A Clinical Trial to Assess the Safety and Efficacy of Moxidectin Combination Treatments vs. Ivermectin Combination Treatments for Bancroftian Filariasis
Phase: PHASE3
Conditions: Lymphatic Filariasis
Sponsor: Washington University School of Medicine

A Clinical Trial to Assess the Safety and Efficacy of Moxidectin 
Combination Treatments vs. Ivermectin Combination Treatments for 
Bancroftian Filariasis 
Protocol Number: TBD 
 
National Clinical Trial (NCT) Identified Number:  NCT04410406 
 
Principal Investigators 
Toki Pascal Gabo, MD  
Centre Hospitalier Régional d’Agboville, Côte d’Ivoire 
 
 
Benjamin Koudou, PhD 
Centre Suisse de Recherches Scientifiques, Côte d’Ivoire 
 
 
Catherine M. Bjerum, MD, MPH 
Case Western Reserve University, USA 
 
 
Philip J. Budge, MD, PhD 
Washington University, USA 
 
 
 
Co Investigators 
Allassane Ouattara 
Centre Suisse de Recherches Scientifiques, Côte d’Ivoire 
Aboulaye Méité 
Programme National de la Lutte Contre la Schistosomiase, les 
Geohelminthiases et la Filariose Lymphatique, Côte d’Ivoire (PNL-
SGF) 
Gary J. Weil, MD 
Washington University, USA 
Peter Fischer, PhD 
Washington University, USA 
Christopher L. King, 
MD, PhD 
Case Western Reserve University, USA 
 
Sponsor: Washington University in St. Louis 
 
Funded by: Bill and Melinda Gates Foundation 
 
Version Number:  v.2.2 
1 June 2021 
 
 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
ii 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
8.1 
Will collect urine and store samples at -20⁰C 
for further studies to identify Wuchereria 
biomarkers 
Identification of new non-invasive 
biomarkers for detecting W. bancrofti 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 6 
2.1 
Study Rationale .................................................................................................................................... 6 
2.2 
Background........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................ 9 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 10 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 10 
4 
STUDY DESIGN ........................................................................................................................................... 11 
4.1 
Overall Design .................................................................................................................................... 11 
4.2 
Scientific Rationale for Study Design.............................................................................................. 12 
4.3 
Justification for Dose ......................................................................................................................... 12 
4.4 
End of Study Definition ..................................................................................................................... 12 
5 
STUDY POPULATION ................................................................................................................................ 13 
5.1 
Inclusion Criteria ................................................................................................................................ 13 
5.2 
Exclusion Criteria ............................................................................................................................... 13 
5.3 
Screen Failures .................................................................................................................................. 13 
5.4 
Strategies for Recruitment and Retention ...................................................................................... 14 
6 
STUDY INTERVENTION ............................................................................................................................ 15 
6.1 
Study Intervention(s) Administration ............................................................................................... 15 
6.1.1 
Study Intervention Description ..................................................................................... 15 
6.1.2 
Dosing and Administration ............................................................................................ 15 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 16 
6.2.1 
Acquisition and accountability ...................................................................................... 16 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 16 
6.2.3 
Product Storage and Stability ....................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 16 
6.4 
Study Intervention Compliance ........................................................................................................ 16 
6.5 
Concomitant Therapy ........................................................................................................................ 16 
7 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ............................................................................ 17 
7.1 
Participant Discontinuation/Withdrawal from the Study ............................................................... 17 
7.2 
Lost to Follow-Up ............................................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 18 
8.1 
Efficacy Assessments ....................................................................................................................... 18 
8.2 
Safety and Other Assessments ....................................................................................................... 21 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 22 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 22 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 22 
8.3.3 
Classification of an Adverse Event .............................................................................. 23 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 24 
8.3.5 
Adverse Event Reporting .............................................................................................. 24 

  
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
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8.3.6 
Serious Adverse Event Reporting ............................................................................... 25 
8.3.7 
Reporting of Pregnancy ................................................................................................ 25 
8.4 
Unanticipated Problems .................................................................................................................... 26 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 26 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 26 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 26 
9.1 
Statistical Hypotheses ....................................................................................................................... 26 
9.2 
Sample Size Determination .............................................................................................................. 27 
9.3 
Populations for Analyses .................................................................................................................. 27 
9.4 
Statistical Analyses............................................................................................................................ 28 
9.4.1 
General Approach .......................................................................................................... 28 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 28 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 28 
9.4.4 
Safety Analyses .............................................................................................................. 31 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 31 
9.4.6 
Planned Interim Analyses ............................................................................................. 31 
9.4.7 
Sub-Group Analyses ..................................................................................................... 31 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 31 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 31 
10.1.1 
Informed Consent Process ........................................................................................... 31 
10.1.2 
Study Discontinuation and Closure ............................................................................. 33 
10.1.3 
Confidentiality and Privacy ........................................................................................... 34 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 34 
10.1.5 
Key Roles and Study Governance .............................................................................. 35 
10.1.6 
Safety Oversight ............................................................................................................. 35 
10.1.7 
Clinical Monitoring .......................................................................................................... 36 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 36 
10.1.9 
Data Handling and Record Keeping ............................................................................ 37 
10.1.10 
Protocol Deviations ........................................................................................................ 38 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 38 
10.2 
Abbreviations ...................................................................................................................................... 39 
11 
REFERENCES ............................................................................................................................................. 40 
 

Moxidectin vs. Ivermectin Combination Therapies for Lymphatic Filariasis 
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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP). All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent forms, recruitment materials, and all participant materials will be 
submitted to the Comité National d’Ethique et de la Recherche (CNER) in Côte d’Ivoire and to the 
Washington University institutional review board (IRB), for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB and CNER before the changes are implemented 
to the study.   
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A Clinical Trial to Assess the Safety and Efficacy of Moxidectin Combination 
Treatments vs. Ivermectin Combination Treatments for Bancroftian 
Filariasis 
Study Description: 
This is an interventional, randomized, parallel-assignment, open-label, 
clinical trial with four treatment arms: 
1. IA:  ivermectin (IVM) plus albendazole (ABZ) 
2. MoxA:  moxidectin (Mox) plus ABZ  
3. IDA:  IVM plus diethylcarbamazine (DEC) plus ABZ  
4. MoxDA:  Mox plus DEC plus ABZ 
The IA group will receive IA annually. Participants in the other groups will 
receive the assigned treatment at baseline and again at 24 months, if 
microfilaremic. If IA is superior to MoxA at 12 months, the MoxA group 
will switch to annual IA treatment for the duration of the study. 
Objectives: 
Primary Objective:  To determine whether Mox combination therapies are 
superior to IVM combination therapies for achieving sustained clearance 
of Wuchereria bancrofti microfilaremia 
Secondary Objectives:  
1. To compare the efficacy of Mox combination therapies to IVM 
combination therapies for reducing W. bancrofti microfilariae (Mf) 
counts (change relative to baseline). 
2. To compare the efficacy of Mox combination therapies to IVM 
combination therapies for reducing the viability of W. bancrofti 
adult worms, as assessed by change in circulating filarial antigen 
(CFA) levels and % inactivation of adult worm nests visible by 
ultrasound. 
3. To compare the safety and tolerability of Mox combination 
therapies to IVM combination therapies in men and women with 
W. bancrofti infection. 

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4. To document the pharmacokinetic parameters of Mox in W. 
bancrofti-infected adults and to determine whether Mox affects 
the peak levels and clearance of DEC and ABZ in individuals with 
W. bancrofti infection, compared to IVM. 
Endpoints: 
Primary Outcomes:  The proportion of participants in each study arm with 
complete clearance of W. bancrofti microfilaremia at 12 months after 
treatment (IA vs. MoxA comparison) or 24 months after treatment (IDA vs. 
MoxDA comparison). 
 
Key Secondary Outcomes: 
Efficacy Outcomes  
1. The proportion of participants in each study arm with complete 
clearance of W. bancrofti microfilaremia at 6, 12, 24, and 36 
months after treatment 
2. Reduction in Mf counts (relative to baseline) at 6, 12, and 24 
months 
3. Reduction in CFA levels (relative to baseline) at 6, 12, and 24 
months 
4. Inactivation of adult worm nests as assessed by ultrasound at 6, 
12, and 24 months after treatment 
Safety Outcome 
5. Frequency and severity of adverse events (AEs) during the first 7 
days after treatment 
Pharmacokinetics Outcome (PK) 
6. Plasma levels of treatment drugs/metabolites post-treatment 
Study Population: 
Adults (men and women age 18-70 years) with W. bancrofti infection and 
> 40 Mf/mL venous blood, residing in or near Agboville district, Côte 
d’Ivoire 
Phase: 
Phase 3 
Description of 
Sites/Facilities Enrolling 
Participants: 
This trial will be conducted at the Centre de Recherche de Filariose 
Lymphatique d’Agboville (CRFLA), located at the Centre Hospitalier 
Regional (CHR) d’Agboville, Cote d’Ivoire and in the surrounding 
communities. It will be done in coordination with the national LF 
elimination program’s regional assessment of LF transmission. This trial 
will be conducted in two parts.  All participants in both parts will be 
treated with combination therapy for LF and will be followed for 36 
months.  Part 1 and Part 2 differ in the intensity of AE monitoring and 
collection of additional blood samples in the first week post-treatment; 
subsequent follow-up visits (at 6, 12, 24, and 36 months) are the same for 
both parts. 
 
Part 1 is a preliminary safety study comprising at least 50 participants (~12 
from each arm), who will be treated as inpatients at CRFLA with 
enhanced AE monitoring and pharmacokinetics (PK) measurements.   
 

Moxidectin vs. Ivermectin Combination Therapies for Lymphatic Filariasis 
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Part 2, comprising the rest of the study participants, will proceed if no 
serious safety signals are observed in Part 1 (i.e. significantly more 
treatment-related severe or serious AEs in participants who have 
been treated with Mox drug combinations). Part 2 participants will 
be treated and followed for safety and efficacy as outpatients in 
their home villages, in or near Agboville. 
Description of Study 
Intervention: 
All participants will receive an oral dose of one of the following drug 
combinations: 
1. IVM 200 µg/kg + ABZ 400 mg (IA) 
2. Mox 8 mg + ABZ 400 mg (MoxA) 
3. IVM 200 µg/kg +  DEC 6mg/kg + ABZ 400 mg (IDA) 
4. Mox 8 mg + DEC 6mg/kg + ABZ 400 mg (MoxDA)  
Arm 1 will receive IA annually. The other arms will receive treatment at 
enrollment and following the 24-month assessment, if Mf positive at 24 
months. 
Study Duration: 
42 Months 
Participant Duration: 
36 Months 
 

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1.2 
SCHEMA 
 
Notes 
1. Prescreening by FTS and nocturnal Mf counts will be done by PNL-CSGF as part of their usual 
public health activities. 
2. Drug levels will be assessed only in Part 1 
3. Part 1 and Part 2 differ in the number and nature of assessments during the first 7 days only.  All 
follow-up assessments are the same for both parts.  See the next section (Schedule of Activities) 
for details.  

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Screening / 
Randomization 
Day 01 
Day 11 
Day 21 
Day 31,2 
Day 7 
6 months 
12 months 
18 months 
24 months 
36 months 
Procedures 
Baseline 
0700 (0 hr) 
0900 (2 hr) 
1000 (3 hr) 
1100 (4 hr) 
1300 (6 hr) 
1900 (12 hr) 
0100 (18 hr)3 
0700 (24 hr) 
1300 (30 hr) 
1900 (36 hr) 
0100 (42 hr)3 
0700 (48 hr) 
1900 (60 hr) 
0700 (72 hr) 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam4 
X 
 
 
 
 
X4 X4 X4 X4 X4 X4 X4 X4 X4 X4 
 
 
 
 
 
 
Vital signs5 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
 
 
 
 
 
AE assessment5 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
 
 
 
 
 
Mf count (filtration) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Filariasis test strip (FTS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Hgb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cr, AST, ALT 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X7 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X7 
 
 
 
 
 
Urine biomarker collection 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Urine pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X8 
 
X8 
 
Skin snip  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma drug levels 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Circulating filarial antigen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Ultrasound (males only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Study drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X9 
 
X9 X9 
Community visit to share results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Shaded fields indicate assessments that are unique to Part 1 (inpatient monitoring / pharmacokinetics). All other assessments apply to 
both Part 1 and Part 2. 
Notes 
1. 
Times of day listed for days 0, 1, 2, and 3 apply only to Part 1. 
2. 
For Part 1, all patients will have a 72 hour assessment.  For Part 2, only patients with grade 2 or higher AEs not resolved by day 2 will 
be visited on day 3. 
3. 
Assessments at 18 and 42 hours (Part 1) may be skipped if patient is sleeping. 
4. 
Targeted physical exam will be performed if any grade 2 or higher AE is observed or if abnormal vital signs are noted. 
5. 
Vital signs will include temperature, pulse rate, respiration rate, and blood pressure. 
6. 
Any participant in Part 1 or Part 2 experiencing grade 2 or higher AE(s) will be followed by the study team until AE severity is <grade 
2 (including beyond 7 days if necessary).  
7. 
If post-treatment biochemistries and urinalysis done on day 7 post-treatment (Part 1 only) represent grade 2 or higher AEs, 
participants will be followed with repeat lab monitoring until AE severity is <grade 2 (including beyond 7 days if necessary)  
8. 
Only participants found to be microfilaremic at 24 months will be re-treated, and only women requiring re-treatment will undergo 
pregnancy test at 24 months. 
9. 
IA group will receive treatment annually.  Individual MoxA, IDA, and MoxDA participants will be retreated at 24 months only if Mf 
positive. Participants in any group who are Mf positive at 36 months will be offered IA treatment as a bridge back to annual mass 
drug administration (standard of care). 
Abbreviations:  Mf = microfilariae, Cr = creatinine, AST = aspartate aminotransferase, ALT = alanine aminotransferase 

Moxidectin vs. Ivermectin Combination Therapies for Lymphatic Filariasis 
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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
The purpose of the current study is to determine whether moxidectin (Mox), will be more effective than 
ivermectin (IVM), when used in single-dose combination therapies for lymphatic filariasis (LF). Mox was 
approved in June 2018 by the U.S. FDA for treatment of the related filarial infection, onchocerciasis (1). 
Its mode of action is similar to that of IVM, and a single treatment dose does not kill adult Onchocerca 
volvulus worms, but is superior to IVM for achieving prolonged clearance of microfilariae (Mf) from the 
skin (2). No clinical trials have been performed to date to assess the efficacy of Mox (alone or in 
combination with DEC or ABZ) for treatment of LF.  This study will provide the first data on the relative 
safety of MoxDA and MoxA vs. IDA or IA for treating bancroftian filariasis. This study will also examine 
whether Mox affects plasma levels of ABZ and/or DEC when given in combination.  
 
2.2 
BACKGROUND  
Lymphatic Filariasis (LF) is a deforming and disabling disease caused by the mosquito-borne parasitic 
nematodes W. bancrofti, Brugia. malayi and B. timori. Infection causes lymphatic dysfunction leading to 
hydroceles (in men) and lymphedema that can progress to elephantiasis. Global efforts to eliminate LF 
transmission have reduced the population at risk for the disease, but LF transmission continues in at 
least 53 countries with 886 million still at risk (3-5).  
 
The World Health Organization’s (WHO) Global Programme to Eliminate LF (GPELF) includes population-
based surveys to determine where LF is endemic (mapping), followed by at least five rounds of annual 
mass drug administration (MDA) to treat the entire eligible population with antifilarial medications (4, 
6). The most recent summary from WHO reported that more than 7 billion doses of MDA medications 
were distributed between 2000 and 2017 (5), making GPELF the largest MDA-based infectious disease 
intervention program attempted to date. The medications given during MDA include IVM, DEC, and 
ABZ.   
 
GPELF recommends the IA combination for LF MDA in areas of Africa where LF is co-endemic with 
onchocerciasis, twice yearly ABZ alone in areas with co-endemic loiasis, and DEC plus ABZ in all other LF-
endemic areas (7). However, triple drug combination therapy with all three medications (IDA) was 
recently found to be superior to the 2-drug combinations in both Papua New Guinea and Cote d’Ivoire 
(8-10). IDA triple therapy produces prolonged Mf clearance after only one dose compared to results 
obtained after either DA or IA. This is a potential "game changer" for GPELF because it suggests that 
MDA with IDA might achieve interruption of transmission with 3 or fewer rounds of MDA, rather than 
the 5 or more rounds required using dual drug combinations (11). Large-scale international community 
safety trials in over 20,000 participants have shown no increase in adverse events (AEs) with IDA 
compared to DA, and IDA is now recommended by WHO for MDA in areas of the world without 
onchocerciasis or loiasis who are unlikely to meet the 2020 goals (7).  
 
Onchocerciasis, or "river blindness", caused by O. volvulus, is another filarial infection targeted for 
elimination through MDA.  WHO calls for MDA with IVM plus ABZ where LF and onchocerciasis are co-
endemic, and IVM alone in areas with only onchocerciasis.  DEC is not used for MDA in LF/onchocerciasis 
co-endemic areas, because it can cause serious ocular AEs in persons with intraocular O. volvulus Mf. 

Moxidectin vs. Ivermectin Combination Therapies for Lymphatic Filariasis 
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Neither DEC nor IVM are safe for routine MDA in areas with loiasis (“African eye worm”) caused by Loa 
loa, since severe AEs (SAEs) including encephalopathy and death have occurred in persons with very 
heavy loiasis (>20,000 L. loa Mf/mL in peripheral blood) infections after treatment with either of these 
medications. This risk of SAEs in loiasis-endemic African countries has delayed effective MDA in these 
areas and remains a major challenge to LF and onchocerciasis elimination in Africa.  Other challenges 
facing the GPELF include the limited macrofilaricidal activity of current MDA regimens, which 
necessitates repeated annual rounds of MDA, and the difficulty of achieving high compliance rates for 
MDA over a period of years (12, 13).  
 
Although Mox is not a macrofilaricidal drug, it likely will work together with DEC and ABZ in a way that is 
similar to IDA. It is also possible that MoxA will be superior to IA for achieving prolonged Mf clearance 
with similar efficacy to IDA without requiring DEC.  If this is the case, it would be a very significant 
advance, because then MoxA could be used to eliminate LF in onchocerciasis coendemic areas without 
having to use DEC. A second reason to test MoxA and MoxDA as treatments for LF is that many 
participants with LF treated with IDA in the clinical trial conducted in Cote d’Ivoire had only transient 
clearance of Mf; many participants were microfilaremic 12 and 24 months after treatment (see 
Rationale for study 1.4, above). This finding makes it important to test whether MoxA or MoxDA are 
superior to IA or IDA, respectively, for achieving prolonged clearance of W. bancrofti microfilaremia in 
Africa. 
 
Drug Mechanisms 
Albendazole (ABZ)  
ALB, a benzimidazole, causes degenerative alterations in the tegument and intestinal cells of the worm 
by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into 
microtubules. The loss of cytoplasmic microtubules leads to impaired uptake of glucose by larval and 
adult stages of the parasite, and depletes glycogen stores (14). Degenerative changes in endoplasmic 
reticulum and mitochondria of the germinal layer, and the subsequent release of lysosomal enzymes 
result in decreased production of adenosine triphosphate, which is the source of energy required for 
survival of the helminth.  Due to diminished energy production, the parasite is immobilized and 
eventually dies.  
  
ABZ is poorly absorbed; its absorption is enhanced 4–5-fold when it is ingested with a fatty meal (15).  
The drug undergoes first-pass metabolism within intestinal mucosal cells; the liver converts most of the 
drug into the active metabolite, albendazole sulfoxide (ABZSO) (16) .  This conversion is catalyzed by 
microsomal flavin monooxygenase and isoforms of cytochrome P450 (CYP). Large inter-individual 
variations in serum concentrations of ABZSO are due either to variation in first-pass metabolism or in 
the rate of absorption of ABZ.  ABZSO is approximately 70% bound to serum proteins and has a highly 
variable half-life.  
 
Ivermectin (IVM)   
IVM is an avermectin compound of macrocyclic lactones derived from the bacterium Streptomyces 
avermitilis (17).  The mechanism by which IVM kills LF microfilariae is not known with certainty, but the 
drug interferes with glutamate gated ion channels that can affect parasite contractility and release of 
immunomodulatory molecules by the parasite (18).  IVM also has direct effects on the parasite nervous 
system and muscle function as it enhances strength of inhibitory neurotransmission pathways.  
Neurotoxicity has not been observed in humans given single dose IVM for LF or other parasitic 
infections, and the drug has been used to treat many millions of people with LF and onchocerciasis (19).  
Peak IVM serum concentrations are reached approximately 4-5 hours after administration. The half-life 

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of IVM in various populations ranges from 12 to 56 hours (20).  The drug is highly bound to serum 
proteins (93%), and is converted to 10 metabolites by CYP3A4, with nearly no IVM detectable in the 
urine.  Animal studies demonstrate that most of the cleared drug is found unchanged in the feces; this is 
likely to be true in humans. There is no evidence of drug:drug interaction between ABZ and IVM (21). 
 
Diethylcarbamazine (DEC)  
DEC is an anthelminthic drug that is structurally distinct from ABZ and IVM (22).  The drug has potent 
microfilaricidal activity against LF (with differing kinetics relative to IVM, which has greater activity than 
DEC during the first few weeks following ingestion), and modest to high efficacy in killing of adult worms 
(ABZ has weaker activity against adult worms, whereas IVM is believed not to affect adult worm 
viability) (23).  DEC inhibits arachidonic acid metabolism by LF, and inducible nitric oxide synthase and 
the cyclooxygenase pathway may be essential for activity in vivo (24). DEC also has anti-inflammatory 
properties.  The drug is rapidly absorbed from the gastrointestinal tract, has a serum half-life of 12 to 14 
hours, and is excreted in the urine with little modification by the liver.   
 
Moxidectin (Mox) 
Mox is a macrocyclic lactone derived from the actinomycete Streptomyces cyanogriseus. It is in the same 
class as ivermectin and has a similar mechanism of action, binding to glutamate-gated chloride channels, 
GABA receptors, and/or ATP-binding cassette transporters. This leads to increased permeability, influx 
of chloride ions, hyperpolarization and muscle paralysis. Mox is more lipophilic than ivermectin and 
distributes widely in tissues. The mean half-life of moxidectin in patients with onchocerciasis is 23.3 
days.  This prolonged half-life is presumed to be one reason for its increased efficacy, compared to IVM, 
in achieving sustained clearance of O. volvulus Mf (25).  
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
The combination of IVM plus ABZ as used in this trial has a strong safety record; it has been provided as 
MDA to millions of recipients of MDA for LF (3). As outlined above, the IDA combination is safe when 
used in areas where loiasis and onchocerciasis are non-endemic (26).  AEs are common following 
treatment of filarial infection and are related to drug efficacy in killing Mf. AEs following MoxA or 
MoxDA treatment are likely to be similar to those following treatment with IA or IDA. AEs correlate with 
microfilarial loads in infected individuals and are usually mild and transient. However, SAEs can occur 
when DEC is given to individuals with onchocerciasis or loiasis, or when ivermectin is given to individuals 
with loiasis (27).  Côte d’Ivoire is non-endemic for loiasis. Onchocerciasis is uncommon in the study area. 
We will screen all potential participants found to have LF for coexisting onchocerciasis by skin snip (2 
biopsy sites—1 from each iliac crest). Individuals with microfiladermia will be excluded from the study. 
 
Immediate risks  
Self-limited mild-to-moderate systemic AEs are common following treatment of LF with microfilaricidal 
medications. These include fever, headache, myalgia, fatigue, arthralgia, pruritus, malaise, and 
gastrointestinal symptoms. Systemic AEs usually resolve within 72 hours of treatment.  In a recent 
clinical trial/pharmacokinetic study of IDA for LF treatment conducted in our target study population 
found that 100% of 66 participants receiving IDA experienced at least one systemic AE; nine (14%) 
experienced a grade 2 AE. There were no SAEs and all grade 1 and 2 AEs were self-limited (10). 
 

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Some individuals experience localized AEs following treatment that are related to dying adult filarial 
worms. These AEs can include tender subcutaneous nodules, swollen and tender lymph nodes, testicular 
swelling and/or pain, epididymitis, hydrocele, and lymphedema. Testicular pain is the most common 
localized AE, and occurred in less than 0.1% of persons treated in the large-scale community safety 
studies of DA and IDA (26). We expect similar rates and severity of all AEs following treatment with 
MoxA or MoxDA. 
 
AE profiles for each of the study medications include: 
• 
DEC. The most common side effects are itching and swelling of face, headache, joint pain, 
unusual tiredness or weakness.  These are transient.  Less common are dizziness, nausea or 
vomiting.  Fever, painful and tender glands in groin, neck armpits or skin rash can occur, and are 
usually associated with high burdens of infection as judged by the level of blood Mf. 
• 
ABZ.  Headache, nausea, stomach pain and vomiting are most common, and usually associated 
with heavy geohelminth infections.   Severe allergic reactions occur very rarely, and include 
rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, 
or tongue, dark urine. High dose ABZ occasionally causes reversible reductions in total white 
blood cell count and sometimes results in elevated liver enzymes, which return to normal with 
cessation of treatment. These abnormalities are associated with prolonged ABZ treatment 
courses given for such diseases as neurocysticercosis and hydatid disease, and are highly 
unlikely following single dose treatment as proposed here (15). 
• 
IVM. The most common side effects are diarrhea, dizziness and nausea. Rare side effects include 
rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, 
or tongue, eye pain, swelling, or redness, fainting, and tachycardia.  Mild decrease in leukocyte 
counts, elevated liver function tests, and orthostatic hypotension rarely occur. Infrequently, 
treatment can exacerbate bronchial asthma. 
• 
Mox. AEs following Mox treatment of onchocerciasis in 2 clinical trials were similar to those 
seen with IVM, including eosinophilia, pruritus, musculoskeletal pain, headache, 
lymphocytopenia, tachycardia, rash, abdominal pain, hypotension, fever, and leukocytosis.  
Hyperbilirubinemia and transaminase elevations above 5x the normal limit were rare, but more 
common with Mox than IVM (28). 
 
Long-range risks 
As described above, mild to moderate, self-limited AEs following LF treatment are common. There are 
no known late-onset AEs following single-dose therapy for LF, but there is a theoretical risk of fetal 
toxicity / teratogenicity in pregnant women, which is why they will be excluded from the study.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Individual subjects will benefit from treatment of their W. bancrofti infection, which may decrease their 
risk of developing lymphedema and eventually elephantiasis. Treatment will decrease microfilaremia 
and thereby decrease the risk that participants serve as a reservoir for infection that can be transmitted 
to others in the community via mosquitoes. Participants with intestinal helminths may also benefit from 
the deworming effects of the study medications; those receiving IVM or Mox may also benefit from the 
effects of those medications on scabies or lice infestations. 
 
This study has potential public health benefits, since millions living in LF-endemic areas worldwide stand 
to benefit if new MDA combinations accelerate LF elimination.   
 

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2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
All treatments that effectively clear Mf induce transient AEs in infected individuals. These AEs are self-
limited and of short duration. Benefits of treatment include reducing the risk of long-term disability and 
of perpetuating disease transmission. 
 
As outlined above, to minimize the risk of severe or serious AEs following treatment (particularly if 
treated with either combination including DEC), we will exclude persons with onchocerciasis.   
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine whether Mox 
combination therapies are 
superior to IVM combination 
therapies for achieving 
sustained clearance of W. 
bancrofti microfilaremia. 
The proportion of participants 
in each study arm with 
complete clearance of W. 
bancrofti microfilaremia at 12 
months (IA vs. MoxA 
comparison) or 24 months after 
treatment (IDA vs. MoxDA 
comparison). 
The primary anticipated benefit 
of MoxA/MoxDA is prolonged 
Mf clearance, compared to IA 
and IDA, respectively. 
Secondary 
 
 
Efficacy Outcomes  
1. To compare the efficacy of 
Mox combination therapies 
to IVM combination 
therapies in reducing W. 
bancrofti Mf levels 
 
 
 
 
 
 
2. To compare the efficacy of 
Mox combination therapies 
to IVM combination 
therapies in reducing the 
viability of W. bancrofti 
adult worms 
 
 
 
 
 
 
 
 
1a. The proportion of 
participants in each study 
arm with complete 
clearance of W. bancrofti 
Mf at 6, 12, 24, and 36 
months 
1b. Percent reduction in Mf 
counts (relative to baseline) 
at 6, 12, 24, and 36 months 
after treatment 
 
2a. Percent reduction in 
circulating filarial antigen 
(CFA) levels (relative to 
baseline), at 6, 12, 24, and 
36 months after treatment 
2b. Percent inactivation of adult 
worm nests, as assessed by 
ultrasound at 6, 12, 24, and 
36 months after treatment. 
Prevalence of worm nests at 
the same time points will 
also be assessed. 
 
 
1. Some study arms may not 
achieve complete Mf clearance; 
examining percent reduction 
will provide important data 
about reductions in Mf levels, 
which correlates with 
transmission risk. 
 
 
 
 
2. This will show whether MoxA 
or MoxDA have any 
macrofilaricidal activity. CFA is a 
marker of adult worm viability. 
U/S at 12 months will show 
whether MoxA/MoxDA can 
clear worm nests. Subsequent 
U/S will assess for the possibility 
of re-infection 
 
 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Safety Outcome  
3. To compare the safety and 
tolerability of Mox 
combination therapies to 
IVM combination therapies 
in men and women with W. 
bancrofti infection 
 
Pharmacokinetic Outcome  
4. To determine the 
pharmacokinetic 
parameters of Mox in W. 
bancrofti infected adults 
and to determine whether 
Mox affects peak levels and 
clearance of DEC and ABZ, 
compared to IVM 
 
3.  Frequency and severity of 
AEs during the first seven 
days after treatment 
 
 
 
 
 
4a. Plasma DEC, ABZ, IVM, and 
Mox levels at baseline, 2, 3, 
4, 6, 12, 24, and 48 hours 
post-treatment 
 
3. AEs following microfilaricidal 
treatment occur in the first 72 
hours, and ~5 days following 
macrofilaricidal treatment. 
 
 
 
 
4. Effect of co-administration of 
Mox may affect DEC and/or ABZ 
levels 
Tertiary/Exploratory  
 
 
To determine the identity of the 
W. bancrofti antigens released 
by treatment 
Liquid chromatography/mass 
spectrometry analysis of W. 
bancrofti antigens released in 
response to treatment. 
May lead to identification of 
improved biomarkers for filarial 
infection 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This study will test the hypothesis that Moxidectin combination therapies are superior to ivermectin 
combination therapies for achieving sustained clearance of W. bancrofti microfilaremia. 
 
This trial is designed as single-site, Phase III, randomized, open-label, masked-observer superiority trial 
with four treatment arms (IA, MoxA, IDA, and MoxDA) with a primary endpoint of proportion of 
participants achieving complete clearance of microfilaremia at 12 months (IA vs. MoxA comparison) or  
24 months (IDA vs. MoxDA comparison).  Block randomization by gender will be used to assign 
treatment arms. The first group of participants will be treated at Agboville Hospital with inpatient AE 
monitoring (Part 1).  The first 48 participants in Part 1 (12 per arm) will also have collection of post-
treatment plasma drug levels for pharmacokinetic analysis (PK study).  For Part 1, active AE surveillance 
will be conducted in the hospital on days 1, 2, and 3, post-treatment, and in the participant’s village of 
residence on day 7 post-treatment and passive surveillance will be conducted by trained village health 
workers on days 4-6.  An interim safety analysis will take place after Part 1.  If no safety concerns are 
identified, the remainder of the participants will be treated in their home villages, with active AE 
monitoring on days 1 and 2 post-treatment (Part 2) with passive surveillance by trained village health 
workers on days 3-7.  Any participant in either Part 1 or Part 2 experiencing AEs of grade 2 or higher will 
be followed until AE severity falls below grade 2. Follow-up assessments for efficacy of treatments for all 
participants (Parts 1 and 2) will be conducted at 6, 12, 24, and 36 months.   

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Due to a prolonged delay between pre-screening and the onset of study enrollment (caused in part by 
the COVID-19 pandemic), participants who had >40 Mf/mL at the time of prescreening may be found to 
have less than 40 Mf/mL at the time of enrollment. The logistics of transporting participants from the 
village and the requirement for nocturnal blood collection for Mf counts make it impractical to await 
results of the baseline Mf count (done the night prior to treatment) before treatment the following 
morning.  The first 48 enrolled participants, including those found to have Mf counts <40/mL at the time 
of enrollment, will be included in the PK analysis.  Because AEs are more likely in participants with high 
Mf counts, total enrollment in Part 1 will continue until at least 12 participants in each study arm with 
>40 Mf/mL have undergone inpatient monitoring. 
 
The study includes both safety and efficacy analyses. The safety assessment (Part 1 only) ends 7 days 
after treatment (unless AEs remain grade 2 or higher). The efficacy assessment (Parts 1 and 2 combined) 
ends when participants are retested for filarial infection 36 months post-treatment.  Participants in the 
IA arm will receive IA annually (standard of care). Participants in the other arms will receive the assigned 
treatment at baseline; those found to be microfilaremic at 24 months post-treatment will be retreated 
with the same treatment received at baseline. If clearance of Mf at 12 months in the IA arm is superior 
to Mf clearance in the MoxA arm, the MoxA group will be switched to annual IA treatment. Participants 
with <40 Mf/mL enrolled in part 1 will be included in the PK and safety analyses, and potentially 
secondary analyses of drug efficacy on adult worms, but only those with Mf counts of at least 40 Mf/mL 
will be included in the primary analysis of efficacy outcomes.  
 
The study design does not currently include stratification, nor do any sub-studies. However, the study 
may stratify based on pre-treatment Mf levels if high variability among pre-screening Mf counts is 
observed.    
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Each of the individual study medications are FDA approved with established dosing recommendations 
and extensive safety data. This will be a superiority study (MoxA vs. IA and MoxDA vs. IDA) because 
significant benefit to the GPELF would only be achieved if MoxA is superior to IA, which is currently the 
standard for LF targeted MDA programs where LF is co-endemic with onchocerciasis. A placebo control 
would be unethical for treatment of persons with microfilaremia.  
 
4.3 
JUSTIFICATION FOR DOSE 
Doses for each of the trial medications are established and FDA-approved.  DEC, IVM, and ABZ doses 
given in this study will match GPELF recommendations for LF MDA; Mox doses will match those 
recommended for onchocerciasis MDA. 
 
4.4 
END OF STUDY DEFINITION 
The end of the study is defined as completion of the last visit or procedure shown in the SOA in the trial 
globally. A participant is considered to have completed the study once he or she has completed the last 
visit (36 month) as shown in the Schedule of Activities (SOA), Section 1.3. 
 

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5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Provision of signed and dated informed consent form 
2. Male or female, aged 18 – 70 years 
3. In good general health as evidenced by medical history  
4. Peripheral night blood W. bancrofti Mf levels >40 Mf/mL 
5. No history of taking antifilarial medications in past 12 months 
6. Resident of the study area with no plans to change residence in the next 36 months 
7. For women of childbearing potential, willing to use appropriate method of contraception for 
one month following each treatment. 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Pregnancy or currently breastfeeding  
2. Known allergic reactions to any of the study medications 
3. Evidence of severe or systemic comorbidities (aside from features of filarial disease), as judged 
by the principal investigator. 
4. Baseline biochemical abnormalities, as indicated by AST, ALT, or creatinine >2 times the upper 
limit of normal. 
5. Evidence of urinary tract infection as indicated by 3+ nitrites on dipstick (individuals with 1+ or 
2+ nitrites will not be excluded) or underlying chronic kidney disease as indicated by 3+ protein 
or 3+ blood on urine dipstick exam. 
6. Hgb <7 gm/dL (any such individuals will be referred to the local health center for evaluation and 
treatment) 
7. Positive skin snip for onchocerciasis 
 
Justification for exclusion of women and children 
Pregnant and/or breastfeeding women will be excluded because ABZ, IVM, and DEC are contraindicated 
in pregnancy and there is insufficient data on Mox safety during pregnancy and during breastfeeding. 
Children will not be included in the trial because Mox is not FDA approved for children aged <12 years, 
and because it will not be logistically feasible to admit children for inpatient observation in Part 1. 
Because we will have no safety data for children from Part 1, we will also exclude children from Part 2. 
 
5.3 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAE. 
 

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Individuals who do not meet the criteria for participation in this trial because of W. bancrofti Mf/mL <40 
at the time of enrollment, or because of elevated AST, ALT, or Cr, may be rescreened one time. If the 
rescreening occurs within 30 days of the initial screening, only the test results not meeting inclusion 
criteria will be repeated at rescreening. If rescreening occurs more than 30 days after initial screening, 
all screening/baseline tests will be repeated. Rescreened participants will be assigned the same 
participant number as for the initial screening. 
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
The study population will be recruited from filariasis-endemic areas of Agboville District (and 
neighboring districts if necessary) in Côte d’Ivoire. We will attempt to recruit equal numbers of men and 
women (18 – 70 years of age) who are willing to participate, although the gender balance will be 
dictated by the availability of subjects meeting inclusion criteria.  
 
Prescreening 
Potential participants will be identified by the Ministry of Health (MOH), as they will conduct their 
routine public health assessment of LF transmission in the Agboville District in the summer of 2019.  
Their activities will include convenience testing of residents in the area for W. bancrofti antigenemia 
using the Filariasis Test Strip (FTS).  In general, the MOH team will coordinate with the village chief and 
local health officers to publicize the screening.  MOH staff will either visit residents at their homes, or, 
more likely, invite residents to be tested for LF at a pre-arranged location (such as the local dispensary, 
school, chief’s home, or other common meeting place). Residents with a positive FTS result of 2+ or 
higher (test line at least as strong as the control line) will be visited at night (between 9:30 PM and 3 
AM) to test for W. bancrofti microfilaremia using either thick blood smear (TBS) of a fingerprick blood 
sample, or Mf filtration of a venous blood sample. This public health assessment will provide the 
necessary pre-screening information (Mf count) to identify potential participants for the study. 
Residents found to have W. bancrofti microfilaremia who have not received MDA for LF within the prior 
12 months will be eligible for screening for inclusion in the trial.  
 
Screening 
Individuals meeting prescreening criteria will be contacted by the study team and invited to participate 
in study screening.  We anticipate that screening for Part 1 will be conducted in two parts: 1) a 
community visit to check nocturnal blood for Mf counts and biochemistries, and urine for dipstick and 
pregnancy test, and 2) prior to treatment at CRFLA for all other baseline assessments. However, if 
logistics dictate otherwise, the activities planned for the community visit may be conducted at CRFLA 
and vice versa.  For Part 2, we anticipate that all screening assessments will be done in the community 
(but may be done at CRFLA if necessary). Screening assessments will include a 10 mL venous blood draw, 
done at night, for serum biochemistry tests, hemoglobin level, physical exam including vital signs, and 
Mf counts by filtration of venous blood. All individuals will also be tested for onchocerciasis by 
examination of skin snip for microfilariae (2 punches, 1 over each iliac crest). Demographic data will be 
collected. Urine will also be tested by dipstick (all participants) and urine pregnancy test (all female 
participants) will be performed.  Male participants will undergo scrotal ultrasound for identification of 
filarial worm nests. 
 
Retention 
Retention in the study will be encouraged/enhanced in several ways.  During inpatient observation (Part 
1), participants will be housed in a comfortable, air-conditioned ward equipped with a dedicated toilet 
and television. None of the 66 participants in a prior inpatient study conducted in the same manner and 

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location left the study during the inpatient observation period. Retention during the 3 years of annual 
follow up (Part 1 and Part 2) will be enhanced by conducting follow-up assessments in participants’ 
home villages. 
 
Compensation 
No compensation will be offered for the MOH community LF assessment (pre-screening).  Individuals 
participating in screening for Part 1 or Part 2, and/or the inpatient observation period (Part 1) will be 
compensated for time and travel expenses (approximately $10/day). No financial compensation will be 
offered for outpatient follow-up visits. However, at each outpatient follow up visit, participants will 
receive a care package of nominal value (for example, soap, canned fish, and bread). 
 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Trial participants will be randomized to receive one of the following interventions:  
Arm 1:  IVM 200 µg/kg + ABZ 400 mg (IA) 
Arm 2: Mox 8 mg + ABZ 400 mg (MoxA) 
Arm 3:  IVM 200 µg/kg + DEC 6mg/kg + ABZ 400 mg (IDA) 
Arm 4:  Mox 8 mg + DEC 6mg/kg + ABZ 400 mg (MoxDA) 
6.1.2 DOSING AND ADMINISTRATION 
Initial treatment 
The study drugs will be taken together orally with liquid. Study drugs will be given as directly observed 
therapy, and participants will be observed for 30 minutes after swallowing of pills. Dosing will follow the 
treatment arms as outlined in 6.1.1 above. Treatment in the hospital (Part I) will occur in cohorts of up 
to 10 participants. This is based on the project’s capacity for transport, examination, and housing of 
participants. In Part 2, treatment medications will also be administered by study staff and be directly 
observed, but will occur in the participant’s village.  
 
Contraception 
Because there is insufficient data about safety of moxidectin during pregnancy, women of childbearing 
potential must agree to adhere to a reliable method of contraception for a period of one months after 
each study treatment. 
 
Repeat treatment  
The IA arm will receive IA annually, which is standard of care for LF MDA in Cote d’Ivoire. All other arms 
will receive the assigned treatment at the time of enrollment. At the 12 month interim analysis, if IA is 
found to be superior to MoxA for the primary endpoint, participants in the MoxA arm will be switched 
to annual IA therapy for the duration of the study. Because it would be unethical to exclude participants 
from ongoing MDA for the duration of the study, participants in the MoxA, IDA, and MoxDA arms who 
do not achieve complete clearance of Mf at 24 months will be re-treated with their assigned therapy 
within one month after the 24 month follow-up visit. All participants who are microfilaremic at the end 
of the study (after the 36-month assessment) will be offered IA treatment per national LF program 
guidelines as a bridge back to annual MDA. 

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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Moxidectin will be donated by Medicines Development for Global Health (MDGH).  IVM, DEC, and ABZ 
will be purchased from Merck, GlaxoSmithKline (GSK), and Pfizer (India), respectively. 
 
Medications will be distributed by a study nurse or other designated staff and ingestion directly 
observed. Unused Moxidectin will be incinerated or returned to MDGH; unused DEC, IVM, and ABZ in 
the original, sealed, packaging will be donated to the CHR Agboville pharmacy. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Package inserts for each of the study medications are attached to this protocol as an appendix.  
 
6.2.3 PRODUCT STORAGE AND STABILITY 
Storage and stability requirements for each study drug are listed below. Study medications will be 
stored at CHR Agboville in a secure, climate-controlled environment between 18 -25°C. Site pharmacist 
will be trained in temperature monitoring for the drugs according to the study SOP for temperature 
monitoring.  
 
Medication 
Package insert storage recommendations 
Albendazole (Albenza) 
Store between 20° and 25°C 
Albendazole (Zentel) 
Store in a dry place at a temperature not exceeding 30°C 
DEC 
Do not store above 30°C; protect from light and moisture 
IVM 
Store at temperatures below 30°C 
Moxidectin 
Store below 30°C; protect from light 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Blinding 
Recognizing that number and appearance of tablets received in each study arm will be noticeably 
different, this will be an open label study. To minimize bias, administration of study medications will be 
performed by a staff member with no role in assessing AEs. AE assessments and all other outcome 
measures will be assessed by observers masked to the treatment assignment. 
 
Randomization 
Allocation sequence for arm assignment will be generated by the study statistician prior to study onset. 
Consenting subjects will be allocated to treatment sequentially according to the randomization list.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Ingestion of study medications will be directly observed. 
 
6.5 
CONCOMITANT THERAPY 
Concomitant medications will be recorded at the time of enrollment/treatment. Medications to be 
reported in the Case Report Form (CRF) are concomitant prescription medications, over-the-counter 

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medications and supplements taken within 48 hours prior to receiving the assigned study treatment 
(medial history), and any medications taken during the safety assessment period (days 1-7 post-
treatment). 
 
Antifilarial medications 
Treatment with antifilarial or other anthelmintic medications other than those provided as part of the 
study is prohibited until after the 36-month assessments are complete. These medications include IVM, 
DEC, ABZ, mebendazole, levamisole, parantel, and doxycycline.  There are no dietary restrictions. 
 
Other prohibited concomitant medications 
The following medications, listed as having class C interactions with albendazole or ivermectin, will not 
be permitted at the time of treatment: warfarin (or other vitamin K antagonists), carbamazepine, 
phenobarbital, phenytoin, azithromycin, erythromycin, or any strong P-glycoprotein inducers/inhibitors, 
listed in the table below.  
 
P-glycoprotein/ABCB1 Inhibitors 
P-glycoprotein/ABCB1 Inducers 
Amiodarone, Azithromycin, Carvedilol, Clarithromycin, 
Cyclosporine, Daclatasvir, Dronedarone, Elagolix, Eliglustat, 
Erythromycin, Flibanserin, Fostamatinib, Glecaprevir and 
Pibrentasvir, Itraconazole, Ivacaftor, Ketoconazole, Lapatinib, 
Ledipasvir, Neratinib, Ombitasvir, Paritaprevir, Propafenone, 
Quinidine, Quinine, Ranolazine, Ritonavir, Rolapitant, Simeprevir, 
Velpatasvir, Vemurafenib, Verapamil 
Apalutamide, Carbamazepine, 
Fosphenytoin, Phenytoin, 
Rifampin, St John's Wort 
 
 
7 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study if any clinical AE, laboratory 
abnormality, or other medical condition or situation occurs such that continued participation in the 
study would not be in the best interest of the participant.   
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
 
7.2 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up for the primary endpoint if he or she cannot be visited 
for the 12-month (IA vs MoxA comparison) or 24-month assessment (IDA vs. MoxA comparison) and is 
unable to be contacted by the study site staff. Persons who miss the 12- or 24-month follow-ups can be 
tested at subsequent visits. 
 

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Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant. These contact attempts should be documented in the participant’s 
medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
The efficacy assessment (procedures) and their timing are summarized in the SOA (section 1.3).  
 
Stay at the health center (Part 1 only) 
Part 1 calls for collection of multiple blood samples and AE assessments for up to 72 hours after 
treatment. Because the study subjects may live some distance from the health center and 
transportation is difficult in the study area, study subjects will be asked to remain in the health center 
during this time.  Part 1 participants will be asked to report at the health center by 6pm.  Baseline 
physical exam, vital signs, AE assessment, and scrotal ultrasound (men only), will be completed the 
evening of admission. Skin snips will be performed if not done previously. Participants will receive study 
treatments the following morning and will remain at the health center for 72 hours after treatment. All 
meals will be provided. CRFLA is equipped with standard hospital beds, private toilets and showers, and 
appropriate staff support. 
 
Ultrasound (Part 1 and Part 2) 
Scrotal ultrasound examination will be performed on all men at baseline, and at 6, 12, 24, and 36 
months post-treatment to identify the presence and number of adult worm nests.  Ultrasound 
examinations will be done by trained examiners and may be done either at CRFLA or at a private 
location in the community. 
 
Treatment 
Study drugs will be administered by study staff as directly observed therapy. 
• 
Part 1: Patients will fast overnight, which is consistent with usual eating patterns in Côte 
d’Ivoire. Following breakfast, study drugs will be administered 
• 
Part 2: Treatment medications will be administered in the participant’s village, and the time of 
day may vary. Because no PK drug levels will be measured in Part 2, there is no requirement for 
pre-treatment overnight fasting. 
 
Collection of samples for drug monitoring (Part 1 only) 
For Part 1 samples (5-10 ml) of heparinized blood will be taken pretreatment and at 2, 3, 4, 6, 12, 24, 
and 48 hours after treatment and at day 7 if there are significant abnormalities at 28 hours. This will be 
accomplished by inserting an indwelling venous catheter into a vein in the forearm using sterile 
technique. The needle will remain inserted for the first 12-24 hours after drug administration.  Five 
milliliters of blood will be taken at time points when only drug tests are performed.  For the time points 
when liver function tests, hematological parameters and Mf counts are also to be evaluated, 5 to 10 ml 
will be removed.  Therefore, a total of 70 to 90 ml of blood will be drawn over a period of approximately 
1 week that includes the screening of individuals prior to enrollment.  Samples will be collected in sterile 
heparinized tubes. Anticoagulated whole blood will be removed for Mf counts (if needed). The 

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remaining whole blood will be centrifuged. Plasma will be aliquoted into cryotubes in duplicate and 
frozen (-20°C) for later testing. Efforts must be made to obtain the pharmacokinetic samples at the listed 
times relative to dosing. However, samples obtained within 10% of the nominal time (e.g., within 6 
minutes of a 60 minute sample) from dosing will not be considered as a protocol deviation, as long as 
the exact time of the sample collection is noted on the source document and CRF. 
 
Collection of venous blood for MF counts and CFA (Parts 1 and 2) 
Approximately 10 ml of blood will be collected at baseline for screening and Mf counts, and at 6, 12, 24 
and 36 months after treatment for Mf counts and CFA assay. An additional 5 ml of blood will be 
collected on day 7 for participants in Part 1 to assess Mf count. 
 
LABORATORY TESTS AND ANALYSIS TO BE PERFORMED AT LOCAL HEALTH CENTER IN CÔTE D’IVOIRE 
OR OTHER COMPARABLE LABORATORIES  
 
Diagnosis of LF and Mf counts  
Individuals will be screened for LF infection based on results of the CFA test and by the presence and 
number of Mf in night blood.  Peripheral venous blood will be obtained after 21:00 hours (Mf counts 
peak at night and are often not detected during the day).  Blood will be collected in heparin-coated 
tubes and 1 mL will be passed through a 5 μM Nuclepore filter. Filters will be dried and stained with 
Giemsa.  The presence and number of Mf on filters will be assessed by light microscopy.  
 
Blood samples for hematologic and biochemical assays  
Biochemistry tests will be performed on site using a portable Piccolo Biochemistry Analyzer (Abbott 
Labs). Hemoglobin will be measured with a HemoCue point of care blood test analyzer.  Aliquots of 
plasma collected as described above will be frozen at -20°C.   Samples will be stored for up to one month 
at -20°C until they can be transferred to CSRS for storage at -80°C.  
 
Urinalysis  
A mid-stream urine will be collected into a clean container.  A dipstick that measures a variety of 
analytes will be used to assess protein, nonhemolyzed blood and nitrates for possible urinary tract 
infection or chronic kidney disease. Urine samples testing strongly positive (2+ or greater) for nitrates, 
leukocyte esterase, or blood, will also be centrifuged for microscopic examination for RBC, WBC, and 
casts.   
 
Samples will be stored for up to one month at -20°C until they can be transferred to CSRS for storage at -
80°C until shipment to the United States. 
 
Skin snips to exclude onchocerciasis  
Two (2) skin snips will be taken (1 from each iliac crest) using a cornea-scleral punch (Holth-type). Each 
snip will be incubated for at least 30 minutes in isotonic saline in a well of a flat-bottomed microtiter 
plate.  The Mf will be counted using an inverted microscope.  The presence and number of O. volvulus 
Mf will be recorded.   
 
ASSAYS TO BE PERFORMED OUTSIDE CÔTE D’IVOIRE   
 
W. bancrofti antigen ELISA 
Serum CFA levels will be quantified at Washington University in St. Louis according to the well-
established Weil lab protocol (29, 30). 

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Plasma drug levels 
Assays for measuring plasma drug levels will be performed in the laboratory of Dr. DJ Murry, College of 
Pharmacy, University of Nebraska Medical Center, as described below. 
 
ABZ and metabolites assay  
Plasma concentrations of ABZ, ABZSO, and ABZSO2 will be determined using a validated liquid 
chromatography-mass spectrometric method using previously published extraction methodology 
(Kitzman, Cheng et al. 2002). The lower limit of quantification for all analytes was 2 ng/mL and the upper 
limit of quantitation was: 520 ng/mL for ABZ and ABZSO2; 1040 ng/ mL for ABZSO. The coefficient of 
variation during validation at LLOQ and the three control levels for intra-day and inter-day precision 
ranged from 1.6% to 13.8%, and 8.0% to 10.7% for ABZ; 3.9% to 10.1% and 7.3% to 14.6% for ABZSO; 
and 2.5% to 12.0% and 7.6% to 10.2% for ABZSO2, respectively. The intra-day and inter-day bias ranged 
from 0.3% to 14.3% and 3.0% to 14.2% for ABZ; -16.2% to 18.5% and -10.6% to 8.8% for ABZSO; and -
11.6% to 16.8% and -10.2% to 15.4% for ABZSO2, respectively.  
 
Diethylcarbamazine assay  
Plasma concentrations of DEC will be determined using a validated liquid chromatography-mass 
spectrometric method using previously published extraction methodology (Miller and Fleckenstein 
2001, Schmidt, King et al. 2014). The calibration curve range is 4 – 2200 ng/mL. The coefficient of 
variation during validation at the three control levels for intra-day and inter-day precision ranged from 
2.1% to 8.2%, and 5.4% to 8.4%, respectively. The intra-day and inter-day bias ranged from -9.7% to 
12.7% and 2.2% to 7.5%, respectively.  
 
Ivermectin assay  
Plasma concentrations of IVM will be determined using a previously published methodology (20). The 
linear range of the calibration curve is 0.20- 400 ng/mL from 0.20 mL plasma.  
 
Moxidectin assay 
Plasma concentrations of Mox will be determined using a previously published methodology (31). 
 
Exploratory assessment of the relationship between cytochrome p450 genotypes and 
pharmacokinetic parameters  
Individual participant cytochrome p450 genotypes may be determined if the investigators feel such 
analysis is warranted based on the results of the PK analyses. For these analyses the screening skin snip 
tissue would be used as a source of genomic DNA (after migration of any O. volvulus Mf out of the 
tissue, the skin snip tissue for participants in Part 1 will be placed in RNAlater and stored at -80°C at 
CSRS in Cote d’Ivoire). If cytochrome p450 analyses are warranted, samples will be shipped to 
Washington University or CWRU for analysis. Any unused skin snip samples will be destroyed at study 
completion. Descriptive statistics for all pharmacokinetic parameters by genotype and drug will be 
calculated for the genotypes found in more than 3 subjects and jointly displayed. For the genotypes 
found in 3 or less subjects, the minimum, median and maximum values for all pharmacokinetic 
parameters by genotype and drug will be displayed. Exploratory plots may be generated if considered 
useful for presentation of the findings. 
 
Additional analyses 
The results of the pre-specified analyses may suggest additional ad hoc analyses that may be 
undertaken. These might include, but may not be limited to, analyses of serum/plasma biomarkers 

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(parasite antigens or human cytokines/inflammatory makers/etc), or additional studies of parasite DNA.  
No human genetic analyses, aside from the cytochrome p450 analysis (if warranted), will be undertaken.  
 
Specimen Preparation, Handling, and Shipping  
Blood plasma and urine samples will be prepared as described above, aliquoted into cryotubes, labeled 
using numbered bar codes and frozen at -20°C in a freezer in the laboratory at the clinic where 
subjects are monitored.   Samples will be transferred to a -80°C freezer in Abidjan until shipment to the 
United States for determination of drug levels.  Following the current study, de-identified samples will 
only be used for other studies if permission was given in the consent form.  If not, samples will be 
destroyed at the completion of the study.  
 
Samples will be shipped to the laboratory of Dr. Christopher L. King at Case Western Reserve University, 
10900 Euclid Ave, Cleveland, OH 44106, and/or to the laboratory of Dr. Philip Budge at Washington 
University in St. Louis, 4444 Forest Park Ave, St. Louis, MO 63108.  Shipping will following International 
Air Transport Association guidelines.   
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Several safeguards are in place to ensure participant safety. No one with evidence of severe comorbidity 
by history, physical exam, or baseline screening labs will be enrolled in the study. The safety of single 
dose LF treatment with IDA has been well established. Self-limited AEs are expected following treatment 
of LF with microfilaricidal medications.  As an extra precaution to ensure that AEs after treatment in this 
trial are consistent with AEs seen in other studies, the first group of at least 48 participants will be 
monitored closely for AEs at CRFLA for three days following treatment. After at least 12 participants with 
Mf counts >40 Mf/mL in each group are treated, if no unexpected safety signals are evident, and with 
approval of the DSMB, the remainder of participants (Part 2) will be treated in the community. Active 
surveillance for AEs for Part 2 will involve visits from the study team on days 1 and 2 following treatment 
and passive surveillance by trained village health workers until day 7.  
 
Monitoring safety variables 
Screening for Cr, AST and ALT will be performed using a portable Piccolo Biochemistry Analyzer (Abbott 
Labs).  Prior to drug administration all subjects will undergo detailed physical examination and urinalysis 
using a dipstick to detect nitrites, protein, and blood. Immediately before drug administration blood 
pressure, pulse, and temperature will be taken. Following drug administration, AE assessments including 
a review of subjective symptoms and vital signs will be performed. If there is any AE with severity grade 
2 or greater, or if there are abnormal vital signs, a targeted physical examination will be performed.  
 
During Part 1, AE assessments will be conducted every 6 hours for the first 48 hours then every 12 hours 
until 72 hours after treatment. If participants are asleep at the AE assessments scheduled for 18 and 42 
hours post-treatment, which will occur at approximately 1 AM, study staff may choose to skip the 
assessment. Urinalysis and venous blood samples to determine serum electrolytes and liver 
transaminases will be obtained at the time of drug administration, and at 24, 48 and 72 hours after 
treatment.  If abnormal and above baseline levels, these will be repeated on day 7 after treatment.  
 
During Part 2, urinalysis, Cr, AST, and ALT will be collected at the day 2 post-treatment visit.  If abnormal 
and above baseline levels, these will be repeated on day 7 after treatment. 
 

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The final study visit for monitoring AEs will be one week following baseline drug administration.  Active 
AE monitoring will not be done following retreatment at 24 months (for those who are Mf positive at 24 
months). As per usual MDA protocol, trained village health workers will be available for passive AE 
surveillance.  In addition, study staff will be accessible post-treatment to assess participants who report 
AEs. 
 
Safety evaluation, AE grading, and safety reporting are described in the accompanying DSMB Charter 
and Safety Plan (Appendices). 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
An AE is any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
A SAE is defined as any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
• 
death 
• 
life-threatening situation (Study participant is at immediate risk of death) 
• 
inpatient hospitalization or prolongation of existing hospitalization (excluding those for Study 
therapy or placement of an indwelling catheter, unless associated with other serious events) 
• 
persistent or significant disability/incapacity (substantial disruption of the ability to conduct 
normal life functions) 
• 
congenital anomaly/birth defect in the offspring of a Study participant who received Study Drug 
• 
Other: Important medical events that may not result in death, be immediately life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse 
 
For clarification: 
• 
Death is an outcome of an AE and not an AE in itself. In reports of death due to “disease 
progression”, where no other information is provided, the death will be assumed to have 
resulted from progression of the disease being treated with the Study Drug(s). 
• 
“Occurring at any dose” does not imply that the participant is receiving Study Drug at the time 
of the event. Dosing may have been given as treatment cycles or interrupted temporarily prior 
to the onset of the SAE, but may have contributed to the event. 
• 
“Life-threatening” means that the Study subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death, if it had occurred 
with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is a SAE 

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• 
“In-patient hospitalization” means the participant has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not include 
presentation and care within an emergency department. 
• 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and/or SAE and not the individual signs/symptoms. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity.   
 
• 
Mild (Grade 1) – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities such as work or school attendance.  
• 
Moderate (Grade 2) –Moderate events may cause some interference with functioning; they 
prevent the participant from working (at home or at their normal work place) or going to school. 
• 
Severe (Grade 3) – Events that interfere with the participant’s usual activities of daily living 
(eating, dressing, walking in the house, getting out of bed) so that the participant requires 
assistance from a friend or family member. Of note, the term “severe” does not necessarily 
equate to “serious”. Persons with severe AEs require medical evaluation to determine whether 
they have a SAE. 
• 
Life-threatening (Grade 4) - Requires transfer to medical facility for inpatient hospitalization and 
treatments. Grade 4 AEs are usually SAEs. 
• 
Death (Grade 5) 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All SAEs must have their relationship to study intervention assessed by the clinician who examines and 
evaluates the participant based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. In a clinical trial, the study product 
must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (de-challenge) should be clinically plausible.  
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 

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can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
8.3.3.3 EXPECTEDNESS  
The principal investigators will be responsible for jointly determining whether an AE is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described in the prescribing information 
(Appendices) for the study medications. 
 
If an AE is graded as severe or serious, the medical monitor will be called upon to give an independent 
opinion on the expectedness and the relatedness to the DSMB for consideration. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits or 
interviews of a study participant presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate CRF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, and time of resolution/stabilization of the event. All AEs occurring during the 7-
day post-treatment observation period must be documented appropriately regardless of relationship. 
All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented as they occur to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
 
The site PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after receipt of the most recent study 
medication.  Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
Procedures for grading and reporting AEs/SAEs during the course of this study are found in the 
corresponding study Safety Plan (Appendix). In general, AEs will be reported to the DSMB in aggregate 
at regular intervals for their review and assessment of risk posed to the participants.  
 

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8.3.6 SERIOUS ADVERSE EVENT REPORTING  
Any SAEs occurring after the first does of Study Drug has been administered must be reported. 
The study clinician will immediately (within 24 hours of becoming aware of the SAE) report the 
occurrence of a SAE to the sponsor, whether or not considered study intervention related, including 
those listed in the Safety Plan. For fatal or life-threatening events, the Investigator is also required to 
send copies of the available hospital case reports, autopsy reports, and other documents when 
requested and applicable. A full SAE report form must be submitted according to the Safety Plan 
procedures including a narrative of the adverse event and an assessment of whether there is a 
reasonable possibility that the study intervention caused the event. SAEs will be reported to the DSMB, 
CNER, and Ivorian FDA within 48 hours of the PI becoming aware of the SAE. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
an unavoidable progression of a chronic condition or at such a time as the participant is stabilized. Other 
supporting documentation of the event may be requested by the Study Sponsor and should be provided 
as soon as possible. 
 
Sponsor’s reporting to the manufacturer 
All SAEs must be reported to the Manufacturer (MDGH) by the Sponsor (Washington University) as soon 
as is practical and within 24 hours of the Sponsor being notified of the event. Follow up information 
provided by the Investigator must also be provided to the MDGH within 24 hours of the Sponsor 
receiving the information. MDGH may request additional information from the Investigator to ensure 
the timely completion of accurate safety reports. 
 
All deaths, regardless of cause, must be reported to the Company for Study subjects on Study and for 
deaths occurring within 90 days of last Study Drug dose or within 30 days of last Study evaluation, 
whichever is longer. 
 
The occurrence and outcome, respectively, of any pregnancy must reported to the Sponsor and the 
Sponsor must notify MDGH within 48 hours of the Sponsor being notified. 
 
8.3.7 REPORTING OF PREGNANCY  
The Investigator is to report all pregnancies within 48 hours of becoming aware of the pregnancy. 
Pregnant and breastfeeding women are not eligible for inclusion in the study. However, if a pregnant or 
breastfeeding woman is accidently treated, the investigators will complete the Pregnancy Report From 
(included as an Appendix of the study Safety Plan) and submit that to the Washington University IRB, the 
Ivorian FDA, and the Ivorian CNER within 48 hours of notification. If a pregnant woman is inadvertently 
dosed, the pregnancy will be followed to its completion (up to one year following the notification) and 
the investigators will report on the outcome of the pregnancy for mother and fetus/infant using the 
associated form (also included as an Appendix in the study Safety Plan).  Any pregnant woman 
inadvertently dosed who has a miscarriage or spontaneous abortion will be reported as a SAE. If a 
participant becomes pregnant more than 30 days after treatment, she may remain in the study, but the 
study will not actively follow the outcome of the pregnancy.  
 
 

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8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
Unanticipated problems involving risks to participants or others to include, in general, any incident, 
experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The site investigator in collaboration with the off-site lead PI will report UPs to the reviewing IRB, the 
Ivorian CNER, and the Ivorian FDA within 48 hours of becoming aware of the UP.  The UP report will 
include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• 
UPs that are SAEs will be reported  
o to the off-site investigators / sponsor within 24 hours (1 calendar day) of the site 
investigator becoming aware of the event.  
o to the Ivorian FDA and Ivorian CNER within 48 hours (2 calendar days) of the 
investigator becoming aware of the event.  
o  to Washington University IRB within 7 calendar days of the investigator becoming 
aware of the event 
• 
Any other UP will be reported to the study sponsor within two weeks of the investigator 
becoming aware of the problem. These will be reported to the Ivorian ERC and FDA and to the 
Washington University IRB within two weeks.  
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
The proposed study is a four-armed (IA annually, MoxA, IDA, and MoxDA), randomized, observer-
masked study to determine the efficacy of moxidectin combination therapy for treating LF in an MDA 
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Hypotheses to be tested:   
1. MoxA is superior to IA for clearance of W. bancrofti Mf at 12 months post-treatment 
2. MoxDA is superior to IDA for clearance of W. bancrofti Mf at 24 months post-treatment 
 
Primary Efficacy Endpoint(s):  
• 
The proportion of each study arm experiencing complete clearance of W. bancrofti Mf at 12 (IA 
vs. MoxA comparison) or 24 months (IDA vs. MoxDA comparison) after treatment 
 
Secondary Efficacy Endpoint(s): 
• 
The proportion of participants in each study arm with complete clearance of W. bancrofti 
microfilaremia at 6, 12, 24, and 36 months after treatment 
• 
Reduction in Mf counts (relative to baseline) at 6, 12, and 24 months 
• 
Reduction in CFA levels (relative to baseline) at 6, 12, and 24 months 
• 
Percent inactivation of worm nests as assessed by ultrasound at 6, 12, and 24 months after 
treatment. Reduction in worm nest count (number of worm nests in all male participants, not 
just among those with nests at baseline) at the same time points will also be assessed. 
 
An exploratory analysis of each of the stated endpoints at 36 months is also anticipated; the utility of 
this analysis will depend on how many participants in the MoxA, IDA, and MoxDA groups require 
retreatment at 24 months. 
 
9.2 
SAMPLE SIZE DETERMINATION 
A prior clinical trial in Cote d’Ivoire found that IDA achieved prolonged clearance of Mf in about 50% of 
participants at 24 months. This study is powered to test the hypothesis that MoxDA is superior to IDA 
for achieving prolonged Mf clearance (80% after MoxDA compared to 50% after IDA at 24 months). A 
sample size of 39 per group is required to have 80% power to detect such a difference in proportions 
with 2-sided type 1 error rate of 0.05. Assuming a loss to follow up rate of up to 22%, we will need to 
enroll 50 participants per arm (200 total) to be able to detect the anticipated difference.  
 
A prior clinical trial in Cote d’Ivoire found that IA achieved complete clearance of Mf in 26% of 
participants at 12 months. A sample size of 44 per group will have 80% power to show a statistically 
significant difference between MoxA and IA, if MoxA achieves clearance in 55% of participants at 12 
months (compared to 26% for IA). Anticipating a loss to follow-up rate of 12% at 12 months, enrollment 
of 50 participants will also provide an adequate sample size for this comparison.  
Although 50 participants per arm will be necessary to test the primary outcomes at 80% power, we aim 
to enroll additional participants, up to 62 per group (248 total), if feasible. This will allow better 
evaluation of secondary outcomes and protect against worse-than-anticipated loss to follow-up. 
 
 
9.3 
POPULATIONS FOR ANALYSES 
A modified intention-to-treat (ITT) analytic approach will be conducted that includes all participants that 
were randomized and have non-missing outcomes at any assessment. Sensitivity analyses may be 
conducted to evaluate the appropriateness of the assumptions made in our analyses. These may include 
multiple imputation, setting missing outcomes to failure to clear Mf, and setting missing outcomes to 
complete clearance of Mf. 
 

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An interim safety analysis will be performed following treatment of the first group participants (Part 1) 
to ensure that the frequency, nature, and severity of AEs occurring after receipt of Mox-combination 
therapy are consistent with AEs following IVM-combination therapy, and with historical data. No pre-
specified interim efficacy analyses are anticipated, but the primary efficacy endpoint for the IA vs. MoxA 
comparison is at 12 months and will determine whether the MoxA arm is continued to study duration or 
is switched to annual IA treatment. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
For descriptive statistics, categorical data will be presented as proportions (or percentages) and 
continuous data will be presented as means (or geometric means) with standard deviations if normally 
distributed or as median, range, and interquartile range if non-normally distributed. For the Mf 
clearance outcome, the subset of participants that are Mf positive in the MoxA, IDA, and MoxDA arms 
will be retreated. In our analysis of Mf clearance, these retreated subjects (those Mf positive at 24 
months) will be assumed to be Mf positive at 36 months (i.e. the 24-month clearance outcome for Mf 
positive subjects will be carried forward to 36 months). For inferential tests a two-sided p-value of 0.05 
will be used to define statistical significance.   
 
Covariates may be pre-specified below or may be added later in the statistical analysis plan (SAP). 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
For the primary endpoints (clearance of Mf at 12 or 24 months), results will be presented as odds ratios 
(with confidence bounds) and the proportion of participants in each arm that achieve complete 
clearance. A repeated measures, logistic regression analysis will be used to assess differences in 
proportion of participants achieving complete Mf clearance between MoxDA and IDA, and between 
MoxA and IA. This analysis will adjust for non-independence due to multiple measurements on the same 
individual. We will also consider adjustment for covariates such as age, sex, and baseline Mf count. The 
primary endpoints will be assessed using planned comparisons to test the statistical null hypotheses of 
(1) no difference in the proportion of participants achieving complete Mf clearance between MoxA and 
IA at 12 months, and (2) no difference in the proportion of participants achieving complete Mf clearance 
between MoxDA and IDA at 24 months. If the Mox treatments have a higher proportion achieving 
complete Mf clearance than their corresponding IVM treatments, then we will conclude that the Mox 
treatments are superior. This same statistical model will also be used for analysis of Mf clearance 
secondary endpoints.  
 
In the unlikely event that we find that IA has statistically greater clearance than MoxA at 12 months, the 
MoxA treatment group will be administered IA annually for the remainder of the study. In this case, 
each of the four groups will still be treated as separate groups in the statistical analyses.   
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Mf clearance at 6, 12, 24, and 36 months will be reported as odds ratios with confidence bounds and 
the proportion of participants that have complete clearance at these time points. Because these 
endpoints are contained within the same statistical model as the primary endpoints (clearance at 12 and 
24 months), we will use the same analytical approach to compare differences in proportions between 
treatments.   
 

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Reduction in Mf count (6, 12, and 24 months) will be reported as the reduction in Mf count compared 
to baseline. Treatment arms will be compared using a repeated measures analysis to account for non-
independence of the outcomes due to multiple measurements on each participant. We will consider 
adjustment for covariates such as age, sex, and baseline Mf count. If the data are highly non-normal 
then an appropriate data transformation (e.g. logarithmic) or a statistical model that assumes a different 
distribution (e.g. negative binomial) will be used. We will also compare Mf “area under the curve” 
(baseline – 24 months) among treatment groups to generate an estimate of transmission potential 
(number of Mf/mL in blood over time). In addition to the change in Mf count, percentage change in Mf 
count (relative to baseline) will be analyzed. If these results are appropriately distributed and provide 
similar statistical inferences as the change in Mf count, then estimates of percentage change will also be 
reported to aid in clinical interpretation of the results. 
 
Reduction in circulating filarial antigen (6, 12, and 24 months) compared to baseline will be analyzed in 
the same manner as reduction in Mf count. 
 
Presence and number of adult worm nests will be assessed for all men at baseline and each follow up 
visit (6, 12, and 24months). The primary focus for this endpoint will be at 12 months post-treatment. 
Any macrofilaricidal effects of treatment should be evident by 12 months, while the presence of worm 
nests at 24 or 36 months might represent re-infection rather than persistence. Because reduction in 
worm nests can only be assessed for the subset of male patients that have active worm nests at 
baseline, one or both of the following analyses will be performed, depending on the proportion of 
participants found to have nests at baseline and the number of worm nests per individual. 
1. Percent inactivation of adult worm nests. The proportion of participants in each group having 
worm nests at baseline who no longer have worm nests.  This will be a binary analysis similar to 
the primary outcome (complete clearance of Mf counts). 
2. Reduction in worm nest counts. This will be analyzed as reduction in number of worm nests 
from baseline. For each participant, the number of nests present at follow-up will be subtracted 
from baseline and the difference (both as a percentage of the baseline, and as a count) will be 
compared between groups. This will be a similar analysis to the Mf and circulating filarial 
antigen analyses. 
The proportion of male participants without worm nests at baseline who are found to have worm nests 
at 6, 12, 24, and 36 months will also be reported, and may indicate the risk of re-infection and/or the 
sensitivity of the assay. 
 
Pharmacokinetic analyses 
This sub-study will test the hypothesis that Mox has no effect on the PK parameters of DEC and ABZ 
(including ABZSO).  
 
Noncompartmental pharmacokinetic analyses of DEC, ABZ, ABZSO, ABZSO2, IVM and Mox 
concentrations will be conducted using WinNonlin (Pharsight Corporation; Cary, North Carolina, USA). 
All calculations will use the nominal blood sampling times as actual times should actual times be 
unavailable. The following parameters will be estimated for the five analytes:  
• 
Cmax: Peak observed concentration post-dose.  
• 
Tmax: Time corresponding to Cmax.  
• 
Half-life: computed as ln(2)/Kel, with Kel being magnitude of the slope of the linear regression 
of the log concentration vs. time profile during the terminal phase. Where R2adj is <0.85 this 
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• 
AUC0-t: Area under the concentration-time curve from Hour 0 through LQCT, where LQCT is the 
time at which the last quantifiable concentration was obtained. Where R2adj is <0.85 this 
parameter will be reported as NE (not estimated). For analytes that did not have at least eight 
calculated values, means and the standard deviation would not be calculated.  
• 
AUC0-inf: Area under the concentration-time curve from 0 to infinity, computed using AUC0-t + 
CLQCT / Kel where CLQCT is the last quantifiable concentration at LQCT. Where R2adj is <0.85 
this parameter will be reported as NE (not estimated). For analytes that did not have at least 
eight calculated values, means and the standard deviation would not be calculated.  
• 
CL/F: Apparent Clearance, will be computed as Dose/AUC0-inf; for ABZ metabolites, dose will be 
adjusted for molecular weight differences relative to the parent. Where R2adj is <0.85 this 
parameter will be reported as NE (not estimated).  
• 
Vz/F: Apparent Volume of Distribution, computed as Dose/(Kel*AUC0-inf); for ABZ metabolites, 
Dose will be adjusted for molecular weight differences relative to the parent. Where R2adj is 
<0.85 this parameter was reported as NE (not estimated).  
 
For all analytes, AUC parameters will be estimated using a linear-log trapezoidal method. The 
pharmacokinetic parameter estimates obtained for each of the analytes will be presented by treatment 
group with provided descriptive statistics including arithmetic mean, standard deviation, coefficient of 
variation, geometric mean, median, minimum, and maximum. Separate descriptive statistics will be 
evaluated by gender.  For all analytes, exposure parameters (Cmax, AUC0-t, and AUC0-inf) adjusted for 
mg/kg dose are provided. For ivermectin, parameter estimates will be adjusted to 200 mcg/kg. For DEC, 
parameters are adjusted to 6 mg/kg. For ABZ, ABZSO, ABZSO2, and Mox, parameters are adjusted to a 
common mg/kg albendazole or Mox dose.  
  
For the drug-disease interaction analysis, individual DEC, ABZSO, and ABZSO2 exposure parameters 
(Cmax, AUC0-t, AUC0-inf) will be natural log transformed. Then, for each analyte and parameter, a 90% 
confidence interval was constructed, in accordance with an independent samples t-test for the 
difference in means between the four study regimens for the Ln transformed parameters. The point 
estimate and limits of each 90% CI will be then exponentiated to yield a 90% CI for the ratio of 
geometric means for each parameter/analyte combination. Comparison of pharmacokinetic parameters 
between treatments will be assessed by ANOVA with treatment as fixed effect and subject within 
treatment as random effect. Exploratory analyses with microfilaria count as a categorical or continuous 
variable may be considered.  
 
Analysis of plasma drug concentrations  
Drug plasma concentrations and computed pharmacokinetic parameters will be listed by subject and 
summarized by drug or metabolite (geometric mean with coefficient of variation, arithmetic mean with 
standard deviation, minimum, maximum, number of observations).  Individual and geometric mean (by 
time) concentrations versus time will be plotted for each treatment group on both linear and natural 
logarithm scales.  
 
Assessment of pharmacokinetic parameters  
The geometric mean, median, arithmetic mean, standard deviation, geometric coefficient of variation, 
minimum, and maximum values for the pharmacokinetic parameters [AUC0-t (primary evaluation 
parameter), AUC0-inf, t1/2, Tmax, Cmax, and residual area of DEC, ABZ, ABZSO, Mox and IVM will be 
reported. Exploratory analyses may be conducted as indicated by the data. 
 
 

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9.4.4 SAFETY ANALYSES 
We will test the hypothesis that the type and frequency of AEs grade >2 will be the same whether Mox 
combination therapy or IVM combination therapy is given. AEs will be MedRA-coded and analyzed both 
as the proportion of participants experiencing each AE (or AE category), and the proportion of 
participants experiencing any AE.  SAEs will be presented in a table or listing.   
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Intervention groups will be compared on baseline characteristics, including demographics (age and 
gender) and laboratory/ultrasound measurements, using descriptive statistics. 
 
9.4.6 PLANNED INTERIM ANALYSES  
One interim analysis for safety will be conducted after Part 1 (inpatient/pharmacokinetics) has been 
completed.  The primary outcome for this analysis will be proportion of participants experiencing AEs. 
These data will be reviewed by the DSMB for the purpose of determining whether the number and 
severity of AEs are consistent with AEs expected following single-dose treatment (27).  The DSMB will 
then make a recommendation about moving forward with treatment in the community (Part 2). Because 
the number of treated participants at the time of this analysis will be small, the decision to proceed to 
community-based treatment or to continue inpatient treatment/monitoring will not rely on inferential 
tests of hypothesis. 
 
Additional interim analyses will be performed at 6, 12, and 36 months post-treatment to evaluate 
secondary endpoints. 
 
9.4.7 SUB-GROUP ANALYSES 
The pharmacokinetic parameter will be analyzed separately by sex, as well as in aggregate. Other 
endpoints may be analyzed by subgroups, but no other subgroups are pre-specified, given the small 
sample size. 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to screening or 
administering study drugs.  The following consent materials are submitted with this protocol. 
• 
Informed consent for study enrollment English (Appendix) 
• 
Informed consent for study enrollment, French (Appendix) 
 

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10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Description of the informed consent process 
The informed consent process will start before enrolment of participants, and it will involve both 
community and individual consent.  The informed consent process recognizes the community and 
cultural values in Côte d’Ivoire and in Agboville district where the study participants reside. Extensive 
discussion of risks and possible benefits of participation in this study will be provided to the community, 
the study participants and their relatives. This will be accomplished through a series of community 
meetings in which the investigators, co-investigators and Ministry of Health representatives explain and 
discuss the purposes of the research study to residents at study sites and to field assistants who may 
refer study participants for more information about this study.  The investigators and study personnel 
who will obtain consent from study participants all have received training in human subjects’ regulations 
and good clinical practice (GCP).  
  
Following consent by community leaders to include participants of their village into the study, the study 
team will invite all interested adult community members in areas known to have levels of LF infection to 
attend information meetings held in several central locations throughout the study areas. At these 
meetings, the study team will describe the purpose and significance of the study, the procedures to be 
followed, the risks and benefits of participation, and state that participation in the study is voluntary and 
that declining to participate will not reduce the level of, or access to, health care for the eligible 
individuals.   
  
Consent forms describing in detail the study procedures and risks will be read at information sessions in 
French.  Formal, written informed consent will be obtained for individuals willing to participate in the 
study and on the evening prior to admission into the health clinic.  The subject will be asked to read, or 
have read to them, and review the informed consent documents. Upon reviewing the document, the 
investigator and/or study staff will explain the research study to the subject and answer any questions 
that may arise.  
  
Only the principal investigators or study staff authorized and certified to obtain informed consent will 
consent subjects for this study.  Only individuals who have signed the consent form and meet eligibility 
criteria will be enrolled in the study.   
  
Entry into the study and participation will be strictly voluntary.  It will be made clear that refusal to 
participate or a decision to withdraw can occur at any time throughout the course of the study and will 
not influence their rights or the care they receive at local health facilities. Potential participants will be 
told that all of their health information will be confidential and that records will be coded without 
personal identifiers before they are shared with statisticians or project scientists outside of Côte 
d’Ivoire. They will also be told that no monetary or other gains are offered in exchange for participation 
apart from compensation for time and reimbursement of travel expenses as described above. 
 
 
Comprehension of informed consent 
Potential participants will have an opportunity to ask additional questions after the information session 
and when they are being consented. To assess comprehension of informed consent and the study, the 
principal investigator and/or authorized consent study staff will ask the following questions:  
  
1. Do you understand the consent form?  
2. Do you have to participate in this study?  
3. Will you stay overnight at the Health Center during the study? (Part 1 only) 

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4. Will we take blood from you during this study?  
5. Can you refuse to participate in the study at any time?  
6. Is there any charge for being in the study?  
7. Will you receive any money for being in the study?  
8. Do you know who to call if you have questions?  
  
The responses will be documented on the consent form, signed by the research staff or principal 
investigator, and a copy given to the study volunteer. In the event a subject indicates a lack of 
understanding of the study, or any aspect of it, the Principal Investigator/study staff will invite questions 
and offer explanations of any particular point.  If, in the judgment of the Principal Investigator, the 
subject’s response still does not reflect an understanding of the study, the subject will not be enrolled in 
the study. 
 
Provisions for Subjects from Vulnerable Populations  
No subjects from vulnerable populations will be included.  Only adult subjects that are otherwise 
healthy and fully capable of making independent decisions on their own will be included.  
 
Plan for women who are pregnant while on study   
Women who are pregnant or breast feeding will not be eligible to enroll in this study because of the 
unknown effects of the drugs and drug combination used in this study.  Women of child bearing age 
who wish to enroll in the study will have a pregnancy test prior to enrolment in the study to ensure they 
are not pregnant. If they are pregnant, they will be eligible for routine MDA for LF that is provided by the 
Ministry of Health after they deliver.   
 
Plan for Inclusion of Illiterate Subjects  
Study participants, if illiterate, will have the information sheet or consent form read to them in the local 
language by a trained field assistant.  Their signature or mark will be witnessed on the consent form, by 
a literate person who understands French and is independent of the study.  For illiterate people who do 
not know French, the field assistant should use the form to explain the study to the participant in 
his/her local language. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated by the principal investigators if 
there is sufficient reasonable cause.  The suspending or terminating party will provide written 
notification, documenting the reason for study suspension or termination, to study participants, 
investigators, and the funding agency. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the CNER, IRB, the DSMB, and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants. A single 
treatment-associated SAE is sufficient to suspend the study, since no SAEs are expected. 
• 
Data that are not sufficiently complete and/or evaluable 
 
If suspended, the study may resume once concerns about safety, protocol compliance, and data quality 
are addressed, and satisfy the sponsor, IRB, DSMB and/or CNER. 

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10.1.3 CONFIDENTIALITY AND PRIVACY  
Privacy of the study participants will be maintained by assigning study participants a unique study 
identification number (UNID). All data, blood samples and laboratory results will be recorded and 
analyzed by UNID with no personal identifiers.  All information collected, including demographic 
information about enrolled subjects will be kept confidential and available only to the investigators and 
authorized study personnel such as the data manager.  After the public information sessions, potential 
participants in the study will have an opportunity to sign the consent form in a private place if they 
choose to be part of the study.    
  
All written forms (i.e. consent and data collection forms) will be securely stored at CRLFA, or alternative 
secured location.  All forms will be labeled and filed in a metal, locked filing cabinet in a secure room 
with a locking door. Keys will be kept by the Data Manager assigned to the study.  All data will be 
entered into a secure electronic data capture system by trained study staff.   The electronic database 
will be password protected and access to password will be authorized by the Principal Investigators.  
Electronic data files will be stored on HIPAA-compliant Washington University (or alternative group-
operated and –dedicated) server. The paper forms will be stored for the duration of the study plus three 
years.  The electronic database will be stored indefinitely by the PI’s.  
  
The Principal Investigators, Co-investigators and key personnel may use the results of this study for 
publications, presentations at scientific meetings or as preliminary data for subsequent grant 
applications. Confidentiality of study participants will be maintained by not including names or personal 
identifiers in records transferred outside of Cote d’Ivoire. Identifiers will be included in a participant key 
that will stay in Cote d’Ivoire.   
  
The study site Project Coordinator will permit access to all documents and records that may require 
inspection by the funding agencies, governmental regulatory agencies, institutional review boards (both 
Washington University IRB and CNER) or its authorized representatives.   
  
The informed consent process and forms are provided in more detail in the appendices. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at Washington University in St. Louis. After the 
study is completed, the de-identified, archived data will be transmitted to and stored at the Digital 
Research Materials Repository at Washington University in St. Louis for use by other researchers 
including those outside of the study.  
 
With the participant’s approval and as approved by local IRBs, de-identified biological samples will be 
stored at Washington University in St. Louis, or at Case Western Reserve University with the same goal 
as the sharing of data. These samples may be used to study the causes of LF, biomarkers for infections, 
complications of filarial infection or treatment, and other conditions for which individuals with LF are at 
increased risk, and to improve treatment. Stored samples will also be provided with a code-link that will 
allow linking the biological specimens with the phenotypic data from each participant, maintaining the 
blinding of the identity of the participant. 
 

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During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data will be provided through Washington University in St. 
Louis. Study samples will not be shared with scientists or institutions that are not participants in the 
study. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigators 
Medical Monitor 
GABO Toki Pascal, MD (Site PI) 
COFFIE Justin Patrick 
Centre Hospitalier Regional d’Agboville, Côte 
d’Ivoire 
PAC-CI, Programme Franco-Ivoirian De 
Recherche Sur Le Vih/Sida Et Les Maladies 
Associées De Côte D’ivoire. 
225 57 45 96 91 
18+225 02 02 47 66 / +225 21 75 59 60 
gabotokipascal@gmail.com 
Emailahuacthi@gmail.com 
 
 
 
Co-Investigators 
KOUDOU Benjamin  
WEIL Gary 
BJERUM Catherine 
FISCHER Peter 
BUDGE Philip 
KING Christopher 
 
The principal investigators ultimately will be responsible for the ethical conduct and compliance of the 
trial. The PIs and co-investigators listed on the title page comprise a Steering Committee responsible for 
overseeing safety and operation of the study.  
 
A local Study Monitor will be hired on a contract basis to ensure the logistical and ethical compliance of 
the trial per ICH standards and Ivorian standards. This will include a pre-study GCP training, site 
assessment and site initiation monitoring.  The study will also contract a Medical Monitor, a physician, 
who will serve to review and evaluate SAEs in collaboration with the site PI of the study. This 
independent clinician will be a local Ivorian. Duties will be to provide un-biased opinion on the narrative 
of the SAE given review of the CRF and relevant diagnostic exam results. The site PI and the U.S. PIs will 
have regular teleconferences to collaboratively reach decisions regarding the conduct and management 
decisions of the trial.  
 
In support of the investigators there are two project management teams – a site team and a U.S. team. 
The U.S team is comprised of a project manager and a data manager who directly support the execution 
and management of the study under the direction of the U.S. PIs. This team provides training and 
technical assistance to the site team. The site team is comprised of physicians, local data managers, 
nurses, technicians, laboratory staff, and other staff as needed. In the day to day conduct of the study, 
the site team reports directly to the site PI. Delegation logs will be maintained throughout the trial to 
document responsibilities.  
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including at least one member with subject matter expertise 

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in LF, one clinical statistician, and one Ivorian physician or scientist. Members of the DSMB will be 
independent from the study conduct and free of conflicts of interest. The DSMB will oversee project 
safety and will therefore be active only during the treatment phase of the study.  The DMSB will operate 
under the rules of an approved charter that will be written and reviewed at the organizational meeting 
of the DSMB, at which time each data element that the DSMB needs to assess will be clearly defined. 
The DSMB will provide its input to the study investigators and study. The DSMB will meet before the first 
participant is treated to approve a charter and discuss the protocol. At a minimum, the DSMB will also 
meet after the inpatient study (Part 1) is completed to review the safety results, and if any SAE is 
reported (treatment-related or not).  It is anticipated that DMSB work will end one week after the last 
participant receives his/her baseline study medications.  The DSMB will not be asked to assess the safety 
of re-treatment of those who are Mf positive at 24 months, since re-treatment will be done according to 
standard MOH MDA practices.  
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with ICH GCP, and with 
applicable regulatory requirements.  
 
Study monitoring will be the responsibility of a qualified clinical monitoring group acceptable to CNER. 
Upon successful approval of the protocol and establishment of the regulatory file, the clinical monitor 
will establish a clinical monitoring plan. To ensure that the investigator and the study staff understand 
and accept their defined responsibilities, the clinical monitor will maintain regular correspondence with 
the site and may be present during the course of the study to verify the acceptability of the facilities, 
compliance with the investigational plan and relevant regulations, and the maintenance of complete 
records. As needed, the clinical monitor may witness the informed consent process or other applicable 
study procedures to assure the safety of subjects and the investigators’ compliance with the protocol 
and GCP. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control (QC) procedures will be implemented beginning with the data entry system.  Edit checks 
will be programmed into the electronic data capture (EDC) system with auditable logs.  Data QC checks 
that will be run on the database will be generated on a regular basis. Any missing data or data anomalies 
will be communicated to the site(s) for query clarification/resolution, preferably during the time while 
the study teams are in the catchment areas. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, ICH GCP, and applicable regulatory requirements.  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 

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10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
CRFs and SOPs have been developed and will be further updated.  All data will be either directly entered 
into an EDC system on tablets (clinical data) or entered on printed forms (laboratory and ultrasound 
data) and subsequently entered into the database. Data management will be performed by persons 
specifically assigned to monitoring and supervising the data entry, its veracity, and confidentiality.   Data 
from the EDC systems will be synced to a secured and dedicated cloud server on a regular basis by the 
on-site data manager. Final database will be stored and archived at the institutions of the study PIs. Data 
will only be shared with personnel with data sharing agreements and will be de-identified. All written 
records will be maintained in locked filing cabinets in a designated room in the originating country and 
will be stored as long as the local in-country IRB requires.       
 
Data Capture Methods  
Data will be electronically entered into the EDC system on portable wifi-enabled tablets by study 
personnel who will be trained in its use prior to enrolment. Paper CRFs will be used as emergency back 
ups and entered into the EDC systems as soon as possible.  
 
Types of Data Collected  
This study will collect the following types of data on each study participant.  The only information that 
will be recorded in the subject’s permanent medical record is that they were diagnosed with LF and 
received a single dose of treatment.   
 
• 
Demographic data (at enrolment only).  This will include age, sex, and village of residence   
• 
Medical history and examination: General physical examination that will include BP, pulse, and 
temperature both at the beginning of the study and throughout the treatment period.  Prior 
history of any symptoms related to LF; chronic symptoms and signs of lymphedema and/or 
hydroceles and history of acute symptoms of lymphangitis and lymphadenitis at onset of the 
study.  
• 
Treatment data – although no treatment for LF will have been given to the study populations 
within the prior 12 months, other drugs subjects might be taking or have recently taken will be 
recorded.    
• 
Subjective behavioral and clinical data (e.g. feeling of nausea, neurological or other subjective 
data related to possible side effects).  Such evaluations will be performed at baseline prior to 
treatment and following treatment.  
• 
Clinical laboratory results, electrolytes and biochemical data  
• 
Prevalence and intensity of Mf levels  
• 
Participant height and weight 
• 
Drug levels (Mox, IVM, ABZ, DEC) 
• 
Results of ultrasound examinations for detection of adult worm nests  
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents will be retained for a minimum of 7 years after the last study visit is complete. 
Documents will be retained longer if required by local regulations. No records will be destroyed without 
the written consent of the sponsor. It is the responsibility of the sponsor to inform the investigator 
when these documents no longer need to be retained. 
 

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10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by 
the site and implemented promptly.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation.  All deviations must be 
addressed in study source documents.  Protocol deviations that affect the safety of subjects and/or the 
integrity of the study must be sent to the reviewing Ivorian CNER and Washington University IRB per 
their policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. Further details about the handling of protocol deviations will be included in the MOP.  
 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
Data will be owned by CSRS. However, it is understood that CSRS will share study data with PIs, co-
investigators, and key personnel for use in publications, presentations at scientific meetings or as 
preliminary data for subsequent grant applications. Confidentiality of study participants will be 
maintained by not using names or personal identifiers in both verbal and electronic communications 
between the site PI and the US PIs. The project will be subject to the DOLF Project Data Sharing and 
Publication Policy (Appendix).  
 
CSRS will permit access to all documents and records that may require inspection by the funding 
agencies, the Ivorian FDA, CNER, the Washington University IRB, or its authorized representatives. 
 
Publication and Authorship 
The results of the study and any interim analyses will be published in one or more papers with 
authorship from the Cote d’Ivoire and the DOLF team. Authorship will be restricted to those persons 
that had significant input into the design, implementation, analysis of the study data, plus significant 
participation in writing or editing the manuscript. A committee comprising the PIs and co-investigators 
listed on the title page will determine when, where and with what authorship order the data will be 
published. 
 

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10.2 ABBREVIATIONS 
 
ABZ 
Albendazole 
ABZSO 
Albendazole Sulfoxide 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
CHR 
Centre Hospitalier Regionale 
(Regional Central Hospital) 
CLQCT 
Concentration at Last 
Quantifiable Concentration 
Time 
CONSORT 
Consolidated Standards of 
Reporting Trials 
Cr 
Creatinine 
CRF 
Case Report Form 
CRFLA 
Centre de Recherche de 
Filariose Lymphatique 
d’Agboville (Filariasis Research 
Center, Agboville) 
CSRS 
Centre Suisse de Recherches 
Scientifiques (Swiss Scientific 
Research Center) 
CYP3A4 
Cytochrome P450-3A4 
DEC 
Diethylcarbamazine 
DOLF 
Death to Onchocerciasis and 
Lymphatic Filariasis Project 
DOT 
Directly Observed Treatment 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-Linked-Immunosorbent 
Assay 
ERC 
Ethics Review Committee 
FA 
Filarial Antigen 
FDA 
Food and Drug Administration 
FTS 
Filariasis Test Strip 
GABA 
Gamma-Aminobutyric Acid 
GCP 
Good Clinical Practices 
GPELF 
Global Programme to Eliminate 
Lymphatic Filariasis 
GSK 
GlaxoSmithKline 
Hgb 
Hemoglobin 
IA 
Ivermectin/Albendazole 
ICH GCP 
International Conference on 
Harmonization of Good Clinical 
Practice 
IDA 
Ivermectin/DEC/Albendazole 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
IVM 
Ivermectin 
LF 
Lymphatic Filariasis 
LQCT 
Last Quantifiable Concentration 
Time 
MDA 
Mass Drug Administration 
MDGH 
Medicines Development for 
Global Health 
MedDRA 
Medical Dictionary for 
Regulatory Activities 
Mf 
Microfilaria 
MOH 
Ministry of Health 
MOP 
Manual of Procedures 
Mox 
Moxidectin 
MoxA 
Moxidectin/Albendazole 
MoxDA 
Moxidectin/DEC/Albendazole 
NCT 
National Clinical Trial 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PNL-SGF 
Programme National de la Lutte 
Contre la Schistosomiase, les 
Geohelminthiases et la Filariose 
Lymphatique 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
SS 
Skin Snip 
STH 
Soil-Transmitted Helminths 
TBS 
Thick Blood Smear 
U/S 
Ultrasound 
UA 
Urinalysis 
UP 
Unanticipated Problem 
WHO 
World Health Organization 
 
 

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11 REFERENCES  
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Budge PJ, Herbert C, Andersen BJ, Weil GJ. Adverse events following single dose treatment of lymphatic 
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28. 
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List of Appendices 
A. Prescribing Information for Study Medications 
B. Informed Consent Forms 
C. Safety Plan 
D. DSMB Charter 
E. DOLF Project Data Sharing and Publication Policy