination 
• 
Albendazole monotherapy 
 
The secondary objectives of the trial are: 
a) To evaluate the safety and tolerability of the treatment regimens  
b) To compare the ERRs of the treatment regimens against T. trichiura 
c) To determine the CRs and ERRs of the drugs in study participants (6-60 years) infected with hookworm, 
A. lumbricoides and S. stercoralis 
d) To investigate potential extended effects on follow-up helminth prevalences (6 and 12 months post-
treatment) of the two treatment regimens (as assessed among participants with cleared infection on days 
21 and 180) 
e) To compare CRs based on infection status determined by novel polymerase chain reaction (PCR)-based 
and standard microscopic diagnosis 
f) 
To assess potential differences in susceptibility to the treatment regimen between the three hookworm 
species, Necator americanus, Ancylostoma duodenale and A. ceylanicum, as classified through the novel 
PCR-based diagnosis 
g) To characterize T. trichiura strains from different epidemiological settings and investigate potential 
resistance markers using a deep sequencing analysis  
h) To determine optimal timing for measuring anthelmintic efficacy in T. trichiura infection 
i) 
To evaluate potential benefits from deworming on morbidity (clinically evaluated and self-rated from 
questionnaire interviews) on microbiome and nutritional indicators  
4. 
Methodology 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 144 of 176 
 
 
 
4.1 
Primary and secondary endpoint 
T. trichiura infection status assessed by Kato-Katz 14-21 days after treatment will be the primary endpoint and 
the main outcome for efficacy be expressed as CR (i.e. conversion from being egg positive pre-treatment to egg 
negative post-treatment) and ERR (secondary end point). Secondary endpoints include further infection status 
with A. lumbricoides, hookworm and S. stercoralis and related efficacy measures, adverse events and infection 
status assessed by PCR. In addition, optimal timing for drug efficacy assessment in T. trichiura infection will be 
determined, T. trichiura strains and the microbiome will be described and potential resistance markers evaluated 
using deep sequencing and potential benefits on nutritional and morbidity indicators from treatment assessed 
(exploratory end points). 
 
4.2 
Type of trial 
Double blind randomized controlled trial. 
 
4.3 
Trial design 
4.3.1 
Baseline survey and screening 
A randomized-controlled trial will be conducted with two treatment arms to be followed-up over a 12 months 
period with an intermediate re-treatment of participants found re-infected after 6 months (Figure ). This parallel 
group trial will be conducted as a multi-country study; thus, in each setting a separate trial according to the 
design described below will be set up, to provide a better basis for the subsequent generalization of its findings. 
This arises from the possibility of recruiting the subjects from a wider population and of administering the 
medication in a broader range of clinical settings, thus presenting an experimental situation that is more typical 
of future use. The study includes one baseline and three follow-up assessments at 3 weeks (day 21), 6 months 
(day 180), and 12 months (day 360). 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 145 of 176 
 
 
 
 
Figure 2. Design and timeline of the randomized-controlled trial to be implemented in each of three settings. 
 
The study is designed as a two-armed trial including one arm with a single drug administration (arm A; 
albendazole) and one arm with combined treatment through co-administration of separate tablets (arm B; 
albendazole and ivermectin).  
The trial will be conducted as a multi-country study with two settings in Africa and one in Asia, namely Côte 
d’Ivoire, Pemba (Zanzibar, Tanzania) and Lao PDR. 
At baseline, all participants will be asked to provide two stool samples of at least 15 grams each (within a 
maximum of 5 days). From every stool specimen, duplicate Kato-Katz thick smears (41.7 mg each) [15] will be 
prepared and read under a microscope for eggs of T. trichiura, A. lumbricoides and hookworm by experienced 
technicians. A small amount of feces (~10 mg and 60μg, respectively) will further be tested on fecal occult blood 
and calprotectin as proxies for gut morbidity and inflammation using a rapid diagnostic test and an 
immunoassay, respectively [16]. Additionally, a portion of 1.5-2 g of stool from each specimen will be frozen 
and preserved in 70% ethanol, respectively and shipped to a reference laboratory at the Swiss Tropical and 
Public Health Institute (Swiss TPH, Basel, Switzerland) for microbiome and PCR analysis [17]. While 
discrimination of hookworm species via morphological comparison during microscopy of Kato-Katz slides is not 
feasible [18], PCR will allow to accurately determining efficacy and for further classification of hookworm 
infection into the three species N. americanus, A. duodenale and A. ceylanicum. The remains of each stool 
sample (ideally 10 to 20 g) will be processed by the Baermann technique for identification of S. stercoralis 
infections and be recorded qualitatively as larvae-positive or negative. Urine samples from each participant will 
be collected together with the 2nd stool sample, fixed and transferred to a laboratory at Khon Kaen University in 
Thailand for subsequent detection of S. stercoralis antibodies using a novel ELISA-based assay. At baseline and 
in the first follow-up (3 weeks post treatment) an additional portion of the second stool sample (1.5-2 g) from a 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 146 of 176 
 
 
 
subsample of 10 participants identified with heavy intensity infections in each case (as assed on the first sample) 
will be preserved in 95% ethanol, shipped to the same reference laboratory at Swiss TPH in Switzerland and 
subjected to deep sequencing for characterization of T. trichiura strains and investigation of potential resistance 
markers [19]. A subsample of 30 participants in each treatment arm will be asked to provide a daily stool sample 
for a period of up to 4 weeks to monitor dynamics of T. trichiura egg output for subsequent determination of the 
optimal timing for drug efficacy assessment as has been done for other STH species earlier [20]. 
A subsequent independent quality control of sample results (approximately 10%) will be conducted. Results are 
considered correct if the following tolerance margin is not exceeded: (i) No difference in presence/absence of 
hookworm, A. lumbricoides and T. trichiura, (ii) egg counts are +/-10 eggs for counts ≤100 eggs or +/-20% for 
counts >100 eggs (for each species separately) [21]. In case discrepancies above the tolerance margin are noted 
in one or more slides, all slides are re-read by the local technicians. The new results are discussed, so that in case 
of discordant results, slides can be re-evaluated to reach consensus. Infection intensity expressed as the 
arithmetic and geometric mean egg count per gram of stool (EPG) will be calculated for each treatment arm. All 
microscopically analyzed quadruplicate Kato-Katz thick smears will be destroyed within one day (after passing 
the quality control). The same sampling procedure and diagnostic approach will be applied at days 21, 180 and 
360 post-treatment. 
In the Asian setting potential complications through albendazole treatment in patients affected by (neuro-) 
cysticercosis due to infection with Taenia solium have to be considered and communities without pig-farming 
activities should be prioritized for study location selection [22]. 
A clinical examination of the study participants assessing general health, anthropometric parameters including 
height, weight, mid-upper arm circumference (MUAC) and skinfold thickness (i.e. triceps and subscapular 
skinfolds) as well as tympanic temperature using an ear thermometer will precede the treatment and will be 
repeated on two follow-up assessments (days 180 and 360) to evaluate potential benefits from deworming. Each 
participant will be asked to provide a finger-prick blood sample for a RDT for Plasmodium spp. infection and to 
evaluate hemoglobin (Hb) levels using a HemoCue analyzer (Hemocue Hb 301 system; Angelholm, Sweden) 
following the same (re-)assessment schedule. To assess potential improvement on nutritional indicators for 
micro- (i.e. (pro-) vitamins, inflammation markers, and iron/ferritin) and macronutrient (i.e. albumin) 
deficiencies and dynamics of biochemical blood parameters as a proxy for functioning of vital organs a venous 
blood sample (approximately 8 ml) will be taken at baseline, day 21, day 180 and 360. These samples will be 
analysed in Switzerland. The biochemical parameters to be assessed (in Laos) include urea, creatinine, bilirubin, 
azotemia, Alanine Amino Transferase (ALAT), Aspartate Amino Transferase (ASAT) as well as blood cell 
counts (e.g. hematocrit, erythrocytes and platelets). Refusal of patients to provide blood samples will be 
accepted. To avoid accidental treatment of pregnant girls/women all female participants (≥ 12 years) will be 
asked to provide a urine sample of at least 10 ml to be subjected to a pregnancy RDT on day 0 and day 180. 
All trial participants will further be asked about existing clinical symptoms before drug administration. 
Additionally, they will be asked to provide subjective short-term (e.g. convenience of treatment) and long-term 
(e.g. effectiveness in reducing symptoms) treatment satisfaction embedded in the re-assessment questionnaires. 
As a measure of patient-rated physical functioning and wellbeing all children (6-16 years) will be administered a 
questionnaire before, 6 and 12 months after treatment, based and adapted from tools already validated in school-
aged children from rural settings in Côte d’Ivoire [23]. Before application this tool will be adapted to local 
conditions of Lao PDR and pre-tested in a comparable school-aged population not otherwise involved in this 
trial. To adjust for known influencing factors with regard to reinfection and morbidity [24, 25] in the subsequent 
analysis and to identify risk factors for residual infections [26] a household-based questionnaire will be 
administered to one adult member of each participating household, assessing information on socioeconomic 
characteristics, access to sanitation and water facilities as well as hygiene behavior.  
4.3.2 
Assessment of efficacy and other benefits after treatment 
The efficacy of the treatment will be determined 21 days post-treatment by collecting another two stool samples 
which will be microscopically examined for T. trichiura using duplicate Kato-Katz thick smears and potential 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 147 of 176 
 
 
 
co-infection with S. stercoralis applying the Baermann technique and the urine-based ELISA assay. Participants 
will be considered T. trichiura cured if no eggs have been found in the stool. EPG will be assessed by adding up 
the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. 
Geometric and arithmetic mean egg counts will be calculated for the different treatment arms before and after 
treatment to assess the corresponding ERRs. The stool samples collected 21 days post-treatment for efficacy 
assessment will further be re-tested with the same rapid diagnostic test (including PCR and microbiome 
sampling) and immunoassay used at baseline to determine fecal occult blood and calprotectin levels. Frequencies 
of subjects found positive with either of the two markers and by intensity category for calprotectin will be 
calculated by treatment arm. 
At the end of the study (approximately 12 months post-treatment) all participants remaining positive for T. 
trichiura and other soil-transmitted helminths will be treated with albendazole-ivermectin, the currently best 
approved and recommended treatment against T. trichiura [27]. 
Potential extended effects on follow-up helminth prevalences will be assessed using the same methodological 
approach as used for the efficacy assessment and will be based on stool samples collected 6 and 12 months post-
treatment. Likewise fecal occult blood and calprotectin will be re-determined on the same stool samples. 
To assess eventual reduction in morbidity and improvement in nutritional indicators all trial participants will be 
asked to provide another finger-prick blood sample at the 6 and 12 month follow-up for Hb measurement and 
rapid diagnostic testing (i.e. malaria) and once more a venous blood sample for micronutrient/blood parameter 
evaluation at all three follow-up time points, respectively. Anthropometric measurement including height, 
weight, MUAC and skinfold thickness will be repeated on the same occasion. Children (6-16 years) will be 
asked to re-assess their own physical functioning in repeated questionnaire interviews during these two last 
follow-ups. Long-term satisfaction with the treatment will be asked 6 months post-treatment. Mean values for 
continuous outcomes and frequencies for binary/categorical outcomes will be calculated for each treatment arm 
and follow-up time point and compared using descriptive and repeated measurement analysis as detailed in 
section 7.3. 
 
4.4 
Measure to minimize bias 
Study participants eligible for treatment will be randomly assigned to one of the treatment arms using a 
computer-generated stratified block randomization code. The random allocation sequence with varying random 
blocks of four or eight and stratified by 2 levels of baseline infection intensity (light: <1000 EPG, and moderate 
plus heavy: ≥ 1000 EPG T. trichiura infections) will be provided by a statistician. The treatment arms will have 
an equal number of participants with light infection intensity, although the number of light versus 
moderate/heavy infections are not expected to be equal in each arm, depending on the distribution of infection 
intensity in the recruited cohort. The study will be double blinded (i.e. study participants and the trial 
team/researchers conducting the treatment and assessing the outcomes will be blinded) using repacked tablets 
including appearance-matched placebos. 
 
4.5 
Study duration and duration of subject participation 
The trial will last fourteen months. The screening for the baseline will start three weeks prior to the treatment. 
Follow-up screening will take place 14-21 days, 180 days and 360 days post-treatment and last each time for 
about three weeks. Schedules of visits are summarized below. 
 
4.6 
Schedule of visits 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 148 of 176 
 
 
 
Table 3. Schedule of visits of parallel group trial. 
 
Screenin
g 
Baseline/Treatment/Safety 
Follow up 
 
-21 to -1 
days 
Hours 
Days 
 
0 
Randomization and treatment 
3 
24 
21 
180 
185 
360 
Diagnosis (stool and urine 
examination) 
X 
 
 
 
X 
X 
Selective re-treatment 
X 
Gut morbidity (stool 
RDTs) 
X 
 
 
 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Clinical examination 
 
X 
 
 
 
X 
X 
Pregnancy testing 
 
X 
 
 
 
X 
 
Hemoglobin measurement 
 
X 
 
 
 
X 
X 
Plasmodium co-infection 
 
X 
 
 
 
X 
X 
Venous blood examination 
 
X 
 
 
X 
X 
X 
Physical functioning 
 
X 
 
 
 
X 
X 
Capturing AEs 
 
 
X 
X 
X 
 
 
Capturing SAE 
 
 
X 
X 
X 
 
 
Treatment satisfaction 
 
 
 
X 
 
X 
X 
 
 
 
5. 
Selection of the trial subjects 
5.1 
Recruitment 
The study will be carried out in community members aged 6‒60 years in areas with moderate to high T. trichiura 
endemicity (communities with a prevalence ≥ 25%) identified from earlier studies and/or based on experience of 
the local collaborating teams. The trial will be implemented as community-based study in order to recruit 
participants from a broad age range (6‒60 years). Ideally, entire communities with population size of < 1000 
inhabitants will be included in the study for pre-screening and identification of T. trichiura cases to avoid 
potential selection bias of households. To identify all potentially eligible households of the respective 
communities and its composition in terms of age groups a preceding population census will be conducted. 
All adult community members, including parents/caregivers of minor participants, will be invited to participate 
in an information meeting to explain the purpose and procedures of the study, including potential benefits and 
risks. Parents/caregivers/potential participants will be encouraged to ask questions in an open discussion forum. 
During this session, they will be informed of preventive actions they can take to help protect their children from 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 149 of 176 
 
 
 
acquiring T. trichiura and other STH infections in the future (e.g. adequate food, preparation and defecation 
behavior). 
Those parents/caregivers and their children who are interested in the study will be invited to complete the 
process of informed consent. See section 9.3 for details on obtaining informed consent. Only those participants 
who have written informed consent will be assessed for study eligibility criteria during screening procedures. 
 
5.2 
Inclusion criteria 
1. Written informed consent signed by either the participant him/herself (≥18 years of age) or by parents 
and/or caregivers for children/adolescents; and oral assent by child/adolescent (aged 6‒17 years). 
2. Agree to comply with study procedures, including provision of two stool samples at the beginning 
(baseline) and on three follow-up assessments (approximately 3 weeks, 6 months, and 12 months later). 
3. Aged ≥6 to 60 years. 
4. At least two slides of the quadruple Kato-Katz thick smears positive for T. trichiura and infection 
intensities of at least 100 EPG. 
 
5.3 
Exclusion criteria 
1. No written informed consent by individual/parents and/or caregiver.  
2. Below age 6 and 15 kg weight 
3. Presence of major systemic illnesses, e.g. severe anemia (below 80 g/l Hb according to WHO [28]), 
clinical malaria as assessed by a medical doctor (positive Plasmodium RDT and ≥38 °C ear temperature), 
upon initial clinical assessment. 
4. History of acute or severe chronic disease (e.g. cancer, diabetes, chronic heart, liver or renal disease). 
5. Recent use of anthelmintic drug (within past 4 weeks). 
6. Attending other clinical trials during the study. 
7. Negative or low egg count (less than 100 EPG or less than 2 out of 4 slides positive) diagnostic result for 
T. trichiura eggs in the stool. 
8. Known allergy to study medications (i.e. albendazole and ivermectin). 
9. Pregnancy or lactating in the 1st week after birth (according to WHO guidelines within LF control 
programs [29]). 
10. Currently taking medication with known interaction (e.g. for albendazole: cimetidine, praziquantel and 
dexamethasone; for ivermectin: warfarin). 
 
5.4 
Criteria for discontinuation of trial 
A subject can be discontinued from the study for the following reasons: 
1. 
Withdraws from the study (this can happen anytime as participation is voluntary and there are no further 
obligations once a participant withdraws). 
2. 
At the discretion of the Principal Investigator (PI) or co-PI, if the participant is not compliant to the 
requirements of the protocol. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 150 of 176 
 
 
 
Discontinued subjects will not be replaced. If, for any reason, a subject is discontinued from the study before the 
end of treatment evaluations, the safety procedures planned (adverse events (AEs) monitoring) will be 
conducted. 
5.5 
Treatment of subjects 
All T. trichiura-infected, consenting, and participating community members will be treated with the respective 
single or combination treatment regimen at day 0. 400 mg albendazole will be the product of Glaxo Smith Kline 
(Zentel®) and a single tablet administered. 3 mg tablets of ivermectin (Stromectol®) will be obtained from 
Merck, France, the weight recorded for each participant and the correct dose evaluated and administered. 
Matching ivermectin placebo tablets (in terms of appearance) will be produced and a certificate of manufacture 
and analysis be provided by the University of Basel. To ensure double-blinding the tablets will be repacked into 
neutral separate plastic bags each containing one albendazole tablet and the maximum number of ivermectin 
tablets with regard to weight and dose or the corresponding number of placebo tablets. Since albendazole and 
ivermectin are known to be better absorbed in humans after a high-fat meal was consumed, participants will 
receive a local high-fat breakfast (sandwich with e.g. oily sardines) prior to treatment [30, 31]. 
All drugs will be administered in the presence of the investigator(s), and ingestion confirmed. This will be 
recorded with the time and date of closing. Subjects will be asked not to take any drugs other than those 
prescribed by the study medical team. After ingestion of the medication, the subjects will be observed for 3 
hours to ensure retention of the drug. Vomiting within 1-hour post-dosing will require re-dosing. The subjects 
will not be allowed more than one repeated dose. No re-administration will be needed for subjects vomiting after 
one hour. The Principal Investigator is responsible for drug accountability at the study site. Maintaining drug 
accountability includes careful and systematic study drug storage, handling, dispensing and documentation of 
administration. 
 
Antimalarial treatment (i.e., artemisinin-based combination therapy) will be provided to participants found with 
clinical malaria (i.e. positive Plasmodium RDT and ≥38 °C ear temperature) or severely anemic in combination 
with a positive RDT result. Iron supplementation will be offered to severely anemic individuals with a negative 
RDT result. 
 
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 helminthiases in study 
participants will be substituted with a free single-dose treatment (i.e. albendazole 400 mg + ivermectin 200 
µg/kg) against STH as well as S. stercoralis infection at the study endpoint (after the day 360 follow-up 
assessment) offered by the study team. At each follow-up time point, participants will be interviewed whether 
they had taken anthelmintic treatment (e.g. self-purchased, obtained from clinics etc).  
 
5.6 
Concomitant therapy 
All medications taken one month before and during the study period until the last stool examination 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. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 151 of 176 
 
 
 
 
Medication(s)/treatment(s) NOT permitted during the trial:  
- No other active drugs against helminths are permitted during the trial. 
- No drugs with known interactions with the study medication are permitted during the trial. 
 
6. 
Safety assessments 
Few AEs have been reported following ivermectin-albendazole co-administration in STH-infected individuals. 
The most common AEs were abdominal cramps, headache, fatigue, nausea, diarrhea, fever and vertigo [7, 8, 32]. 
The safety profile of co-administered ivermectin and albendazole will be assessed through the recording, 
reporting and analysis of baseline medical conditions, AEs and a physical and clinical examination. 
6.1 
Adverse event definitions 
The term “adverse event” could include any of the following events which develop or increase in severity during 
the course of the study, after administration of the study product: 
a) 
Any 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 AEs but be considered baseline medical conditions. For the purpose of this trial, disease 
progression and relapse will be considered as treatment failure, not as an AE.  
The observation time for AEs starts when the treatment is initiated until day 21 (3 weeks after last drug 
administration).  
These data will be recorded on the appropriate case report form (CRF) sections, regardless of whether they are 
thought to be associated with the study or the drug under investigation. Associated with the use of the drug 
means that there is a reasonable possibility that the event may have been caused by the drug (see also relatedness 
definitions below). 
6.1.1 
Severity grading 
Adverse signs or symptoms will be graded by the Investigator as mild, moderate, severe or life threatening 
according to the following definitions:  
Grade 
Definition 
1 
Mild: the subject is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
2 
Moderate: the subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity. 
3 
Severe: significant impairment of functioning: the subject is unable to carry out his or her 
usual activities. 
4 
Life threatening or disabling  


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 152 of 176 
 
 
 
5 
Death related to adverse events 
 
6.1.2 
Relatedness 
Relatedness will be assessed as defined below based on the temporal relationship between the AE and the 
treatment, known side effects of treatment, medical history, concomitant medication, course of the underlying 
disease and trial procedures. 
Possibly related: an AE which can medically (pharmacologically/clinically) be attributed to the study treatment. 
Unrelated: an 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 co-administration of ivermectin-albendazole 
reported in the literature or on the drug package leaflets and listed in the consent form. 
Unexpected adverse drug reaction: Any AE possibly related to the study product administration, the nature, 
frequency, specificity or severity of which is unanticipated and not consistent with the available risk information 
described for these drugs.  
6.1.4 
Serious adverse events 
According to the ICH “Clinical Safety Data Management: Definitions and standards for expedited Reporting 
E2A” [33], 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 subject was, in the view of the Investigator, at immediate risk 
of death from the reaction as it occurred, i.e. it does not include a reaction that, had it occurred 
in a more serious form, might have caused death; 
3. results in persistent or significant disability/incapacity, i.e. the event causes a substantial 
disruption of a person’s ability to conduct normal life functions; 
4. requires in patient hospitalization or prolongation of existing hospitalization; 
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” AE does not necessarily meet the criteria for a “serious” AE. SAEs are reported from consent to 3 
weeks post-treatment (Day 21).  
SAEs that are still ongoing at the end of the study period will be followed up to determine the final outcome.  


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 153 of 176 
 
 
 
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 SAEs.  
6.2 
Methods of recording and assessing adverse events 
Subjects will be kept for observation for at least 3 hours following treatment for any acute AEs. If there is any 
abnormal finding, the local study physician will perform a full clinical and physical and biochemical 
examination and findings will be recorded. An emergency kit will be available on site to treat any medical 
conditions that warrant urgent medical intervention. In addition patients will also be interviewed 3 and 24 hours 
and again 3 weeks after treatment about the occurrence of AEs (see chapter 4.6). 
Information on all AEs (onset, duration, intensity, seriousness and causality) will be immediately entered in the 
appropriate AE module of the CRF that serves as source document. For all AEs, sufficient information will be 
pursued and/or obtained so as to permit i) an adequate determination of the seriousness of the event (i.e. whether 
the event should be classified as a SAE); ii) an assessment of the casual relationship between the AE and the 
study treatments and iii) an assessment of intensity of AEs will be judged by the study physician. 
 
All SAEs or SUSARs must be reported as described in Section 6.3. 
 
6.3 
Reporting of serious adverse events 
Any study-related unanticipated problem posing risk of harm to subjects or others (including all unexpected 
adverse drug reactions), and any type of SAE will be immediately (within a maximum of 24 hours after 
becoming aware of the event) notified to the study sponsor-investigator and co-PIs: 
 
 
Prof. Dr. Jennifer Keiser (Sponsor-investigator) 
Swiss Tropical and Public Health Institute 
Socinstrasse 57, 4051 Basel, Switzerland 
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@swisstph.ch 
 
 
Dr. MD Somphou Sayasone (Co-PI) 
Lao Tropical and Public Health Institute 
Samsenthai Street, Sisattanak District Vientiane, Lao PDR, 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 154 of 176 
 
 
 
Tel: 856-21-250 670 (304) or +856-20-5567 9603 
E-mail: somphou.sayasone@swisstph.ch, somphou.sayasone@yahoo.com  
 
 
 
Within the following 48 hours, the local co-investigator must provide to study sponsor-investigator further 
information on the SAE or the unanticipated problem in the form of a written narrative. This should include a 
copy of a completed SAE form, and any other diagnostic information that will assist the understanding of the 
event. In exceptional circumstances, a SAE may be reported by telephone. In these cases, a written report must 
be sent immediately thereafter by fax or e-mail. Names, addresses and telephone for SAE reporting will be 
included in the trial-specific SAE form. Relevant pages from the CRF may be provided in parallel (e.g. medical 
history, concomitant medications).  
 
6.4 
Safety reporting to Health Authorities and Ethics Committees 
The sponsor-investigator will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. Additionally, this information will be provided to ‘Ethikkomission Nordwest- 
und Zentralschweiz’ (EKNZ, Switzerland) and the ethics committee of Lao PDR 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. 
 
7. 
Statistics 
7.1 
Definition of primary endpoint 
CR of co-administered ivermectin-albendazole against T. trichiura is the primary endpoint in our study. Since 
treatment success is influenced by infection intensity, stratified block randomization will be used (baseline 
infection intensity: light infections and moderate/heavy infections) to ensure balanced treatment groups in terms 
of infection intensity. 
7.2 
Justification of number of trial subjects  
Based on available summarized efficacy measures from a recent review [1] and the published literature, we 
assume that the CR of albendazole against T. trichiura is 30% compared to 50% in the albendazole-ivermectin 
treatment regimen. To detect a difference with 90% power at a two-sided 5% significance level, we require 121 
participants per study arm and 143 to account for potential loss to follow-up of 15%. We further assume the 
same treatment efficacy in the mid-term treatment and a 6-months reinfection risk of 10%. Consequently we 
expect a proportion of negative patients after 12 months of 44% in the albendazole arm and of 65% in the 
albendazole-ivermectin arm resulting in a required sample size of 111 participants per arm. To account for a loss 
to follow-up of 30% after 6 months and 40% at final assessment (12 months) we aim to recruit 300 participants 
in each treatment group (600 in total) in each country.  
Subgroup analysis will be conducted stratifying the study population by age category (school-aged and adults). 
For the subgroup analysis we will pool the data from all 3 countries to ensure sufficient statistical power. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 155 of 176 
 
 
 
7.3 
Description of statistical methods 
The primary available case analysis will include all participants with primary end point data. In addition, an 
intention-to-treat analysis will be conducted considering all participants with missing endpoint data as treatment 
failure or all as treatment success to ensure that the results are not sensitive to potential loss to follow-up bias. CRs 
will be calculated as the percentage of egg-positive (larvae-positive for S. stercoralis) children at baseline who 
become egg-negative (larvae-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. For S. stercoralis 
infection no further quantification of larvae in stool will be done. The ERR of STH infection will be calculated as: 
 
𝐸𝑅𝑅=  1 − 
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝 + 1) −1
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 1)      −1  
 
In the primary model we estimate the difference among CRs by using unadjusted logistic regressions. In a 
subsequent analysis an adjusted logistic regression (adjustment for age, sex, and weight) will be performed.  
Geometric mean egg counts will be calculated for the different treatment arms before and after treatment to assess 
the corresponding ERRs. Bootstrap resampling method with 5,000 replicates will be used to calculate 95% 
confidence intervals (CIs) for ERRs and the difference between the ERRs. 
Results from the stool RDT for fecal occult blood will be categorized as negative, trace and positive. For 
calprotectin, individuals with levels exceeding 50 μg/g will be considered as positive and concentrations be 
classified into low (51–149 μg/g), medium (150–299 μg/g) and high (≥300 μg/g) intensity [16]. 
Anthropometric measurements such as height and weight of school-aged children will be translated into weight- 
and height-related z-scores using readily available Stata macros calculating growth indicators for children 5-19 
years [34]. Body mass index and indicators for muscle and fat tissue such as MUAC and skinfold thickness will 
serve as additional indicators of nutritional status for adults and will further be classified using a percentiles 
approach to compare within populations [35]. 
Questionnaires on physical functioning and treatment satisfaction will be evaluated by creating summary scores 
by summing up and transforming the single question scores according to the following formula: [(actual raw score-
lowest possible raw score)/(possible raw score range)]*100 [23]. 
Nutritional and morbidity indicators will be analysed using logistic and linear regression as appropriate. To 
compare individual’s changes in nutrition/morbidity categories as an effect from treatment McNemar’s test will 
be applied. The analysis after 6 and 12 month of follow-up will be complemented by generalized estimating 
equation (GEE) models with independent correlation structure and empirical estimators to account for missing 
data. 
AEs will be evaluated descriptively as the difference of proportion reporting AEs before and after treatment. 
 
7.4 
Description of 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 with the investigators and their study coordinators and a member from Swiss 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 156 of 176 
 
 
 
TPH. This meeting will include a detailed discussion of the protocol, performance of study procedures (standard 
operating procedures (SOPs) from previous studies available on site), CRF completion, and specimen collection 
and diagnostic methods. 
The data produced from this research project will fall into the following categories:  
 
1. Eggs counts of T. trichiura, A. lumbricoides and hookworm and infection status with S. stercoralis based 
on participants’ stool samples analyzed using the Kato-Katz and Baermann technique, respectively,  
before (baseline) and at 3 time points after treatment (follow-ups after 3 weeks, 6 and 12 months). 
Presence of fecal occult blood and elevated calprotectin levels will be evaluated and recorded applying 
RDTs on the same stool samples and assessment time points. 
2. Personal information such as name, age, gender and household composition of trial participants. 
3. Anthropometric and clinical characteristics of the trial participants collected using the study’s CRF such 
as weight, height, skinfold thickness, blood pressure, temperature, hemoglobin level, infection status with 
Plasmodium spp., any abnormal medical condition or chronic disease as well as pregnancy in female 
participants 10 years and above. 
4. Number and type of AEs registered in the CRF actively probed for 3 and 24 hours after treatment. The 
same data will be collected during the collection of the first sample at the 3-week follow-up. 
5. Scales for participant-rated treatment satisfaction and self-rated physical functioning in school-aged 
children captured on different time points (i.e. 3 weeks and 6 months and baseline, 6 and 12 months after 
treatment, respectively) and recorded on the CRF. 
6. Concentration levels of blood and biochemical parameters together with indicators for micronutrient 
status as well as presence of S.stercoralis antibodies in urine before (baseline) and at 3 time points after 
treatment (follow-ups after 3 weeks, 6 and 12 months).  
7. Household-level data on socioeconomic characteristics, presence and use of water and sanitation as well 
as hygiene-related attitudes and practices. 
All data on parasitology and questionnaires about AEs, self-reported clinical signs and symptoms, physical 
functioning, and treatment satisfaction (data in category 1 to 5) will be paper-captured and subsequently entered 
(data entry SOP) into tablets using Open Data Kit (ODK; free electronic data collection software) and uploaded 
to a server hosted at Swiss TPH by trained team members. For quality assurance in-built error, range and 
consistency checks will be programmed for the ODK data entry masks. Data in category 6 will be provided in a 
paper or electronic format, as appropriate, by the respective external laboratories examining these parameters, 
and be subjected to double entry into ACCESS data entry masks by two independent persons; all double-entered 
data will be cross-checked using the Data Compare utility of EpiInfo. Any discrepancies identified from 
programmed quality checks or from comparing double entries will be corrected by consulting the hard copy. 
Data in category 7 will be directly entered while collecting into tablets using ODK and subsequently uploaded to 
the server at Swiss TPH. All categories will be merged into a single master file saved in .dta, .xlsx and .csv. Data 
will then be analysed as described in section 7.3. Hard copies of the data collected within the trial country such 
as parasitological, stool RDT, blood parameter sheets and CRFs will remain at Lao Tropical and Public Health 
Institute (Lao TPHI). Digital copies along with the databases will be transferred to the Swiss TPH after a 
Material Transfer Agreement has been signed by both the Swiss TPH and Lao TPHI. All data is expected to not 
exceed 5GB. 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 157 of 176 
 
 
 
Invited and screened patients will be listed in a confidential “subject identification list and screening log”. 
Enrolled patients will be listed in a confidential “subject enrolment log” and attributed a unique study number; 
this document will constitute the only source to decode the pseudonymised data and will only be accessible to 
the local principal investigator. All study-specific data will only contain this unique identifier instead of any 
names. All data that have been hand-entered in the ACCESS database will be verified by a double-key entry 
procedure in a validated electronic data base system and error, range and consistency checks will be 
programmed. Any discrepancies will be reviewed against the hard copy CRF and corrected. Electronic data files 
will be stored on secured network drives with restricted access for study personnel only. Data analysis will be 
conducted with pseudonymised data and reporting of findings will be fully anonymised. All databases will be 
password secured. 
Essential infrastructure such as lockable cabinets for safe storage of hardcopy data will be made available. 
Network drives with restricted access for authorized personnel only and appropriate analysis software are 
available.  
 
8. 
Duties of the investigator  
8.1 
Investigator’s confirmation 
This trial will be conducted in accordance with the protocol, International Conference on Harmonization Good 
Clinical Practice E6 (R2) (ICH-GCP) and the current version of the Helsinki Declaration. 
All protocol modifications must be documented in writing. A protocol amendment can be initiated by either the 
Sponsor/PI or any Investigator. The Investigator will provide the reasons for the proposed amendment in writing 
and will discuss with the Sponsor/PI and Co-PIs. Any protocol amendment must be approved and signed by the 
Sponsor/PI and must be submitted to the appropriate Independent Ethics Committee (IEC) for information and 
approval, in accordance with local requirements, and to regulatory agencies if required. Approval by IEC must 
be received before any changes can be implemented, except for changes necessary to eliminate an immediate 
hazard to trial subjects, or when the change involves only logistical or administrative aspects of the trial, e.g. 
change of telephone number(s). 
 
8.2 
Damage coverage 
A general liability insurance of the Swiss TPH is in place (Winterthur Police Nr. 4746321) and patient liability 
insurances will be issued in the respective trial countries. 
 
8.3 
Project management 
The trial team will include the PI (Prof. Jennifer Keiser), two Co-PIs (Dr. Eveline Hürlimann and Dr. Somphou 
Sayasone) whereof the latest also acts as a study physician, a trial statistician (Dr. Jan Hattendorf), nurses and 
laboratory technicians. Prof. Jennifer Keiser, Dr. Eveline Hürlimann and a 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. Somphou Sayasone and the 
PhD student will monitor all field activities at the study site.  
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 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 158 of 176 
 
 
 
the participants, whether specified in the protocol or not. Any such steps must be documented. During the 
treatment the records are maintained by the responsible medical doctor. All entries have to be made clearly 
readable with a pen. The investigator must be thoroughly familiar with the properties, effects and safety of the 
investigational pharmaceutical product.  
 
9. 
Ethical considerations 
9.1 
Independent ethics committee 
The study will be submitted for approval by the institutional research commission of the Swiss TPH and the 
ethics committees of Switzerland (EKNZ) and the ethics committee of Lao PDR. The study will be undertaken 
in accordance with the Declaration of Helsinki and good clinical practice (GCP). 
 
9.2 
Evaluation of the risk-benefit ratio 
Ivermectin in combination with albendazole are well-known, widely used drugs in mass treatment programs 
against filariasis, and have little and mainly mild AEs (headache, abdominal pain etc.). 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 ivermectin (200 μg/kg)-albendazole (400 mg) 
considering higher efficacy compared to the existing standard treatment (albendazole monotherapy) and recent 
inclusion as recommended treatment scheme on the Essentials Medicines List [27] following national 
recommendations. 
 
9.3 
Subject information and consent 
Community meetings allowing for open exchange will be organized in every study locality where a prescreening 
for identification of positive cases is to be conducted. The purpose and procedures, the benefits and risks of the 
study will be explained in order to make sure that all community members are at the same level in terms of 
information. All parents or caregivers of eligible children and all adult participants (≥18 years) will be 
individually informed about benefits and risk associated to the trial. They will have sufficient time for reflection 
of their child’s or their own participation, respectively. They will then be asked to sign a written informed 
consent sheet. In case the person is illiterate, an impartial witness that can read and write has to sign the consent 
and the illiterate participant to give a thumb print. In addition to a written informed consent form signed by their 
parent or caregiver, minor participants (aged 6-17 years) will also be briefed verbally and asked orally for assent. 
Even if the minor participant gives written assent, the parent/caregiver has to sign the consent. 
Information sheets are printed in English but will additionally be verbally translated into local languages (i.e. 
Lao) during community meetings. To all participants and parents/caregivers a signed copy of the informed 
consent form will be given. Participation is voluntary and all participants have the right to withdraw from the 
study at any given point in time with no further obligations. Participation itself will not be awarded with 
compensation. 
Patients will be informed in case irregularities are observed on their health status during clinical examination and 
the assessment of biochemical blood parameters and if necessary referred to a health care center.    
9.4 
Subject confidentiality 
The obtained data will be handled strictly confidentially. Only members of the study team will have access to the 
data. Personal data will be coded for data analysis. The codes will be filled with the participant’s identity on a 
separate file (subject identification list and screening log) and stored in a secured place at the local institutions 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 159 of 176 
 
 
 
(i.e. Côte d’Ivoire: Centre Suisse de Recherches Scientifiques en Côte d’Ivoire (CSRS), Lao PDR: Lao TPHI, 
and Pemba: Public Health Laboratory Ivo de Carneri) and will only be accessible to investigators. No names will 
be published at any time, and published reports will not allow for identification of single subjects. 
Confidentiality and anonymity will be ensured throughout the entire research project. 
The investigators have all been trained in GCP. None of the investigators declare to have any conflicts of 
interest. 
 
9.5 
Subjects requiring particular protection 
This study will include school-aged children, since T. trichiura infection occurs often in children; hence this age 
group is at high risk of infection and is therefore the major target group in MDA campaigns. Our trial will 
produce more evidence to support the search for a safe and effective treatment scheme against STH infections in 
children and whole communities. 
 
10. Quality control and quality assurance 
10.1 
Monitoring and auditing 
We will work with locally based monitors. These will conduct site visits to the investigational facilities for the 
purpose of monitoring the study. Details will be described in a separate monitoring plan. The investigator will 
permit them access to study documentation and the clinical supplies dispensing and storage area. Monitoring 
observations and findings will be documented and communicated to appropriate study personnel and 
management. A corrective and preventative action plan will be requested and documented in response to any 
audit observations. No sponsor initiated audits are foreseen, but audits and inspections may be conducted by the 
local regulatory authorities or ethics committees. The Investigator agrees to allow inspectors from regulatory 
agencies to review records and is encouraged to assist the inspectors in their duties, if requested. 
 
10.2 
Access to data, handling of data and samples (data protection), archiving (place, duration) and 
destruction 
Information about study subjects will be kept confidential and managed accordingly. A paper CRF will be 
completed for each subject enrolled into the clinical study. The investigators will review, and approve each 
completed CRF. The study CRF is the primary data collection instrument for the study. All data requested on the 
CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank because the 
procedure was not done or the question was not asked “N/D” will be entered. If the item is not applicable to the 
individual case “N/A” will be written. All entries will be printed in black ink. All corrections must be initialed 
and dated.  
All data on parasitology and questionnaires about AEs, self-reported clinical signs and symptoms, physical 
functioning, treatment satisfaction and household-based socioeconomic factors and access to water and 
sanitation will be doubled entered into a database by two independent persons and cross-checked. Discrepancies 
between data entries will be corrected by consulting the hard copy.  
The results of the research study will be published, but subjects’ names or identities will not be revealed. 
Records will remain confidential. To maintain confidentiality, the Sponsor-Investigator will keep records in 
locked cabinets and the results of tests will be coded to prevent association with participant’s names. Data 
entered into the ACCESS data entry mask will be accessible only by authorized personnel directly involved with 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 160 of 176 
 
 
 
the study and will be encoded. Subject-specific information may be provided to other appropriate medical 
personnel only with the subject’s permission for adults or the parent/caregiver’s permission for minors. 
After the study has been completed all samples will be destroyed and research data and related material will be 
kept for a minimum of 15 years to enable understanding of what was done, how and why, which allow the work 
to be assessed retrospectively and repeated if necessary. Storage and backup will be in three places: personal 
laptops of Jennifer Keiser, Eveline Hürlimann, and Somphou Sayasone, Swiss TPH shared server and 
SWITCHdrive (a cloud storage supported by University of Basel). Archiving conditions will be made strictly 
confidential by password protection. 
 
10.3 
Data entered directly in the CRF – definition of source data 
Source Data are the clinical findings and observations, laboratory data maintained at the study site. Source data 
are contained in source documents. Local authorities are allowed to access the source data. Data will be entered 
directly onto the CRFs. The CRF is considered as a source document. All CRFs will be kept for at least 15 years. 
The study site will retain the original of the CRF to ensure that local collaborators can provide access to the 
source documents to a monitor, auditor, or regulatory agency while a copy of the CRF will be taken to Swiss 
TPH. 
 
10.4 
Data and safety monitoring board/ data monitoring committee 
In our study no data and safety monitoring board will be established, since we work with well-known drugs in a 
limited number of participants and using a single dose treatment. This study is anticipated to be no greater than 
minimal risk to participants. 
 
10.5 
Study Documents: Translations - Reference language 
- Protocol: Master document in English, all further language versions are translations thereof. 
- CRF: Master document in English, all further language versions are translations thereof. 
- ICF: Master document in English, all further language versions are translations thereof. 
 
11. Dissemination of results and publication 
The final results of this study will be published in a scientific journal and presented at scientific conferences. The 
Bill & Melinda Gates Foundation will be acknowledged as study funder. All results from this investigation are 
considered confidential and shall not be made available to any third party by any member of the investigating 
team before publication. A summary of study conclusions will be shared with the local ethics committees and the 
national regulatory authorities. 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 161 of 176 
 
 
 
12. References 
1. 
Moser W, Schindler C, Keiser J: Efficacy of recommended drugs against soil transmitted helminths: 
systematic review and network meta-analysis. BMJ 2017, 358:j4307. 
2. 
Hughes D, Andersson DI: Evolutionary consequences of drug resistance: shared principles across 
diverse targets and organisms. Nat Rev Genet 2015, 16(8):459-471. 
3. 
Palmeirim MS, Hürlimann E, Knopp S, Speich B, Belizario V, Jr., Joseph SA, Vaillant M, Olliaro P, 
Keiser J: Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-
transmitted helminths: A systematic review, meta-analysis and individual patient data analysis. 
PLoS Negl Trop Dis 2018, 12(4):e0006458. 
4. 
Belizario VY, Amarillo ME, de Leon WU, de los Reyes AE, Bugayong MG, Macatangay BJ: A 
comparison of the efficacy of single doses of albendazole, ivermectin, and diethylcarbamazine alone 
or in combinations against Ascaris and Trichuris spp. Bull World Health Organ 2003, 81(1):35-42. 
5. 
Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C: A comparative trial of a single-
dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and 
other soil-transmitted helminth infections in children. Am J Trop Med Hyg 1996, 55(5):477-481. 
6. 
Ismail MM, Jayakody RL: Efficacy of albendazole and its combinations with ivermectin or 
diethylcarbamazine (DEC) in the treatment of Trichuris trichiura infections in Sri Lanka. Ann Trop 
Med Parasitol 1999, 93(5):501-504. 
7. 
Knopp S, Mohammed KA, Speich B, Hattendorf J, Khamis IS, Khamis AN, Stothard JR, Rollinson D, 
Marti H, Utzinger J: Albendazole and mebendazole administered alone or in combination with 
ivermectin against Trichuris trichiura: a randomized controlled trial. Clin Infect Dis 2010, 
51(12):1420-1428. 
8. 
Speich B, Ali SM, Ame SM, Bogoch, II, Alles R, Huwyler J, Albonico M, Hattendorf J, Utzinger J, 
Keiser J: Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, 
albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and 
concomitant soil-transmitted helminth infections: a four-arm, randomised controlled trial. Lancet 
Infect Dis 2015, 15(3):277-284. 
9. 
Betson M, Søe MJ, Nejsum P: Human trichuriasis: whipworm genetics, phylogeny, transmission and 
future research directions. Current Tropical Medicine Reports 2015, 2(4):209-217. 
10. 
Ghai RR, Simons ND, Chapman CA, Omeja PA, Davies TJ, Ting N, Goldberg TL: Hidden population 
structure and cross-species transmission of whipworms (Trichuris sp.) in humans and non-human 
primates in Uganda. PLoS Negl Trop Dis 2014, 8(10):e3256. 
11. 
Hawash MB, Betson M, Al-Jubury A, Ketzis J, LeeWillingham A, Bertelsen MF, Cooper PJ, Littlewood 
DT, Zhu XQ, Nejsum P: Whipworms in humans and pigs: origins and demography. Parasit Vectors 
2016, 9:37. 
12. 
Speich B, Moser W, Ali SM, Ame SM, Albonico M, Hattendorf J, Keiser J: Efficacy and reinfection 
with 
soil-transmitted 
helminths 
18-weeks 
post-treatment 
with 
albendazole-ivermectin, 
albendazole-mebendazole, albendazole-oxantel pamoate and mebendazole. Parasit Vectors 2016, 
9:123. 
13. 
Anderson R, Farrell S, Turner H, Walson J, Donnelly CA, Truscott J: Assessing the interruption of the 
transmission of human helminths with mass drug administration alone: optimizing the design of 
cluster randomized trials. Parasit Vectors 2017, 10(1):93. 
14. 
Lo NC, Addiss DG, Hotez PJ, King CH, Stothard JR, Evans DS, Colley DG, Lin W, Coulibaly JT, 
Bustinduy AL, Raso G, Bendavid E, Bogoch, II, Fenwick A, Savioli L, Molyneux D, Utzinger J, Andrews 
JR: A call to strengthen the global strategy against schistosomiasis and soil-transmitted 
helminthiasis: the time is now. Lancet Infect Dis 2017, 17(2):e64-e69. 
15. 
Katz N, Chaves A, Pellegrino J: A simple device for quantitative stool thick-smear technique in 
Schistosomiasis mansoni. Rev Inst Med Trop São Paulo 1972, 14(6):397-400. 
16. 
Bustinduy AL, Sousa-Figueiredo JC, Adriko M, Betson M, Fenwick A, Kabatereine N, Stothard JR: 
Fecal occult blood and fecal calprotectin as point-of-care markers of intestinal morbidity in 
Ugandan children with Schistosoma mansoni infection. PLoS Negl Trop Dis 2013, 7(11):e2542. 
17. 
Kaisar MMM, Brienen EAT, Djuardi Y, Sartono E, Yazdanbakhsh M, Verweij JJ, Supali T, van Lieshout 
L: Improved diagnosis of Trichuris trichiura by using a bead-beating procedure on ethanol 
preserved stool samples prior to DNA isolation and the performance of multiplex real-time PCR 
for intestinal parasites. Parasitology 2017, 144(7):965-974. 
18. 
Becker SL, Vogt J, Knopp S, Panning M, Warhurst DC, Polman K, Marti H, von Muller L, Yansouni CP, 
Jacobs J, Bottieau E, Sacko M, Rijal S, Meyanti F, Miles MA, Boelaert M, Lutumba P, van Lieshout L, 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 162 of 176 
 
 
 
N'Goran EK, Chappuis F, Utzinger J: Persistent digestive disorders in the tropics: causative infectious 
pathogens and reference diagnostic tests. BMC Infect Dis 2013, 13:37. 
19. 
Avramenko RW, Redman EM, Lewis R, Bichuette MA, Palmeira BM, Yazwinski TA, Gilleard JS: The 
use of nemabiome metabarcoding to explore gastro-intestinal nematode species diversity and 
anthelmintic treatment effectiveness in beef calves. Int J Parasitol 2017, 47(13):893-902. 
20. 
Scherrer AU, Sjoberg MK, Allangba A, Traore M, Lohourignon LK, Tschannen AB, N'Goran EK, 
Utzinger J: Sequential analysis of helminth egg output in human stool samples following albendazole 
and praziquantel administration. Acta Trop 2009, 109(3):226-231. 
21. 
Speich B, Ali SM, Ame SM, Albonico M, Utzinger J, Keiser J: Quality control in the diagnosis of 
Trichuris trichiura and Ascaris lumbricoides using the Kato-Katz technique: experience from three 
randomised controlled trials. Parasit Vectors 2015, 8:82. 
22. 
Okello AL, Thomas LF: Human taeniasis: current insights into prevention and management 
strategies in endemic countries. Risk Manag Healthc Policy 2017, 10:107-116. 
23. 
Fürst T, Müller I, Coulibaly JT, Yao AK, Utzinger J, N'Goran EK: Questionnaire-based approach to 
assess schoolchildren's physical fitness and its potential role in exploring the putative impact of 
helminth and Plasmodium spp. infections in Côte d'Ivoire. Parasit Vectors 2011, 4:116. 
24. 
Campbell SJ, Nery SV, McCarthy JS, Gray DJ, Soares Magalhaes RJ, Clements AC: A critical appraisal 
of control strategies for soil-transmitted helminths. Trends Parasitol 2016, 32(2):97-107. 
25. 
Strunz EC, Addiss DG, Stocks ME, Ogden S, Utzinger J, Freeman MC: Water, sanitation, hygiene, and 
soil-transmitted helminth infection: a systematic review and meta-analysis. PLoS Med 2014, 
11(3):e1001620. 
26. 
Kepha S, Mwandawiro CS, Anderson RM, Pullan RL, Nuwaha F, Cano J, Njenga SM, Odiere MR, Allen 
E, Brooker SJ, Nikolay B: Impact of single annual treatment and four-monthly treatment for 
hookworm and Ascaris lumbricoides, and factors associated with residual infection among Kenyan 
school children. Infect Dis Poverty 2017, 6(1):30. 
27. 
WHO: The selection and use of essential medicines: report of the WHO Expert Committee, 2017 
(including the 20th WHO model list of essential medicines and the 6th WHO model list of essential 
medicines for children). WHO technical report series, vol. no. 1006. Geneva: World Health 
Organization; 2017. 
28. 
WHO: Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. 
Vitamin and Mineral Nutrition Information System. Geneva: World Health Organization; 2011: 
(WHO/NMH/NHD/MNM/11.11). 
29. 
WHO: Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs 
in control interventions: a manual for health professionals and programme managers. Geneva: 
World Health Organization; 2006: 62. 
30. 
Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, 
Lasseter KC: Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in 
healthy adult subjects. J Clin Pharmacol 2002, 42(10):1122-1133. 
31. 
Pawluk SA, Roels CA, Wilby KJ, Ensom MH: A review of pharmacokinetic drug-drug interactions 
with the anthelmintic medications albendazole and mebendazole. Clin Pharmacokinet 2015, 
54(4):371-383. 
32. 
Ndyomugyenyi R, Kabatereine N, Olsen A, Magnussen P: Efficacy of ivermectin and albendazole 
alone and in combination for treatment of soil-transmitted helminths in pregnancy and adverse 
events: a randomized open label controlled intervention trial in Masindi district, western Uganda. 
Am J Trop Med Hyg 2008, 79(6):856-863. 
33. 
ICH Expert Working Group: ICH harmonised tripartite guideline. Clinical safety data management: 
definitions and standards for expedited reporting E2A. International conference on harmonisation of 
technical requirements for registration of pharmaceuticals for human use; 1994. 
34. 
Duggan MB: Anthropometry as a tool for measuring malnutrition: impact of the new WHO growth 
standards and reference. Ann Trop Paediatr 2010, 30(1):1-17. 
35. 
Wang Y, Chen H: Use of Percentiles and Z-Scores in Anthropometry. In: Handbook of Anthropometry. 
Edited by Preedy V. New York: Springer; 2012: 29-48. 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 163 of 176 
 
 
 
7. Statistical Analysis Plan (SAP)  
 
Clinical trial protocol title:  
Efficacy and safety of ivermectin and albendazole co-administration in 
school-aged children and adults infected with Trichuris trichiura: a multi-
country randomized controlled trial 
Principal Investigator 
 
Jennifer Keiser 
ClinicalTrials.gov identifier  
03527732 
Author  
 
 
Jan Hattendorf 
Version/Date 
 
 
v1.0/14.9.2020 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 164 of 176 
 
 
 
 
Contents 
Signatures .............................................................................................................................................................165 
Introduction ..........................................................................................................................................................166 
Study Objectives and Endpoints ..........................................................................................................................167 
Study Objectives ..............................................................................................................................................167 
Primary Objective ............................................................................................................................................167 
Secondary Objectives ......................................................................................................................................167 
Study Endpoints ...............................................................................................................................................167 
Primary ............................................................................................................................................................167 
Secondary ........................................................................................................................................................167 
Statistical Hypotheses ..........................................................................................................................................167 
Study Design ........................................................................................................................................................168 
Planned Analyses .................................................................................................................................................169 
Interim Analyses ..............................................................................................................................................169 
Final Analysis ..................................................................................................................................................169 
Sample size consideration ....................................................................................................................................169 
Populations for analysis .......................................................................................................................................169 
Subgroup analyses................................................................................................................................................169 
Data handling conventions and missing data .......................................................................................................169 
Protocol deviations ...............................................................................................................................................170 
Demographics and other baseline characteristics .................................................................................................171 
Efficacy analysis ..................................................................................................................................................171 
Safety analysis......................................................................................................................................................175 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 165 of 176 
 
 
 
Signatures 
The following persons have read and agreed on the SAP: 
 
Jan Hattendorf                    
Trial Statistician 
Date of signature 14.9.2020    
 
Jennifer Keiser                    
Principal investigator 
Date of signature 14.9.2020    
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 166 of 176 
 
 
 
Introduction 
This Statistical Analysis Plan (SAP) is based on the current trial protocols versions v1.01_19.09.2018 (Lao 
PDR), v1.03_22.11.2018 (Côte d'Ivoire) and v1.01_13.2.18_(Zanzibar). 
Where statistical methods differ substantially between this SAP and the protocol, the differences will be 
identified in the SAP.  
This SAP describes the datasets and the statistical methods to be used for the reporting and analysis of all data 
collected 3 weeks after treatment in three randomized controlled trials. If a future protocol amendment 
necessitates a substantial change to the statistical analysis of the trial data, this SAP will be amended 
accordingly.  
If, after database lock, deviations or additional analyses are required to supplement the planned analyses 
described in this SAP, those will not be described in an amended SAP, but they will be identified in the related 
publication.  
This SAP has been written in consideration of the following guidelines:   
 
International Conference on Harmonization (ICH) E9, Guidance for Industry: Statistical Principles for 
Clinical Trials (ICH E9 1998)1 
 
ICH E3, Guidance for Industry: Structure and Content of Clinical Study Reports (ICH E3 1995) 
Statistical analysis will be done using R 5.3.1 on a Windows 64 bit system. 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 167 of 176 
 
 
 
Study Objectives and Endpoints 
Study Objectives 
Primary Objective 
To assess the efficacy and safety of standard doses of co-administered ivermectin (200 µg/kg) and albendazole 
(400 mg) against Trichuris trichiura compared to albendazole (400 mg) alone in community members aged 6-60 
years. 
Secondary Objectives 
To evaluate the safety and tolerability of the treatment regimens  
To compare the egg reduction rate (ERR) of the treatment regimens against T. trichiura 
To determine the CRs and ERRs of the drugs in study participants (6-60 years) infected with hookworm, Ascaris 
lumbricoides and Strongyloides stercoralis 
 
Study Endpoints  
Primary 
T. trichiura cure rate (CR) defined as infection status assessed by Kato-Katz 14-21 days after treatment 
expressed as cure rate, i.e. conversion from being egg positive pre-treatment to egg negative post-treatment. 
Secondary 
ERR against T. trichiura  
CRs and ERRs against A. lumbricoides, hookworm and S. stercoralis 
Adverse events 
Infection status assessed by PCR  
Safety 
 
Statistical Hypotheses  
Primary hypothesis: albendazole-ivermectin has a higher efficacy against T. trichiura infections compared to 
albendazole alone. 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 168 of 176 
 
 
 
Study Design 
This is a multi-center, blinded, randomised, SoC-controlled, parallel-group, single-dose, superiority trial. 
Participants in the albendazole monotherapy arm will receive a matching ivermectin placebo. Double blinded 
(study participants, trial team/researchers conducting the treatment and outcome assessors) using repacked 
tablets including appearance-matched placebos. Computer-generated stratified block randomization code. The 
random allocation sequence with varying random blocks of four or eight and stratified by 2 levels of baseline 
infection intensity. Tablets together with the respective treatment arm label were pre-packed by researchers not 
involved in this trial into small opaque envelopes labelled with the unique IDs to ensure allocation concealment. 
 
Time and Events Table 
 
Screening 
Baseline/Treatment/Safety 
Follow up 
 
-21 to -1 
days 
Hours 
Days 
 
0 
Randomization and treatment 
3 
24 
21 
180a 
185a 
360a 
Diagnosis (stool and urine 
examination) 
X 
 
 
 
X 
X 
Selective re-treatment 
X 
Gut morbidity (stool 
RDTs) 
X 
 
 
 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Clinical examination 
 
X 
 
 
 
X 
X 
Pregnancy testing 
 
X 
 
 
 
X 
 
Hemoglobin measurement 
 
X 
 
 
 
X 
X 
Plasmodium co-infection 
 
X 
 
 
 
X 
X 
Venous blood examination 
 
X 
 
 
X 
X 
X 
Physical functioning 
 
X 
 
 
 
X 
X 
Capturing AEs 
 
 
X 
X 
X 
 
 
Capturing SAE 
 
 
X 
X 
X 
 
 
Treatment satisfaction 
 
 
 
X 
 
X 
X 
 
 
a not subject of this SAP 
 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 169 of 176 
 
 
 
Planned Analyses 
Interim Analyses 
Because of the short follow-up period, no interim analyses are planned.  
Final Analysis 
The database will be locked after all subjects have completed the study and the data have been entered, validated 
and all queries are resolved.  
 
Sample size consideration 
Each of the three trials was powered to detect a difference with 90% power at a two-sided 5% significance level 
assuming a CR of albendazole against T. trichiura is 30% and 50% in the albendazole-ivermectin treatment 
regimen. We anticipate to enrol 143 participants per study arm (including a potential loss to follow-up of 15%). 
For sub group analysis the data from all trials will be pooled to ensure sufficient power. Further details on the 
justification of study subjects are provided in the trial protocols. 
 
Populations for analysis 
Available case population: All participants randomized, excl. those who entered the study even though they did 
not satisfy the entry criterion 'positive at baseline' with at least one non-missing endpoint data. 
Per protocol population: All participants who meet all inclusion and exclusion criteria, have no major protocol 
deviations and received the correct treatment. 
Intention to treat population: All participants randomized, excl. those who entered the study even though they 
did not satisfy the entry criterion 'positive at baseline' 
Safety population: All subjects who received at least one dose of treatment with at least one non-missing safety 
endpoint with no major protocol deviations. 
Efficacy endpoints will be analysed using the available case population according to the ITT principles. The 
primary analysis will be confirmed using the per-protocol population. Safety endpoints will be analysed using 
the safety population as treated. 
 
Subgroup analyses 
The following pre-specified sub group analyses will be conducted:  
 
by age category (6-12 years vs. 13+ years) 
 
by baseline infection intensity (light vs moderate & heavy) 
For sub group analyses the data from all trials will be pooled to ensure sufficient power. 
 
Data handling conventions and missing data 
All subjects who withdraw prematurely from the study or study drug will be included in the statistical analyses. 
Experience from previous trials indicated that the proportion of missing data is usually below 10%; therefore, no 
imputation of missing data is planned. In case the proportion of missing data will be considerably higher than 
expected the primary analysis using the available case population will be complemented by an analysis using the 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 170 of 176 
 
 
 
intention-to-treat population. For this purpose missing data will be imputed by multiple imputations as 
implemented in R's 'mi' package.  
 
Protocol deviations 
Before closing the database, data listings will be reviewed to identify any significant deviations and determine 
whether the data should be excluded from any analysis populations. 
Protocol deviations leading to exclusion from all analyses populations 
 
Participants who were negative for T. trichuria infection at baseline. 
Major protocol deviations include subjects who: 
• Entered the study even though they did not satisfy other entry criteria. 
• Met the criteria for withdrawal from the study but were not withdrawn. 
• Received no treatment, the wrong treatment or incorrect dose. 
• Received an excluded concomitant therapy. 
Minor protocol deviations include subjects who: 
• Provided fewer stool samples than specified in the protocol 
• Provided stool samples later than specified in the protocol (measurements taken outside the allowable 
windows given in the protocol) 
• Vomiting within 1-hour post-dosing without re-treatment. 
Participants with major protocol deviations will be excluded from the per-protocol population. Minor protocol 
deviations will remain in all analysis populations. 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 171 of 176 
 
 
 
Demographics and other baseline characteristics 
Baseline characteristics will be calculated and presented as outlined below 
Pemba Island 
Côte d'Ivoire 
Lao PDR 
Characteristics 
ALB 
(n=xxx) 
IVM-ALB 
(n=xxx) 
ALB 
(n=xxx) 
IVM-
ALB 
(n=xxx) 
ALB 
(n=xxx) 
IVM-
ALB 
(n=xxx) 
Age, 6-12 
Age, 13-24yrs 
Age, 25 years and above  
Sex, n (%) 
Females 
 
Males 
 
 
 
 
 
 
Weight, kg  
Height, cm 
T. trichiura infection 
 
 
 
 
 
 
Geometric mean EPG 
Infection intensitya, n (%) 
 
 
Light 
 
 
 
 
 
 
Moderate 
Heavy 
A. lumbricoides infection 
 
Infected, n (%) 
 
 
 
 
 
 
 
Geometric mean EPG 
 
 
 
 
 
 
Infection intensityb, n (%) 
Light 
Moderate 
Heavy 
Hookworm infection 
 
Infected, no. (%) 
 
 
 
 
 
 
 
Geometric mean EPG 
 
 
 
 
 
 
Infection intensityc, n (%) 
Light 
 
 
Moderate 
 
 
 
 
 
 
 
 
Heavy 
 
 
 
 
 
 
S. stercoralis infectiond 
Infected, n (%) 
a T. trichiura infection intensity classified according to mean eggs per gram of stool (EPG) into: light=1-999 
EPG, moderate=1000-9999 EPG and heavy=≥10000 EPG 
b A. lumbricoides infection intensity classified according to mean eggs per gram of stool (EPG) into: light=1-
4999 EPG, moderate=5000-49999 EPG and heavy=≥50000 EPG 
c Hookworm infection intensity classified according to mean eggs per gram of stool (EPG) into: light=1-1999 
EPG, moderate=2000-3999 EPG and heavy=≥4000 EPG 
d Baermann technique to detect S. stercoralis infection was only applied to stool samples collected in Lao PDR 
 
 
Efficacy analysis 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 172 of 176 
 
 
 
In the unadjusted analysis the differences in cure rates will be assessed using a Melded Binomial Confidence 
Intervals and Tests with mid-p correction as implemented in the 'exact2x2' package. 
library(exact2x2) 
binomMeld.test( ... ,   # insert n[pos] and n[total] 
    parmtype = "difference", conf.level = 0.95, conf.int = TRUE,  
    alternative = "two.sided", midp = T) 
 
This analysis has been chosen because most biomedical journals prefer the absolute difference over the relative 
difference. However, adjustment for confounder or effect modifier is not possible; therefore, the adjusted 
analysis will use standard logistic regression.  
Egg reduction rates (geometric mean based) will be calculated using the following formula  
𝐸𝑅𝑅=  1 − 
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑓𝑜𝑙𝑙𝑜𝑤−𝑢𝑝 + 1) −1
1
𝑛 𝑒 ∑log(𝐸𝑃𝐺𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 1)      −1  
Differences in geometric mean based ERR will be analysed via bootstrap resampling using the following code 
# 1st column in data 'd' = baseline, 2nd = follow-up, arm = 'arm'  
# Egg reduction rates geometric mean 
ERRgm <- function(d, i) { 
return(1-(exp(sum(log(d[i ,2]+1))/length(d[i ,2]))-1)/ 
(exp(sum(log(d[i ,1]+1))/length(d[i ,1]))-1)) 
} 
 
# Difference Egg reduction rates geometric mean 
diffgm <- function(d,i) { 
d <- d[i,] 
gmbl <- tapply(X=d[,1], INDEX=d$arm, gm) 
gmfu <- tapply(X=d[,2], INDEX=d$arm, gm) 
Diff <- (1-(gmfu[1]/gmbl[1])) - (1-(gmfu[2]/gmbl[2])) 
return(Diff) 
}  
 
library(boot)   
difgm <- boot(data = d, statistic = diffgm, R = 2000, strata = d$arm) 
 
The arithmetic based ERR will be estimated in the same way. 
If the sample size of study participants infected with hookworm, Ascaris lumbricoides and Strongyloides 
stercoralis is considered sufficiently large, efficacy against these parasites will be assessed in the same way. If 
the number of participants will be below 100 per arm the trial arms will only be compared descriptively.  
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 173 of 176 
 
 
 
Efficacy results and estimates will be presented as outlined below  
 
 
Pemba Island 
Côte d'Ivoire 
Lao PDR 
Total 
Variable 
ALB 
(n=xxx) 
IVM-
ALB 
(n=xxx) 
ALB 
(n=xxx) 
IVM-
ALB 
(n=xxx) 
ALB 
(n=xxx) 
IVM-
ALB 
(n=xxx) 
ALB 
(n=xxx) 
IVM-
ALB 
(n=xxx) 
T. trichiura 
No. of participants positive for 
infection 
Before 
treatment  
 
After treatment 
 
 
 
 
 
 
 
 
Cure rate, % (95% CI) 
 
 
 
 
 
 
 
 
No. of participants cured n (%) 
 
 
 
 
 
 
 
 
From light 
infection 
 
 
 
 
 
 
 
 
From moderate 
infection  
From heavy 
infection 
Geometric mean EPG 
Before 
treatment 
After treatment 
GM Egg-reduction rate, 
% (95% CI) 
 
 
 
 
 
 
 
 
Arithmetic mean EPG 
Before 
treatment 
After treatment 
AM Egg-reduction rate, 
% (95% CI) 
A. lumbricoides 
 
 
 
 
 
 
 
 
N participants positive 
Before 
treatment  
 
After treatment 
 
 
 
 
 
 
 
 
Cure rate, % 
N participants cured (%) 
From light 
infection 
From moderate 
infection  
From heavy 
infection 
Geometric mean EPG 
 
 
 
 
 
 
 
 
Before 
treatment 
After treatment 
Egg-reduction rate, % 
Hookworm 
N participants positive 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 174 of 176 
 
 
 
Before 
treatment  
After treatment 
Cure rate, %  
N participants cured (%) 
 
 
 
 
 
 
 
 
 
From light 
infection 
 
 
 
 
 
 
 
 
 
From moderate 
infection  
 
 
 
 
 
 
 
 
 
From heavy 
infection 
 
 
 
 
 
 
 
 
Geometric mean EPG 
 
 
 
 
 
 
 
 
 
Before 
treatment 
 
 
 
 
 
 
 
 
After treatment 
Egg-reduction rate, % 
S. stercoralisa 
 
 
 
 
 
 
 
 
No. of participants positive for 
infection 
Before 
treatment  
After treatment 
Cure rate, % 
 
EPG: eggs per gram of stool 
a S. stercoralis infection was assessed qualitatively only (positive vs negative) in stool samples collected in Lao 
PDR 
 
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 175 of 176 
 
 
 
Safety analysis 
Adverse events will be analysed descriptively and summarized (for each country) as outlined in the 2 tables 
below. 
Table: Adverse events assessed at baseline, 3 hours and 24 hours post treatment by treatment arm 
  
Before treatment 
3h post treatment 
24h post treatment 
After 24h 
ALB 
  
  
  
  
Total participants assessed 
Participants with AE 
% participants with AE 
Number of AEs 
IVM-ALB 
  
  
  
  
Total participants assessed 
Participants with AE 
% participants with AE 
Number of AEs 
TOTAL 
  
  
  
  
Total participants assessed 
Participants with AE 
% participants with AE 
Number of AEs 
  
  
  
  
 


Study protocols and SAP: Efficacy and safety of co-administered ivermectin and albendazole against T. trichiura    
 
 
 
Page 176 of 176 
 
 
 
 Table: Specific adverse events by treatment arm and time point 
 
 
 
Baseline 
3h post-treatment 
24h post-treatment 
 
ALB 
IVM-
ALB 
TOTA
L 
ALB 
IVM-
ALB 
TOTAL 
ALB 
IVM-
ALB 
TOTAL 
Adver
se 
event 
N, 
A
ny 
gr
ad
e 
N, 
Gr
ad
e 
≥2 
N, 
A
ny 
gr
ad
e 
N, 
Gr
ad
e 
≥2 
N, 
A
ny 
gr
ad
e 
N, 
Gr
ad
e 
≥2 
N, 
A
ny 
gr
ad
e 
N, 
Gr
ad
e 
≥2 
N, 
A
ny 
gr
ad
e 
N, 
Gr
ad
e 
≥2 
N, 
An
y 
gr
ad
e 
N, 
Gr
ad
e 
≥2 
N, 
A
ny 
gr
ad
e 
N, 
Gr
ad
e 
≥2 
N, 
A
ny 
gr
ad
e 
N, 
Gr
ad
e 
≥2 
N, 
An
y 
gra
de 
N, 
Gr
ad
e 
≥2 
Heada
che 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdo
minal 
pain 
Itching 
Nause
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiti
ng 
Diarrh
ea 
Fever 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allergi
c 
reactio
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other