Clinical trial NCT04848688
Conditions: Strongyloides Stercoralis Infection
Sponsor: Jennifer Keiser
Start date: 2022-02-05; Completion date: 2022-07-17
Enrollment: 332 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is an extension to the study StrongMoxi NCT04056325 and entails modifications based on the outcome of NCT04056325 part A.

The study is a phase 3, double-blinded and randomized clinical trial conducted in Cambodia. It aims at providing evidence on efficacy, safety and pharmacokinetic measures of 8 mg of moxidectin compared to 200 μg/kg ivermectin in adults infected with S. stercoralis. The efficacy of the treatment will be assessed by collecting three stool samples once per-treatment and once 21-28 days post-treatment. The stool samples will be analyzed by a quantitative duplicate Baermann assay.

Detailed description:
The study is a phase 3 trial and will determine the efficacy and safety of:

8 mg of moxidectin in comparison to the standard treatment dose of ivermectin (200 μg/kg) in adults infected with S. stercoralis and to measure moxidectin disposition in adults using a microsampling device.

Our primary objective is to demonstrate non-inferiority in terms of cure rate (CR) against S. stercoralis in adults of an oral 8 mg of moxidectin compared to 200 μg/kg of ivermectin.

The secondary objectives of the trial are:

1. to evaluate the safety and tolerability of moxidectin
2. to compare the larval reduction rate (LRR) of the two different treatment groups against S. stercoralis
3. to evaluate the CRs of the different treatment drugs and regimens against soil-transmitted helminths (STH) co-infections.
4. to investigate potential extended effects on follow-up helminth prevalence at 42-49 and 63-70 days post-treatment
5. to relate socioeconomic characteristics (SES), access to sanitation, water facilities, hygiene to baseline infection intensity.
6. to determine the larval excretion pattern till day 70 in the moxidectin treatment arm, determined at every second day between day zero and 70 post-treatment in a subset of 50 adults.
7. to determine the origin of the remaining worm burden after treatment to treatment failure and reinfection based on genetic profiling.

Three stool samples will be collected at baseline analysed in duplicates by a quantitative Baermann method for S. stercoralis infection. Co-infection with other Helminths species will be identified using duplicate Kato-Katz thick smears on two stool samples. The medical history of the participants will be assessed with a standardized questionnaire, in addition to a clinical and physical examination carried out by the study physician shortly before the treatment day. Each participant will be asked to provide a finger-prick blood sample for haemoglobin measurements at baseline. Enrolled participants will be treated with either 8 mg of moxidectin or with the standard treatment ivermectin (200 μg/kg). The adults will be interviewed a) before treatment, 2-3 and 24 hours as well as 14-21, 42-49 and 63-70 days after treatment about the occurrence of adverse events. The efficacy of the treatment will be determined 14-21 days of post-treatment. All stool samples will be examined with quantitative sixtuplicate Baermann assays and quadruplet Kato-Katz thick smears. At 42-49 and 63-70 days post-treatment another three stool samples will be collected and quantified for S. stercoralis larvae using Baermann assay to assess potential long-term benefits of the study drugs and treatment regimen. Of 50 adults in the moxidectin arm only, additional stool samples will be collected every second day between treatment and 70 days post treatment to evaluate larval secretion patterns.

To all participating households, a brief questionnaire will be administered assessing information on socioeconomic characteristics (SES) and access to sanitation, water facilities, and hygiene behaviour.

An available case analysis (full analysis set according to the intention to treat principle) will be performed, including all participants with primary endpoint data.

CRs will be calculated as the percentage of larvae-positive subjects at baseline who become larvae-negative after treatment, assessed 14-21 days post-treatment by sextuplicate Baermann. Uncertainty estimates around the differences among CRs will be assessed using melded confidence intervals with mid-p correction. The non-inferiority.

Arms: arm 1: 8 mg Moxidectin at day 0 administered orally arm 2: 200 ug/kg Ivermectin at day 0 administered orally
Interventions: intervention 1: Moxidectin 2 mg intervention 2: Ivermectin 3 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Monotherapy, oral administration, single-dose, fixed-dose, 4 tablets of 2 mg each to yield an 8 mg final dose. intervention 2: Monotherapy, oral administration, single-dose, weight dependent, The number of tablets will be adjusted according to the patients' weight to yield 200 ug/kg final dose. intervention 3: Monotherapy, oral administration, single dose, matching number of tablets to either moxidectin or ivermectin

Protocol documents:
Prot_SAP_000.pdf: 
Efficacy and safety of moxidectin in comparison to ivermectin 
against Strongyloides stercoralis infection in adults: a randomized 
controlled non-inferiority trial 
 
NCT Number: NCT04848688 
 
Document date: 10 February 2022 


Page 1 of 38 
 
 
Study Protocol 
 
 
Efficacy and safety of moxidectin in comparison to ivermectin against 
Strongyloides stercoralis infection in adults: a randomized controlled non-
inferiority trial 
 
 
Protocol Number 
1 
Version Number 
V1.02 
Document Date 
10.02.2022 
Sponsor Contact 
Prof. Dr. Jennifer Keiser 
Swiss Tropical and Public Health Institute 
Tel.: +41 61 284 82 18 
Fax: +41 61 284 81 05 
E-mail: jennifer.keiser@unibas.ch 
Principal Investigator 
Prof. Dr. Jennifer Keiser 
Swiss Tropical and Public Health Institute 
Tel.: +41 61 284 82 18 
Fax: +41 61 284 81 05 
E-mail: jennifer.keiser@unibas.ch 
Funding Agency 
Swiss National Science Foundation (EU-Southeast Asia) 


Page 2 of 38 
 
1. General Information 
 
I. 
List of investigators and other persons involved 
 
Title 
Names 
Institution 
Position 
Function in trial 
Prof. Dr. 
Jennifer Keiser 
Swiss Tropical and 
Public Health 
Institute (Swiss 
TPH) 
Unit head 
Principal 
investigator 
Dr. 
Rekol Huy 
National Centre for 
Parasitology, 
Entomology and 
Malaria Control 
Phnom Penh, 
Cambodia 
Director 
Principal 
investigator 
Dr. 
Virak Khieu 
National Centre for 
Parasitology, 
Entomology and 
Malaria Control 
Phnom Penh, 
Cambodia 
Project 
leader, 
Physician 
Co-investigator, 
Physician 
MSc 
Viviane 
Sprecher 
Swiss Tropical and 
Public Health 
Institute 
PhD Student 
Co-investigator 
Dr. 
Jan Hattendorf 
 
Swiss Tropical and 
Public Health 
Institute 
Project 
leader, 
Postdoc 
Statistician 
 
 
 
 


Page 3 of 38 
 
 
II. 
Signatures 
 
Statistician 
Signature 
 
 
 
 
Date of Signature 
10.02.2022 
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, Kreuzstrasse 2, 
CH-4123 Allschwil, Switzerland 
Phone 
+41 61 284 81 93 
 
 
Principal investigator 
Signature 
 
Date of Signature 
10.02.2022 
Name  
Jennifer Keiser 
Title 
Prof. Dr. 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 
CH-4123 Allschwil, Switzerland 
Phone 
+41 61 284 82 18 
 
I have read this protocol and agree that it contains all necessary details for carrying out this 
trial. I will conduct the trial as outlined herein and will complete the trial within the time 
designated. I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this trial. I will discuss this material with them 
to ensure they are fully informed regarding the drug and the conduct of the trial. 
I will use only the informed consent forms approved by the Sponsor or its representative and 
will fulfill all responsibilities for submitting pertinent information to the Independent Ethics 
Committees responsible for this trial. I agree that the Sponsor or its representatives shall have 
access to any source documents from which Case Report Form information may have been 
generated. 
 


Page 4 of 38 
 
Co-investigator and Physician 
Signature 
 
Date of Signature 
10.02.2022 
Name  
Virak Khieu 
Title 
Dr. 
Institution 
National Centre for Parasitology, Entomology and Malaria Control 
Phnom Penh, Cambodia 
Address 
#477 Betong Street, Village Trapangsvay, Sanakat  Phnom Penh Thmey, Khan 
Sen Sok, Phnom Penh 
Phone 
+(855)-12 677 244 
 
 
Co-investigator 
Signature 
 
Date of Signature 
10.02.2022 
Name  
Rekol Huy 
Title 
Dr. 
Institution 
National Centre for Parasitology, Entomology and Malaria Control 
Phnom Penh, Cambodia 
Address 
#477 Betong Street, Village Trapangsvay, Sanakat  Phnom Penh Thmey, Khan 
Sen Sok, Phnom Penh 
Phone 
+(855)-12 829 481 
 
 
Co-investigator 
Signature 
 
Date of Signature 
10.02.2022 
Name  
Viviane Sprecher 
Title 
MSc 
Institution 
Swiss Tropical and Public Health Institute 
Address 
Department of Medical Parasitology and Infection Biology 
Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 
CH-4123 Allschwil, Switzerland 
Phone 
+41 61 284 82 86 
 
 
 


Page 5 of 38 
 
III. 
Table of contents 
 
1. General Information ........................................................................................................... 2 
2. Background information ....................................................................................................12 
3. Trial objective and purpose ...............................................................................................15 
4. Methodology .....................................................................................................................15 
4.1. Primary and secondary endpoint ................................................................................15 
4.2. Type of trial ................................................................................................................15 
4.3. Trial design ................................................................................................................15 
4.4. Measure to minimize bias ..........................................................................................19 
4.5. Study duration and duration of participation ...............................................................20 
4.6. Schedule of visits .......................................................................................................20 
5. Selection of the trial participants .......................................................................................21 
5.1. Recruitment ...............................................................................................................21 
5.2. Inclusion criteria .........................................................................................................21 
5.3. Exclusion criteria ........................................................................................................21 
5.4. Criteria for discontinuation of trial ...............................................................................22 
5.5. Treatment of participants ...........................................................................................22 
5.6. Concomitant therapy ..................................................................................................23 
6. Assessment of safety .......................................................................................................24 
6.1. Adverse event definition .............................................................................................24 
6.2. Methods of recording and assessing adverse events .................................................26 
6.3. Reporting of serious adverse events ..........................................................................27 
6.4. Safety reporting to Health Authorities and Ethics Committees ....................................27 
7. Data management and data quality control ......................................................................28 
7.1. Source data ...............................................................................................................28 
7.2. Data collection and documentation ............................................................................28 
7.3. Ethical, legal and security issues ...............................................................................29 
7.4. Data storage and preservation ...................................................................................30 
7.5. Definition of reference language – translation of study documents .............................30 


Page 6 of 38 
 
8. Statistics ...........................................................................................................................30 
8.1. Definition of primary endpoint .....................................................................................30 
8.2. Justification of number of trial participants ..................................................................31 
8.3. Description of statistical methods ...............................................................................31 
9. Duties of the investigator ..................................................................................................32 
9.1. Investigator’s confirmation .........................................................................................32 
9.2. Damage coverage ......................................................................................................32 
9.3. Project management ..................................................................................................32 
10. Ethical considerations .....................................................................................................33 
10.1. Independent Ethics Committee (IEC) .......................................................................33 
10.2. Evaluation of the risk-benefit ratio ............................................................................33 
10.3. Participant information and consent .........................................................................33 
10.4. Participant confidentiality .........................................................................................34 
10.5. Participants requiring particular protection ...............................................................34 
10.6. Other aspects...........................................................................................................34 
11. Quality control and quality assurance .............................................................................35 
11.1. Monitoring and auditing ............................................................................................35 
11.2. Data and safety monitoring board (WHO) / data monitoring committee (EU/FDA) ....35 
12. Dissemination of results and publication .........................................................................35 
13. References .....................................................................................................................36 
 


Page 7 of 38 
 
IV. 
Synopsis 
Study Title 
Efficacy and safety of moxidectin in comparison to ivermectin 
against Strongyloides stercoralis infection in adults: a randomized 
controlled non-inferiority trial 
Study Acronym 
StrongMoxi 
Study Type 
Phase 3 trial 
Sample size 
350 
Indication 
Strongyloides stercoralis infection 
Investigational Product 
and Reference 
Treatment 
Investigational product: moxidectin 
Reference treatment: ivermectin 
Protocol Number, Date 
and Version 
1, 10.02.2022, v1.02 
Trial registration 
Registered on https://www.clinicaltrials.gov/ (NCT04848688) 
Study Rationale 
To provide evidence on: 
 
Efficacy and safety of an 8 mg dose moxidectin compared to 200 
µg/kg dose ivermectin in adults against infection with S. 
stercoralis in Cambodia. 
Study Objectives 
To determine the efficacy and safety of: 
8 mg of moxidectin in comparison to the standard treatment dose 
of ivermectin (200 µg/kg) in adults infected with S. stercoralis. 
Our primary objective is to demonstrate non-inferiority in terms 
of CR against S. stercoralis in adults of an oral 8 mg of moxidectin 
compared to 200 µg/kg of ivermectin. 
The secondary objectives of the trial are:  
1) to evaluate the safety and tolerability of moxidectin 
2) to compare the larval reduction rate (LRR) of the two 
different treatments against S. stercoralis 
3) to evaluate the CRs of the different treatments against 
STH co-infections 
4) to investigate potential extended effects on follow-up 
helminth prevalence at 42-49 and 63-70 days post-
treatment 
5) to relate socioeconomic characteristics (SES), access to 
sanitation, water facilities, hygiene to baseline infection 
intensity 


Page 8 of 38 
 
6) to determine the larval excretion pattern until day 28, 
determined at every second day between day 0 and 28 
post-treatment in a subset of 50-100 adults 
7) to determine the origin of remaining worm burden after 
treatment to treatment failure and reinfection based on 
genetic profiling 
Study design 
Randomized controlled, double-blinded, 2-arm, parallel group, 
non-inferiority trial 
Study product / 
intervention 
Administration of an oral single-dose of moxidectin (8 mg), or an 
oral single-dose of ivermectin (200 µg/kg) 
Comparator(s) 
Ivermectin (200 µg/kg) 
Key inclusion / 
Exclusion criteria 
Inclusion: Adults (≥ 18-65 years) infected with S. stercoralis. 
Exclusion: 
Any 
abnormal 
medical 
conditions, 
negative 
diagnostic result for S. stercoralis, no written informed consent by 
individual. Pregnancy, lactating or planning to become pregnant 
within the next six months. 
Primary Endpoints 
CR against S. stercoralis at 14-21 days post-treatment derived 
from larvae per gram (LPG) assessed by quantitative sextuplet 
Baermann. 
Secondary Endpoints 
- 
LRRs against S. stercoralis assessed 14-21, 42-49 and 
63-70 days post- treatment by quantitative sextuplet 
Baermann or every second day between day 0 and day 
28 by quantitative duplicate Baermann (50-100 adults) 
- 
Adverse events 
- 
CRs against T. trichiura, A. lumbricoides, hookworms or 
Taenia ssp. assessed 14-21 days post-treatment by 
quadruple Kato-Katz 
- 
Genetic profiling of all S. stercoralis positive participants 
(first stool sample at each time point) 
Exploratory Endpoints 
None 
Interim Analyses 
None 
Study Duration 
12 months in total, 16 weeks per participant 
Schedule 
03/2022 of first-participant in (planned) 
02/2023 of last-participant out (planned) 
Measurements & 
procedures 
Three stool samples will be collected at baseline analysed in 
duplicates by a quantitative Baermann method for S. stercoralis 
infection. Co-infection with T. trichiura, A. lumbricoides, 
hookworm or Taenia ssp. will be identified using duplicate Kato-
Katz thick smears on two stool samples. The medical history of 


Page 9 of 38 
 
the participants will be assessed with a standardized 
questionnaire, in addition to a clinical and physical examination 
carried out by the study physician shortly before treatment day. 
Each participant will be asked to provide a finger-prick blood 
sample for haemoglobin measurements at baseline. Enrolled 
participants will be treated with either 8 mg of moxidectin or with 
the standard treatment ivermectin (200 µg/kg). 
The adults will be interviewed a) before treatment, 3 and 24 hours 
as well as 14-21, 42-49 and 63-70 days after treatment about the 
occurrence of adverse events. The efficacy of the treatment will 
be determined 14-21 days post-treatment. All stool samples will 
be examined with quantitative sextuplet Baermann assays and 
quadruplet Kato-Katz thick smears. 
At 42-49 and 63-70 days post-treatment another three stool 
samples will be collected and quantified for S. stercoralis larvae 
using Baermann assay to assess potential long-term benefits of 
the study drugs and treatment regimen. From all positive S. 
stercoralis cases, the larvae will be stored in 70% ethanol and 
shipped to Australia for sequencing. Of 50-100 adults  additional 
stool samples will be collected every second day between 
treatment and 28 dayspost-treatment to evaluate larval secretion 
patterns. 
To all participating households, a brief questionnaire will be 
administered 
assessing 
information 
on 
socioeconomic 
characteristics (SES) and access to sanitation, water facilities, 
and hygiene behaviour. 
Statistical Analyses 
An available case analysis (full analysis set according to the 
intention to treat principle) will be performed, including all 
participants with primary endpoint data. Supplementary, a per-
protocol analysis will be conducted. 
CRs will be calculated as the percentage of larvae-positive 
participants at baseline who become larvae-negative after 
treatment, assessed 14-21 days post-treatment by sextuplicate 
Baermann. Uncertainty estimates around the differences among 
CRs will be assessed using melded confidence intervals with mid-
p correction. The non-inferiority margin is set to a 10%-points 
absolute difference in CR. 
CRs of coinfections will be calculated as the percentage of egg-
positive participant at baseline who become egg-negative after 
treatment, assessed 14-21 days post-treatment with quadruple 
Kato Katz assays. 
LPG will be assessed by calculating the mean of the larvae counts 
from the Baermann assays and divided by the mean weighted 
amount of these stool samples. The LRR will be calculated 
following: (LRR = (1-(LPG at follow-up/LPG at baseline))*100). 
Geometric and arithmetic mean larvae counts will be calculated 
for the different treatment arms before and after treatment to 


Page 10 of 38 
 
assess the corresponding LRRs. Bootstrap resampling method 
with 5,000 replicates will be used to calculate 95% confidence 
intervals (CIs) for LRRs and differences between LRRs. 
Adverse events and efficacy outcomes stratified by infection 
intensities will be compiled into frequency tables and compared 
between treatment groups using descriptive summaries. 
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. 
Recruitment procedure The trial will be conducted in Cambodia in adults aged 18-65. It 
will take place in areas with moderate to high infection risk in 
Kampong Chhnang province (prevalence: approx. 41.5%, 
identified from earlier studies and/or based on experience of the 
local collaborating teams). 
Coverage of damages 
Policy No: D/001/CPID/21/000002 
Storage of data and 
samples 
for 
future 
research aims 
After the study has been completed, all samples will be destroyed 
and case report forms, informed consents, source data and trial 
master file 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. 


Page 11 of 38 
 
Abbreviations 
 
AE 
Adverse event 
CI 
Confidence interval 
CR 
Cure rate 
CRF 
Case report form 
DALYs 
Disability-adjusted life years 
DF 
Dose finding 
DSMB 
Data and safety monitoring board 
EKNZ 
Ethikkommission Nordwest- und Zentralschweiz 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
Hb 
Haemoglobin 
ICH 
International council for harmonization of technical requirements for 
pharmaceuticals for human use 
IEC 
Independent ethics committee 
LPG 
Larvae per gram 
LRR 
Larvae reduction rate 
NTD 
Neglected tropical disease 
PI 
Principal investigator 
RDT 
Rapid diagnosis test 
SAE 
Serious adverse event 
STH 
Soil-transmitted helminths 
WHO 
World Health Organization 


Page 12 of 38 
 
2. Background information 
Over the last decades, increasing evidence has linked major neglected tropical diseases 
(NTDs) to significant adverse impacts on human and economic development. NTDs affect 
more than one billion people globally, in particular poor, and marginalized tropical populations, 
and contribute to an estimated 3.3 million disability-adjusted life years (DALY) lost globally. 
NTDs also include soil-transmitted helminthiasis such as strongyloidiasis, which is the target 
of this clinical study [1]. 
Strongyloides stercoralis is a soil-transmitted nematode belonging to the most neglected 
infections among the NTDs and found almost worldwide, though with largest prevalence in 
tropical and subtropical regions, as an example Cambodia [2-4]. 
Infectious larvae are found in humid soil that is contaminated with faeces. Upon penetration of 
the intact skin of their host, S. stercoralis can reproduce within their human host. This 
endogenous autoinfection may result in long-lasting infections, which is not seen in other soil-
transmitted helminth (STH) infections. Furthermore, S. stercoralis is known for its unique and 
threatening feature to cause systemic infection, which can persist for a lifetime, if appropriate 
therapy is not administered. S. stercoralis infections are typically most intense and debilitating 
in adults causing significant morbidity [6-8]. However, most infections, particularly chronic low-
intensity infections remain non-specific and might be expressed as suffering from malnutrition, 
physical and cognitive retardation, and reduced work performance [5]. 
Chemotherapy combined with health education and water, sanitation and hygiene (WASH) 
programs remain the core to reduce the serious health impacts. The currently advocated 
treatments by the World Health Organization (WHO) are a single dose of ivermectin or multiple 
doses of albendazole, while albendazole is less efficacious compared to ivermectin [9, 10]. 
Since drug pressure is high and resistance is a threat it is of uttermost importance to develop 
new treatment alternatives. Among new candidates in the human anthelminthic drug 
development pipeline, moxidectin, a macrocyclic lactone might be a promising alternative. 
Moxidectin has been recently approved by the Food and Drug Administration (FDA) for use 
against onchocerciasis (http://www.who.int/tdr/news/2018/moxidectin-approved-as-treatment-
for-river-blindness/en/) [11]. Moxidectin offers some advantages over ivermectin. First of all, 
moxidectin is used weight independent (for onchocerciasis at an 8 mg fixed dose), which 
renders the administration easier to handle, especially when treating large communities. 
Second, moxidectin has been shown to have a lower neurotoxic potential than ivermectin [12]. 
Thirdly, the pharmacokinetic profile of moxidectin in healthy individuals (very long t1/2, and a 
large Vd/F, compared to ivermectin) arises prospects for efficacy also against long-term 
parasitic activity – as is particularly important when treatment of S. stercoralis is desired [13]. 


Page 13 of 38 
 
Finally, most importantly moxidectin has been successfully used in veterinary medicine against 
certain ivermectin-resistant strains [14]. 
Moxidectin was evaluated as an extremely safe drug. A single-dose of 36 mg moxidectin in 
healthy adults was the highest dose tested to date that still represented a well-tolerated dose 
[13]. The 1 x 8 mg, therefore, selected, as the highest dose in our study will not pose any health 
risk. Most common side effects include hypotension, itching, headache, abdominal pain, fever, 
dizziness or diarrhea. Serious or even fatal encephalopathy may occur in patients co-infected 
with Loa Loa. Furthermore, moxidectin is known to worsen onchodermatitis in patients with 
hyperactive onchodermatitits. Cambodia is not endemic neither for Loa Loa nor 
onchodermatitits and thus these symptomatic advents shall not constitute a risk in our study. 
Nevertheless, patients with symptoms for onchodermatitits will be excluded from the study. 
Additionally, although conclusive teratogenic data on moxidectin are missing, decreased fetal 
survival and increased fetal born with malfunctions is observed in some animals studies. Thus, 
pregnant patients as well as females planning to become pregnant within the next six months 
will strictly be excluded. Last, owing to the lipophilic nature of moxidectin, extraction of 
moxidectin to the breast milk of nursing mothers is very likely and could be demonstrated in 
lactating cows [15]. The risk of moxidectin in nursing infants is though unknown, thus 
breastfeeding females will also be excluded in this study. 
In a small exploratory study using the veterinary formulation, a single-dose of 8 mg of 
moxidectin, and a small sample size (127 participants) moxidectin has been found to be 
efficacious against S. stercoralis (cure rates of 93.7%) and well tolerated in participants [16]. 
The follow-up phase 2a, randomized, placebo-controlled, dose-escalation trial conducted this 
year in northern Lao PDR evaluated the efficacy and safety of 2 mg to 12 mg of the human 
formulation of moxidectin in 209 participants. All tested moxidectin doses showed a promising 
tolerability with no safety concerns. 4-12 mg of moxidectin displayed a good efficacy profile in 
the treatment against S. stercoralis infections in adults (CR of 83.1%-88.3%). Since the 8 mg 
dose (CR of 87.0%; 95% CI: 79.8-91.9) is used for onchocerciasis and currently evaluated for 
other helminth infections this dose was recommended to take forward in phase 2b and phase 
3 trials. 
In this trial, we will test for non-inferiority of the recommended 8 mg of moxidectin against the 
standard dose of 200 µg/kg ivermectin. 
Moreover, there is a need to explore whether the longer half-life of moxidectin (T1/2: 491-832 
h) compared to ivermectin (T1/2: 16-32 h) could reveal a benefit in the treatment of S. stercoralis 
infections [13, 22]. Potential extended effects will be examined through a prolonged efficacy, 
safety and tolerability assessment scheme. Thus, additional follow-ups (besides the standard 
14-21 days) will be conducted, namely 42-49 days post-treatment in correlation to the duration 


Page 14 of 38 
 
of an autoinfection cycle and 63-70 days post-treatment analogous to a second auto-infection 
cycle as well as the elimination time of moxidectin from blood [13, 23]. 
Besides the study will be complemented by displaying larval excretion pattern over the whole 
time course after treatment until 28 days post-treatment and guide more appropriate follow-up 
periods. The appropriate follow-up time points are today not evaluated for infections with S. 
stercoralis. 
Last, strongyloidiasis cannot solely be fought with chemotherapy, yet there is a need for 
multifaceted approaches including environmental and behavioral adaptation to attain disease 
control and elimination [30]. This study will be complemented by assessing socioeconomic 
characteristics, access to sanitation and water facilities as well as hygiene to identify 
influencing factors with regard to infection intensity and reinfection [30, 31]. 
Ultimately, results from this trial will inform decision on how moxidectin could be used to treat 
strongyloidiasis on a patient level and evidence will be strengthened to include moxidectin in 
the drug armamentarium for future community-wide chemotherapy. 
 
 


Page 15 of 38 
 
3. Trial objective and purpose 
The primary study objectives are  
To determine if the efficacy in terms of cure rate of an oral 8 mg of moxidectin is non-inferior 
to the standard dose of a single oral ivermectin application (200 µg/kg), in 350 S. stercoralis-
infected adults in Cambodia. 
 
The secondary study objectives are 
1.) to determine safety and tolerability of an oral moxidectin dose in 175 adults infected with 
S. stercoralis. 
2.) to compare the efficacy based on larvae reduction rates of the different treatments drugs 
and regimens in 350 adults infected with S. stercoralis. 
3.) to evaluate the CRs of the different treatments against STH co-infections. 
4.) to investigate potential extended effects on follow-up helminths prevalence of the different 
treatment drugs and regimens around 42-49 and 63-70 days post-treatment. 
5.) to relate socioeconomic status (possession of indicator assets), access to sanitation, water 
facilities and hygiene to baseline infection intensity. 
6.) to assess the larval excretion pattern of S. stercoralis after treatment with moxidectin up to 
28 days post-treatment. 
7.) to assess the origin of the larvae positive stool samples by genetic profiling. 
 
4. Methodology 
4.1. Primary and secondary endpoint 
CR is the primary endpoint. In addition, LRR will be determined and safety and tolerability of 
treatment evaluated (secondary endpoints). CRs against co-infections are considered as 
exploratory endpoints. 
4.2. Type of trial 
Double-blinded, randomized controlled parallel group trial (non-inferiority between 8 mg of 
moxidectin versus ivermectin, 200 µg/kg) with masked primary outcome assessors. 
4.3. Trial design 
A randomized trial will be conducted with two treatment arms to be followed-up over a 14-21 
follow-up period with additional assessments at 42-49 and 63-70 days after treatment. The trial 


Page 16 of 38 
 
will test for non-inferiority of a 8 mg dose of moxidectin versus ivermectin 200 µg/kg with a 
margin of 10%-points. 
 
The study cohorts are presented in the figure below: 
 
 
Figure 1. Design and timeline of the non-inferiority trial to be implemented. A loss to follow-up of 10% is assumed. 
 
 
 


Page 17 of 38 
 
4.3.1. Diagnosis 
At baseline, all participants will be asked to provide three stool samples. The stool samples 
will be collected until a total of approximately 400 S. stercoralis-infected adults are registered, 
which assumes a lost to follow-up of 10%. As diagnosing very low-intensity chronic infections 
remains a major challenge for quantitative and qualitative analysis for S. stercoralis, Baermann 
assays will be done in duplicates and the average over three stool samples will be taken for 
analysis [36, 37]. 
To this end, a quantitative Baermann funnel concentration technique will be used for the 
quantitative assessment of S. stercoralis infections [37-39] using stool samples from three 
different days. The stool samples will be warmed in a water bath to 36°C. A 5 g stool sample 
will be placed on gauze inserted into a glass funnel and covered with temperature 36°C water. 
Following two hours of artificial light exposure, the collected liquid will be centrifuged and the 
sediment prepared for analysis by microscope [40, 41]. 
Moreover, from the first two stool samples from each participant a duplicate Kato-Katz thick 
smear will be prepared to detect co-infections with any of the three major STHs, namely A. 
lumbricoides, T. trichiura and the hookworms as well as Taenia ssp. [42]. In case we identify 
positive Taenia ssp. cases stool samples will be used for the further development of new 
diagnostic tools. 
The slides from the Baermann and Kato-Katz thick smears will be analyzed under a 
microscope by experienced technicians and a subsequent independent quality control of 
sample results (approximately 10%) will be conducted. S. stercoralis larvae will be counted 
quantitatively. Co-infections with STH eggs will be recorded qualitatively for the different 
species and assigned as egg positive or negative. Results are considered correct if the 
following tolerance margin is not exceeded: (i) No difference in presence/absence of each 
species separately for counts ≥1 egg/larvae, (ii) larvae counts are +/-10% larvae for counts 
≤100 larvae or +/-20% for counts >100 larvae [43]. In case discrepancies above the tolerance 
margin are noted, 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 larvae count per gram of stool will 
be calculated. All microscopically analyzed Baermann samples as well as the Kato-Katz thick 
smears will be destroyed after passing the quality control. 
The same sampling procedure and diagnostic approach will be applied at the defined follow-
up time points. 
 
 


Page 18 of 38 
 
4.3.2. Clinical examination 
A clinical examination of the study participants assessing general health, anthropometric 
parameters including height and weight as well as frontal temperature using an frontal no-
touch thermometer will precede the treatment. Each participant will be asked to provide a 
finger-prick blood sample for haemoglobin (Hb) levels, which will be detected using a 
HemoCue analyzer (Hb 301 system, Angelholm, Sweden). To avoid accidental treatment of 
pregnant women all female participants will be asked to provide a urine sample to be subjected 
to a pregnancy rapid diagnostic test at baseline. Women will be strongly advised to avoid 
becoming pregnant during the entire study period. All trial participants will further be asked 
about existing clinical symptoms before drug administration. 
 
4.3.3. Adverse effects assessment  
Participants will be kept for 3 hours after treatment administration to observe any possible 
acute adverse events (AEs) and re-assessment will be done at 24 hours post-treatment. 
Additionally, interviews will be conducted to determine the emergence of clinical symptoms 
such as headache, abdominal pain, itching, nausea, vomiting and diarrhea directly before 
treatment within the scope of baseline assessment. At 3 and 24 hours after treatment and 
retrospectively at days 14-21, 42-49 and 63-70 days post-treatment, participants will again be 
interviewed for the assessment of adverse events. Symptoms arising within the time span of 
14 days after treatment and the respective follow-up time points will be monitored actively by 
local health workers who will report incidences to the study team. Any symptoms will be 
recorded in the case report form (CRF) and immediate action will be pursued if indicated. 
 
4.3.4. Assessment of efficacy after treatment 
The efficacy of the treatment will be determined 14-21 days post-treatment by collecting 
another three stool samples. Stool samples will be microscopically examined for S. stercoralis 
applying each duplicate Baermann technique as well also for potential co-infection with A. 
lumbricoides, T. trichiura, hookworm and Taenia ssp. eggs using each duplicate Kato-Katz 
thick smears on the first two stool samples. The efficacy of the moxidectin and ivermectin will 
further be assessed 42-49 days after treatment and 63-70 days after treatment by duplicate 
Baermann technique. 
Participants will be considered S. stercoralis cured if no larvae have been found in any of the 
stool samples. Infection is calculated as larvae per gram stool (LPG). LPG will be assessed by 
calculating the mean of the larvae counts from the corresponding multiple Baermann assays  
and adjusted to the previously weighted used amount of stool sample. At the end of the study 
(day 70) all participants remaining positive for S. stercoralis will be treated with ivermectin (200 


Page 19 of 38 
 
µg/kg), the current standard drug against S. stercoralis [9]. Study participants positive for co-
infection will be treated with the currently and locally standard treatment option. 
 
4.3.5. Household Questionnaire 
A household-based questionnaire will be administered to one member of each participating 
household to adjust for known influencing factors with regard to re-infection and infection 
intensity [30, 31] in the subsequent analysis and to identify risk factors for residual infections 
[44]. The questionnaire will assess information on socioeconomic characteristics (e.g condition 
and amenities), access to sanitation and water facilities (e.g. latrine, toilet, shower, water 
source) as well as hygiene behavior (e.g. defecation, hand washing, water use). The 
questionnaire is based on the core questions recommended by WHO and UNICEF. 
 
4.3.7 Daily stool sampling 
Larval excretion pattern is determined from 50-100 participants. Stool will be collected of these 
participants every day after treatment administration until day 28. 
 
4.3.8 Genetic Profiling 
From all S. stercoralis positive participants, the extracted larvae will be stored in 70% Ethanol 
after examination by Baermann at each analysis time point (baseline, follow-up 1, 2 and 3). 
Samples will be shipped to the investigating laboratory (La Trobe University) at room 
temperature. 
 
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 4 and 6 will be provided by a statistician not involved 
in enrolment, treatment, and data collection. Separate sequences will be generated for three 
levels of baseline infection intensity (light ≤1 LPG, moderate >1-10 LPG and heavy >10 LPG). 
The codes will be held at the Swiss Tropical and Public Health Institute. A copy of this code 
will be kept in a sealed envelope by one of the co-investigators and will only be opened in 
emergency situations, determined by the principal investigator (PI) upon consultation with the 
co-investigators (co-PI). Allocation concealment will be maintained by masking the 
randomization sequence from the team member conducting the recruitment. Participants are 
blinded towards the study drugs (double-blinded). 
Masking of the outcome assessor is ascertained in all treatment arms since the laboratory 
technicians determining the larvae counts and presence of egg for efficacy assessment will 


Page 20 of 38 
 
have no knowledge of the participants assignment to treatment arm. The blinding will be 
maintained throughout the trial until data entry and processing are complete and the data have 
been verified. Following release of the final data, the randomization codes will be released. 
 
4.5. Study duration and duration of participation 
The trial will last a maximum of 26 weeks. The screening for the baseline will start 12 weeks 
prior to the treatment. Follow-up screening will take place 14-21, 42-49 and 63-70 days post-
treatment and last for about one week. Schedules of visits are summarized below (Table 1). 
 
 
4.6. Schedule of visits 
Table 1. Schedule of visits 
                                                Screening / Baseline / Treatment / Safety 
Follow-up period 
 
Day 
-90 
Day 
-3 - 0 
0 h 
Randomization and administration of  treatment 
1-3 h 
24 h 
Day 
14-21 
Day 
42-49 
Day 
63-70 
Informed consent 
X 
 
 
 
 
 
 
 
Diagnosis (stool exam) (a) 
X 
 
 
 
 
X 
X 
X 
Baseline data (b) 
X 
 
 
 
 
 
 
 
Questionnaire 
X 
 
 
 
 
 
 
 
Medical history (c) 
 
X 
 
 
 
 
 
 
Clinical examination (d) 
 
X 
 
 
 
 
 
 
Physical examination (e) 
 
X 
 
 
 
 
 
 
Randomization 
administration of treatment 
 
 
X 
 
 
 
 
 
Capturing AEs (f) 
 
 
 
X 
X 
X 
X 
X 
Capturing SAE (f) 
 
 
 
X 
X 
X 
X 
X 
(a) based on duplicate Baermann assays of three stool samples. Daily stool sample will take place in 50-100 adults between day 
0 and day 28. 
(b) date of birth, age, sex, height, weight, body temperature, pulse rate, blood pressure, Hb measurement, pregnancy test and 
recording of breastfeeding. 
(c) information gained by asking specific questions concerning chronic disease and concomitant medications. 
(d) investigation for signs of disease: head ache, abdominal pain, nausea, vomiting, diarrhea, itching, other symptoms. 
(e) physical examination on ear, nose, throat, eyes, lungs, lymph nodes and skin. 
(f) a standardized symptom questionnaire is used, that includes the recording of headache, abdominal pain, itching, nausea, 
vomiting, diarrhea, allergic reaction, others. 
 
 


Page 21 of 38 
 
5. Selection of the trial participants 
5.1. Recruitment 
The study will be carried out in adults in areas endemic for S. stercoralis in Kampong Chhnang 
province, Cambodia. 
The adult community members will be invited to participate in an open community information 
meeting to explain the purpose and procedures of the study, including potential benefits and 
risks. Potential participants will be encouraged to ask questions in an open discussion followed 
by this meeting. 
Those adults 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.  
Males and females aged 18-65 years infected with S. stercoralis (positive in at least 
one of the three provided stool samples or at least two of the sextuplicate Baermann 
assays (0.07 LPG in 10 g of stool). 
2. 
Written informed consent signed by the participant him/herself. In case the person is 
illiterate, an impartial witness that can read and write has to sign the consent and the 
illiterate participant has to give a thumbprint. 
3. 
Agree to comply with the study procedures, including to be examined by a study 
physician before treatment and to provide three stool samples at the beginning 
(baseline) and three stool samples approximately two to three weeks after receiving 
treatment (follow-up 1). Further three stool samples are asked for at each long-term 
follow-up scheduled at 42-49 and 63-70 days-post-treatment. 
 
5.3. Exclusion criteria 
- 
Presence of acute or uncontrolled systemic illnesses (e.g. severe anemia, fever) as 
assessed by a medical doctor, upon initial clinical assessment. 
- 
History of severe chronic disease or major systemic illnesses, e.g. severe anemia, severe 
chronic heart, liver or renal disease as asked by the medical doctor, upon initial clinical 
assessment. 
- 
Treatment with anthelmintics (e.g. diethylcarbamazine [DEC], suramin, ivermectin, 
mebendazole or albendazole) within 4 weeks before study start. 


Page 22 of 38 
 
- 
Attending other clinical trials during the study period. 
- 
Pregnancy, lactating, and/or planning to become pregnant within the study period. 
- 
Known allergy to study medications (i.e. moxidectin or ivermectin). 
- 
Use of medication with known interaction on the study drug. 
 
Participants who were diagnosed with a STH infection, but who were excluded from the study 
due to one or several of the above-mentioned exclusion criteria, including withdrawals, will be 
offered standard anthelminthic treatment (i.e. ivermectin at a single dose of 200 µg/kg). 
5.4. Criteria for discontinuation of trial 
A participant can be discontinued from the study for the following reasons: 
1. 
withdraws from the study. 
2. 
at the discretion of the PI or co-PI, if the participant is not compliant to the 
requirements of the protocol. 
Discontinued participants will not be replaced. If, for any reason, a participant is discontinued 
from the study before the end of treatment evaluations, the planned procedures (AEs 
monitoring) will be conducted. Data obtained prior to the participant’s withdrawal will be 
included in analysis. Data of withdrawn participants are fully anonymized once analysis is 
completed. 
5.5. Treatment of participants 
2 mg tablets of moxidectin and moxidectin placebo tables will be obtained from Medicines 
Development for Global Health (MDGH), Australia. Ivermectin (3 mg) will be purchased from 
Merck, Switzerland and matching ivermectin placebo tablets will be produced and a certificate 
of manufacture and analysis provided by the University of Basel. The body weight of each 
participant will be recorded to calculate and administer the correct dose of ivermectin (200 
µg/kg). 8 mg (4 pills of moxidectin or moxidectin placebo) and the appropriate doses of weight-
dependent ivermectin or its placebo will be calculated and administered to all participants. 
Each person (i.e. moxidectin 8 mg and ivermectin 200 µg/kg) will receive the maximum number 
of ivermectin tablets with regard to their weight category or the corresponding number of 
placebo tablets, and the four 2 mg moxidectin tablets or equal number of placebo tablets. The 
tablets will be handed out from the drug container according to the randomization list. The 
person conducting the recruitment and defining the order in which patients receive treatment 
will be masked to the randomization sequence so to warrant allocation concealment. 
 


Page 23 of 38 
 
All drugs will be administered in the presence of the PI or co-PI and the physician, and ingestion 
confirmed. This will be recorded with the time and date of dosing. The tablets will as long as 
applicable be stored in the original package and at any time (except treatment day) be stored 
according to manufacture prescription, sealed and away from light. The PI or co-PI is 
responsible for drug accountability at the study site. Maintaining drug accountability includes 
careful and systematic study drug storage, handling, dispensing and documentation of 
administration. 
 
After ingestion of the medication at every administration time point, the participants will be 
observed for 3 hours to ensure retention of the drug. Vomiting within 1 hour post-dosing will 
require re-dosing. The participants will not be allowed more than one repeated dose. No re-
administration will be needed for participants vomiting after one hour. In case any SUSAR will 
be observed, any further treatment will be put on hold until the data has been reviewed and a 
decision taken within the entire study team whether the study can be continued or has to be 
stopped. On the treatment day, participants presenting a serious medical situation, as judged 
by the physician, will be kept at the hospital level under close supervision by a medical team. 
Also, in order to not break the surveillance of the undesirable effects of those whom we will 
allow to go back home at the end of the treatment day, security measures will be taken: (i) a 
card containing at least three phone numbers of the investigators and the study physician will 
be given to the participant him/herself. Participants will further be asked not to take any drugs 
other than those prescribed by the study medical team. 
 
Treatment will be done community-based in local community buildings. Infrastructure as 
required for the study needs (i.e. tables, chairs, a cover from rain and sun) will be installed as 
necessary at the specific study days. Participants will receive a local breakfast two hours prior 
to treatment as well as lunch and snacks during the day once absorption of the drug is 
complete. 
5.6. Concomitant therapy 
All medications taken one month before and during the study period must until the last stool 
examination at day 63-70 (follow-up) be recorded with indication, dose regimen, date and time 
of administration. 
 
Medication(s)/treatment(s) permitted during the trial 
- 
Analgesics and antipyretics are allowed to be given to the participants in case of fever, 
antiemetics to prevent nausea and vomiting and/or antibiotics to prevent or treat 
bacterial superinfection. 


Page 24 of 38 
 
Medication(s)/treatment(s) NOT permitted during the trial 
- 
No other active drugs against helminths are permitted during the trial. Participants 
receiving active anthelminthic concomitant medication during the trail will not be 
discontinued; however a case-specific assessment will be done at the time of data-
analysis.  
6. Assessment of safety 
6.1. Adverse event definition 
Few adverse events have been reported following moxidectin or ivermectin administration in 
STH-infected individuals. The most common AEs were abdominal cramps, headache, nausea, 
diarrhea, fever and vertigo [11, 12, 45, 46]. 
 
6.1.1. Types of adverse events 
The term “adverse event” is defined as: 
Any untoward medical occurrence in participants or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. 
 
An AE can therefore include any of the following events, which develop or increase in severity 
during the course of the study, after administration of the study product: 
a) Any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
b) Any abnormality detected during physical examination. 
 
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 
drug” means that there is a reasonable possibility that the event may have been caused by the 
drug. 
 
6.1.2. Severity grading 
Adverse signs or symptoms will be graded by the investigator as mild, moderate, severe or life 
threatening according to the following definitions: 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). 
 
Grade      Definition  
 
 
 
 
 


Page 25 of 38 
 
1. 
Mild: the participant is aware of the event or symptom, but the event or symptom is 
easily tolerated. 
2. 
Moderate: the participant experiences sufficient discomfort to interfere with or 
reduce his or her usual level of activity. 
3. 
Severe: significant impairment of functioning: the participant is unable to carry out 
his or her usual activities. 
4. 
Life threatening or disabling. 
5. 
Death related to adverse events. 
 
6.1.3. 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 adverse even 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”. 
 
6.1.4. Types of adverse events 
Expected adverse event: Any adverse event possibly related to the study drug 
administration reported in the literature and/or on the drug package leaflets for moxidectin 
and/or ivermectin. 
Unexpected adverse event: Any adverse event possibly related to the study drug 
administration, the nature, frequency specificity or severity of which is unanticipated and 
not consistent with the available risk information described for these drugs. 
 
6.1.5. Serious adverse events 
According to the ICH “Clinical Safety Data Management: Definitions and standards for 
expedited Reporting E2A” 
(https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step
4/E2A_Guideline.pdf) a serious SAE includes any event (experience) or reaction in any 
untoward medical occurrence that at any dose: 
1. 
is fatal, results in death; 


Page 26 of 38 
 
2. 
is life threatening, meaning, the participant was, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred, i.e., it does not include a 
reaction that, had it occurred in a more serious form, might have caused death; 
3. 
is a persistent or significant disability or incapacity, i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions; 
4. 
requires, or prolongs in-patient hospitalization; 
5. 
is a congenital anomaly or birth defect; 
6. 
is an important medical event, based upon appropriate medical judgment, that may 
jeopardize the patient or participant or may require medical or surgical intervention to 
prevent one of the other outcomes defining serious. 
 
A “severe” AE does not necessarily meet the criteria for a “serious” AE. Serious adverse events 
are reported from the first dose of study medication to 21 days post-treatment. 
 
SAEs that are still ongoing at the end of the study period will be followed up to determine the 
final outcome. Any SAE that occurs after the study period and is considered to be possibly 
related (definitions will be used according to the WHO-UMC system; see: http://who-
umc.org/Graphics/24734.pdf) to the study treatment or study participation will be recorded and 
reported immediately. 
 
6.1.6. Suspected unexpected serious adverse reactions 
A suspected unexpected serious adverse reaction (SUSAR) is an unexpected adverse drug 
reaction which also meets the definition of serious adverse events. 
6.2. Methods of recording and assessing adverse events 
The observation time for AE starts when the treatment is initiated. Participants will be kept for 
observation for at least 3 hours following each morning treatment for any acute AEs. During 
the reporting period, any unfavorable changes in the participant’s condition will be recorded as 
adverse events, whether reported by the participant or observed by the investigator. In case 
of any abnormal finding, the local study physician will perform a full clinical examination and 
findings will be recorded. An emergency kit will be available on site to treat any medical 
conditions that warrant urgent medical intervention. 
In addition, participants will also be interviewed by a health worker about the occurrence of 
AEs 24 hours after treatment. 
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 


Page 27 of 38 
 
(i.e. whether the event should be classified as an adverse drug reaction); and iii) an 
assessment of intensity of AEs by the study physician. Intensity of AE will be judged by the 
study physician, following guidelines by the European Medicine Agency (Note for Guidance on 
Clinical Safety Data Management). 
 
All SAE, unexpected adverse drug reactions, or SUSARs must be reported as described in 
Section 6.3. 
 
6.3. Reporting of serious adverse events 
Any study-related unanticipated problem posing risk of harm to participants or others, and any 
type of serious adverse event including SUSAR, will be reported (within 24 hours after 
capturing the event and notification) to 
 
Prof. Dr. Jennifer Keiser (principal investigator) 
Swiss Tropical and Public Health Institute,  
Tel.: +41 61 284-8218 
Fax: +41 61 284-8105 
E-mail: jennifer.keiser@swisstph.ch 
 
Within the following 48 hours, the local co-PI must provide to study sponsor-investigator further 
information on the serious adverse effect 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 serious adverse event 
reporting will be included in the trial-specific SAE form. Relevant pages from the CRF will be 
provided in parallel (i.e., 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 the ‘Ethik Kommission Nordwest- und Zentralschweiz’ (EKNZ, Switzerland) and the National 
Ethic Committee for Health Research (NECHR) according to national rules. Fatal or life-
threatening serious adverse events or SUSARs will be reported within 24 hours (between 
sponsor-investigator’s knowledge about the event and notification) followed by a complete 


Page 28 of 38 
 
report within seven additional calendar days. Other SAE and SUSARs that are not fatal or life-
threatening will be filed as soon as possible but no later than 14 days after first knowledge by 
the sponsor-investigator. 
7. Data management and data quality control 
The investigators are responsible for an adequate data quality. Prior to the initiation of the 
study, an investigators meeting will be held with the investigators and their study coordinators 
and a member of the Swiss TPH. This meeting will include a detailed discussion of the protocol, 
performance of study procedures (SOPs), CRF completion, specimen collection and 
diagnostic methods. 
 
7.1. Source data 
Source data are comprised of clinical findings and observations as well as laboratory data 
maintained and compiled at the study site. Source data are contained in source documents 
and are allowed to be accessed by local authorities. Source data will be directly entered in the 
following documents: 
1. CRF: Primary data collection instrument for the study. It holds records of all clinical and 
physical examination data, treatment information and AEs. For every participant 
enrolled in the clinical trial, a corresponding CRF exists. All data requested on the CRF 
must be recorded, and investigators will review and approve each CRF for completion. 
2. Census: secondary data collected from previously completed census in communities. 
Holds name, age and sex of each potential participant. 
3. Laboratory parasitology sheets: Record of the Strongyloides larvae counts and 
presence of STH eggs at all sample collection time points. 
 
7.2. Data collection and documentation 
The data collected and produced from this research project will fall into the following 
categories: 
1. Larvae counts of Strongyloides stercoralis, presence of eggs of Ascaris lumbricoides 
and Trichuris trichiura, hookworms and Taenia ssp. found in participants’ stool using 
either the Baermann technique or standard Kato-Katz microscopy. 
2. Personal information such as name, age and gender of trial participants. 


Page 29 of 38 
 
3. Baseline and clinical characteristics of the trial participants collected using the study’s 
CRF such as weight, height, blood pressure, temperature, any abnormal medical 
condition or chronic disease. 
4. Number and type of adverse events registered in the CRF and actively probed for 3 
and 24 hours after treatment. The same data will further be collected during the 
collection of the three follow-up periods. 
5. Socioeconomic data of each participant’s household including behavioural 
characteristics based on the questionnaire. 
6. Genetic profiling of S. stercoralis larvae in positive stool samples. 
Data from categories 1-4, will be both paper-captured and directly into tablets using 
CommCare HQ (Digmagi, Inc., Cambridge, MA) or a comparable data-entry software. Data 
from category 5 will be captured by software only, data from category 6 by paper only. For all 
data, the software entries will represent the primary data source. 
CommCare HQ is a routine data management system ensuring complete, consistent and 
reliable data entry. For quality assurance error, range and consistency checks will assessed. 
15% of data will be controlled by a standard operating procedure; any discrepancies will be 
corrected by consulting the hard copy and corrected accordingly. If more than 1% of the double 
entered data display discrepancies, all data in categories 1-4 will be double entered by two 
independent people for quality assurance and verified as described. 
Data compiled using the software will be directly saved on the personal, password-protected 
laptop of one of the Co-PIs and uploaded to a server hosted at Swiss TPH, Basel. Data analysis 
will be conducted with pseudonymized data and reporting of findings will be fully anonymized. 
In paper-based data collection, all missing data must be explained. All entries will be printed 
in blue ink. All corrections must be noted with the initials of the respective team member and 
dated. All categories will be merged into a single master file saved in .xlsx and .csv. Digital 
copies along with single databases and compiled masterfiles will be transferred to the Swiss 
TPH, Basel after a Material Transfer Agreement has been signed by both the Swiss TPH and 
National institute of Cambodia (see Appendix). All data is expected to not exceed 5 GB. 
Essential infrastructure such as a locked room for safe storage of hardcopy data will be made 
available. Digital copies along with the databases will be transferred to the Swiss TPH. Data 
will then be analyzed as described in section 8. 
7.3. Ethical, legal and security issues 
Information about study participants will be kept confidential and managed accordingly. 
Screened participants will be listed in a confidential “participant screening log” and attributed 
a unique study number. Enrolled participants will be listed in a confidential “participant 


Page 30 of 38 
 
enrolment log”; this document will constitute the only source to decode the pseudonymized 
data and will only be accessible to the investigators. Personal data will be coded for data 
analysis. No names will be published at any time, and published reports will not allow for 
identification of single participants. Confidentiality will be ensured throughout the entire 
research project. All databases will be password secured. None of the investigators declare to 
have any conflicts of interest. 
 
7.4. Data storage and preservation 
All samples will be destroyed after completion of the study. Paper-based and electronic source 
data and related material will be preserved for a minimum of 15 years to enable understanding 
of the study procedures, which allows the work to be assessed retrospectively and repeated if 
necessary. The study site will retain a copy of the documents to ensure that local collaborators 
can provide access to the source documents to a monitor, auditor, or regulatory agency. 
Electronic source documents will be stored on a flash drive and kept at the study site (Phnom 
Penh, Cambodia). The primary data storage and backup will be in the Swiss TPH shared 
server and secondary data storage will be on personal, password-protected laptops of the PI 
and co-PI on a password-protected memory stick and/or SWITCHdrive (a cloud storage 
supported by University of Basel). Electronic data files and archiving conditions will be made 
strictly confidential by password protection. 
7.5. Definition of reference language – translation of study documents  
- Protocol: Master document in English and Khmer, all further language versions are 
translations thereof. 
- CRF: Master document in English and Khmer, all further language versions are translations 
thereof. 
- ICF: Master document in English and Khmer, all further language versions are translations 
thereof. 
8. Statistics 
8.1. Definition of primary endpoint 
Infection status of S. stercoralis assessed 14-21 days post-treatment by Baermann's method 
is the primary outcome. 


Page 31 of 38 
 
8.2. Justification of number of trial participants 
The main hypothesis of this trial is that an 8 mg dose of moxidectin is non-inferior against S. 
stercoralis compared to the standard of care therapy (ivermectin). We assume a similar true 
CR for moxidectin and ivermectin of 89% [16]. The sample size determination revealed, that 
we need 154 participants in each trial arm to demonstrate non-inferiority of moxidectin with a 
non-inferiority margin of 10%-points with 80 power at the 95% confidence interval (equivalent 
to the 97.5% lower confidence bound). 
 
To account for an expected loss to follow-up of 10%, we target to enroll 175+175 = 350 
participants. 
8.3. Description of statistical methods 
An available case analysis (full analysis set according to the intention to treat principle) will be 
performed, including all participants with any primary endpoint data. Supplementary, a per-
protocol analysis will be conducted consisting of all participants who meet all inclusion and 
exclusion criteria, have no major protocol deviations and received the correct treatment. CRs 
will be calculated as the percentage of worm-positive adults at baseline who become worm-
negative after treatment at the defined follow-up time points. Uncertainty estimates around the 
differences among CRs will be assessed using melded confidence intervals with mid-p 
correction as implemented in R's 'exact2x2' package. 
LPG will be assessed by calculating the mean of the larvae counts from the Baermann assays 
(sextuplets for primary endpoint) per gram of stool. The LRR will be calculated (LRR = (1-
(mean at follow-up/mean at baseline))*100). Bootstrap resampling method with 5,000 
replicates will be used to estimate 95% confidence intervals (CIs) for LRRs and the difference 
between the LRRs. 
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 [47]. 
AEs will be evaluated descriptively as the difference of proportion reporting adverse events 
before and after treatment. 


Page 32 of 38 
 
9. Duties of the investigator 
9.1. Investigator’s confirmation 
This trial will be conducted in accordance with the protocol, International Conference on 
Harmonisation Good Clinical Practice E6 (ICH-GCP E6 (R2)) and the current version of the 
Helsinki Declaration. 
All protocol modifications must be documented in writing and implemented only with ethical 
approval. A protocol amendment can be initiated by any investigator. The investigator will 
provide the reasons for the proposed amendment in writing upon discussion with the Sponsor-
Investigator. Any protocol amendment must be approved and signed by the Sponsor-
investigator and must be submitted to the appropriate Independent Ethics Committee (IEC) for 
evaluation and approval, in accordance with local requirements, and to regulatory agencies if 
required. Approval by IEC must be received before any changes can be implemented, except 
for changes necessary to eliminate an immediate hazard to trial participants, or when the 
change involves only logistical or administrative aspects of the trial, e.g. change of telephone 
number(s). 
9.2. Damage coverage 
A general liability insurance of the Swiss TPH is in place (Winterthur Police Nr. 4746321). 
Clinical trial insurance is set up with the FORTE INSURANCE (Policy Number: 
D/001/CPID/21/000002) in Cambodia. 
9.3. Project management 
The trial team will include the PI (Prof. Jennifer Keiser), a Co-PI (Dr. Rekol Huy in Cambodia), 
a Co-PI and physician (Dr. Virak Khieu in Cambodia), a Co-PI (Ms. Viviane Sprecher), a trial 
statistician (Dr. Jan Hattendorf), and laboratory technicians, health workers and nurses. Prof. 
Jennifer Keiser and Ms. Viviane Sprecher 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 Rekol Huy will be 
responsible for the administration of the Project. Dr. Virak Khieu has the main medical 
responsibility and is responsible for supervision of the lab- and field technicians, staff 
management, recruitment monitoring, supply of the material, contact with the local authorities 
and participating institutions. 
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 


Page 33 of 38 
 
or danger to a study participant. The investigator will work according to the protocol, GCP and 
GLP. The investigator may take any steps judged necessary to protect the safety of the 
participants, whether specified in the protocol or not. Any such steps must be documented. 
During the treatment the records are maintained by the responsible medical doctor. All entries 
have to be made clearly readable with a pen. The investigator must be thoroughly familiar with 
the properties, effects and safety of the investigational pharmaceutical product. 
 
10. Ethical considerations 
10.1. Independent Ethics Committee (IEC) 
The study will be submitted for approval by the institutional research commission of the Swiss 
TPH and the ethical committees of Switzerland and Cambodia. The study will be undertaken 
in accordance with the Declaration of Helsinki and good clinical practice (GCP E6 (R2)). 
10.2. Evaluation of the risk-benefit ratio 
Moxidectin is a well-known, FDA-approved drug against onchocerciasis and has little and 
mainly mild adverse events (headache, abdominal pain etc.). All community members enrolled 
in the study will benefit from a clinical examination and a treatment against STHs. All 
participants remaining positive for S. stercoralis will be treated with ivermectin (according to 
WHO recommendations) upon evaluation of the follow-up stool data. Participants still showing 
co-infection with hookworm, A. lumbricoides, T. trichiura or Taenia ssp. at follow-up 
assessment will be provided the current standard treatment. 
10.3. Participant information and consent 
Information sessions in the respective communities allowing for open exchange will be 
organized in every study locality where a screening, potentially also 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 participants will be individually informed about 
benefits and risk associated to the trial. They will have sufficient time for reflection of their own 
participation. All eligible adults (≥18 years) 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 has to sign or give a thumbprint. 


Page 34 of 38 
 
Information sheets (ICS) are printed in Khmer and will additionally be verbally explained in the 
local languages during community meetings. To all participants 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. However, transport and meals will be covered and free 
treatment for all diagnosed worms will be provided. 
10.4. Participant confidentiality 
The obtained data will be handled strictly confidentially. Only members of the study team will 
have access to the data. 
Screened patients will be listed in a confidential “participant screening log”. Enrolled patients 
will be listed in a confidential “participant enrolment log” and attributed a unique study number; 
this document will constitute the only source to decode the pseudonymized data and will only 
be accessible to the local principal investigator. Data analysis will be conducted with 
pseudonymized data and reporting of findings will be fully anonymised; personal data will be 
coded for data analysis. No names will be published at any time, and published reports will not 
allow for identification of single participants. Confidentiality and anonymity will be ensured 
throughout the entire research project. All databases will be password secured. Participant-
specific information may be provided to other appropriate medical personnel only with the 
participant’s permission. 
The investigators have all been trained in GCP. None of the investigators declare to have any 
conflicts of interest. 
10.5. Participants requiring particular protection 
This study will be carried out in adults, since S. stercoralis infection occurs most often in adults; 
hence this age group is at high risk of infection. Non-inferiority studies to the standard treatment 
options have not been conducted to date in this population. Our trial will provide more evidence 
and pave the further way for a safe and effective treatment of Strongyloides infections in adults 
and the whole community. 
10.6. Other aspects 
We will not include a placebo arm. Owing to the auto-infection cycle of S. stercoralis and due 
to the rather long follow-up periods, we prefer not to expose any adults to the risk of developing 
medical concerns. Considering all security measures (i.e. clinical and physical exams) set up 
for inclusion of trial participants in combination with the expected high true CR of roughly higher 


Page 35 of 38 
 
than 90% for each treatment arm, we believe that a follow-up period of 70 days is not expected 
to cause any problem. 
11. Quality control and quality assurance 
11.1. Monitoring and auditing 
We will work with a locally based monitor. He/she will conduct site visits to the investigational 
facilities for the purpose of monitoring the study. Details on scope and frequency of monitoring 
activities 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 preventive action plan will be requested 
and documented in response to any significant deviation. No sponsor-initiated audits are 
foreseen, but audits and inspections may be conducted by the local regulatory authorities or 
ethics committees and ethics committees. The investigator agrees to allow inspectors from 
regulatory agencies to review records and is encouraged to assist the inspectors in their duties, 
if requested. 
11.2. Data and safety monitoring board (WHO) / data monitoring committee 
(EU/FDA) 
In our study no data and safety monitoring board will be established, since we work with well-
known drugs. However, advisors will be informed regularly and the findings discussed. 
12. Dissemination of results and publication 
The final results of this study will be published in a scientific journal and presented at scientific 
conferences. The EU-Southeast Asia and the Adiuvare Foundation will be acknowledged as 
study funder. All results from this investigation are considered confidential and shall not be 
made available to any third part by any member of the investigating team before publication. 
A study report will be shared with the local ethics committees and the national regulatory 
authorities. After publication, study results will be made available to study participants. 


Page 36 of 38 
 
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