A Randomized, Double Blind, Parallel Trial in the Democratic Republic of Congo (DRC) Comparing the Safety and Efficacy of Annual or Biannual Doses of Moxidectin or Ivermectin for Treatment of Onchocerciasis
Phase: PHASE3
Conditions: Onchocerciasis
Sponsor: Medicines Development for Global Health

 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
Study Title: 
A randomized, double blind, parallel trial in the Democratic 
Republic of Congo (DRC) comparing the safety and efficacy of 
annual or biannual doses of moxidectin or ivermectin for 
treatment of onchocerciasis  
Sponsor: 
Medicines Development for Global Health 
Level 1, 18 Kavanagh Street 
Southbank, Victoria 3006, Australia 
Investigational New Drug 
(IND) Number (if applicable): 
IND 126876 
Protocol Number: 
MDGH-MOX-3001 
Medical Monitor: 
Dr Jolanta Airey 
Consultant Clinical Development Physician 
SJA Consulting Services, Australia 
Telephone: +61 409 020 209  
Protocol Version/Date: 
Current: 
Final v 04 
(incorporating 
Amendments 1, 
2 and 3) 
Date: 
12 Jan 2023 
 
Prior version: 
Final v 03 
(including 
Amendments 1 
and 2) 
Date: 
30 Jun 2020 
 
CONFIDENTIALITY STATEMENT 
This study is being performed in compliance with Guidelines for Good Clinical Practice (GCP) as 
described in this protocol and all essential documents are being archived. 
Until publication of this protocol following approval by the Ministère de la Santé Publique de la 
République Démocratique du Congo (MdSP) and the Ethics Committee (EC) assigned by the 
MdSP, any unpublished information contained in this document is the property of, or under the 
control of the Sponsor, and is provided to you in confidence as an Investigator, potential 
Investigator, or consultant, for review by you, your staff, and the MdSP and the EC. The 
information is only to be used by you in connection with authorized clinical studies of the 
investigational product described in the protocol. Prior to publication, you will not disclose any of 
the information to others without written authorization from the Sponsor, except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 
 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 2 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
 
STUDY ACKNOWLEDGEMENT 
 
 
 
A randomized, double blind, parallel trial in the Democratic Republic of 
Congo (DRC) comparing the safety and efficacy of annual or biannual doses of 
moxidectin or ivermectin for treatment of onchocerciasis  
 
Protocol Number: MDGH-MOX-3001 
 
This protocol has been approved by the Sponsor. The following signature documents this 
approval. 
 
 
 
 
 
Name (Printed) 
Signature 
 
 
 
 
Date (dd mmm yyyy) 
 
 
 
 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 3 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details to conduct this study as described. I will conduct this study as outlined herein and in 
accordance with the principles outlined in the Declaration of Helsinki (2013), the International 
Ethical Guidelines for Health-related Research Involving Humans (2016), the ICH Good 
Clinical Practice guidelines (ICH E6(R2), 2016) and all applicable regulations and any updates 
to these if issued during the course of this study. I will make a reasonable effort to complete the 
study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by the Sponsor. I will discuss this material with them to ensure that they 
are fully informed about the drugs and the study. 
 
 
 
 
 
 
Principal Investigator’s Name (Printed) 
Signature 
 
 
 
 
Date (dd mmm yyyy) 
 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 4 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
STUDY SYNOPSIS 
Protocol No.: 
MDGH-MOX-3001 
Study Title: 
A randomized, double blind, parallel trial in the Democratic Republic 
of Congo (DRC) comparing the safety and efficacy of annual or 
biannual doses of moxidectin or ivermectin for treatment of 
onchocerciasis.  
Investigational Products: 
moxidectin, ivermectin, placebo 
Indication: 
Onchocerciasis. 
Development Phase: 
3b 
Treatment arms: 
1. Annual moxidectin treatment with 8 milligram (mg) per oral at 
Day 0, Months 12 and 24. 
2. Annual ivermectin treatment with approximately 
150 microgram/kilogram (µg/kg) per oral at Day 0, Months 12 
and 24. 
3. Biannual moxidectin treatment with 8 mg per oral at Day 0, 
Months 6, 12, 18 and 24. 
4. Biannual ivermectin treatment with approximately 150 µg/kg per 
oral at Day 0, Months 6, 12, 18 and 24.  
To maintain the study blind, participants randomized to annual 
moxidectin or ivermectin will receive placebo at Months 6 and 18.  
The randomization algorithm will yield the following allocation ratios 
among the 4 treatment arms: 1:1 allocation ratio for the moxidectin 
biannual vs moxidectin annual treatment arms, 1:1 allocation ratio for 
the ivermectin biannual vs ivermectin annual treatment arms, 3:1 
allocation ratio for moxidectin vs ivermectin for both the biannual and 
annual treatment arms. 
Primary objectives: 
To evaluate and compare: 
• The efficacy of moxidectin 8 mg at Month 12 after administration 
of one dose (at Day 0) and after administration of two doses (at 
Day 0 and Month 6) in individuals with O. volvulus infection; and  
• The safety of repeat dosing of moxidectin 8 mg and ivermectin 
(approximately) 150 µg/kg administered annually for three doses 
or biannually for five doses, up to 12 months after the last dose 
(Month 36). 
Secondary objectives: 
To evaluate and compare the efficacy of moxidectin 8 mg and 
ivermectin (approximately) 150 µg/kg administered annually or 
biannually to individuals with O. volvulus infection, in terms of 
microfilariae densities in the skin and the anterior chamber of the eyes 
up to Month 36. 
Exploratory objectives: 
To evaluate the impact of the four treatment regimens on: 
• Clinical signs and symptoms of onchocerciasis; and 
• O. volvulus macrofilariae.  

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
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(incorporating Amendments 1, 2 and 3) 
Primary endpoints: 
• Proportion of Full Analysis Set (FAS) participants in the 
moxidectin annual and biannual treatment arms with zero 
O. volvulus skin microfilariae at both Months 6 and 12 (sustained 
microfilariae response, SMR12);  
Microfilaridermia is determined by the count of four skin snips for 
each participant at each assessment;   
• Safety across all dose groups will be evaluated by the incidence 
and severity of adverse events (AEs) and measurement of vital 
signs up to and including Month 36 and liver function tests up to 
and including Month 12.   
Secondary endpoints:  
The following will be determined for each treatment arm: 
• 
SMR, defined as zero O. volvulus skin microfilariae sustained at 
all post-Baseline assessments up to and including each of Months 
12, 18, 24, 30 and 36, respectively;  
• Sustained ocular microfilariae response, defined as zero live 
O. volvulus microfilariae in the anterior chambers of the eyes at 
all post-Baseline assessments up to and including each of 
Months 12, 18, 24, 30 and 36, respectively, in those with live 
microfilariae in the anterior chambers of the eyes before the first 
treatment;  
• Mean and median percent reduction (from pre-treatment) of skin 
microfilariae density (microfilariae per milligram, mf/mg) and live 
microfilariae in the anterior chambers of the eyes at Months 6, 12, 
18, 24, 30 and 36;  
• The proportion of participants in each treatment group with zero 
skin microfilariae and zero live microfilariae in the anterior 
chambers of the eyes at each post-Screening assessment; 
• Mean skin microfilariae density at each post-Screening 
assessment and the mean and mean change from baseline; and 
the same endpoints for the number of live microfilariae in the 
anterior chambers of the eyes at each post-Screening 
assessment in those with live microfilariae in the anterior 
chambers of the eyes before the first treatment. 
Exploratory endpoints: 
The following will be determined across all dose groups: 
• The proportion of participants with, and nature and severity of, 
signs and symptoms of onchocerciasis at 
Months 6, 12, 18, 24, 30 and 36 in those with onchocerciasis 
signs and symptoms at Screening; and 
• The viability and fertility of male and female macrofilariae as 
determined by histopathology after nodulectomy 12 months after 
the last treatment. Nodulectomies will be performed only if the 
number of individuals with palpable nodules and who may agree 
to nodule excision is considered sufficiently high to support 
conclusions on the relative effect of the four treatment regimens. 
Study design: 
This is a randomized, double-blind, active controlled, single center, 
parallel clinical trial.  
Number of participants: 
At least 320. 
Study duration/participant: 
Approximately 3 years. 
Number of centers: 
One coordinating center. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
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(incorporating Amendments 1, 2 and 3) 
Inclusion criteria: 
1. Provision of written informed consent, or assent with parental or 
guardian written consent. 
2. Mean ≥ 10 O. volvulus mf/mg skin, determined by four skin snips. 
3. Living in a village selected for the study.  
4. Age ≥ 12 years.  
5. All female participants of childbearing potential must commit to 
the use of a reliable method of birth control for the duration of 
treatment and until 3 months after completion of dosing with 
investigational product. 
Exclusion criteria: 
1. Pregnant or breast-feeding. 
2. Any concurrent condition that, in the opinion of the Investigator, 
would preclude evaluation of response to treatment or would pose 
undue risk to the participant's health. 
3. Has received ivermectin, oral diethylcarbamazine (DEC) or 
doxycycline (for > 2 weeks) within 6 months of Baseline. 
4. Has received treatment with an investigational agent within the 
last 30 days (or 5 half-lives, whichever is longer) prior to Baseline. 
5. Known or suspected allergy to ivermectin or moxidectin or their 
excipients. 
6. Self-reported planned or ongoing activities within the study period 
that would make it unlikely that a participant will be available for 
all planned treatment rounds and follow-up examinations. 
7. Weight > 88 kilograms. 
8. Infection with Loa loa. 
Duration of treatment per 
participant: 
24 months. 
Study procedures: 
Individuals who provide voluntary written informed consent (or for 
minors, assent with parental/guardian consent) will be screened for 
eligibility. Those meeting all of the inclusion and none of the exclusion 
criteria will be eligible to participate. 
Participants will be randomized to one of the four treatment arms and 
treatment will be observed.  
Participants will be assessed for AEs (type, incidence, severity, 
temporal association with treatment and relatedness), vital signs, liver 
function (until 5 days after Month 12 study drug administration), skin 
microfilariae density, and, if present at Screening, selected 
onchocerciasis signs and symptoms and live microfilariae in the 
anterior chambers of the eyes. Nodulectomies for assessment of 
potential investigational product effect on macrofilariae will be 
conducted 12 months after the last treatment in those providing 
separate written consent. 
Refer to the Schedule of Assessments (Table 1). 
Safety parameters: 
See parameters detailed in Table 1. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
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Specialized analyses: 
Assessment of skin microfilariae densities will be based on four skin 
snips from each participant (one from each iliac crest and each calf) at 
each assessment (i.e. Screening and every 6 months throughout the 
study). The samples will be weighed, immersed in normal saline for at 
least 8 hours and the emerging microfilariae counted by trained 
laboratory staff using an inverted microscope.  
Live microfilariae in the anterior chamber of the eye will be determined 
with a portable slit lamp.  
Viability and fertility of macrofilariae in the excised nodules will be 
determined via histopathology, provided nodulectomies are performed 
because the number of individuals with palpable nodules and who 
may agree to nodule excision is considered sufficiently high to support 
conclusions on the relative effect of the treatment regimens. 
Sample size: 
The total sample size of 320 participants and randomization ratio will 
provide safety data for up to a total of 960 exposures to moxidectin 
and 320 exposures to ivermectin, providing a probability of around 
0.99 and 0.80 to detect at least 1 or more AEs with a true background 
rate of 0.005, respectively, assuming exposures are independent. This 
is considered to provide sufficient data for assessment of safety. 
The sample size of 120 subjects per moxidectin group provides an 
approximate power of 90% at a two-tailed alpha level of 0.05 for the 
comparison of the primary outcome, SMR at Month 12 (SMR12) in the 
biannual versus annual moxidectin treatment arms. 
Statistical analyses: 
The primary efficacy hypothesis is a test of the average treatment 
effect with respect to achieving a sustained microfilariae response at 
Month 12 (SMR12) when comparing FAS participants in the 
moxidectin biannual versus annual treatment arms. The average 
treatment effect will be estimated by the standardized risk difference 
(RD) using the methodology outlined by Steingrimsson and 
colleagues (Steingrimsson et al. 2017).   
Further analyses: 
The data from this study will be combined with the data from other 
studies to model the time to O. volvulus elimination with annual or 
biannual mass drug administration with moxidectin or ivermectin and 
the cost-effectiveness of each strategy. 
Data Safety Monitoring 
Board Review: 
A data safety monitoring board (DSMB) will undertake a review of 
serious adverse events (SAEs) reported during the first month after 
each round of treatment to advise the Sponsor on continuation of the 
study.  
 
 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
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Table 1: Schedule of Assessments 
 
 
Screenin
g  
Baseline 
Follow Up 
Ear
ly 
Exi
t i 
D-30 to -1 D-1 
to D0 D0 
D1 
to 5 
M6 
(+/-
1M) 
M6 
+D1 
to 5 
M12 
(+/-
1M) 
M12 
+D1 
to 5 
M18 
(+/-
1M) 
M18 
+D1 
to 5 
M24 
(+/-
1M) 
M24 
+D1 
to 5 
M30 
(+/-
1M) 
M36 
(+/-
2M) 
Written informed 
consent a 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Concurrent 
Conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concurrent 
Medications 
X 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs b 
X 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nodule count 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Onchocerciasis signs 
and symptoms 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Urine pregnancy test c 
X 
Xf 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Ocular microfilariae 
count d 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Ocular examination d 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Loa assessment e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin snips 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Determination of 
eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function tests g  
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X h 
Randomization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational 
product 
administration 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Blood pressure and 
pulse rate 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Nodulectomy j 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviations:  D: day; M: month. 
a Written informed consent (or assent with parental/guardian written consent) will be obtained separately for Screening, study participation and 
nodulectomy. 
b Body temperature, respiratory rate, pulse rate and blood pressure assessed semi-supine at Screening and before each treatment; Pulse rate and 
blood pressure on Day 1 to 5 after each investigational product administration. 
c For women and girls of childbearing potential who will also undergo counselling on contraception. 
d Follow up examinations for participants as indicated by findings at Screening. 
e If participant has lived or worked or is currently temporarily working in an area endemic for loaisis or reports symptoms compatible with Loa infection 
such as a history of eye worm. 
f Targeted physical examination, concurrent medication, and vital signs if > 3 days, and pregnancy test only if > 1 day have elapsed since Screening. 
g Pre-treatment and at Day 5 after dosing (D0, Month 6 and Month 12 only). 
h If early exit is before Day 5 after dosing at Day 0, Month 6 or Month 12  
i Not required in case of withdrawal at or after the Month 30 visit. 
j If the number of individuals with palpable nodules is sufficiently high to support conclusions of histopathological evaluation on the relative effect of the 
treatment regimens, or if requested by participants 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
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1 
TABLE OF CONTENTS 
1 TABLE OF CONTENTS ................................................................................................... 9 
2 INTRODUCTION............................................................................................................. 17 
 
ONCHOCERCIASIS .................................................................................................... 17 
 
CURRENT TREATMENT AND UNMET NEED ................................................................. 17 
 
MOXIDECTIN ............................................................................................................ 18 
2.3.1 
Nonclinical Data ....................................................................................... 19 
2.3.1.1 
Pharmacology ................................................................................... 19 
2.3.1.2 
Nonclinical Safety ............................................................................. 19 
2.3.1.2.1 Safety Pharmacology ........................................................................ 19 
2.3.1.2.2 Toxicology ......................................................................................... 20 
2.3.1.3 
Absorption, Distribution, Metabolism and Excretion ......................... 20 
2.3.2 
Clinical Data ............................................................................................. 21 
2.3.2.1 
Clinical Pharmacology ...................................................................... 21 
2.3.2.2 
Clinical Safety ................................................................................... 22 
2.3.2.2.1 Overview of Safety in Healthy Volunteers ......................................... 22 
2.3.2.2.2 Overview of Safety in Individuals with Onchocerciasis ..................... 22 
2.3.2.3 
Clinical Efficacy ................................................................................. 24 
 
STUDY OVERVIEW ................................................................................................... 24 
2.4.1 
Design Rationale...................................................................................... 25 
2.4.2 
Study Population and Location ................................................................ 26 
2.4.3 
Rationale for Efficacy Assessments ......................................................... 29 
3 OBJECTIVES AND ENDPOINTS ................................................................................... 30 
 
OBJECTIVES ............................................................................................................ 30 
3.1.1 
Primary Objectives ................................................................................... 30 
3.1.2 
Secondary Objective ................................................................................ 30 
3.1.3 
Exploratory Objectives ............................................................................. 30 
 
ENDPOINTS ............................................................................................................. 30 
3.2.1 
Primary Endpoints .................................................................................... 30 
3.2.2 
Secondary Endpoints ............................................................................... 30 
3.2.3 
Exploratory Endpoints .............................................................................. 31 
4 STUDY DESIGN ............................................................................................................. 32 
 
STUDY DESIGN ........................................................................................................ 32 
 
DOSING REGIMENS .................................................................................................. 32 
 
NUMBER OF PARTICIPANTS AND RANDOMIZATION ..................................................... 32 
 
STUDY SITE ............................................................................................................. 32 
 
STUDY DURATION FOR EACH PARTICIPANT ............................................................... 32 
 
ESTIMATED DURATION OF THE STUDY ...................................................................... 32 
 
CONCURRENT SAFETY STUDY.................................................................................. 32 
5 PRE-STUDY ENGAGEMENT ......................................................................................... 34 
 
COMMUNITY MOBILIZATION ...................................................................................... 34 
 
COORDINATION AND COLLABORATIONS WITH THE LOCAL HEALTH SYSTEM ................ 34 
5.2.1 
National Program for Neglected Tropical Diseases Control using 
Preventive Chemotherapy ....................................................................... 34 
5.2.2 
National Program of Reproductive Health ............................................... 34 
5.2.3 
Local Health Facilities .............................................................................. 34 
5.2.4 
Relais Communautaires (Community Liaisons) ....................................... 35 
 
INFORMATION TO LOCAL MEDIA ................................................................................ 36 
 
CONSULTATIONS WITH RELIGIOUS, VILLAGE/COMMUNITY LEADERS, AND ELDERS ...... 36 
 
CONSULTATION WITH VILLAGE COMMUNITIES ........................................................... 36 
5.5.1 
Cultural and Socio-economic Characteristics of the Population from 
which Participants will be Recruited ......................................................... 36 
5.5.1.1 
Primary Recruitment Area ................................................................. 36 
5.5.1.2 
Backup Recruitment Area ................................................................. 37 
5.5.2 
Community Meetings ............................................................................... 37 

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6 STUDY PARTICIPANT POPULATION .......................................................................... 39 
 
PARTICIPANT RECRUITMENT AND RETENTION ........................................................... 39 
 
INFORMED CONSENT AND ASSENT WITH PARENTAL/GUARDIAN CONSENT ................. 40 
6.2.1 
Informed Consent and Assent with Parental/Guardian Consent for 
Screening ................................................................................................. 40 
6.2.2 
Informed Consent and Assent with Parental/Guardian Consent for 
Study Participation ................................................................................... 41 
6.2.3 
Informed Consent and Assent with Parental/Guardian Consent to 
Nodulectomies ......................................................................................... 41 
 
ELIGIBILITY CRITERIA ............................................................................................... 41 
6.3.1 
Inclusion Criteria ...................................................................................... 41 
6.3.2 
Exclusion Criteria ..................................................................................... 42 
 
OTHER ELIGIBILITY CONSIDERATIONS....................................................................... 42 
6.4.1 
Pregnant and Breast-feeding Women ...................................................... 42 
6.4.2 
Loa loa Infection ....................................................................................... 43 
 
REFERRAL OF INDIVIDUALS NOT ELIGIBLE FOR STUDY PARTICIPATION ...................... 43 
 
RESCREENING ......................................................................................................... 44 
7 SCHEDULE OF ASSESSMENTS AND PROCEDURES ............................................... 45 
 
STUDY SCHEDULE OF EVALUATIONS ........................................................................ 45 
 
VISIT WINDOWS ....................................................................................................... 45 
 
STUDY PROCEDURES .............................................................................................. 45 
7.3.1 
Screening (Day -30 to Day -1) ................................................................. 45 
7.3.2 
Randomization and Investigational Product Preparation ......................... 46 
7.3.3 
Baseline and Confirmation of Eligibility (Day – 1 to 0) ............................. 46 
7.3.4 
Investigational Product Administration (Day 0) ........................................ 46 
7.3.5 
Daily Assessments on the First Five Days after Each Investigational 
Product Administration ............................................................................. 46 
7.3.6 
Assessment on the Fifth Day after Investigational Product 
Administration at Day 0, Month 6 and Month 12 ...................................... 47 
7.3.7 
On-Treatment Visits (Months 6, 12, 18, and 24) ...................................... 47 
7.3.8 
Post-Treatment Visit (Month 30) .............................................................. 47 
7.3.9 
End of Study Visit (Month 36) .................................................................. 48 
7.3.10 
Exit Examination at Early Withdrawal or Early Study Termination ........... 49 
 
DETAILS OF SCHEDULED ASSESSMENTS .................................................................. 49 
7.4.1 
Demography ............................................................................................ 49 
7.4.2 
Medical History, Concurrent Conditions and Prior and Concurrent 
Medications .............................................................................................. 50 
7.4.3 
Physical Examination ............................................................................... 50 
7.4.4 
Onchocerciasis Signs and Symptoms ..................................................... 50 
7.4.5 
Vital Signs ................................................................................................ 50 
7.4.6 
Weight and Height ................................................................................... 51 
7.4.7 
Pregnancy Test ........................................................................................ 51 
7.4.8 
Quantification of Skin Microfilariae Density .............................................. 51 
7.4.9 
Ophthalmological Assessments ............................................................... 51 
7.4.10 
Liver Function Tests ................................................................................. 52 
7.4.11 
Diagnosis of Loa loa Infection .................................................................. 52 
7.4.12 
Evaluation of the Effect on Macrofilariae ................................................. 52 
7.4.12.1 Nodulectomy ..................................................................................... 52 
7.4.12.2 Histopathological Examination of Excised Nodules .......................... 53 
7.4.13 
Collection and Processing of Biological Specimens ................................ 53 
8 INVESTIGATIONAL MEDICINAL PRODUCT ................................................................ 54 
 
RANDOMIZATION AND TREATMENT ALLOCATION ........................................................ 54 
 
BLINDING ................................................................................................................ 54 
 
UNBLINDING ............................................................................................................ 54 
 
FORMULATION ......................................................................................................... 55 

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SUPPLY, PACKAGING AND LABELLING, STORAGE AND HANDLING ............................... 55 
 
DOSAGE AND ADMINISTRATION ................................................................................ 56 
8.6.1 
Moxidectin ................................................................................................ 56 
8.6.2 
Ivermectin ................................................................................................ 56 
 
DISPENSING AND ACCOUNTABILITY .......................................................................... 57 
 
SHIPMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 57 
9 CONCURRENT MEDICATIONS .................................................................................... 58 
 
SPECIAL DIETARY REQUIREMENTS ........................................................................... 58 
 
PROHIBITED CONCURRENT MEDICATIONS ................................................................ 58 
 
PERMITTED INVESTIGATIONAL PRODUCTS ................................................................ 58 
10 ADVERSE EVENTS AND MANAGEMENT ................................................................... 59 
 SAFETY ASSESSMENTS ............................................................................................ 59 
 ADVERSE EVENTS ................................................................................................... 59 
10.2.1 
Adverse Event Definition .......................................................................... 59 
10.2.2 
Grading of Severity of Adverse Events and Evaluation of 
Relationship to Investigational Product .................................................... 59 
10.2.3 
Adverse Event Reporting ......................................................................... 60 
 SERIOUS ADVERSE EVENTS ..................................................................................... 61 
10.3.1 
Definition .................................................................................................. 61 
10.3.2 
Clarification of Serious Adverse Events Definition and Terminology ....... 61 
10.3.3 
Serious Adverse Event Reporting Requirements .................................... 61 
10.3.3.1 SAE Reporting to the Sponsor .......................................................... 61 
10.3.3.2 SAE Reporting to Regulatory Authority and Ethics Committee ........ 62 
 FOLLOW UP OF SERIOUS AND NON-SERIOUS ADVERSE EVENTS ............................... 62 
 PRECAUTIONS FOR TREATMENT WITH MOXIDECTIN OR IVERMECTIN .......................... 63 
10.5.1 
Adverse Reactions Associated with Moxidectin or Ivermectin ................. 63 
10.5.1.1 Clinical, Ophthalmological and/or Systemic Adverse Reactions ....... 64 
10.5.1.2 Edema and Worsening of Onchodermatitis in Individuals with 
Hyperreactive Onchodermatitis (Sowda) .......................................... 64 
10.5.1.3 Encephalopathy in Loa loa Co-infected Individuals .......................... 64 
10.5.1.4 Comparative Data on Adverse Events after Moxidectin and 
Ivermectin Treatment ........................................................................ 65 
10.5.2 
Risks during Pregnancy ........................................................................... 65 
 REPORTING OF PREGNANCIES AND FOLLOW UP OF PREGNANCIES ............................ 65 
 RISKS OF STUDY PROCEDURES NOT ROUTINELY USED IN HEALTH CARE .................. 66 
10.7.1 
Skin Snips ................................................................................................ 66 
10.7.2 
Nodulectomies ......................................................................................... 66 
11 POTENTIAL BENEFITS TO STUDY PARTICIPANTS .................................................. 67 
12 DATA SAFETY MONITORING BOARD REVIEW ......................................................... 68 
13 PARTICIPANT COMPLETION OR WITHDRAWAL AND FOLLOW UP ....................... 69 
 PARTICIPANT COMPLETION ...................................................................................... 69 
 PREMATURE WITHDRAWAL FROM TREATMENT OR THE STUDY ................................... 69 
13.2.1 
Criteria for Premature Withdrawal from Treatment or the Study .............. 69 
13.2.2 
Follow up of Participants Withdrawing or Withdrawn from Further 
Treatment ................................................................................................. 69 
13.2.3 
Follow up of Participants Withdrawing or Withdrawn from the Study ...... 69 
 REPLACEMENT OF WITHDRAWN PARTICIPANTS ......................................................... 70 
 TEMPORARY SUSPENSION OF STUDY CONDUCT ....................................................... 70 
 PREMATURE TERMINATION OF THE STUDY ................................................................ 71 
14 STATISTICAL ANALYSIS .............................................................................................. 72 
 PRIMARY EFFICACY ENDPOINT ................................................................................. 72 
 SECONDARY EFFICACY ENDPOINTS .......................................................................... 72 
14.2.1 
Sustained Skin Microfilariae Response (SMR) ........................................ 72 
14.2.2 
Mean Skin Microfilariae Density ............................................................... 72 

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14.2.3 
Mean and Median Percent Change (Reduction) from Screening 
(Baseline) in Skin Microfilariae Density .................................................... 73 
14.2.4 
Proportion of Participants with Zero Skin Microfilariae at Each 
6 Monthly Assessment ............................................................................. 73 
14.2.5 
Endpoints for Live Microfilariae in the Anterior Chambers ....................... 73 
 EXPLORATORY ENDPOINTS ...................................................................................... 74 
14.3.1 
Signs and Symptoms of Onchocerciasis ................................................. 74 
14.3.2 
Viability and Fertility of Male and Female Macrofilariae ........................... 74 
 SAFETY ENDPOINTS ................................................................................................. 74 
 PRIMARY EFFICACY HYPOTHESIS ............................................................................. 74 
 SAMPLE SIZE ........................................................................................................... 75 
 RANDOMIZATION AND RANDOMIZATION RATIO .......................................................... 76 
 ANALYSIS POPULATIONS .......................................................................................... 76 
14.8.1 
Full Analysis Set ...................................................................................... 76 
14.8.2 
Safety Analysis Set .................................................................................. 76 
14.8.3 
Per Protocol Analysis Set ........................................................................ 76 
 GROUP COMPARABILITY .......................................................................................... 76 
 DATA ANALYSIS METHODS ....................................................................................... 76 
 STATISTICAL AND ANALYTICAL PLAN ......................................................................... 77 
14.11.1 Statistical Analysis of the Primary Efficacy Hypothesis ........................... 77 
14.11.2 Statistical Analysis of Secondary and Exploratory Efficacy 
Endpoints ................................................................................................. 78 
14.11.2.1 SMR12 Additional Pairwise Group Comparisons ............................. 78 
14.11.2.2 SMR18, SMR24, SMR30, and SMR36 ............................................. 78 
14.11.2.3 Mean Skin Microfilariae Density ........................................................ 78 
14.11.2.4 Mean and Median Percent Change (Reduction) from Baseline 
in Skin Microfilariae Density .............................................................. 78 
14.11.2.5 Proportion of FAS Participants with 0 Skin Microfilariae at Each 
6 Monthly Assessment ...................................................................... 78 
14.11.2.6 Live microfilariae in the Anterior Chambers of the Eye ..................... 79 
14.11.2.7 Signs and Symptoms of Onchocerciasis .......................................... 79 
14.11.2.8 Viability and Fertility of Male and Female Macrofilariae as 
Determined by Histopathology of Nodules Excised at Month 36 ...... 79 
14.11.3 Description of Subgroups to Be Analyzed ............................................... 79 
14.11.4 Analysis of Participant Disposition, Demographics, and Baseline 
Characteristics ......................................................................................... 79 
14.11.5 Analysis of Safety .................................................................................... 80 
14.11.5.1 Adverse Events ................................................................................. 80 
14.11.5.2 Vital Signs ......................................................................................... 80 
14.11.5.3 Liver Function Tests .......................................................................... 80 
14.11.5.4 Concomitant medications .................................................................. 81 
14.11.5.5 Pregnancy Outcomes ....................................................................... 81 
14.11.6 Handling of Missing Data ......................................................................... 81 
14.11.7 Interim Analysis ........................................................................................ 81 
14.11.8 Supplemental Analyses for Informing Guidelines and Policies ................ 82 
14.11.9 Update of Statistical Analysis Plans in View of Potential Impact of 
COVID-19 Pandemic on Study Conduct and Data .................................. 82 
15 ETHICAL ASPECTS....................................................................................................... 83 
 DECLARATION OF HELSINKI AND APPLICABLE REGULATIONS ..................................... 83 
 APPROVAL OF STUDY CONDUCT BY THE REGULATORY AUTHORITY ........................... 83 
 ETHICS COMMITTEE APPROVAL ................................................................................ 83 
 REPORTS TO RA AND ECS ....................................................................................... 83 
 PROTOCOL AMENDMENTS ........................................................................................ 83 
 STUDY SITE CAPACITY ............................................................................................. 84 
 STUDY TEAM ........................................................................................................... 84 

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 STUDY INITIATION .................................................................................................... 85 
 INFORMED CONSENT AND ASSENT WITH PARENTAL/GUARDIAN CONSENT ................. 85 
15.9.1 
Considerations during the Development of the Participant 
Information Documents ............................................................................ 86 
15.9.2 
Provisions for Informed Consent and Assent with Parental/Guardian 
Consent by Illiterate Individuals ............................................................... 86 
15.9.3 
Provisions for Informed Assent for Minors with Parental/Guardian 
Informed Consent .................................................................................... 86 
 INFORMATION TO STUDY PARTICIPANTS IN CASE OF NEW DATA EMERGING 
DURING THE COURSE OF THEIR STUDY PARTICIPATION ............................................ 87 
 INFORMATION TO STUDY PARTICIPANTS ABOUT ‘INCIDENTAL FINDINGS’ ..................... 87 
 RISKS DUE TO STUDY PROCEDURES ........................................................................ 88 
 RISKS ASSOCIATED WITH INVESTIGATIONAL PRODUCTS ............................................ 88 
 COMPENSATION OF STUDY PARTICIPANTS FOR TIME SPENT ON THE STUDY AND 
COSTS INCURRED FOR TREATMENT OF AN AE IN A LOCAL HEALTH FACILITY .............. 88 
 SAFETY OF STUDY PARTICIPANTS WITHDRAWING PREMATURELY FROM FURTHER 
TREATMENT OR THE STUDY ..................................................................................... 88 
 VOLUME OF BLOOD SAMPLED .................................................................................. 88 
 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PARTICIPANT RECORDS ...................... 89 
 CLINICAL TRIAL INSURANCE ..................................................................................... 89 
 OWNERSHIP AND FUTURE USE OF BIOLOGICAL SPECIMEN REMAINING AFTER 
COMPLETION OF THE PROTOCOL REQUIRED EXAMINATIONS ..................................... 89 
 MAXIMIZATION OF STUDY OUTPUTS FOR IMPROVED TOOLS AND STRATEGIES FOR 
CONTROL/ELIMINATION OF ONCHOCERCIASIS AND OTHER NEGLECTED TROPICAL 
DISEASES ................................................................................................................ 90 
15.20.1 Modelling of Time to Onchocerciasis Elimination and Cost-
Effectiveness of Ivermectin vs Moxidectin-Based Elimination 
Policies..................................................................................................... 90 
15.20.2 Use of Skin Microfilariae and Macrofilariae .............................................. 90 
15.20.3 Use of Left-over Serum and Urine ........................................................... 91 
 COMPLAINTS PROCESS ............................................................................................ 92 
 OWNERSHIP OF STUDY DATA ................................................................................... 92 
 POST-STUDY ACTIVITIES.......................................................................................... 92 
15.23.1 Post-Study Reports to RA and EC ........................................................... 92 
15.23.2 Post-Study Information about the Study to Study Participants ................ 92 
15.23.3 Post-Study Reports to Other Stakeholders .............................................. 92 
 POST-STUDY ACCESS TO MOXIDECTIN ..................................................................... 92 
 PROVISIONS FOR THE IMPLEMENTATION OF THE STUDY DURING THE COVID-19 
PANDEMIC ............................................................................................................... 93 
16 STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING .................................. 95 
 SOURCE RECORDS .................................................................................................. 95 
 ELECTRONIC CASE REPORT FORMS AND DATA MANAGEMENT .................................. 95 
 INVESTIGATOR’S FILES/RETENTION OF DOCUMENTS ................................................. 95 
17 MONITORING, AUDITING AND INSPECTION OF THE STUDY .................................. 97 
 ACCESS TO SOURCE RECORDS ................................................................................ 97 
 MONITORING OF THE STUDY .................................................................................... 97 
 AUDITS AND INSPECTIONS ........................................................................................ 97 
18 CONDUCT OF THE STUDY UNDER US FDA INVESTIGATIONAL NEW DRUG 
APPLICATION ................................................................................................................ 98 
 REPORTING TO US FDA DURING THE STUDY ........................................................... 98 
 REPORTING TO US FDA AFTER THE STUDY ............................................................. 99 
19 PUBLICATIONS ........................................................................................................... 100 
20 REFERENCES ............................................................................................................. 101 
21 APPENDICES ............................................................................................................... 106 
 APPENDIX 1: ADVERSE EVENTS TOXICITY GRADING SCALE ..................................... 106 

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 APPENDIX 2: OVERVIEW OF MEASURES TO MINIMIZE RISK OF TRANSMISSION OF 
SARS-COV-2 VIRUS DURING STUDY CONDUCT BASED ON NATIONAL/LOCAL 
GUIDANCE AS OF 30 JUNE 2020 ............................................................................. 125 
 APPENDIX 3: SUMMARY OF PROTOCOL AMENDMENTS ............................................. 130 
LIST OF TABLES 
Table 1: Schedule of Assessments ....................................................................................... 8 
Table 2: Abbreviations and Acronyms ................................................................................. 15 
Table 3: Treatment Emergent Adverse Events Occurring in > 10% of Moxidectin-
treated Patients with Onchocerciasis in ONCBL60801 (Phase III) ...................... 23 
Table 4: Moxidectin Tablet Components ............................................................................. 55 
Table 5: Ivermectin Tablet Components .............................................................................. 55 
Table 6: Ivermectin Weight Based Dosing Schedule ........................................................... 57 
Table 7: Adverse Event Severity Assessments for Events not Included in the DAIDS 
Table ................................................................................................................... 60 
Table 8: Investigational Product Causality Assessments .................................................... 60 
Table 9: Sample Size by Randomized Treatment Group .................................................... 75 
LIST OF FIGURES  
Figure 1: Skin Microfilariae Densities 1, 6, 12 And 18 Months after a Single Dose of 
Ivermectin (A-D) and after a Single Dose of Moxidectin (E-H) in the 
Phase III Study By Study Area and Pre-Treatment Skin Microfilariae 
Density................................................................................................................. 24 
Figure 2: Map of the Democratic Republic of Congo with its 26 Provinces ......................... 26 
Figure 3: Map of the Zone de Santé Rurale (ZSR) Logo with adjacent ZSR Nyarambe 
in Ituri Province (primary recruitment area) ......................................................... 27 
Figure 4: Map of the Zone de Santé Rurale (ZSR) Aru in Ituri Province (backup 
recruitment area) ................................................................................................. 27 
Figure 5: Results of Rapid Epidemiological Mapping (REMO) of onchocerciasis 
conducted by the national onchocerciasis control program Ituri Nord in 2002 
with the primary and backup recruitment areas encircled in red ......................... 28 
Figure 6: Overview of Recruitment with Stepwise Informed Consent/Assent ...................... 39 
LIST OF APPENDICES  
 
Appendix 1: Adverse Events Toxicity Grading Scale ........................................ 106 
 
Appendix 2: Overview of Measures to Minimize Risk of Transmission of 
SARS-CoV-2 virus during study conduct based on national/local guidance 
as of 30 June 2020 ............................................................................................ 125 
 
Appendix 3: Summary of Protocol Amendments ............................................... 130 
 

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Table 2: Abbreviations and Acronyms 
Abbreviation 
Term 
% 
percent 
< 
less than 
> 
greater than 
± 
plus or minus 
≤ 
less than or equal to 
≥ 
greater than or equal to 
°C 
degrees Celsius 
β-HCG 
beta-human chorionic gonadotrophin 
µg 
microgram 
µL 
microliter 
µM 
micromolar 
µmol 
micromole 
ADaM 
analysis data model 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AP 
alkaline phosphatase 
APOC 
African Programme for Onchocerciasis Control (1995-2015) 
AST 
aspartate aminotransferase 
CECA/20 
20ème Communauté Evangélique au Centre de l’Afrique  
CI 
confidence interval 
CIOMS 
Council of International Organizations of Medical Sciences 
cm 
centimeters 
CNS 
central nervous system 
CRMT 
Centre de Recherche en Maladies Tropicales 
CYP 
cytochrome 
DAIDS 
Division of AIDS 
DEC 
diethylcarbamazine 
DPS 
Division Provinciale de la Santé  
DRC 
Democratic Republic of Congo 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDCTP 
European & Developing Countries Clinical Trials Partnership 
eSource 
Electronic Source, defined as data captured directly into a permanent 
electronic record 
FAS 
full analysis set 
FRRRC, or FR3 
NIH-NIAID Filariasis Research Reagent Resource Center 
GABA 
gamma aminobutyric acid 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
Ha 
alternative hypothesis 
H0 
null hypothesis 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IC50 
50% inhibitory concentration 
IND 
investigational new drug 
kg 
kilogram 
LDH 
lactate dehydrogenase 
LD50 
50% lethal dose 
MDGH 
Medicines Development for Global Health 
MdSP 
Ministère de la Santé publique (Ministry of Health) 
mf 
microfilariae 
mg 
milligram 

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Abbreviation 
Term 
mmHg 
millimeter of mercury 
mL 
milliliter 
N 
number 
NDA 
new drug application 
NTD 
neglected tropical diseases (MTN Maladies Tropicales Négligées) 
O. volvulus 
Onchocerca volvulus 
OR 
odds ratio 
P-gp 
P-glycoprotein 
PICF 
participant information document and informed consent and assent forms 
PK 
pharmacokinetics 
QT 
cardiac Q-wave to T-wave 
RA 
Regulatory authority, the unit in the MdSP responsible for authorizing and 
overseeing use of investigational products 
REMO 
Rapid Epidemiological Mapping of Onchocerciasis 
RD 
risk difference 
SAE 
serious adverse events 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SFP 
study focal point (village member(s) selected by the villagers to serve as focal 
point(s) within a village) 
SMR 
sustained microfilariae response 
SMR12 
zero O. volvulus skin microfilariae counts at both Months 6 and 12 
SMR18 
zero O. volvulus skin microfilariae counts at all of Months 6, 12, and 18 
SMR24 
zero O. volvulus skin microfilariae counts at all of Months 6, 12, 18 and 24 
SMR30 
zero O. volvulus skin microfilariae counts at all of Months 6, 12, 18, 24, and 30 
SMR36 
zero O. volvulus skin microfilariae counts at all of Months 6, 12, 18, 24, 30, 
and 36 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half life 
TEAE 
treatment emergent adverse event defined as AEs which start after the first 
administration of investigational product 
tmax 
median time of maximum observed concentration 
US$ 
United States dollars 
US FDA 
Food and Drug Administration of the United States of America 
WHO 
World Health Organization 
WHO/TDR 
UNICEF/UNDP/World Bank/WHO Special Programme for Research and 
Training in Tropical Diseases 
ZSR 
Zone de Santé Rurale (Rural Health Zone), administrative health care unit in 
rural areas of DRC. A ZSR includes several Aire de Santé. 
 

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2 
INTRODUCTION 
 
Onchocerciasis 
Onchocerciasis (river blindness) is a serious, debilitating, and stigmatizing parasitic disease 
caused by the helminth Onchocerca volvulus (O. volvulus). It is recognized as an important 
public health issue by health authorities worldwide and is listed by the World Health 
Organization (WHO) (World Health Organization and African Programme for 
Onchocerciasis Control 2015) and United States (US) Food and Drug Administration (FDA) 
(United States Food and Drug Administration 2020) as one of the Neglected Tropical 
Diseases (NTDs) for which new treatments are sought.  
Onchocerciasis is endemic in sub-Saharan Africa. More than 200 million people are 
currently considered to be at risk of infection (World Health Organization 2018). 
Onchocerciasis is the second leading cause of infectious blindness (after trachoma) and the 
fourth leading cause of preventable blindness worldwide. In addition to substantial ocular 
and cutaneous morbidity, excess mortality of visually impaired and non-impaired individuals 
with heavy onchocercal infection accounted for 5% of deaths in the area of the 
Onchocerciasis Control Program in West Africa (a WHO managed international 
collaboration that ran between 1974 to 2002) (Prost and Vaugelade 1981, Pion et al. 2002, 
Little et al. 2004). 
O. volvulus larvae are transmitted to humans by the bite of black flies (genus Simulium), 
which breed in fast-flowing rivers and streams. The larvae develop into mature adult worms 
(macrofilariae) and become encapsulated in nodules, from which they release millions of 
microfilariae that migrate through the skin and into the eyes. Macrofilariae have an 
estimated life span of approximately 10 to 14 years. The O. volvulus microfilariae are the 
cause of the clinical manifestations of onchocerciasis which include pruritus, dermatitis, 
depigmentation and atrophy of the skin, lymphadenitis, and visual impairment leading to 
blindness. The skin microfilariae are the reservoir of transmission of the parasite by the 
vector (Remme et al. 2017)  
The Global Burden of Disease 2013 study estimated that onchocerciasis is the sixth highest 
cause of NTD-related years lived with disability, predominantly due to onchocercal skin 
disease (Herricks et al. 2017). In the Global Burden of Disease study 2017, it was identified 
as the leading cause of years lived with disability for the Democratic Republic of the Congo 
(DRC) (Vos et al. 2017). The disease reduces income-generating capacity, incurs substantial 
health expenditures, and exerts a devastating socioeconomic effect on already challenged 
communities. 
 
Current Treatment and Unmet Need 
Ivermectin is an endectocide approved in 1996 for the treatment of onchocerciasis in the US 
and is available through the Mectizan Donation Program to all onchocerciasis endemic 
countries, including 29 countries in sub-Saharan Africa, for treatment of onchocerciasis. It is 
the current standard of care for onchocerciasis. The recommended regimen for the treatment 
of onchocerciasis is a single oral dose of ivermectin 150 μg/kg.  
In sub-Saharan Africa, including the DRC, ivermectin mass drug administration is now the 
standard strategy of onchocerciasis control programs. It is implemented as community 
directed treatment with ivermectin, with height, rather than weight-based dosing, and most 
commonly with a retreatment interval of 12 months. More than 200 million people are 
currently considered to require community directed treatment with ivermectin. In the DRC, 
39.8 million people received ivermectin in 2018 among an estimated 50.4 million requiring 
mass drug administration (World Health Organization 2018). 

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Epidemiological evaluations via microscopic examination of skin snips and health impact 
assessments conducted by the African Programme for Onchocerciasis Control (APOC, 1995 
to 2015) in collaboration with country control programs (including in the DRC) have shown 
that long term community directed treatment with ivermectin significantly reduces 
O. volvulus infection prevalence and morbidity (Coffeng et al. 2014, Tekle et al. 2016).   
Despite the positive impact of ivermectin treatment, onchocerciasis is still a cause of 
significant morbidity. Incomplete clearance of dermal or ocular microfilariae and/or rapid 
repopulation have been observed in a substantial subset of both ivermectin-naïve and 
ivermectin-experienced O. volvulus-infected individuals (World Health Organization and 
African Progamme for Onchocerciasis Control 2015, Awadzi et al. 2004, Awadzi et al. 2004, 
Ardelli et al. 2005, Osei-Atweneboana et al. 2007, Basanez et al. 2008, Pion et al. 2011, 
Bakajika et al. 2013, Coffeng et al. 2013). This also occurred in ivermectin-treated 
participants in the moxidectin Phase III study, which included 472 participants from Ituri and 
487 from Nord-Kivu of the DRC (Opoku et al. 2018, Bakajika et al. 2022). Using a 
responder definition of < 20% of pre-treatment skin microfilariae density at 6 months and 
≤ 40% of pre-treatment skin microfilariae density at 12 months, there were no suboptimal 
responders at Month 6 in the moxidectin group and 10/941 (1.1%) at Month 12. By contrast, 
59/492 (12.0%) and 88/481 (18.3%) ivermectin recipients were suboptimal responders at 
Months 6 and 12, respectively. 
The primary goal of onchocerciasis control in Africa has recently shifted from control as a 
public health problem (reduction of morbidity and transmission in meso- and hyperendemic 
areas: i.e. areas with villages with around 35 to 60% and > 60% infection prevalence, 
respectively (Prost 1987)) to elimination of infection and transmission across all endemic 
areas. The time of elimination using ivermectin alone is predicted to be after 2040 in some 
territories (Kim et al. 2015). As summarized by APOC, which supported onchocerciasis 
control until 2015, the global health community recognizes that onchocerciasis will not be 
eliminated without new tools and strategies (World Health Organization and African 
Programme for Onchocerciasis Control 2015). 
In the Phase II and III studies conducted in Ghana, Liberia and the DRC (Ituri, Nord Kivu), a 
single dose of moxidectin was superior to a single dose of ivermectin in reducing 
microfilaridermia and in maintaining low microfilariae densities for 18 months after dosing 
(Awadzi et al. 2014, Opoku et al. 2018). Consequently, moxidectin has the potential to 
accelerate progress towards elimination of onchocerciasis (Turner et al. 2015). 
 
Moxidectin 
Moxidectin is a macrocyclic lactone of the milbemycin class. It is semi-synthetically derived 
from the actinomycete Streptomyces cyanogriseus. 
Evaluation of moxidectin for its utility for onchocerciasis control was initiated by the 
UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in 
Tropical Diseases (WHO/TDR) executed by WHO. The pharmaceutical company with 
which WHO/TDR was working for potential regulatory registration of moxidectin 
discontinued the collaboration. WHO licensed all data to Medicines Development for Global 
Health (MDGH), the Sponsor of this study. MDGH raised the funds, initiated discussions for 
registration with the US FDA, completed development and assembly of the New Drug 
Application (NDA) and submitted the NDA to the US FDA in 2017 (Sullivan and Kuesel 
2018). 
Moxidectin 8 mg was approved in June 2018 by the US FDA for the treatment of 
onchocerciasis due to O. volvulus in patients aged 12 years and older (information available 
at www.accessdata.fda.gov/scripts/cder/daf). This study corresponds to one of the 

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commitments MDGH made to the US FDA. It is, along with a pediatric study to determine 
the moxidectin dose for 4 to 11 year olds (MDGH-MOX-1006, Study 1006, 
https://clinicaltrials.gov/ct2/show/NCT03962062), being conducted under a US FDA 
Investigational New Drug (IND) Application. For further information see Sections 15.24 
and 1). In addition, MDGH will concurrently conduct a large single-dose safety study 
(Protocol number MDGH-MOX-3002, Study 3002) in Ituri (and potentially other locations) 
based on discussions with the WHO Neglected Tropical Disease Department. 
Prior to submission of this protocol to the Regulatory Authority (RA) within the Ministère 
de la Santé publique de la République Démocratique du Congo (MdSP) and the ethics 
committee (EC) in DRC, it underwent scientific and regulatory review by the US FDA and 
requested changes were implemented.  
This section presents a brief summary of the known preclinical and clinical data of 
moxidectin that formed the basis for the June 2018 US FDA approval. A detailed description 
of the chemistry, pharmacology, efficacy and safety of moxidectin is provided in the current 
moxidectin Investigator’s Brochure. The current approved prescribing information for use of 
moxidectin tablets for onchocerciasis is available at Drugs@FDA 
(www.fda.gov/drugsatfda).  
2.3.1 
Nonclinical Data 
2.3.1.1 
Pharmacology 
The primary pharmacology of moxidectin is proposed to be through binding to the 
glutamate-gated chloride channels. Moxidectin also binds to gamma-aminobutyric acid 
(GABA) receptors and/or adenosine triphosphate-binding cassette transporters. This leads to 
increased permeability, influx of chloride ions, hyperpolarization and muscle 
paralysis (Arena et al. 1995, Martin et al. 2002, Yates et al. 2003). Additionally, there is a 
reduction in parasite motility (Tompkins et al. 2010) and reduced excretion of 
immunomodulatory proteins of both male and female adult worms (Wolstenholme and 
Rogers 2005, Geary and Moreno 2012, Wolstenholme et al. 2016). Studies also suggest that 
while moxidectin is not effective in killing adult worms, it does reduce adult worm fertility 
(Bourguinat et al. 2007, Stitt et al. 2011). 
Moxidectin exhibits anthelminthic activity across the nematode and arthropod phyla (Geary 
and Moreno 2012) and has demonstrated efficacy in a number of Onchocerca species, 
including O. ochengi in cattle (Trees et al. 2000), O. cervicalis in horses (Monahan et al. 
1995, Mancebo et al. 1997), as well as Dirofilaria immitis in dogs (Nolan and Lok 2012). 
Moxidectin was not macrofilaricidal in the O. ochengi model in cattle (Trees et al. 2000).  
For further information, please refer to the Investigator’s Brochure. 
2.3.1.2 
Nonclinical Safety 
2.3.1.2.1 
Safety Pharmacology 
The safety pharmacology of moxidectin has been studied using a panel of in vitro and in vivo 
pulmonary, neurofunctional and cardiac assessments. Moxidectin did not show significant 
binding activity to 64 different biological receptors in the NovaScreen assay. The IC50 value 
for a 50% decrease in the human Ether-a-go-go Related Gene current was calculated at 
> 10 micromolar (µM) (6.4 µg/milliliter (mL)) moxidectin.  
Moxidectin caused mild neurofunctional and respiratory effects in rats as well as a mild 
reduction in heart rate relative to baseline in dogs. Oral administration of 1.0 mg/kg 
moxidectin to beagle dogs resulted in a statistically significant decrease in heart rate, but no 
consistent changes in systolic, diastolic, or mean arterial blood pressure. There were no 

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effects on the electrocardiogram (ECG), including the cardiac Q-wave to T-wave (QT) 
interval.  
For more information, please refer to the Investigator’s Brochure.  
2.3.1.2.2 
Toxicology 
The nonclinical toxicology profile of moxidectin is characterized by low acute toxicity, 
consisting mostly of transient central nervous system (CNS)-related clinical signs. Decreased 
body weight and/or body weight gain were also common findings, which were attributed to a 
change in consumption of food. In single and repeat dose toxicity studies with moxidectin, 
transient CNS signs were reported in mice, rats and dogs. There was no target organ toxicity 
in any of the studies based on evaluation by clinical and anatomic pathology.  
Moxidectin was not genotoxic and showed no carcinogenic potential in lifetime mouse and 
rat bioassays. Moxidectin resulted in increased incidence of malformations in rats at 
maternally toxic doses, but not in rabbits, and decreased pup survival during the lactation 
period in one and three generation pre- and post-natal rat studies.  
Macrocyclic lactones are known to interact with GABA-A receptors, expressed in 
nematodes and in the mammalian CNS. There was no histological evidence for direct 
neurotoxicity of moxidectin in nonclinical studies, but transient neurobehavioral effects were 
noted. Entrance into the brain is restricted by the P-glycoprotein (P-gp) efflux transporter, 
while toxicity is mediated through the brain GABA-A receptors. In P-gp-deficient mice, 
moxidectin was less toxic than ivermectin (50% lethal dose (LD50) was 0.46 and 
2.3 micromole (mol)/kg for ivermectin and moxidectin, respectively), had a lower brain-to-
plasma concentration ratio and entered into the brain more slowly than ivermectin (Menez et 
al. 2012). Higher brain concentrations are required for moxidectin toxicity than ivermectin, 
which causes a greater potentiation of GABA action. Differences in the accumulation of 
ivermectin and moxidectin in the brain and in the interaction of ivermectin and moxidectin 
with GABA-A receptors account for differences in neurotoxicity seen in nonclinical studies 
(Menez et al. 2012). 
For more information, please refer to the Investigator’s Brochure.  
2.3.1.3 
Absorption, Distribution, Metabolism and Excretion 
Moxidectin is a Biopharmaceutics Classification System Class 2 compound with high 
permeability and low solubility, which is not affected by pH.  
The pharmacokinetics of moxidectin in rats and dogs was characterized by oral absorption, 
low plasma clearance, and a high volume of distribution, leading to a long terminal 
elimination half-life (t½). The distribution of moxidectin is governed primarily by its high 
degree of lipophilicity; in rats, moxidectin was shown to be distributed to and reside 
predominantly in fat. Moxidectin is minimally metabolized in vivo. Moxidectin has also 
been shown to be a weak substrate of breast cancer resistance protein/ABCG2 (Perez et al. 
2009). Moxidectin produced weak or no inhibition of seven major human cytochrome (CYP) 
P450 enzymes in vitro but did induce CYP3A4 messenger ribonucleic acid and enzyme 
activity in vitro. However, a subsequent clinical study showed that moxidectin was not a 
CYP3A4 inducer in vivo (Section 2.3.2.1). 
In rats, moxidectin is likely cleared by a combination of biliary excretion of unchanged drug 
and oxidative metabolism. 
For more information, please refer to the Investigator’s Brochure. 

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2.3.2 
Clinical Data 
The moxidectin clinical program to date encompasses eight single oral dose trials spanning 
Phases I to III and involving a total of 1904 participants.  
In the six Phase I studies, 243 healthy volunteers received moxidectin at doses of 3 to 36 mg 
and 16 healthy volunteers received placebo: 
• A single-ascending dose, placebo-controlled, double-masked, safety, tolerability, 
and pharmacokinetic study of orally administered moxidectin in normal volunteers 
(Study 100, protocol 3110A1-100-EU) (Cotreau et al. 2003); 
• A study of the relative bioavailability of a tablet and a liquid formulation of 
moxidectin in healthy participants (Study 101, protocol 3110A1-101-EU)  
(Korth-Bradley et al. 2012); 
• An open-label, single-dose study to evaluate the excretion of moxidectin into the 
breast milk of lactating, non-breastfeeding women (Study 1002, 
protocol 3110A1-1002-EU) (Korth-Bradley et al. 2011); 
• An open-label, single-dose, four-period, sequential study to determine the effect of 
moxidectin on CYP3A4 activity in healthy participants using midazolam as a 
probe substrate (Study 1004, protocol 3110A1-1004-EU) (Korth-Bradley et al. 
2014); 
• An open-label, randomized, single-dose, parallel-group study to determine the 
effect of a high-fat meal on the relative bioavailability and pharmacokinetics of a 
single dose of moxidectin administered orally to healthy participants (Study 1005, 
protocol 3110A1-1005-EU) (Korth-Bradley et al. 2012); and 
• A randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the potential effect of a single oral dose of moxidectin on the cardiac Q-wave to 
T-wave (QT interval) of healthy volunteers (Study 1008, 
protocol MDGH-MOX-1008) (Kinrade et al. 2018). 
In one Phase II and one Phase III study enrolling participants with onchocerciasis, 
1105 participants received moxidectin at doses of between 2 and 8 mg while 539 received 
ivermectin at the standard-of-care dose of 150 µg/kg and as used in ivermectin-based control 
programs: 
• A randomized, single-ascending-dose, ivermectin-controlled, double-blind, safety, 
tolerability, pharmacokinetic, and efficacy study of orally administered 
moxidectin in participants with Onchocerca volvulus infection (Phase II, 
protocol 3110A1-200-GH) (Awadzi et al. 2014); and 
• A single dose, ivermectin-controlled, double blind, efficacy, safety, and 
tolerability study of orally administered moxidectin in participants infected with 
Onchocerca volvulus (Phase III, protocol ONCBL60801) (Opoku et al. 2018). 
2.3.2.1 
Clinical Pharmacology 
Moxidectin displays linear, dose-proportional pharmacokinetics. Following a single oral 
moxidectin dose administered to fasting healthy volunteers, the noncompartmentally derived 
apparent moxidectin plasma clearance ranged from 2760 to 3506 mL/hour in healthy 
volunteers and was 3500 mL/hour in O. volvulus infected individuals. The mean t½ ranged 
from 485 to 1139 hours (approximately 20 to 47 days) in healthy volunteers and was 559 
hours in O. volvulus infected individuals. Moxidectin was rapidly absorbed; the median time 
of maximum observed plasma concentration (tmax) in a fasted state was 3 to 4 hours post-
dose. Moxidectin has a large apparent volume of distribution, and rapid decline of 
moxidectin concentrations occurred within 48 hours of dose administration in all studies, 

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and, thereafter, plasma concentrations declined slowly in accordance with the long t½. 
Population pharmacokinetic analyses showed that the long t½ was governed by tissue 
distribution rate-limited elimination. 
There were no clinically relevant effects of age, sex, race, weight, renal function, or hepatic 
function on the pharmacokinetics of moxidectin from a population-pharmacokinetic model. 
Moxidectin absorption is resilient to the effects of food. Administration of moxidectin in a 
fed state modestly slows absorption and increases bioavailability, although not to a clinically 
relevant extent. Moxidectin does not induce or inhibit clinically relevant drug-drug 
interactions and it is unlikely to be a victim of drug-drug interactions via concomitant 
medications. 
Moxidectin is minimally metabolized and primarily excreted unchanged in the feces. Renal 
clearance of moxidectin and its metabolites is low. Moxidectin was observed in the breast 
milk of lactating women after single dose administration at a relative infant dose of less than 
10% of the maternal dose. 
For more information, please refer to the Investigator’s Brochure.  
2.3.2.2 
Clinical Safety  
2.3.2.2.1 
Overview of Safety in Healthy Volunteers 
Safety data are available from 6 studies in healthy adult volunteers. Moxidectin was well 
tolerated when given as a single dose of between 3 and 36 mg to healthy volunteers. There 
was no treatment or dose relationship in the incidence, nature and severity of AEs identified. 
There were no clinically relevant or treatment-related changes in laboratory parameters, 
physical examination findings, vital signs, or electrocardiograms (ECGs)/cardiac function. In 
placebo-controlled studies, moxidectin had a safety profile similar to placebo. No participant 
withdrew due to an AE and there were no SAEs or deaths. 
AE and laboratory findings reported for each of the completed Phase I studies are 
summarized in the Investigator’s Brochure. 
2.3.2.2.2 
Overview of Safety in Individuals with Onchocerciasis 
In individuals infected with O. volvulus who received treatment that led to the death of 
microfilariae, the common AEs observed are the signs and symptoms associated with 
microfilariae death, i.e. drug efficacy associated AEs, referred to as the “Mazzotti reaction”. 
These reactions are caused by an immune reaction to the dead and dying microfilariae and 
manifest as pruritus, headache, pyrexia, rash, urticaria, hypotension (including symptomatic 
orthostatic hypotension and dizziness), tachycardia, edema, lymphadenopathy, arthralgia, 
myalgia, chills, paresthesia and asthenia. Ophthalmological manifestations include 
conjunctivitis, eye pain, eye pruritus, eyelid swelling, blurred vision, photophobia, changes 
in visual acuity, hyperemia, ocular discomfort and watery eyes. These adverse reactions 
generally occur and resolve in the first week post-treatment. 
The safety of moxidectin has been evaluated in comparison to the safety of ivermectin in two 
studies in O. volvulus infected individuals (3110A1-200-GH and ONCBL60801) (Awadzi et 
al. 2014, Opoku et al. 2018). In both studies, the profile of AEs reported for individuals 
having received moxidectin was similar to the profile in ivermectin recipients.  
In these studies, the most commonly occurring events were signs and symptoms attributable 
to the body's response to dying microfilariae: pruritus, edema, headache, hypotension and 
compensatory tachycardia, rash and urticaria, myalgia, arthralgia, pyrexia and chills, 
lymphadenopathy, paresthesia and asthenia. These events were transient and self-limiting, 
generally occurring and resolving within the first week of treatment. In general, there was a 

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transient (first 48 hours) increase in the number of moxidectin participants reporting 
efficacy-associated AEs compared to ivermectin. There was not an increased need for 
medical or therapeutic intervention for management of efficacy-related events with 
moxidectin when compared to ivermectin. Given that the spectrum of symptoms and severity 
were similar, the treatment guidance to patients and physicians in the US FDA prescribing 
information for moxidectin are otherwise unchanged compared to ivermectin. 
Treatment Emergent Adverse Events (TEAEs) occurring in > 10% of moxidectin-treated 
participants in the Phase III study compared with ivermectin-treated participants are 
summarized in Table 3.  
For further information refer to the Investigator’s Brochure. 
Table 3: Treatment Emergent Adverse Events Occurring in > 10% of Moxidectin-treated 
Patients with Onchocerciasis in ONCBL60801 (Phase III) 
Treatment Emergent Adverse Events 
Moxidectin 
N = 978 
n (%) 
Ivermectin 
N = 494 
n (%) 
Eosinophilia 
721 (74) 
390 (79) 
Pruritus 
640 (65) 
268 (54) 
Musculoskeletal pain a 
623 (64) 
257 (52) 
Headache 
566 (58) 
267 (54) 
Lymphocytopenia* 
470 (48) 
215 (44) 
Tachycardia b 
382 (39) 
148(30) 
  Orthostatic tachycardia c 
333 (34) 
130 (26) 
  Non-orthostatic tachycardia d 
179 (18) 
57 (12) 
Rash e 
358 (37) 
103 (21) 
Abdominal pain f 
305 (31) 
173 (35) 
Hypotension g 
289 (30) 
125 (25) 
  Orthostatic hypotension h 
212 (22) 
81 (16) 
Pyrexia/Chills 
268 (27) 
88 (18) 
Leukocytosis 
240 (25) 
125 (25) 
Influenza like illness 
226 (23) 
102 (21) 
Neutropenia** 
197 (20) 
112 (23) 
Cough 
168 (17) 
88 (18) 
Lymph node pain 
129 (13) 
28 (6) 
Dizziness 
121 (12) 
44 (9) 
Diarrhea/Gastroenteritis/Enteritis 
144 (15) 
84 (17) 
Hyponatremia 
112 (12) 
65 (13) 
Peripheral swelling 
107 (11) 
30 (6) 
a Includes “myalgia”, “arthralgia”, “musculoskeletal pain”, “pain” and “back pain” 
b Includes “orthostatic heart rate increased”, “postural orthostatic tachycardia syndrome”, “heart rate increased” and “sinus 
tachycardia” 
c Includes “orthostatic heart rate increased” and “postural orthostatic tachycardia syndrome” 
d Includes “heart rate increased”, “tachycardia”, and “sinus tachycardia” 
e Includes “rash,” “papular rash” and “urticaria” 
f Includes “abdominal pain”, “abdominal pain upper” and “abdominal pain lower” 
g Includes “orthostatic hypotension”, “blood pressure orthostatic decreased”, “blood pressure decreased”, “mean arterial 
pressure decreased”, “hypotension” 
h Includes “orthostatic hypotension”, and “blood pressure orthostatic decreased” 
*Lymphocytopenia is defined as absolute lymphocyte count less than 1 x 109/L 
**Neutropenia is defined as absolute neutrophil count less than 1 x 109/L 
 
There was no pattern indicating a temporal association with treatment or with body system 
of SAEs occurring in either the 3110A1-200-GH or the ONCBL60801 studies. In both 
studies, there were no SAEs regarded by the investigator (or Sponsor) as being treatment-
related. Treatment-emergent SAEs (occurring during the first 180 days post-dose) are 
presented in the Investigator’s Brochure.   

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2.3.2.3 
Clinical Efficacy 
In the two studies conducted in O. volvulus infected individuals (3110A1-200-GH and 
ONCBL60801), a single dose of moxidectin was superior to a single dose of ivermectin in 
reducing skin microfilariae density and maintaining low skin microfilariae density (Awadzi 
et al. 2014, Opoku et al. 2018). 
In the Phase III study (ONCBL60801), the mean skin microfilariae density at 12 months 
after treatment was significantly lower in the moxidectin group (1.79 mf/mg) than in the 
ivermectin group (9.83 mf/mg) (95% Confidence Interval (CI) for the 
difference -9.11, -6.98, p < 0.0001) (moxidectin Prescribing Information, available at 
www.fda.gov/drugsatfda). Skin microfilariae densities were also significantly lower in the 
moxidectin than the ivermectin treatment group at all other post-treatment time points 
evaluated in this study (Figure 1).  
Figure 1: Skin Microfilariae Densities 1, 6, 12 And 18 Months after a Single Dose of 
Ivermectin (A-D) and after a Single Dose of Moxidectin (E-H) in the Phase III Study By Study 
Area and Pre-Treatment Skin Microfilariae Density 
 
X-axis shows pre-treatment skin microfilariae density on a logarithmic scale; y-axis shows post-treatment skin microfilariae 
density on an arithmetic scale. From Opoku, Bakajika et al. 2018 (Opoku et al. 2018). 
Both ivermectin and moxidectin reduced the number of live microfilariae in the anterior 
chambers of the eyes. 
 
Study Overview 
Onchocerciasis affects all members of a community, with risk of infection increasing with 
transmission exposure over time. A single dose of moxidectin 8 mg was shown to be 
superior to ivermectin 150 µg/kg in suppressing skin and ocular microfilariae in the 
moxidectin Phase II and III studies, in more patients, to a greater extent and for longer.  

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Based on the Phase II and III data, it is anticipated that biannual moxidectin administration 
may be better than annual re-treatment to achieve complete clearance of microfilariae 
between treatments, thus minimizing onchocerciasis symptoms in infected individuals and 
the reservoir for parasite transmission.  
This study is designed to provide comparative data on the safety and efficacy of moxidectin 
given at annual and biannual re-treatment frequencies for two years to assess whether 
biannual dosing with moxidectin results in even greater treatment benefit than annual dosing. 
Furthermore, this study will provide comparative data on the safety and efficacy of 
moxidectin and ivermectin.  
Study 3001 is open to participants meeting all the inclusion and none of the exclusion 
criteria, including adolescents aged 12 to 17 years. This age group was also enrolled in the 
Phase III study and the adolescent data was submitted in 2017 to the US FDA in support of 
moxidectin’s marketing application and is reflected in the US FDA moxidectin Prescribing 
Information. 
An appropriate dose for children under 12 years is yet to be established. A study in children 
4 to 11 years (Study MDGH-MOX-1006, Study 1006)  is being conducted to establish an 
appropriate dose for this age group (https://clinicaltrials.gov/ct2/show/NCT03962062). 
The data from study 3001 will complement already available data as well as those obtained 
from the pediatric study (Study 1006) and the large single dose safety study (Study 3002) to 
inform potential inclusion of moxidectin in onchocerciasis control and elimination 
guidelines and policies.  
2.4.1 
Design Rationale  
A randomized, double-blind study design was selected to minimize bias in treatment 
allocation, participant assessment and recording and management of the study data. Annual 
and biannual treatment was chosen because this reflects the most common ivermectin dosing 
frequencies used by African onchocerciasis control and elimination programs.  
The two year treatment duration with three annual or five biannual treatments was chosen 
because it is expected to be sufficient to inform onchocerciasis elimination programs about 
the relative benefits and risks of the four treatment regimens. To further increase the 
information available for decision making by the programs, the data generated in this study 
will complement those available from previous studies to model time-to onchocerciasis 
elimination with annual or biannual mass administration of moxidectin or ivermectin and the 
cost-effectiveness of these four strategies (Section 15.20.1).  
Randomization in a ratio 3:1 to moxidectin: ivermectin treatment for both the annual and 
biannual treatment arms was chosen to maximize the amount of safety data available for 
moxidectin treatment while ensuring sufficient concurrently obtained data on the safety of 
ivermectin treatment. 
Randomization will be stratified by Aire de Santé of residence to minimize the potential 
impact of confounding effects of the incidence of new infections (which depends on local 
vector density and prior history of ivermectin treatment in the area where study participants 
live and work).  Furthermore, randomization will be stratified by screening skin 
microfilariae density (< 20 mf/mg skin vs. ≥ 20 mf/mg skin) because the frequency and 
severity of some Mazzotti reactions as well as the post-treatment increase in skin 
microfilariae density are impacted by pre-treatment skin microfilariae density (Opoku et al. 
2018). 

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2.4.2 
Study Population and Location 
The study population is designed to be similar to the population recruited into the Phase III 
study: people ≥ 12 years with at least 10 mf/mg skin from areas where community directed 
treatment with ivermectin has not yet or only relatively recently been implemented.  
The study will be conducted in Ituri Province (Figure 2), principally in the Zone de Santé 
Rurale (ZSR) of Logo, with possible extension of the recruitment area into the ZSR of 
Nyarambe (primary recruitment area) (Figure 3). 
In view of civil unrest in these areas or the Ebola outbreak possibly preventing 
implementation or completion of the study in that area, the ZSR of Aru is planned as the 
backup recruitment area (Figure 4).  
Figure 2: Map of the Democratic Republic of Congo with its 26 Provinces 
 

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Figure 3: Map of the Zone de Santé Rurale (ZSR) Logo with adjacent ZSR Nyarambe in Ituri 
Province (primary recruitment area) 
 
 
Figure 4: Map of the Zone de Santé Rurale (ZSR) Aru in Ituri Province (backup recruitment 
area) 
 

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The primary as well as the backup recruitment areas were selected for the following reasons: 
• Epidemiological surveys conducted by the national onchocerciasis control program 
in 2002 indicate that many villages are onchocerciasis meso- or hyper-endemic 
(Figure 5);  
• Data obtained during screening in the ZSR Logo for the Phase III moxidectin study 
found 66.7% were infected with O. volvulus (by skin snip);  
• The areas are not endemic for Loa loa infection; and 
• Ivermectin treatment has not yet been implemented (ZSR Logo and Aru) or only 
relatively recently (since 2016 in the ZSR Nyarambe for lymphatic filariasis 
control).  
 
Figure 5: Results of Rapid Epidemiological Mapping (REMO) of onchocerciasis conducted by 
the national onchocerciasis control program Ituri Nord in 2002 with the primary and backup 
recruitment areas encircled in red  
 
 
Considerations for identifying the villages from which individuals will be recruited will 
include the following: 
• Acceptability of the research to the village community; 
• Prior information on onchocerciasis endemicity including, but not limited to, 
available endemicity data and/or proximity to known vector breeding sites; 

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• The number and timing of prior ivermectin treatment rounds;  
• Accessibility of the village; and 
• Proximity of the village to local health facilities. 
2.4.3 
Rationale for Efficacy Assessments  
Efficacy will be determined by microscopic measurement of O. volvulus skin microfilariae 
density in skin snips, the method used in previous ivermectin and moxidectin studies and the 
most accepted, robust and reproducible quantitative measure of efficacy for microfilaricidal 
drugs. Skin microfilariae are the primary cause of non-ocular morbidity and the reservoir for 
transmission. 
Effects on ocular microfilariae will be assessed by the standard and field-suitable method for 
counting live microfilariae in the anterior chambers of the eyes using a portable slit lamp. 
Ocular microfilariae are the primary cause of ocular morbidity. 
The effect on macrofilariae viability and reproductive activity will be explored via 
histopathology, the standard method used in clinical studies examining this effect, provided 
the number of individuals with palpable nodules and who agree to nodule excision is 
sufficiently high to support conclusions on the relative effect of the treatment regimens. The 
macrofilariae are the source of dermal and ocular microfilariae.  
The effect on onchocerciasis clinical signs and symptoms will be explored for those signs 
and symptoms that are reversible and can be attributed with reasonable certainty to 
O. volvulus infection (reactive skin lesions and pruritus). 
 

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3 
OBJECTIVES AND ENDPOINTS 
 
Objectives  
3.1.1 
Primary Objectives  
The primary objectives of this study are to evaluate and compare: 
• The efficacy of moxidectin 8 mg at Month 12 after administration of one dose (at 
Day 0) and after administration of two doses (at Day 0 and Month 6) in individuals 
with O. volvulus infection; and  
• The safety of repeat dosing of moxidectin 8 mg and ivermectin (approximately) 
150 g/kg administered annually for three doses or biannually for five doses, up to 
12 months after the last dose (Month 36). 
3.1.2 
Secondary Objective  
The secondary objective of this study is to evaluate and compare the efficacy of moxidectin 
8 mg and ivermectin (approximately) 150 µg/kg administered annually or biannually to 
individuals with O. volvulus infection, in terms of microfilariae densities in the skin and the 
anterior chamber of the eyes up to Month 36. 
3.1.3 
Exploratory Objectives  
The exploratory objectives of this study are to evaluate the impact of the four treatment 
regimens on: 
• Clinical signs and symptoms of onchocerciasis; and 
• O. volvulus macrofilariae. 
 
Endpoints  
3.2.1 
Primary Endpoints  
The primary endpoints for this study are: 
• Proportion of FAS participants in the moxidectin annual and biannual treatment arms 
with zero O. volvulus skin microfilariae at both Months 6 and 12 (sustained 
microfilariae response, SMR12);  
Microfilaridermia is determined by the count of four skin snips for each participant at 
each assessment;  
• Safety across all dose groups will be evaluated by the incidence and severity of 
adverse events (AEs) and measurement of vital signs, up to and including Month 36 
and liver function tests up to and including Month 12.   
3.2.2 
Secondary Endpoints 
The secondary endpoints for this study will be determined for each treatment arm and are: 
• SMR, defined as zero O. volvulus skin microfilariae sustained at all post-Baseline 
assessments up to and including each of Months 12, 18, 24, 30 and 36, respectively;  
• Sustained ocular microfilariae response, defined as zero live O. volvulus 
microfilariae in the anterior chambers of the eyes at all post-Baseline assessments up 
to and including each of Months 12, 18, 24, 30 and 36, respectively, in those with 
live microfilariae in the anterior chambers of the eyes before the first treatment;  
• Mean and median percent reduction (from pre-treatment) of skin microfilariae 
density (mf/mg) and live microfilariae in the anterior chambers of the eyes at Months 
6, 12, 18, 24, 30 and 36;  

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• The proportion of participants in each treatment group with zero skin microfilariae 
and zero live microfilariae in the anterior chambers of the eyes at each post-
Screening assessment; 
• Mean skin microfilariae density at each post-Screening assessment, and the mean and 
mean change from Baseline, and the same endpoints for the number of live 
microfilariae in the anterior chambers of the eyes at each post-Screening assessment 
in those with live microfilariae in the anterior chambers of the eyes before the first 
treatment. 
3.2.3 
Exploratory Endpoints 
The exploratory endpoints for this study will be determined across all dose groups and are: 
• The proportion of participants with, and nature and severity of, signs and symptoms 
of onchocerciasis at Months 6, 12, 18, 24, 30 and 36 in those with onchocerciasis 
signs and symptoms at Screening;  
• The viability and fertility of male and female macrofilariae as determined by 
histopathology after nodulectomy 12 months after the last treatment. Nodulectomies 
will be performed only if the number of individuals with palpable nodules and who 
may agree to nodule excision is considered sufficiently high to support conclusions 
on the relative effect of the four treatment regimens. 
 

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4 
STUDY DESIGN 
 
Study Design 
This is a randomized, double blind, active controlled, single center, parallel clinical trial. For 
further details and the rationale, see Section 2.4.1. 
 
Dosing Regimens 
Participants will be randomized to one of the following four treatment regimens: 
1. Annual moxidectin: 8 mg per oral given on Day 0, Months 12 and 24. 
2. Annual ivermectin: approximately 150 µg/kg per oral on Day 0, Months 12 and 24. 
3. Biannual moxidectin: 8 mg per oral on Day 0, Months 6, 12, 18 and 24. 
4. Biannual ivermectin: approximately 150 µg/kg per oral on Day 0, Months 6, 12, 18 
and 24. 
To maintain the study blind, participants randomized to annual moxidectin or ivermectin will 
receive placebo at Months 6 and 18.  
 
Number of Participants and Randomization 
At least 320 eligible participants will be randomized in a ratio of 3:1:3:1 to annual 
moxidectin, annual ivermectin, biannual moxidectin or biannual ivermectin treatment, 
respectively.  
 
Study Site 
This will be a community-based study conducted in the north-east of the DRC coordinated 
by the Centre de Recherche en Maladies Tropicales (CRMT) de l'Ituri. The CRMT was 
established for the moxidectin Phase III study. The infrastructure provided for the Phase III 
study will be utilized and expanded upon for this study. Some of the personnel involved in 
the Phase III study will also work on this study.  
Details on the areas in which participants will be recruited are provided in Section 2.4.2 . 
 
Study Duration for Each Participant 
The study duration for each participant is approximately 3 years including approximately 1 
month for screening and 36 months for treatment and follow up.  
 
Estimated Duration of the Study 
It was originally anticipated that the total duration of the study from initiation to completion 
would be approximately 50 months, comprised of approximately 5 months for recruitment, 
36 months treatment and post-treatment follow up, and 9 months for data analysis and 
reporting. Based on recruitment rates to date, the duration of recruitment has been extended 
to approximately 24 months resulting in a total estimated study duration of approximately 69 
months.  
 
Concurrent Safety Study  
People ineligible for this study (e.g. because their mean skin microfilariae density is 
< 10 mf/mg) and/or people who don’t want to commit to participation in the 3 year Study 
3001 which includes multiple efficacy assessments, will be offered participation in a 
concurrent study.  
In the concurrent study (Study 3002), participants with any skin microfilariae density and 
without detectable skin microfilariae will be randomized to receive a single dose of 
moxidectin 8 mg or ivermectin approximately 150 µg/kg and followed up for adverse events 
for 3 months.  

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Study 3002 will be conducted under a separate protocol (numbered MDGH-MOX-3002) in 
response to information obtained from the WHO Neglected Tropical Disease Department 
regarding safety data required to inform WHO Guidelines on the use of moxidectin for 
onchocerciasis control and elimination. Please refer to that study protocol for more 
information.  
 

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5 
PRE-STUDY ENGAGEMENT 
 
Community Mobilization 
All relevant communities will be provided with general information about onchocerciasis 
and its control, clinical research, and the two studies planned to be conducted in the area 
(this protocol and Study 3002).  
For the purpose of this study, “Community” includes the following groups: 
• Government authorities, including the Governor of the Ituri Province, Ministry of 
Health of the Ituri Province and local security forces;  
• Members of the provincial and national parliament representing the area from 
which participants will be recruited; 
• Civil society (e.g. associations of different professional, religious groups, non-
governmental organizations); 
• Health care authorities including the Director of the Division Provinciale de la 
Santé de l’Ituri (DPS), Health District Officers, coordinators of onchocerciasis and 
lymphatic filariasis control within the Program for Neglected Tropical Diseases 
Control using Preventive Chemotherapy of Ituri Sud at Bunia and/or Ituri Nord at 
Aru as applicable;  
• The National Program of Reproductive Health within the DPS Ituri (supporting 
birth control initiatives and contraceptive use as well as antenatal and postnatal 
care); 
• Staff of the local health care facilities; 
• Local staff of non-governmental organizations including Malteser International 
which supports health care and Sightsavers which supports the local NTD control 
and elimination programs in the implementation of onchocerciasis and lymphatic 
filariasis control activities in Ituri;  
• Staff of local news, radio stations and social media (local media); 
• Village/community leaders and elders, religious leaders; and 
• Inhabitants of the villages from which study participants are planned to be 
recruited (Section 2.4.2 and Section 6.1).  
 
Coordination and Collaborations with the Local Health System 
5.2.1 
National Program for Neglected Tropical Diseases Control using 
Preventive Chemotherapy 
Conduct of this study will be in consultation with the National Program for Neglected 
Tropical Diseases Control using Preventive Chemotherapy, including both the coordinators 
of the program in Ituri and the non-governmental organizations which support this program. 
5.2.2 
National Program of Reproductive Health 
This study will be conducted in consultation with the National Program of Reproductive 
Health within the DPS Ituri so that the contraceptives offered to study participants are 
consistent with those offered by this program in the ZSR of Logo and/or Aru, as applicable. 
This will also ensure that messaging on contraception will be consistent with the messaging 
of that program. 
5.2.3 
Local Health Facilities 
A collaborative relationship will be established with all local healthcare facilities that study 
participants might approach for AEs (whether treatment-related or not). This is to ensure that 

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the study team will be informed about and can report the relevant data in the electronic Case 
Report Form (eCRF) for the following: 
(1) AEs reported by study participants along with any medication/procedures provided 
by the local healthcare staff; 
(2) The findings during ante-natal care visits and any medication/procedures provided by 
the local health care staff should a study participant become pregnant between the 
first, and 3 months after the last investigational product administration (or the partner 
of a study participant becoming pregnant during the equivalent time period, provided 
she agrees to the study team accessing these data); 
(3) The findings of post-natal care visits during the first year of life of any babies born to 
study participants becoming pregnant between the first, and 3 months after the last 
investigational product administration (or the partner of a study participant becoming 
pregnant during the equivalent time period, provided she agrees to the study team 
accessing these data).  
Study participants will be informed about the need for collection of these data from the local 
health facilities and consent (or assent with parental/guardian consent) to this 
(see Section 6.2.2). All data collected from local health facility records during the study are 
subject to the same confidentiality provisions as data collected directly by the study team 
(see Section 15.17 and Section 17). 
Staff of these facilities will receive training on this study, with particular emphasis on AEs 
expected after treatment with ivermectin or moxidectin (see Section 10.5), assessment of 
AEs and current Good Clinical Practice (GCP) compliant documentation. 
5.2.4 
Relais Communautaires (Community Liaisons) 
Collaboration will be established with the Relais Communautaires (Community Liaisons). 
Relais Communautaires are selected by their communities to support the implementation of 
public health programs (e.g. they serve as drug distributors for community-directed 
treatment with ivermectin).  
Collaboration with them will be sought when they are selected by the village communities as 
points of contact (Study Focal Point, SFP) with the study team within their villages. The SFP 
will also be part of the system established for facilitating participants contacting the study 
team or local health facilities when they experience AEs outside the scheduled study team 
visits and for reminding participants of upcoming follow up visits by the study team.  They 
will furthermore be the conduit for any complaints the study participants have regarding the 
study conduct for those participants who prefer not to convey these complaints directly or 
via another person of their choice (such as the village chief).  
It is anticipated that depending on the size of a village and the geographic terrain it covers 
the number of Relais Communautaires in the villages (and/or those willing and selected by 
the village community to be an SFP) may be below the number of SFP necessary. 
Depending on the outcome of discussions with the village leaders and elders and during 
community meetings, villagers will be asked to select additional community members as 
SFP for this study during the initial meetings and consultation (Section 5.5).  
The SFP will receive the training they require to fulfill their role in this study, be provided 
with the material they need (for example a mobile phone with phone units) and compensated 
for the time they spend on study related activities. 

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Information to Local Media 
Information to staff of local media (local online news, radio and/or social media) will be 
provided to ensure that they have correct information about clinical research in general, and 
the two moxidectin studies (Study 3001 and Study 3002) planned in the area specifically.  
This information will not be provided with the objective of this information being published 
or for the purpose of participant recruitment but only for the benefit of education of the local 
media staff. Informing the local media (including new staff coming on board during study 
conduct) was proven helpful in the moxidectin Phase III study to reduce the possibility of 
incorrect information (rumors) being distributed in the study area.  
 
Consultations with Religious, Village/Community Leaders, and Elders 
As per local customs and the procedures of the DPS Ituri for introduction of any new 
activities in the area, informing village/community leaders and elders, religious leaders and 
leaders of subgroups (e.g. youth groups) about the study will precede any contact with the 
villagers. Their guidance will be sought on: 
• How to organize the study conduct and who should be involved in discussions on 
study conduct organization (including set up of areas where individuals can be 
examined in privacy); 
• How to inform community members about onchocerciasis and the two studies 
planned in the area; and 
• Suggestions from them for any other topic related to study conduct.   
The agreement and support for village community meetings (or meetings with subgroups) 
will be obtained from the village/community leaders and elders before community meetings 
are held. 
 
Consultation with Village Communities  
5.5.1 
Cultural and Socio-economic Characteristics of the Population from 
which Participants will be Recruited 
5.5.1.1 
Primary Recruitment Area 
In the rural areas of the ZSR of Logo and in the villages in the ZSR Nyarambe, 98% of the 
population are from the Alur ethnic group.  In the Aire de Santé targeted for recruitment, 
100% of the population speak the Alur language (Dhu-Alur). The other languages spoken 
are Lingala (20% of the population) and French (60% of the literate population) and 
Kiswahili (5%).  
Consequently, the information documents and the discussion about the studies will be in 
Dhu-Alur. The Principal Investigator is Alur. 
The most practiced religion across the primary recruitment area is Catholicism (80%). There 
is a growing presence of traditional religions such as “Mungu lonycon” or “Karwo” who 
believe that God is all powerful and able to solve all problems in response to prayers and 
whose leaders are preaching against all modern health care.  Special advocacy work with 
these leaders is required to encourage participation in health programs, as well as to obtain 
their permission to approach the communities regarding research studies.  
The belief in the effectiveness of traditional healers is also high.  
The majority of the population is poor and lives off agricultural activities, including 
subsistence farming. The area is known for production of coffee, mostly sold in Uganda, 
which constitutes the main source of income and employment in this region. 

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The area is characterized by high fertility rates, poor nutrition and low educational 
attainment with high rates of illiteracy. Fewer than 20% of the girls complete secondary 
school.  
Children have a very high degree of respect for their parents and the elderly. Children and 
adolescents usually live with their parents until they get married. Orphans live with other 
family members. The head of the household is their ‘guardian’ and makes all decisions for 
these minors without there necessarily being an ‘official document’ attesting this.  Minors 
may also be sent by their parents to live with other relatives.  
The average daily earning is around 5 US Dollars. The currency most frequently used is the 
Ugandan Shilling. 
5.5.1.2 
Backup Recruitment Area 
The majority of the population in the ZSR Aru are from the Lugbara ethnic group (around 
90%) and speak Lugbara-tii (75%) and Lingala (25%). However, Lingala speakers live in the 
urban areas, not the rural areas where recruitment would take place. 
Consequently, to prepare for conduct of the study exclusively or partly in this area, the 
information documents have been translated into Lugbara-tii and the discussion about the 
studies will be in Lugbara-tii.  
The most practiced religions are Catholicism (40%) and Protestantism (35%) with other 
religions practiced by around 25% of the population. Aru territory is, like Logo, 
characterized by high levels of fetishism practice and belief in traditional healers.  
The other cultural and socioeconomic characteristics are similar to the ones described for the 
primary recruitment area.  
The average daily earning is around 5 US Dollars. The currency most frequently used is the 
Ugandan Shilling. 
5.5.2 
Community Meetings 
After RA and EC approval of the protocols and Participant Information Documents and 
Informed Consent/Assent Forms (PICF) for this Study 3001 and for Study 3002 
(Section 4.7, Section 15.2, Section 15.3) and in consultation with village leaders and elders 
(Section 5.4), two community meetings will be held in the villages from which participants 
are planned to be recruited. Villagers ≥ 12 years will be invited to these meetings.  
The objective of the first meeting will be to inform the villagers about onchocerciasis, 
current DRC onchocerciasis control strategies, information about moxidectin already 
available, the plan and rationale for conducting this study and the single dose safety study 
and the requirements for study conduct. Details provided on the studies will be limited to 
those required to obtain community input into the implementation plans including:  
• Identification of location(s) where study procedures can be conducted in privacy; 
• Selection of Relais Communautaires and possibly other community members willing 
to be SFP (Section 5.2.4), i.e. to serve as conduit for questions, suggestions or 
complaints study participants may prefer not to address directly to the study team, 
remind villagers of upcoming follow up visits, support villagers in contacting the 
study team or local health facilities in case of AEs, and any other roles the villagers 
consider useful;  
• Selection of literate witnesses for informed consent and assent with parental consent 
(Section 15.9); 

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• Planning for the next community meeting to inform the villagers about details of the 
study and discuss these with them; and 
• Any other study related topics the villagers want to discuss. 
If villagers indicate that they would like their village to be included among the villages from 
which study participants are to be recruited, a second community meeting will be arranged to 
which villagers ≥ 12 years will again be invited.  The objectives of this second community 
meeting will be to: 
• Inform the participants about and discuss with them all details of the studies they 
need to have to decide whether or not they want to give written informed consent or 
assent with parental/guardian consent to study participation; and 
• Arrange meetings between community members interested in participation in one or 
the other study and study team members for further discussion of the details of the 
studies. 
The information to be provided in both meetings is included in the PICF submitted to the 
ECs. During each meeting the relevant section of the PICF will be read and discussed 
paragraph by paragraph in the local language.  
 

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6 
STUDY PARTICIPANT POPULATION 
 
Participant Recruitment and Retention 
Section 2.4.2 and Section 5 provide details on the selected study area and activities that will 
precede participant recruitment and the characteristics of the population from which 
participants will be recruited. 
The process for identifying individuals willing to participate in Screening and, if eligible, 
willing to participate in the study is described below. As described in Section 4.7, a 
comparative single dose safety study (Study 3002) will be run concurrently.  Concurrent 
conduct and recruitment into both this study and/or Study 3002 (Figure 6) was decided upon 
to avoid having to tell people not eligible for study 3001 or not wanting to commit to this 
study, but interested in participating in a study to come back later when individuals with 
their characteristics and interests ‘are wanted’. Such an approach is considered disrespectful 
of their interests and their time, since they would have to be screened again and may, at that 
time, not be eligible for Study 3002.   
Figure 6: Overview of Recruitment with Stepwise Informed Consent/Assent 
 
IC/IA = Informed Consent/Assent, Tx = Treatment, HC = Health Center/Facility, IVM = ivermectin 
 
The main retention strategy will consist of implementation of lessons learnt from public 
health programs, the Phase III study and other research studies:  
• Ensuring that the communities from which participants will be recruited are engaged 
in study preparation and implementation;  
• Treating participants with the respect they deserve as ‘partners’, not ‘subjects’ in this 
research (which includes e.g. concurrent recruitment into this study and study 3002 
and provisions such as the SFP that allow the study team to quickly learn about and 
respond to questions and concerns); and  

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• Maintaining communication with participants via the trained site staff and SFPs, 
including about the importance of attending the follow-up visits organized in their 
villages.  
 
Informed Consent and Assent with Parental/Guardian Consent 
The principles guiding obtaining informed consent and assent from minors with 
parental/guardian informed consent (subsequently referred to as consent/assent) are 
described in Section 15.9.  
Informed consent/assent in this study is divided into informed consent/assent for Screening 
for eligibility (Section 6.2.1), and informed consent/assent for study participation 
(Section 6.2.2). In addition, at Month 36, and provided the number of participants with 
palpable nodules is sufficiently high to support conclusions from histopathological 
evaluation of the excised nodules (Section 7.4.12), participants with palpable onchocercal 
nodules will be asked whether they will consent/assent to nodulectomy (Section 6.2.3). 
Should that not be the case, participants with palpable nodules will be asked whether they 
wish to have their nodules removed and, if yes, to document their consent/assent.  
The amount of information potential participants need to understand before deciding on 
study participation for themselves and/or their children/ward is substantial. Therefore, the 
information document is written in language considered suitable for 12 year old adolescents, 
allowing adults and adolescents to be informed simultaneously.  
6.2.1 
Informed Consent and Assent with Parental/Guardian Consent for 
Screening  
Following approval of the study by the RA, the MdSP-assigned EC and the WHO Ethics 
Review Committee, the study team will initiate the community meetings described in 
Section 5.5.2.  
The 2nd meeting to which villagers at least 12 years old will be invited and which will be 
attended by the witnesses the community chose during the first meeting, is the first step in 
recruitment:  
• The section of the approved participant information document designed for this 
2nd community meeting will be read and discussed in the local language paragraph 
by paragraph. This will allow all to benefit from answers to questions others are 
asking;   
• Meeting participants will then be asked to approach study team members for 
further information and discussion in the presence of the selected witness if they 
are interested in participation in this study or the single dose safety study being 
conducted concurrently (Study 3002, Section 4.7); 
• Those who continue to be interested in participating after having had adequate 
time to consider the study information and telling the study team members they 
want to participate, will be asked specific questions included in the EC approved 
PICF to confirm their understanding of key screening elements in the presence of 
the selected witness (Section 15.9.2).  These questions are not meant as a ‘pass-
fail test’ but to allow the team to identify key elements of consent/assent that 
require further discussion with the participant and/or parent(s)/guardian before 
they can provide informed consent/assent; and  
• Subsequently, the potential participant and, if applicable, his/her 
parents(s)/guardian will provide written informed consent/assent with 
parental/guardian consent to Screening which will be confirmed by the witness. 

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Individuals who have signed (or finger printed/marked) and dated the written informed 
consent/assent will be assigned a participant code and invited to attend screening.  
See Section 15.9 for further information on the informed consent process, including for 
illiterate participants and minors. 
6.2.2 
Informed Consent and Assent with Parental/Guardian Consent for 
Study Participation 
The results of Screening will be presented to each individual (and parents/guardian, if 
applicable).  
Their options for participation in this study, or the single dose safety study (Study 3002) 
being conducted concurrently (or the need to exclude them from either study with or without 
referral to the local health care system, if applicable (see Section 6.5), will be discussed and 
considered further by each person (or each person and their parent(s)/guardian).  
Eligible individuals having decided that they want to participate in a study (and their 
parents/guardian, if applicable) will be asked specific questions included in the EC approved 
PICF to confirm their understanding of key elements of the study they are eligible for and/or 
have chosen in the presence of the selected witness. As for the consent for screening, these 
questions are not meant as a ‘pass-fail test’ but to allow the team to identify key elements of 
consent/assent for which additional clarification needs to be provided to the potential 
participant and/or his/her parents(s)/guardian.  
Subsequently, eligible participants (with their parent(s)/guardian, if applicable) will provide 
written informed consent/assent to participation in the study they are eligible for and/or in 
which they have chosen to participate which will be confirmed by the witness. 
See Section 15.9 for further information on the informed consent process, including for 
illiterate participants and minors. 
6.2.3 
Informed Consent and Assent with Parental/Guardian Consent to 
Nodulectomies 
Information about nodulectomies will be provided when potential participants are informed 
about the study for their decision to participate in screening and the study. However, 
considering that the time between informed consent to study participation and the 
nodulectomies is 36 months, detailed information on the nodulectomy procedure, its risks 
and benefits, and that it is voluntary, will be provided to those with palpable onchocercal 
nodules and written consent/assent sought at the Month 36 visit as appropriate for the 
objectives of the nodulectomies (see Section 6.2). Confirmation of the understanding of key 
elements will be done as described above for consent/assent to screening and study 
participation. Only those who have given written consent/assent parental/guardian at this 
time will have nodulectomies performed. 
See Section 15.9 for further information on the informed consent process, including for 
illiterate participants and minors. 
 
Eligibility Criteria 
Study participants must satisfy all eligibility criteria to participate. There will be no 
exemptions. Inclusion and exclusion criteria are to be determined at Screening unless 
otherwise indicated.  
6.3.1 
Inclusion Criteria 
The criteria for entry into the study are: 

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1. Provision of written informed consent, or assent with parental or guardian written 
consent. 
2. Mean ≥ 10 O. volvulus microfilariae/mg skin, determined by four skin snips.  
3. Living in a village selected for the study. 
4. Age ≥ 12 years.  
5. All female participants of childbearing potential must commit to the use of a 
reliable method of birth control for the duration of treatment and until 3 months 
after completion of dosing with investigational product. 
6.3.2 
Exclusion Criteria 
The criteria for exclusion from the study are: 
1. Pregnant or breast-feeding. 
2. Any concurrent condition that, in the opinion of the Investigator, would preclude 
evaluation of response to treatment or would pose undue risk to the participant's 
health. 
3. Has received ivermectin, oral diethylcarbamazine (DEC) or doxycycline (for > 2 
weeks) within 6 months of Baseline. 
4. Has received treatment with an investigational agent within the last 30 days (or 
5 half-lives, whichever is longer) prior to Baseline. 
5. Known or suspected allergy to ivermectin or moxidectin or their excipients. 
6. Self-reported planned or ongoing activities within the study period that would make 
it unlikely that a participant will be available for all treatment rounds and follow-up 
examinations. 
7. Weight > 88 kilograms. 
8. Infection with Loa loa. 
 
Other Eligibility Considerations 
In order to assess any potential impact of a concurrent condition identified during Screening 
on participant eligibility and/or the safety of potential study participants, the Investigator 
must refer to the information on adverse reactions, precautions and warnings outlined in 
Section 10.5 and the documents referenced in that section (and reviewed at the Initiation 
visit, see Section 15.8). 
6.4.1 
Pregnant and Breast-feeding Women 
As no adequate and well-controlled studies of moxidectin or ivermectin in pregnant women 
have been conducted, the safety of moxidectin or ivermectin in pregnancy has not been 
established (information available at 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm ; 
https://www.merck.com/product/usa/pi_circulars/s/stromectol/stromectol_pi.pdf ; 
http://edenbridgepharma.com/Ivermectin%20PI.pdf ). 
Consequently, girls and women of childbearing potential must undergo a pregnancy test 
(Section 7.4.7) and must commit to using a reliable method of birth control until Month 27 
of the study. Women of childbearing potential who withdraw from the study within 3 months 
of investigational product administration should be advised to avoid becoming pregnant until 
3 months after their last treatment.  
All girls and women of childbearing potential will be counselled on reliable methods of birth 
control (including abstinence) and available contraceptive measures recommended by the 
National Program of Reproductive Health. The chosen contraceptives will be made available 
to these study participants by the Sponsor free of charge.  

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For participants not choosing abstinence, reliable methods (failure rate of less than 1% when 
used consistently and correctly) of contraception offered by the National Program of 
Reproductive Health include: 
• combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation, 
• progestogen-only hormonal contraception associated with inhibition of ovulation, 
• intrauterine devices. 
A pregnancy test will be conducted at Month 6, 12, 18, 24 and 30. 
Study staff counselling women on contraception will have the relevant experience. 
Women who are not of childbearing potential (before menarche or those who have been 
postmenopausal for at least 12 consecutive months without alternative medical cause or have 
undergone hysterectomy, bilateral oophorectomy, or tubal ligation) are not required to 
undergo pregnancy testing or to commit to contraception. 
A study in lactating, non-breastfeeding women (Study 1002) showed that after a single dose 
of 8 mg moxidectin, moxidectin was present in the breast milk at a relative infant dose of 
less than 10% of the maternal dose (Korth-Bradley et al. 2011). There is currently 
insufficient data on the potential risk of moxidectin exposure for the breast-feeding infant.  
For ivermectin, the US FDA approved prescribing information advises that ivermectin is 
excreted in human milk in low concentrations and that ivermectin treatment of mothers who 
intend to breast-feed should only be undertaken when the risk of delayed treatment to the 
mother outweighs the possible risk to the newborn 
(https://www.merck.com/product/usa/pi_circulars/s/stromectol/stromectol_pi.pdf; 
http://edenbridgepharma.com/Ivermectin%20PI.pdf). 
Consequently, women who are breast-feeding are not eligible for the study. 
6.4.2 
Loa loa Infection 
Individuals heavily infected with Loa loa may develop a serious or even fatal 
encephalopathy either spontaneously or following treatment with an effective 
microfilaricide. In these patients, the following adverse experiences have also been reported: 
pain (including neck and back pain), red eye, conjunctival hemorrhage, dyspnea, urinary 
and/or fecal incontinence, difficulty in standing/walking, mental status changes, confusion, 
lethargy, stupor, seizures, or coma.  
Moxidectin has not been tested in patients co-infected with Loa loa.  
Consequently, neither the primary nor the back-up recruitment area selected for this study 
are Loa loa co-endemic. Individuals will be asked about their exposure to Loa loa endemic 
areas. Those reporting a history of living or working or still temporarily working in Loa loa 
endemic areas or symptoms suggestive of Loa loa infection (e.g. ‘eye worm’) will undergo 
screening for loiasis (Sections 7.3.1 and 7.4.11). 
 
Referral of Individuals Not Eligible for Study Participation 
Individuals identified as O. volvulus infected but not qualifying for or willing to participate 
in this study (or Study 3002) will be given referral information for the local health system/ 
Program for Neglected Tropical Diseases Control using Preventive Chemotherapy for 
ivermectin treatment if community-directed treatment with ivermectin is not implemented in 
their village or else be advised to participate in each round of community-directed treatment 
with ivermectin.  

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Individuals not eligible for participation in either study because of a health condition 
requiring medical attention will be given referral information for the local health system. 
Individuals not eligible for participation because of Loa loa infection will be provided with a 
written note to that effect for presentation at future community directed treatment with 
ivermectin campaigns so that national program mandated precautions for the treatment of 
these individuals can be taken as per national guidelines. 
 
Rescreening 
Individuals may be rescreened once under a new participant code if, in the opinion of the 
Investigator, the eligibility criteria are likely to be met upon rescreening.  
 

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7 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
 
Study Schedule of Evaluations 
The schedule of assessments is presented in Table 1. 
 
Visit Windows 
The assessments on the first five days after each investigational product administration must 
occur on the specified days.  
For other assessments, the visit windows are:  
• plus or minus one month for each of the Month 6, 12, 18, 24 and 30 visits; and  
• plus or minus two months for the Month 36 visit. 
 
Study Procedures 
The study procedures to be conducted for each individual participating in the study are listed 
below. The results will be documented in the source records and, as required, entered or 
uploaded into the eCRF (Section 16.1 and Section 16.2).  
No study procedures will be conducted prior to the provision of written informed 
consent/assent for the relevant procedures. Unless otherwise indicated, all procedures will be 
conducted in the villages in a private place set up as agreed with village communities (see 
Section 5.4 and Section 5.5.2). 
Additional detail on study procedures is provided in Section 7.4. 
Any deviation from study procedures will be noted in the source records and eCRF, as 
required, and the Sponsor will be notified. 
After each visit, participants will be informed about the results obtained. 
7.3.1 
Screening (Day -30 to Day -1) 
Following the provision of written informed consent/assent to Screening, the following 
procedures will be undertaken to determine eligibility:  
• 
Demography (date of birth and sex, history of living or working or still temporarily 
working in loiasis endemic areas) (Section 7.4.1); 
• 
Medical history (medical conditions or surgical history, and potential history of 
Loa loa infection/eye worm) (Section 7.4.2); 
• 
Prior and concurrent medication (Section 6.3.2 and Section 9); 
• 
Vital signs assessment (blood pressure, temperature, heart rate and respiratory rate) 
(Section 7.4.5);  
• 
A complete physical examination (Section 7.4.3) including:  
 Body weight and height (Section 7.4.6); 
 Assessment of all body systems to determine study eligibility (Section 7.4.3); 
 Onchocerciasis signs and symptoms (Section 7.4.4); and 
 Palpation for subcutaneous nodules (Section 7.4.3); 
• 
A urine pregnancy test for women and girls of childbearing potential (Section 7.4.7); 
• 
Ocular examinations including visual acuity, fundoscopy and slit lamp examination 
to assess ocular lesions and count live microfilariae in the anterior chambers of the 
eyes (Section 7.4.9); 
• 
Calibrated blood smear for determination of Loa loa infection in individuals who 
have lived or worked in loiasis endemic areas and/or who report symptoms 
suggestive of Loa loa infection. (Section 7.4.11);  

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• 
Collection of four skin snips (one from each iliac crest and each calf) for assessment 
of skin microfilariae density (Section 7.4.8);  
• 
AE assessment (Section 10). 
7.3.2 
Randomization and Investigational Product Preparation 
For all participants who meet all the inclusion criteria and none of the exclusion criteria, and 
have given informed consent/assent to study participation, randomization and investigational 
product preparation will occur as described in Section 8.1 and Section 8.6.  
7.3.3 
Baseline and Confirmation of Eligibility (Day – 1 to 0) 
To confirm eligibility and/or obtain up to date baseline data, the following assessments will 
be performed, if required: 
• 
If more than 1 day has passed between the Screening pregnancy test and planned 
study drug administration: 
o Urine pregnancy test for women and girls of childbearing potential 
(Section 7.4.7); and 
• 
If more than 3 days have passed between Screening and planned study drug 
administration, or if clinically indicated: 
o A targeted physical examination (based on previous findings and current 
symptoms or health issues that have occurred since Screening) 
(Section 7.4.3);  
o Vital signs assessment (blood pressure, temperature, heart rate and respiratory 
rate) (Section 7.4.5);  
o Concurrent medication review (Section 10). 
If participants continue to be eligible, the following Baseline assessments will be performed: 
• 
3.0 mL of blood will be collected for liver function tests (Section 7.4.10); 
• 
AE assessment (Section 10). 
7.3.4 
Investigational Product Administration (Day 0) 
Participants continuing to meet all the inclusion criteria and none of the exclusion criteria 
will be administered investigational product while being observed by study staff 
(Section 8.6).  
Any investigational product dispensed but not administered will be returned to the Pharmacy 
and accounted for as described in Section 8.7. 
7.3.5 
Daily Assessments on the First Five Days after Each Investigational 
Product Administration  
For the first five days after each investigational product administration, the following 
assessments will be conducted:  
• AE assessment (Section 10); 
• Concurrent medication assessment (Section 9); 
• A targeted physical examination (based on symptoms) (Section 7.4.3);  
• Blood pressure (semi-supine) and pulse measurement (Section 7.4.5). 
Should the participant experience signs and symptoms of the Mazzotti reaction or other 
adverse events, treatment should be provided if requested by the participant or considered 
clinically indicated (see Section 10.5). Any medication provided by the study team or in a 
local health facility (see Section 9) must be documented and reported in the source records 
and eCRF together with the indication for which it was provided.  

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Additional follow-up visits will be scheduled should they be indicated for appropriate 
follow-up of AEs and recorded in the source records and eCRF as unscheduled visits. 
7.3.6 
Assessment on the Fifth Day after Investigational Product 
Administration at Day 0, Month 6 and Month 12 
Five (5) days after investigational product is administered at Day 0, Month 6 and Month 12 
(Day 5), 3.0 mL of blood will be collected for liver function tests (Section 7.4.10). 
7.3.7 
On-Treatment Visits (Months 6, 12, 18, and 24) 
Each participant will be assessed at Months 6, 12, 18, and 24 (± 1 month). 
The following assessments will be performed prior to investigational product administration:  
All participants at all on-treatment visits: 
• AE assessment (Section 10); 
• Concurrent medication (Section 9); 
• Vital signs (blood pressure, temperature, heart rate and respiratory rate) 
(Section 7.4.5); 
• Body weight (Section 7.4.6); 
• A targeted physical examination (based on symptoms) (Section 7.4.3); 
• Collection of four skin snips (one from each iliac crest and each calf) for assessment 
of skin microfilariae density (Section 7.4.8); 
Selected participants at all on-treatment visits: 
• Evaluation for selected onchocerciasis signs and symptoms in those with these signs 
and symptoms at Screening (Section 7.4.4); 
• Pregnancy test for girls and women of childbearing potential (Section 7.4.7); 
• Slit lamp examination for counting of live microfilariae in the anterior chambers of 
the eyes in those with live microfilariae in the anterior chambers of the eyes at 
Screening (Section 7.4.9); 
• Girls who were pre-menarche before the first treatment or the applicable previous On-
Treatment Visit will be asked whether they have had menarche.   
All participants only at Month 6 and 12:  
• At Month 6 and 12, 3.0 mL of blood for determination of liver function tests 
(Section 7.3.6 and Section 7.4.10); 
Selected participants at Month 12 and Month 24: 
• Fundoscopy or slit lamp examination for those with onchocerciasis related ocular 
lesion(s) at Screening, as indicated by the lesion(s) (Section 7.4.9). 
Once assessments are completed, investigational product should be administered as 
described in Section 8.6.  
Participants will receive post-treatment follow up daily for five days as described in 
Section 7.3.5 and have blood drawn for liver function tests 5 days after Month 6 and Month 
12 investigational product administration as described in Section 7.3.6.  
7.3.8 
Post-Treatment Visit (Month 30) 
Each participant will be assessed at Month 30 (± 1 month). 

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The following assessments will be performed:  
All participants: 
• AE assessment (Section 10); 
• Concurrent medication (Section 9); 
• Vital signs (blood pressure, temperature, heart rate and respiratory rate) 
(Section 7.4.5); 
• A targeted physical examination (based on symptoms) (Section 7.4.3); 
• Collection of four skin snips (one from each iliac crest and each calf) for assessment 
of skin microfilariae density (Section 7.4.8);  
Selected participants: 
• Evaluation for selected onchocerciasis signs and symptoms for those with these signs 
and symptoms at Screening (Section 7.4.4); 
• Pregnancy test for women and girls of childbearing potential (Section 7.4.7); 
• Slit lamp examination for counting of live microfilariae in the anterior chambers of 
the eyes in those with live microfilariae in the anterior chambers of the eyes at 
Screening (Section 7.4.9). 
7.3.9 
End of Study Visit (Month 36) 
Each participant will be assessed at Month 36 (± 2 months).  
The following assessments will be performed:  
All participants: 
• AE assessment (Section 10); 
• Concurrent medication (Section 9); 
• A targeted physical examination (based on symptoms) (Section 7.4.3); 
• Palpation for subcutaneous nodules (Section 7.4.3); 
• Vital signs (blood pressure, temperature, heart rate and respiratory rate) 
(Section 7.4.5); 
• Collection of four skin snips (one from each iliac crest and each calf) for assessment 
of skin microfilariae density (Section 7.4.8);  
Selected participants: 
• Evaluation for selected onchocerciasis signs and symptoms for those with these signs 
and symptoms at Screening (Section 7.4.4); 
• Slit lamp examination for counting of live microfilariae in the anterior chambers of 
the eyes in those with live microfilariae in the anterior chambers of the eyes at 
Screening (Section 7.4.9);  
• Fundoscopy or slit lamp examination for those with onchocerciasis related ocular 
lesion(s) at Screening, as indicated by the lesion(s) (Section 7.4.9). 
Discussion will be held with participants with palpable nodules considered onchocercal 
about the procedure, risks and potential benefits of voluntary nodulectomies and their 
objectives (Section 6.2). Written informed consent (or assent with parental or guardian 
written consent) will be obtained from all individuals deciding to have a nodulectomy 
(Section 6.2.3); 
Individuals who have given written informed consent/assent to nodulectomies will be 
scheduled for the nodulectomy and followed up to assess wound healing as described in 
Section 7.4.12.1.  

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7.3.10 
Exit Examination at Early Withdrawal or Early Study Termination 
Participants have the right to withdraw from the study or withdraw from treatment at any 
time for any reason and without giving any reason for the decision to do so or may be 
withdrawn by the investigator (for criteria for withdrawal from treatment or the study and 
follow up, see Sections 13.2).  
Study team members will attempt to visit each participant who withdraws or is withdrawn. 
The reason for withdrawal should be recorded, including, if applicable, that the participant 
prefers not to provide a reason or could not be reached.  
If permitted by the participant, an exit examination should be conducted 3 months after the 
last treatment or another time of the participants choosing to allow evaluation for 
investigational product related adverse events (for further information on the rationale for 
this examination, see Section 13.2.3).  No Exit examination is required if a participant 
withdraws on or after the 30 Month visit.   
The Exit Examination will include the following: 
All participants: 
• AE assessment (Section 10), including need for further follow-up; 
• Concurrent medication assessment (Section 9); 
• A targeted physical examination (based on symptoms) (Section 7.4.3); 
• Vital signs (blood pressure, temperature, heart rate and respiratory rate) 
(Section 7.4.5); 
• Four skin snips (one from each iliac crest and each calf) will be collected for 
assessment of skin microfilariae density (Section 7.4.8). 
• Liver function test if participants’ Exit Examination occurs at or before the Day 5 
assessment following Month 12 (Section 7.4.10); 
Selected participants: 
• Evaluation for selected onchocerciasis signs and symptoms in participants who had 
these signs and symptoms at Screening (Section 7.4.4). 
This exit examination will also be performed in case of early termination of the study for all 
study participants who have not yet had a Month 36 evaluation (Section 13.5). 
 
Details of Scheduled Assessments 
The results of all assessments will be recorded in the source records. On the source records, 
participants will be identified via their participant code as well as their initials and/or names.  
As required, data from the source records will be entered or uploaded to the eCRF 
(Section 16.1 and Section 16.2). In the eCRF, study participants will be identified only by 
their participant code: their name or initials are not collected, to ensure participant 
confidentiality.  
Confidential Screening logs will be completed with details of both participant codes and 
participant names (Section 16.3).  
The following provides details of the assessments to be undertaken. Scheduling of 
assessments is described in Section 7.3 and Table 1.  
7.4.1 
Demography 
Demographic data includes sex, date of birth, and history of living or working or still 
temporarily working in an area(s) where Loa loa is endemic.  

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7.4.2 
Medical History, Concurrent Conditions and Prior and Concurrent 
Medications 
This will include any past or current medical conditions or surgical history, prior and 
concurrent medication, and questioning about a potential history of Loa loa infection (eye 
worm). 
7.4.3 
Physical Examination 
A complete physical examination (including head, ears, nose, throat, lungs, lymph nodes, 
heart, abdomen and skin) will be conducted at the Screening visit to determine study 
eligibility. Abnormalities will be recorded.  
At the Screening visit and at Month 36, the number and location of all palpable nodules will 
be determined during the physical examination including, if identifiable, likely sources other 
than onchocerciasis. 
At all other visits, a targeted physical examination will be performed as clinically indicated, 
guided by symptoms.  
Any new abnormalities or worsening of screening conditions detected during physical 
examinations must be recorded as AEs (see Section 10 for details). 
7.4.4 
Onchocerciasis Signs and Symptoms 
At Screening, each participant will be examined for signs of reactive skin lesions associated 
with onchocerciasis (acute papular onchodermatitis, chronic papular onchodermatitis, 
lichenified onchodermatitis), atrophy (if participant is under 50 years old) and 
depigmentation, and questioned about the presence of pruritus (itching of skin).  
Participants with acute papular onchodermatitis, chronic papular onchodermatitis and/or 
lichenified onchodermatitis, and/or pruritus considered by the Investigator as at least 
possibly related to O. volvulus infection at Screening will be re-examined for these skin 
signs and questioned about pruritus (and other symptoms) at Months 6, 12, 18, 24, 30 and 36 
and at the Exit Examination in case of early withdrawal or study termination, if permitted by 
the participant.  
Each area of skin lesion and pruritus will be graded for severity with a scale informed by that 
described by Murdoch and colleagues (Murdoch et al. 1993).  
Signs and symptoms of onchocerciasis that worsen or emerge after commencement of 
treatment must also be reported as AEs (see Section 10 for details).  
7.4.5 
Vital Signs 
Vital signs to be measured after the participant has been semi-supine for 5 minutes are: 
• Body temperature (degrees Celsius [°C]); 
• Respiratory rate (breaths per minute); 
• Pulse rate (beats per minute); and 
• Blood pressure (millimeters of mercury [mmHg]). 
If abnormally high or low blood pressure is observed, two further measurements, taken 
5 minutes apart should be performed and recorded. 
Blood pressure and pulse rate will also be measured daily during the first five days after each 
treatment. 
Vital signs should also be measured at other times if deemed clinically appropriate. 

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7.4.6 
Weight and Height 
Height will be measured in centimeters (cm) without shoes.  
Weight will be measured in kilograms (kg) wearing light clothing without shoes. 
7.4.7 
Pregnancy Test 
A β-HCG urine pregnancy test will be performed for women and girls of childbearing 
potential before each investigational product administration. They will be instructed by the 
study staff in how to collect a urine sample for testing.  
Upon completion of the pregnancy test, study staff will review the result to confirm that the 
woman is not pregnant prior to proceeding to administration of investigational product.  
Pregnancy will require immediate withdrawal of the woman from further treatment.  
Pregnancy does not, however, require withdrawal from the study unless the participant elects 
to withdraw, or the Investigator decides that the participant should be withdrawn in the 
interest of her health and pregnancy. Sections 10.6 and 13.2 provide details on follow up of 
pregnancies and in case of withdrawals for any reason.  
Urine remaining from these samples will be stored frozen for potential future use 
(Sections 15.19 and  15.20.3), provided the participant has given informed consent/assent to 
this. 
7.4.8 
Quantification of Skin Microfilariae Density 
Four skin snips will be taken (one from each of the left and right iliac crest, and left and right 
calf) using a 2 mm Holth-type corneoscleral punch after cleansing the snip sites with 
70% alcohol.  
Punches will be steam-sterilized before use on the next individual.   
Briefly, each snip will be weighed and incubated for at least 8 hours in isotonic saline. The 
microfilariae that have emerged from the skin snip will be counted using an inverted 
microscope. At Screening, the mean mf/mg across the four skin snips will be calculated to 
assess study eligibility and, if applicable, determine the participant randomization stratum 
(< 20 mf/mg skin vs. ≥ 20 mf/mg skin, Section 8.1).  
Microfilariae will be preserved in alcohol after counting for future use (Sections 15.19 and 
15.20.2).   
If microfilariae of Mansonella streptocerca are present in the skin specimen (identified 
visually on microscopy), their number will be noted on the source records but not collected 
in the participant’s eCRF. 
7.4.9 
Ophthalmological Assessments 
Ophthalmological assessment will comprise visual acuity measurement in daylight with 
tumbling E chart and examination of the anterior segment of the eyes by portable hand-held 
slit lamp. The number of live microfilariae in the anterior chambers of the eyes will be 
counted after the participant has been in a head-down position for at least 5 minutes.  
The disc and retina will be assessed by non-mydriatic fundus camera. Photos will be retained 
as source records. 
Participants with live microfilariae in the anterior chambers of the eyes at Screening will be 
followed up for live microfilariae in the anterior chambers at Months 6, 12, 18, 24, 30 and 
36.  

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Ophthalmologic abnormalities at Screening will be recorded and classified as possibly 
onchocerciasis-related or unrelated. Participants with ocular lesion(s) at Screening classified 
as onchocerciasis-related will have repeat fundoscopy and/or slit lamp examination at 
Months 12, 24, and 36, as indicated by the lesions identified at Screening.  
Any new abnormalities or worsening of conditions present at Screening must be recorded as 
AEs (see Section 10.2 for details).  
Individuals with ophthalmological diagnoses amenable to treatment (e.g. glaucoma) will be 
provided with this treatment or referred to the appropriate intervention.  
7.4.10 
Liver Function Tests 
A 3.0 mL blood sample will be collected for liver function tests that will examine aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase 
(GGT), alkaline phosphatase (AP), lactate dehydrogenase (LDH), and conjugated and 
unconjugated bilirubin.  
Follow up of abnormal values will be determined by the Investigator based on clinical 
judgement. Grade 3 or 4 abnormalities (see Section 10.2.2) should be retested as soon as 
possible and both values with the date of sampling and testing will be collected in the eCRF. 
Serum remaining from these samples will be stored frozen for potential future use 
(Sections 15.19 and  15.20.3), provided the participant has given informed consent/assent to 
this. 
7.4.11 
Diagnosis of Loa loa Infection 
Individuals with a history of living or working or still temporarily working in an area where 
Loa loa is endemic or with a history of eye worm or other symptoms suggestive of Loa loa 
infection will undergo a test for Loa loa infection. For these participants, diagnosis of Loa 
loa infection will be performed via calibrated blood smear. Briefly, blood will be collected 
(between approximately 1100 and 1400 hours) by finger prick with a 60 μL non-heparinized 
capillary tube, after careful cleaning of the finger. The blood will be spread on a labeled 
slide, dried and Giemsa stained and dried at ambient temperature. All Loa loa microfilariae 
on the slide will be counted at a magnification of 100x.   
If Loa loa microfilariae are present, the number of parasites will be recorded in the source 
records and the individual will be excluded from the study. 
7.4.12 
Evaluation of the Effect on Macrofilariae  
7.4.12.1 
Nodulectomy 
Palpable nodules clinically judged to be onchocercal will be surgically excised by physicians 
experienced in minor surgery in the surgical theater of the local health facility close to where 
the participant lives in the ZSR Logo, or Nyarambe (or Aru in case the study is conducted 
completely or partly in the back-up recruitment area, see Sections 5.5.1.1 and 5.5.1.2).  
When consenting/assenting to nodulectomy, participants can designate nodules they wish to 
have removed.  
The procedure will be conducted under local anesthesia (1% xylocaine) using sterile 
technique to minimize pain and the risk of infection at the incision site.  
Wound management by the study team will include daily examination for bleeding, 
hematoma formation and dehiscence. Approximately two days after the procedure, 
participants will be returned to their villages where a study nurse will continue daily wound 
management. Participants will be advised to stay off work for the first week after surgery to 

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assist in wound healing. They will be compensated for each day they do not work 
(Section 15.12). The first change of dressing is done on the first day after nodulectomy. 
Subsequent dressing changes will occur on alternate days until the wound is completely 
healed. Participants will be provided with medication to reduce pain once the local 
anesthesia has worn off both in the hospital and during follow up in their village.  
Approximately 7 days post-nodulectomy, sutures will be removed by a study nurse.  
7.4.12.2 
Histopathological Examination of Excised Nodules 
Excised nodules will be processed for histopathology and slices stained with hematoxylin-
eosin or specific stains available at that time, provided nodulectomies are performed to 
compare the effect of the study drugs (Section 6.2). Slides will be read by one and if feasible 
a second experienced reader to determine viability and reproductive capacity of the 
macrofilariae contained within the nodule. Details of macrofilarial morphology including 
number of live, moribund, dead, or dead and calcified worms by sex, absence or presence of 
embryos overall and by developmental stage (oocytes, stretched, pretzel etc.) and absence or 
presence of spermatogenetic stages will be recorded.  This will be performed by researchers 
specializing in histopathological examination of excised nodules.  Given that this will occur 
only at the end of the study, these researchers will be selected close to the time of the first 
nodulectomies.  The ECs will be informed about the selection and the transfer of the nodules 
will be under a Material Transfer Agreement as described in Section 15.19 for left-over 
biospecimen.  Some of the material in the nodules will be preserved in alcohol for research 
for new tools for onchocerciasis elimination programs (Section 15.20.2).   
7.4.13 
Collection and Processing of Biological Specimens 
Skin, blood and urine specimens collected during the trial may contain harmful pathogens. 
All personnel involved in collecting and handling biological specimens will be trained on 
Prevention and Control of Infection in order to be able to implement appropriate 
precautionary procedures for handling biohazardous materials as currently recommended by 
the WHO Emerging and Communicable Diseases, Surveillance and Control 
Guidelines (World Health Organization 1997) or relevant updates or country guidance. The 
processing of all biological specimens will be in accordance with relevant standard operating 
procedures (SOPs) and as required for the objectives of their collection, as described above.   
For storage, ownership and future use of left over serum, urine and O. volvulus parasites, see 
Sections 15.19, 15.20.2 and 15.20.3. 
 

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8 
INVESTIGATIONAL MEDICINAL PRODUCT 
In this study investigational medicinal product is moxidectin, ivermectin and/or placebo. 
 
Randomization and Treatment Allocation 
The randomization code will be generated using computer-generated random treatment 
allocations with randomly permuted blocks, which may include random block sizes. Each 
block of sequential numbers will include in random order moxidectin annual, ivermectin 
annual, moxidectin biannual and ivermectin biannual treatment allocations, reflective of the 
3:1:3:1 treatment allocation planned for this study (Section 4.3).  
The randomization will be stratified by Screening skin microfilariae density (< 20 mf/mg 
skin or   20 mf/mg skin) and by Aire de Santé. 
Individuals found to be eligible for study participation will be allocated the next available 
number in sequential order, from lowest to highest, on the randomization list for their Aire 
de Santé and Screening skin microfilariae density stratum. The staff randomizing 
participants will not be involved in participant follow up.    
The randomization algorithm will be generated by an independent statistician not otherwise 
participating in the study. A separate document outlining the specifics of the randomization 
algorithm will be prepared and available upon study completion. 
 
Blinding 
The study will be conducted as a double-blind study. To maintain the blind, each participant 
will receive four matching capsules prepared by unblinded staff authorized by DRC law to 
dispense drugs and who will not be involved in participant assessment. Neither the 
participants nor staff involved in their follow up or examination of participant samples will 
know which treatment is being administered, nor whether it is being given annually or 
biannually.  
Participants randomized to annual treatment will receive four placebo capsules at Months 6 
and 18.  
 
Unblinding 
The Investigator has the right to break the blind or authorize a study team member to break 
the blind when knowledge of the study treatment is considered important for optimal 
medical management of a participant. For this purpose, sealed envelopes (or equivalent) with 
the treatment assigned to each randomization number will be held at the site by the 
Investigator (or delegate). Duplicate envelopes (or equivalent) will be held by the 
Sponsor/Medical Monitor.  
Wherever possible without jeopardizing participant safety, the Investigator should discuss 
the intention to break the blind with the Medical Monitor before breaking the blind. The 
final decision rests with the Investigator. 
If the code is broken, the envelope must be signed and dated on both seals by the code 
breaker. The name and signature of the code breaker, and date and time of the code break 
needs to be recorded on the outside of the envelope. Information must be entered into the 
participant’s source records and the relevant eCRF page, explaining the reason and date that 
the sealed envelope was opened. This must be countersigned by the Investigator.  
The Investigator must notify the Sponsor/Medical Monitor by e-mail at 
sae@medicinesdevelopment.com. or if that is not feasible, via telephone (+61 409 020 209) 
within 24 hours after having broken the blind including the participant code, randomization 
number and the circumstances leading to the decision to unblind. Furthermore, the 

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Investigator must provide a written report of the event to the Sponsor within five working 
days.  
 
Formulation 
The investigational products to be administered in this clinical trial are encapsulated 
moxidectin tablets, 2 mg (manufactured by MDGH) and ivermectin tablets, 3 mg 
(manufactured by Edenbridge LLC).  
Moxidectin tablets contain 2 mg of moxidectin supplied as 100 mg white to pale yellow, 
uncoated, oval-shaped tablets. Moxidectin tablet components are provided in Table 4. 
Table 4: Moxidectin Tablet Components 
Components  
Quality Reference 
Function  
Micronized moxidectin  
United States Pharmacopeia 
Active ingredient  
Microcrystalline cellulose  
US Pharmacopeia National Formulary 
Diluent  
Lactose, anhydrous  
US Pharmacopeia National Formulary 
Diluent  
Sodium lauryl sulfate  
US Pharmacopeia National Formulary 
Surfactant  
Colloidal silicon dioxide  
US Pharmacopeia National Formulary 
Glidant  
Croscarmellose sodium  
US Pharmacopeia National Formulary 
Disintegrant  
Magnesium stearate  
US Pharmacopeia National Formulary 
Lubricant  
Ivermectin will be a 3 mg tablet (US Authorized product National Drug Code NDC 42799-
806-01) containing the ingredients as per Table 5. 
Table 5: Ivermectin Tablet Components 
Component 
Function 
Ivermectin 3 mg 
Active ingredient 
Microcrystalline cellulose  
Inactive 
Pregelatinized starch 
Inactive 
Magnesium stearate  
Inactive 
Colloidal silicon dioxide 
Inactive 
Croscarmellose sodium 
Inactive 
Each moxidectin or ivermectin tablet will be overencapsulated in a Size#1, opaque, white, 
hypromellose (hydroxypropyl methylcellulose) hard shell capsule. Each capsule will be 
backfilled with inert excipient powder (microcrystalline cellulose). 
Matching placebo capsules will be filled with the same inert excipient powder.  
 
Supply, Packaging and Labelling, Storage and Handling 
Investigational product will be supplied by the Sponsor as moxidectin 2 mg in capsules, 
ivermectin 3 mg in capsules or placebo capsules. The investigational product will be 
supplied in white high density polyethylene bottles with a polypropylene closure and 
induction seal, a pharmaceutical coil (filler) and silica gel desiccant sachet.  
Investigational product will be shipped to the site after receipt of required documentation of 
study approval and in accordance with applicable regulatory requirements.  
The Investigator or authorized designee will ensure that the investigational product is stored 
below 25°C and protected from light and moisture in a secure area with access limited to 
authorized staff, and according to relevant regulations. The capsules must not be frozen or 
stored at temperatures above 30°C. Temperature excursions are permitted up to 30°C for up 
to 12 months. 

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Labelling of the bottles with moxidectin in capsules, with ivermectin in capsules or with 
placebo-to-match capsules will be in accordance with local regulations and as approved by 
the regulatory authority and include at a minimum: 
• Sponsor name;  
• Protocol number;  
• Product name; 
• Product strength; 
• Route of administration; 
• Lot number; 
• Expiry date or retest date; and 
• ‘For Clinical Trial Use Only’.  
 
Dosage and Administration 
After randomization and determination of the regimen to which the participant is allocated, a 
dose of investigational product will be dispensed.  
Dispensed investigational product will be administered only to participants confirmed to be 
eligible on Day -1 to Day 0.  
Participants will swallow the investigational product with water under the direct observation 
of study staff. 
8.6.1 
Moxidectin 
The dosing of moxidectin does not depend on participant weight or height. 
Participants randomized to annual moxidectin will receive four moxidectin capsules at each 
of Months 0, 12 and 24 and four placebo capsules at each of Months 6 and 18. 
Participants randomized to biannual moxidectin will receive four moxidectin capsules at 
each of Months 0, 6, 12, 18 and 24. 
8.6.2 
Ivermectin 
Ivermectin is provided as 3 mg tablets and dosing is weight-based (150 g/kg).  
The Prescribing Information for ivermectin (available at 
http://edenbridgepharma.com/Ivermectin%20PI.pdf) translates this into the number of 
ivermectin 3 mg tablets for individuals up to 84 kg/weight, resulting in actual dose/kg of 
between 136 µg/kg and 231 µg/kg. For weights ≥ 85 kg, the prescribing information 
specifies only that dosing should be 150 µg/kg. Administration of four 3 mg ivermectin 
tablets to individuals weighing 85 to 88 kg results in an actual dose/kg of between 136 µg/kg 
and 141 µg/kg. Above that weight, five 3 mg tablets are required to achieve the dose range 
equivalent to that of lower weight groups described in the prescribing information.  
Given that this is a blinded study and to eliminate the need for all participants to take 
additional placebo capsules, individuals with a weight of > 88 kg will be excluded. Based on 
the target recruitment population, it is not anticipated that this will result in exclusion of 
many individuals. 
The number of ivermectin capsules to be administered is determined according to the weight 
of the participant at each timepoint, as per ivermectin label and described in Table 6.  

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Table 6: Ivermectin Weight Based Dosing Schedule 
Bodyweight# (kg) 
Number of Ivermectin 
3 mg Capsules 
Number of Placebo 
Capsules 
Range of Actual 
Ivermectin dose 
(µg/kg) 
26 to 44 
2 
2 
231 - 136 
45 to 64 
3 
1 
200 - 141 
65 to 88 
4 
0 
185 - 136 
# Rounded to the nearest whole kg 
Participants randomized to annual ivermectin treatment will receive the number of 
ivermectin and placebo capsules corresponding to their weight at Months 0, 12 and 24 and 
four placebo capsules at Months 6 and 18. 
Participants randomized to biannual ivermectin treatment will receive the number of 
ivermectin and placebo capsules corresponding to their weight at Months 0, 6, 12, 18 and 24. 
 
Dispensing and Accountability 
The Investigator is responsible for ensuring that the investigational product is dispensed in 
accordance with the protocol. Only individuals legally authorized by the DRC to dispense 
drugs and by the Investigator will dispense investigational product. 
For each participant, the investigational product corresponding to their randomized treatment 
allocation will be prepared.  
The date of investigational product preparation, participant code, randomization code and the 
number and types of capsules dispensed must be recorded in the Drug Dispensing and 
Accountability log provided for the study.  
Any investigational product dispensed but not administered to a participant must be recorded 
in the log and the unused capsules stored in a separate container, appropriately labelled, for 
accountability review by the unblinded Study Monitor. 
The Investigator will be responsible for ensuring accurate records are maintained for all 
investigational products received, dispensed, dispensed and not administered, returned or 
destroyed. The inventory and dispensing logs must be available to the unblinded 
Study Monitor. Investigational product supplies, including partially used or empty bottles, 
and dispensed and not administered investigational product must be accounted for by the 
unblinded Study Monitor and returned to the Sponsor for destruction at the end of the study. 
Copies of the records of investigational product returned to the Sponsor must be retained by 
the Investigator.  
As required by national law and in consultation with the Sponsor, unused investigational 
product supplies may be destroyed locally consistent with the local regulations.  Copies of 
records on the destroyed investigational product shall be retained by the Investigator. These 
records must show the identification and quantity of each investigational product capsule 
disposed of, the method of destruction, and the person who disposed of the investigational 
product. Copies of such records shall be submitted to the Sponsor. 
 
Shipment of Investigational Medicinal Product 
Investigational product will be shipped to the site only after export is permitted from the US, 
an import permit into DRC has been received by the Sponsor and the Sponsor has confirmed 
that all relevant DRC required authorizations and Sponsor documentation requirements for 
the study have been met. Shipment of investigational product may occur before the Site 
Initiation Visit with secure storage at the site under quarantine until the study has been 
initiated.  

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9 
CONCURRENT MEDICATIONS  
At each study visit or contact, the Investigator should ask the participant about any 
concurrent medications or medications taken since the previous visit or contact.  
All concurrent medications, including any traditional medicines, herbal remedies as well as 
traditional spiritual interventions, must be recorded in the appropriate section of the eCRF, 
including start and stop date, dose and dosing indication.  
 
Special Dietary Requirements 
There are no special dietary requirements during the study. 
 
Prohibited Concurrent Medications 
Throughout the study, participants should not receive any of the following medications 
without a physician having determined that this medication is necessary for the health of the 
participant: 
• 
Anti-onchocercal treatments including ivermectin, oral DEC;  
• 
Doxycycline for a duration of more than 2 weeks; and 
• 
Other investigational products for non-life threatening conditions. 
In case of non-compliance, the prohibited concurrent medication taken should be 
documented in the source records and the information requested on the concomitant 
medication page of the eCRF should be completed. 
 
Permitted Investigational Products 
In the interest of the health of study participants, as well as potentially public health, 
investigational products for life threatening conditions for which no or insufficient effective 
and safe treatments or vaccines are available are permitted. This includes, but is not 
necessarily limited to, Ebola Virus Disease Vaccination. 
The Ebola Virus vaccine rVSVΔGP-ZEBOV-GP (ERVEBO, Merck & Co, Inc.) has been 
prequalified by WHO (World Health Organization 2020) and received conditional marketing 
authorization by the European Medicines Agency in November 2019 (European Medicines 
Agency 2020).   
Ring vaccination with rVSVΔGP-ZEBOV-GP is deployed at large scale by the MdSP for 
control of the outbreak in Nord Kivu and Ituri. Thus, its use is authorized by the MdSP 
outside clinical trials. Consequently, and in the interest of the health of study participants, 
their communities and public health, rVSVΔGP-ZEBOV-GP is not considered an 
investigational product in this protocol and consequently rVSVΔGP-ZEBOV-GP 
vaccination is permitted.   
Applications for European Medicines Agency approval have been submitted for each of the 
two components of another Ebola Virus vaccine consisting of a dose of Ad26.ZEBOV 
followed by a dose of MVA-BN-Filo and are undergoing Accelerated Assessment. The RA 
has authorized use of this vaccine within a Phase III study in North Kivu 
(https://clinicaltrials.gov/ct2/show/NCT04152486).  Should this or subsequent studies, or 
MdSP authorized deployment of this vaccine, be implemented in the area where Study 3001 
is being conducted, participants may receive this vaccine.  
The study team will coordinate assessment activities for this study and the vaccine study 
with the staff involved in the evaluation of the vaccine.  
Vaccination will be documented in the source records and eCRF as required for all 
concomitant medication.  

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10 
ADVERSE EVENTS AND MANAGEMENT 
 
Safety Assessments 
Safety assessments will include physical examinations, ocular examinations, AEs, 
concomitant treatments (pharmacological or non-pharmacological), vital sign measurements 
and liver function tests. 
 
Adverse Events 
10.2.1 
Adverse Event Definition 
As per International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH), an AE is any untoward medical occurrence in a 
clinical investigation participant administered an investigational product and which does not 
necessarily have a causal relationship with the investigational product.  
An AE can therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the product. 
Pre-existing signs, symptoms, or diseases, which increase in frequency or severity or change 
in nature following administration of the investigational product are also considered an AE.  
Post-treatment complications that occur as a result of protocol-mandated procedures (e.g. as 
a result of skin snips or nodulectomies) are also AEs.  
AEs as per ICH definition are referred to as ‘Treatment Emergent Adverse Events’ (TEAE). 
In addition to the events defined as AE by the ICH, any new event, exacerbation of a pre-
existing condition or complication from a protocol mandated procedure with onset after 
written informed consent/assent up to the first investigational product administration will 
also be recorded in the source records and reported as an AE on the appropriate eCRF 
page(s). 
The following are not AEs: 
• 
Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, 
transfusion); in contrast, the condition that leads to the procedure is an AE if it started 
or worsened informed consent/assent but not if it was present before informed 
consent/assent; 
• 
Pre-existing diseases or conditions (i.e. present prior to informed consent/assent) that 
do not worsen; 
• 
Situations where an untoward medical occurrence has not occurred 
(e.g. hospitalization for elective surgery, or overnight stays in a health care facility or 
the research center for social and/or convenience reasons e.g. because of road 
conditions it is not considered safe to transport the participant back to the home 
village at night); and 
• 
Overdose of either investigational product or concomitant medication without any 
signs or symptoms unless the participant is hospitalized for observation. 
10.2.2 
Grading of Severity of Adverse Events and Evaluation of 
Relationship to Investigational Product 
All AEs will be assessed by the Investigator and recorded in the source records and on the 
appropriate eCRF page, including the date of onset and resolution, severity, relationship to 
investigational product, outcome and action taken including regarding further treatment with 
investigational product. 

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Each AE will be graded for severity using the Division of AIDS (DAIDS) Table for Grading 
the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 
(Appendix 1: Adverse Events Toxicity Grading Scale). For AEs not specifically described in 
the DAIDS grading table, the grades presented in Table 7 should be applied.  
Table 7: Adverse Event Severity Assessments for Events not Included in the DAIDS Table 
Grade 
Severity 
For CLINICAL events not otherwise described in the DAIDS AE 
grading table, the following descriptions of severity apply 
1 
Mild 
Mild symptoms causing no or minimal interference with usual social & 
functional activities with intervention not indicated.  
2 
Moderate 
Moderate symptoms causing greater than minimal interference with 
usual social & functional activities with intervention. 
3 
Severe 
Severe symptoms causing inability to perform usual social & functional 
activities with intervention or hospitalization indicated.  
4 
Potentially life-
threatening 
Potentially life-threatening symptoms causing inability to perform basic 
self-care functions with intervention indicated to prevent permanent 
impairment, persistent disability, or death. 
The relationship to investigational product should be assessed using the following definitions 
(Table 8). 
Table 8: Investigational Product Causality Assessments 
Causality 
Comment 
Unrelated 
AE is clearly due to extraneous causes (e.g. underlying disease, environment, 
known effect of another drug). 
Unlikely 
The temporal association between the AE and investigational product is such that 
investigational product is not likely to have any reasonable association with the AE. 
Possible 
The AE could have been produced by the participant’s clinical state or 
investigational product. 
Probable 
The AE follows a reasonable temporal sequence from the time of investigational 
product administration, and cannot be reasonably explained by the known 
characteristics of the participant’s clinical state. 
Definite 
The AE follows a reasonable temporal sequence from the time of investigational 
product administration, and/or reappears when investigational product is re-
introduced. 
 
10.2.3 
Adverse Event Reporting  
All AEs, regardless of severity, causality or seriousness (Section 10.3), and whether initially 
recorded at a local health facility a participant may choose to go to (Section 5.2.3), or by a 
study team member during the protocol-scheduled follow up visits, or ad-hoc visits at the 
request of a participant, must be reported from the date of written informed consent/assent 
up to the last day on the study or for 3 months after the last dose of investigational product, 
whichever is later.  
This is required to obtain as comprehensive an AE data set as possible to support further 
characterization of the safety profile of moxidectin and ivermectin: a priori it is not possible 
to know which AEs may have a relationship to the study drugs and thus exclude some from 
collection/reporting.  Participants will be informed about collection of data related to health 
problems they report to local health facilities during the discussions preceding Informed 
Consent/Assent.  All AEs, whether initially recorded at a local health facility or by a study 
team member are subject to the same confidentiality provisions (see Section 15.17 and 
Section 17).  
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 

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documented as the AE in the eCRF and, if applicable, reported as a SAE, and not the 
individual signs/symptoms recorded in the source documents. 
 
Serious Adverse Events 
10.3.1 
Definition 
A serious adverse event is defined as any AE that results in any of the following outcomes: 
• 
Death; 
• 
Life-threatening situation (participant is at immediate risk of death); 
• 
In-patient hospitalization or prolongation of existing hospitalization; 
• 
Persistent or significant disability/incapacity; and/or 
• 
Congenital anomaly/birth defect in the offspring of a participant who received 
investigational product. 
Furthermore, the following are considered a SAE: 
• 
Important medical events that may not result in death, be immediately life-
threatening, or require hospitalization, if, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention 
to prevent one of the outcomes listed above.  
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; and/or 
o development of drug dependency or drug abuse.  
10.3.2 
Clarification of Serious Adverse Events Definition and Terminology 
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 investigational product. 
“Life-threatening” means that the participant 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, that AE is a SAE. 
“In-patient hospitalization” means the participant has been formally admitted to a hospital 
(or another type of health facility) for medical reasons, not for a protocol specified procedure 
(nodulectomy), for any length of time. This may or may not be overnight. It does not include 
presentation and care within an emergency department or an overnight stay at a hospital for 
'social/convenience reasons' (i.e. the participant cannot be safely brought home at night). 
10.3.3 
Serious Adverse Event Reporting Requirements 
10.3.3.1 
SAE Reporting to the Sponsor 
The Sponsor must be notified immediately about any SAE that occurs after the informed 
consent/assent has been obtained.   
The study site was provided with internet access to ensure that SAE report forms can be sent 
expeditiously. If that is not feasible, notification will be via phone to the medical monitor 
until the SAE report forms can be sent electronically.  
The procedures for reporting all SAEs occurring until the last study visit, regardless of 
causal relationship and outcome, are as follows: 

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• 
Complete the “Serious Adverse Event Report”; and   
• 
Send the completed “Serious Adverse Event Report” by e-mail to the MDGH safety 
desk (sae@medicinesdevelopment.com), or as otherwise advised in writing by the 
Sponsor within 24 hours of the Investigator’s knowledge of the event.  
o For fatal or life-threatening events, also send copies of hospital case reports, 
autopsy reports, and other documents when requested by the Safety Desk and 
available. Participant name and other participant identifying information on 
these documents must be obscured and the participant code added. 
• 
Medical Monitor phone number for notification until reporting to the e-mail address 
is feasible: +61 409 020 209 
Regardless of the cause, all deaths occurring up to the last study visit or 3 months after the 
last treatment, whichever is later, must be reported to the Sponsor within 24 hours of the 
Investigator's knowledge of the death to the e-mail address or phone number provided for 
SAE reporting. 
The Sponsor may request additional information from the Investigator to ensure the timely 
completion of accurate safety reports to the regulatory authorities. All additional information 
requested has to be sent anonymized and with the participant code added.  
The Investigator must take all therapeutic measures necessary for resolution of the SAE. 
Any medications necessary for treatment of the SAE must be recorded in the source records 
and the concurrent medication section of the participant’s eCRF. 
A SAE may qualify for expedited reporting to regulatory authorities if the SAE is considered 
to have a possible causal relationship to the investigational product and is unexpected 
(Suspected Unexpected Serious Adverse Reaction (SUSAR)). An unexpected adverse 
reaction is defined by the ICH as 'An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information'. The applicable product information for 
this study are the Investigator’s Brochure for moxidectin and the Ivermectin Prescribing 
Information (available at 
www.merck.com/product/usa/pi_circulars/s/stromectol/stromectol_pi.pdf ; 
http://edenbridgepharma.com/Ivermectin%20PI.pdf).    
10.3.3.2 
SAE Reporting to Regulatory Authority and Ethics Committee 
The Investigator will notify the RA and the EC of SAEs as per the reporting requirements 
specified in the regulatory authority and ethics committee approval letters. 
If the letters do not include specific requirements for expedited reporting of SAEs or 
SUSARs, all SAEs will be included in the Investigator's annual update to the EC and RA.  
 
Follow Up of Serious and Non-Serious Adverse Events 
Follow-up of serious and non-serious AEs will continue through to the last day on study. For 
participants completing the study, this will be the Month 36 visit. The Month 36 visit 
includes completion of the post-nodulectomy follow up period for participants having 
nodulectomies.  
If a participant withdraws early from the study, AEs will continue to be collected until 
3 months after last dose of investigational product, if permitted by the participant.  
The Sponsor may request that certain AEs be followed until resolution or until the 
Investigator and/or the Sponsor determine that the participant’s condition is stable. For 
participants who have withdrawn from the study, their agreement is required. 

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Based on prior experience of treatment related AEs in the Phase II and Phase III clinical 
trials of moxidectin and ivermectin, it is anticipated that the majority of AEs will occur and 
resolve within the first five to six days after administration of investigational product without 
treatment (i.e. day of administration (Day 0) to 5 days later). In these previous studies, when 
treatment was provided, it was primarily administered for alleviation of symptoms such as 
itch or minor pain. To capture such AEs in this study, an appropriately trained member of 
the study team will visit each participant daily during the five days following each 
investigational product administration (see Section 7.3.5). The need for treatment will be 
assessed and treatment provided as clinically indicated and the treatment and the reason 
documented in the source records and eCRF. 
For illnesses that are common in the study population and that occur while on study, for 
example malaria, respiratory infections, diarrhea or conjunctivitis, the study team will in 
general provide appropriate treatment.  
Else, and for other conditions not related to the investigational products or study procedures 
that occur on study and require hospital treatment or ongoing management (e.g. appendicitis, 
broken bones, snake bite, epileptic attacks), study participants will be referred to a local 
health clinic or hospital. Costs of treatment for conditions not possibly, probably or 
definitely related to investigational product or study conduct will not be covered by the 
study. 
Study participants may prefer to visit local health care staff/clinics rather than to contact a 
study team member (directly or via the SFP in their village) in case of an AE they experience 
after Day 5 after each treatment. As outlined in Section 5.2.3, collaborations with the local 
health care system will be set up to ensure that the study team is informed and can collect all 
AE and treatment data, as well as compensate the health system for treatment of all AEs 
possibly, probably, or definitely related to treatment with investigational product, or due to a 
study procedure. This is included in the PICF.  
 
Precautions for Treatment with Moxidectin or Ivermectin 
For more information regarding precautions and AEs with ivermectin, the Investigator is 
referred to the Prescribing Information (available at 
https://www.merck.com/product/usa/pi_circulars/s/stromectol/stromectol_pi.pdf ; 
http://edenbridgepharma.com/Ivermectin%20PI.pdf).  
For more information regarding precautions and AEs with moxidectin, the Investigator is 
referred to the Prescribing Information (available at Drugs@FDA; www.fda.gov/drugsatfda) 
and the Investigator’s Brochure. 
Warnings and precautions associated with treatment of individuals with onchocerciasis with 
moxidectin or ivermectin are summarized below.  
10.5.1 
Adverse Reactions Associated with Moxidectin or Ivermectin 
Treatment of O. volvulus infected individuals with moxidectin or ivermectin may cause 
cutaneous, ophthalmological, and/or systemic reactions of varying severity (Mazzotti 
reactions).  
These adverse reactions are due to allergic and inflammatory host responses to the death of 
microfilariae following treatment. Just as with the signs and symptoms of onchocerciasis, 
there is both significant variability in the frequency and severity of these reactions between 
individuals and a trend toward an increased incidence and severity of some of these reactions 
in individuals with higher microfilarial burden.  

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Treatment of severe Mazzotti reactions has not been evaluated in controlled clinical trials. 
Symptomatic treatments such as oral hydration, recumbency, intravenous normal saline, 
and/or parenteral corticosteroids have been used to treat orthostatic hypotension. 
Antihistamines and/or analgesics have been used for most mild to moderate Mazzotti 
reaction cases.  
10.5.1.1 
Clinical, Ophthalmological and/or Systemic Adverse Reactions 
The clinical manifestations of Mazzotti reactions include pruritus, headache, pyrexia, rash, 
urticaria, hypotension (including symptomatic orthostatic hypotension and dizziness), 
tachycardia, edema, lymphadenopathy, arthralgia, myalgia, chills, paresthesia and asthenia.  
An increased number of participants in the Phase III study who received moxidectin 
developed symptomatic orthostatic hypotension, with inability to stand without support, after 
lying down for at least 5 minutes in an orthostatic hypotension provocation test: 47/978 (5%) 
compared with 8/494 (2%) who received ivermectin. The decreases in blood pressure were 
transient, managed by resumption of recumbency and most commonly occurred on Days 1 
and 2 post-treatment with moxidectin and slightly later post-treatment with ivermectin. 
Study participants should be advised that if they feel dizzy or light-headed after taking 
investigational product, they should lie down until the symptoms resolve.  
Ophthalmological manifestations include conjunctivitis, eye pain, eye pruritus, eyelid 
swelling, blurred vision, photophobia, changes in visual acuity, hyperemia, ocular 
discomfort and watery eyes. These adverse reactions generally occur and resolve in the first 
week post-treatment without intervention.  
Laboratory changes include eosinophilia, eosinopenia, lymphocytopenia, neutropenia, and 
increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyl transferase (GGT) and lactate dehydrogenase (LDH) Proteinuria has also been 
reported. These changes generally resolve without intervention. 
10.5.1.2 
Edema and Worsening of Onchodermatitis in Individuals with 
Hyperreactive Onchodermatitis (Sowda)  
Moxidectin has not been evaluated in patients with hyper-reactive onchodermatitis (sowda), 
but based on the experience with other microfilaricidal drugs, such patients may be more 
likely than others to experience severe edema and worsening of onchodermatitis following 
the use of moxidectin tablets.  
The same information is provided in the ivermectin Prescribing Information 
(https://www.merck.com/product/usa/pi_circulars/s/stromectol/stromectol_pi.pdf ; 
http://edenbridgepharma.com/Ivermectin%20PI.pdf).  
Symptomatic treatment has been used to manage patients who have experienced edema and 
worsening of onchodermatitis. 
10.5.1.3 
Encephalopathy in Loa loa Co-infected Individuals  
Individuals heavily infected with Loa loa may develop a serious or even fatal 
encephalopathy either spontaneously or following treatment with an effective 
microfilaricide. In these patients, the following adverse experiences have also been reported: 
pain (including neck and back pain), red eye, conjunctival hemorrhage, dyspnea, urinary 
and/or fecal incontinence, difficulty in standing/walking, mental status changes, confusion, 
lethargy, stupor, seizures, or coma.  
This syndrome has been seen very rarely following the use of ivermectin (ivermectin 
Prescribing Information, 

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(incorporating Amendments 1, 2 and 3) 
https://www.merck.com/product/usa/pi_circulars/s/stromectol/stromectol_pi.pdf ; 
http://edenbridgepharma.com/Ivermectin%20PI.pdf).  
Moxidectin has not been studied in individuals infected with Loa loa. Therefore, it is 
recommended that individuals who have had exposure to Loa loa-endemic areas undergo 
diagnostic screening for loiasis prior to treatment.  
Consequently, both the primary and the back-up study area selected for this study are not 
Loa loa co-endemic. Individuals with a history of living or working or still temporarily 
working in Loa loa endemic areas or symptoms suggestive of Loa loa infection such as eye 
worm will undergo screening for loiasis and, if found to be Loa loa infected, will be 
excluded from this study (Sections 7.3.1 and 7.4.11). 
10.5.1.4 
Comparative Data on Adverse Events after Moxidectin and 
Ivermectin Treatment 
For comparative data on the incidence of AEs reported in the moxidectin and ivermectin 
treatment arms of the Phase II and Phase III studies, the Investigator is referred to the 
moxidectin Prescribing Information (available at Drugs@FDA; www.fda.gov/drugsatfda) or 
the Investigator’s Brochure.  
10.5.2 
Risks during Pregnancy 
The risks of treatment with moxidectin during pregnancy have not been evaluated.  
There are no adequate and well-controlled studies of ivermectin in pregnant women and the 
US FDA approved prescribing information advises ‘Ivermectin should not be used during 
pregnancy since safety in pregnancy has not been established’ 
(https://www.merck.com/product/usa/pi_circulars/s/stromectol/stromectol_pi.pdf ; 
http://edenbridgepharma.com/Ivermectin%20PI.pdf).  
Therefore, pregnant women are excluded from the study and women of childbearing 
potential must commit to using a reliable method of birth control for the duration of 
treatment and until 3 months after completion of dosing. See Sections 6.4.1 and 7.4.7 for 
further details on pregnancy testing and contraceptive requirements. 
 
Reporting of Pregnancies and Follow up of Pregnancies 
The participants must be instructed to inform the Investigator immediately (women) if she 
becomes pregnant or (men) if his partner becomes pregnant during the study period.  
The Investigator should report all pregnancies to the Sponsor Safety Desk (Section 10.3.3.1) 
within 24 hours of becoming aware of the pregnancy. Pregnancies, pregnancy outcomes and 
the findings should be reported using the appropriate form(s) for reporting the occurrence 
and outcome of pregnancies in participants having received at least one dose of 
investigational product in the study, or their partner. 
Any participants (or their partner, if she agrees) who become pregnant up to 3 months after 
administration of the last dose of investigational product (Month 27 or earlier in case of early 
withdrawal) should be monitored until the end of the pregnancy. In addition, the outcome of 
the pregnancy should be followed for the first year of life and reported to the Sponsor. 
The required information will be obtained from the local health clinics (see Section 5.2.3).  
The study team will advise women becoming pregnant up to 3 months after administration 
of the last dose of investigational product to attend all ante-natal care visits, deliver at a 
health care facility and attend all post-natal care visits for the first year after birth provided 
by the local health care system.  If necessary, the study team will facilitate attendance at 
these visits and delivery at the health care facility.  The study team will collect the findings 

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of the local health care staff for reporting in the eCRF.  The same applies for the partner of a 
male participant who becomes pregnant within 3 months of the male participant having 
received the last administration of investigational product, provided she agrees to her 
identity being provided to the study team and, if applicable, collection of the information 
from the health care clinics. In case of any abnormalities during the pregnancy or in the 
development of the baby during its first year of life for which a role of investigational 
product cannot be excluded, the team will arrange and pay for a specialist to evaluate the 
mother and/or the baby, as applicable. 
 
Risks of Study Procedures Not Routinely Used in Health Care 
10.7.1 
Skin Snips 
Skin snipping is the gold standard for quantifying infection with O. volvulus. Skin snipping 
with microscopic determination of microfilariae in the snips was the standard method used 
by the Onchocerciasis Control Program in West Africa and APOC in collaboration with the 
National Onchocerciasis Control and Elimination Programs for assessing patent O. volvulus 
infection.  This included assessing progress towards onchocerciasis elimination in DRC 
(Bas-Congo, Sankuru and Uélé), Congo (Bouenza, Pool), Burundi, Cameroon, Central 
African Republic, Chad, Ethiopia, Liberia, Malawi, Nigeria, Tanzania, and Uganda (Tekle et 
al. 2016).   
Skin snip sites heal within four to eight days without intervention. Therefore, it is expected 
that most skin snip sites will be healed by the end of the five daily visits by a study team 
member after each investigational product administration (Section 7.3.5). Should this not be 
the case, and for follow up after the skin snips at Month 30 and Month 36, additional visits 
to the participant will be conducted as indicated.  
Participants will be advised not to self-medicate but to contact a study team member or a 
local health facility should they need medical attention (Section 5.2.3 and 15.12).  
10.7.2 
Nodulectomies 
Excision of palpable nodules (subcutaneous nodules containing macrofilariae) involves 
minor surgery. Large scale implementation of nodulectomies in Guatemala, Mexico and 
Ecuador (WHO Expert Committee on Onchocerciasis 1987, Guderian 1988) have been used 
as part of onchocerciasis control efforts. The effect of nodulectomy as a means of reducing 
parasite transmission has been evaluated in Africa (Liberia, Burkina Faso) (WHO Expert 
Committee on Onchocerciasis 1987). Today, nodulectomies remain a standard procedure in 
the majority of studies of new anti-onchocercal treatments but are no longer used for 
onchocerciasis control.  
Nodulectomies will be conducted under local anesthesia and using sterile technique to 
minimize pain and the risk of infection at the incision site and participants followed up by a 
study team member to complete healing (Section 7.4.12.1).  

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POTENTIAL BENEFITS TO STUDY PARTICIPANTS 
Participation in the study is anticipated to provide a direct benefit as all participants will 
receive repeat doses of an anti-onchocercal therapy. Based on data from the Phase III study, 
direct benefits anticipated include reduction in skin microfilariae density and, if applicable, 
in live microfilariae in the anterior chambers of the eyes. Reduction in microfilariae is a 
meaningful measure of treatment efficacy as clinical symptoms of onchocerciasis are caused 
by the hosts’ inflammatory reactions to microfilariae in the skin and eyes. 
Participants excluded from the study because of a condition identified at Screening that 
requires medical attention will benefit from the Screening examination and receipt of referral 
information to a health facility.  
Participants with a history of living or working or still temporarily working in areas where 
they might have become infected with Loa loa or signs and symptoms potentially caused by 
Loa loa infection, will benefit from having their Loa loa infection status evaluated. Those 
found to be Loa loa-infected will be given a note recording their infection status for 
presentation to the local onchocerciasis control/elimination (or lymphatic filariasis 
control/elimination) program and during ivermectin mass distribution so that the program 
can act accordingly (Section 6.4.2).   
 

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12 
DATA SAFETY MONITORING BOARD REVIEW 
A Data Safety Monitoring Board (DSMB) has been established by the Sponsor that is 
independent of the Sponsor, Investigator and site study team. DSMB members were selected 
to include expertise in research methodology and statistics, pharmacology, clinical 
management and treatment of onchocerciasis, and pediatric and adult infectious diseases.  
Meeting objectives and schedule are specified in a DSMB charter and span the requirements 
of this study, the large single dose safety study (Study 3002) conducted concurrently in the 
same study area(s) in DRC, and the pediatric dose-finding study (Study 1006, conducted in 
Ghana). The DSMB may request additional review meetings. 
Attendance at meetings will include DSMB members and non-voting members as required. 
Review of unblinded data may only occur in the presence of DSMB voting members and an 
unblinded biostatistician. Sponsor representatives may only attend that part of the meeting 
where data to be discussed remains blinded.  
The first DSMB data review for this study will be convened after approximately 150 
participants have completed a one month period after the first round of investigational 
product administration. 
The DSMB will review all SAEs reported during the first month after each round of 
investigational product administration and provide a recommendation to the Sponsor on 
study continuation as planned, protocol amendment, or study discontinuation, following 
which the Sponsor will determine study continuation, protocol amendment, or study 
discontinuation.  
The outcome of the deliberations and recommendations of the DSMB to the Sponsor will be 
documented.  The recommendations will be provided to the Investigator and the ECs.  
 

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13 
PARTICIPANT COMPLETION OR WITHDRAWAL AND FOLLOW UP 
 
Participant Completion 
A participant will be deemed to have completed the study once all trial procedures have been 
conducted.  
Any AEs or SAEs still ongoing at the End of Study Visit (Month 36, Section 7.3.9), at the 
Exit Examination for individuals withdrawing/withdrawn early (Section 7.3.10) or at the 
Exit Examination in case of Early Study Termination (Section 7.3.10), will be followed in 
accordance with Section 10.4. 
 
Premature Withdrawal from Treatment or the Study 
13.2.1 
Criteria for Premature Withdrawal from Treatment or the Study 
Participants have the right to withdraw from treatment or the study at any time for any 
reason and without providing a reason. This will be discussed in the village meetings and 
with individuals (and their parent(s)/guardian for minors) as per the information in the EC 
approved participant information document (Section 5.1 and Section 15.9). 
The Investigator has the obligation to withdraw study participants from further treatment in 
case of pregnancy.  
The Investigator may also withdraw participants from further treatment or from the study in 
the event of concurrent illness or an AE if it is considered to be in the best interest of the 
participant.   
The Investigator also has the right to withdraw participants from further treatment or the 
study in the case of protocol violations (e.g. continued failure or inability of the participant 
to be available for follow up visits; treatment with doxycycline for more than 2 weeks). The 
Sponsor and Investigator will discuss and agree whether withdrawal from the study may also 
be necessary. 
13.2.2 
Follow up of Participants Withdrawing or Withdrawn from Further 
Treatment 
If a participant permanently discontinues dosing with investigational product, for example as 
a result of an AE or pregnancy, the investigator should discuss continued participation in the 
study with the participant so that, if the participant agrees, the study-required follow-up and 
procedures can be performed to Month 30. 
The reason for withdrawal from further treatment should be noted in the source records and 
on the eCRF (including if there is no reason given). If a participant is withdrawn from 
further treatment because of a treatment-limiting AE, thorough efforts must be made by the 
investigator to obtain agreement from the participant for follow up of this AE so that the 
investigator can clearly document the outcome of the AE in the source records and on the 
eCRF. 
Women who are withdrawn from further treatment because of a pregnancy should be asked 
to allow evaluation of the outcome of the pregnancy and newborn to the end of its 1st year of 
life. (Section 10.6). 
13.2.3 
Follow up of Participants Withdrawing or Withdrawn from the Study 
Should a participant decide to withdraw from the study, all efforts should be made to contact 
them, determine the reason for the withdrawal (and resolve any misconceptions that might 
motivate participant withdrawal) if the participant is willing to provide it. Furthermore, the 
investigator should ask the participant for his/her agreement for an Early Exit Examination 

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(Section 7.3.10). Unless an earlier time is chosen by the former participant, the Exit 
Examination should be conducted at least 3 months after the last treatment to monitor the 
participant for possible investigational product related AEs.  
The request to participants withdrawing from the study to agree to an Early Exit 
Examination (Section 7.3.10) is motivated by the following considerations:  
• 
The Early Exit Examination is designed to characterize the health at the time of 
withdrawal. This is important independent of whether the participant withdraws 
because of an AE or for other reasons (including reasons they choose not to disclose). 
Participants withdrawing for AE-unrelated reasons may nevertheless have AEs that 
the investigator should identify for two reasons: (a) to offer the participant follow up 
of ongoing AEs, and (b) to obtain as complete as possible characterization of the 
safety profile of the study drug. 
• 
Determine the number of skin microfilariae at the time of withdrawal. This will serve 
two purposes: (a) motivate those likely to benefit most from further treatment i.e. 
those with detectable skin microfilariae levels, to take ivermectin when distributed in 
their community, and (b) it will allow inclusion of actual skin microfilariae counts at 
that time in the analysis, thus increasing the accuracy of efficacy evaluation.  
Advice regarding participation in ivermectin distribution in the area will be provided. 
Furthermore, if permitted by the participant, follow up of AEs ongoing at the Exit 
Examination to resolution should be conducted. 
As applicable, inability to reach the participant, reason for withdrawal (including unknown 
or unwillingness of the participant to provide it), refusal of the participant of the Exit 
Examination, or, if applicable, follow up of ongoing AEs or of a pregnancy should be 
recorded in the source records and on the eCRF.  
If the Investigator withdraws a participant from the study, the principal reason will be 
recorded in the source records and on the eCRF and the relevant activities specified above 
for the case of a participant withdrawing implemented (provided the former participant 
agrees).   
 
Replacement of Withdrawn Participants 
Participants who decide to withdraw from treatment or this study or are withdrawn by the 
Investigator will not be replaced.  
 
Temporary Suspension of Study Conduct 
Continuation of the study, in particular further treatment, may be temporarily suspended by 
the Sponsor, or on the recommendation of the Investigator or the DSMB based on 
identification of AEs that require further examination before resumption of treatment or 
continuation of the study. Study conduct will continue once the concerns that resulted in 
suspension have been addressed. The RA and ECs will be informed about the suspension, its 
rationale and resolution of the concerns. 
Continuation of the study may also be put on hold if requested by the RA or the responsible 
ECs, or the Sponsor in response to information it generates/receives from sources outside of 
the study, including communications from the US FDA. Study conduct will continue once 
authorized by the RA, the responsible ECs, or the Sponsor, respectively. 

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Premature Termination of the Study 
The study will be completed as planned unless the following criteria are met: 
• New information regarding safety that indicates a change in the risk/benefit profile 
for moxidectin, such that this may no longer be acceptable to study participants, as 
per recommendation of the DSMB, the Sponsor (including in response to information 
it generates/receives from sources outside of the study, including communications 
from the US FDA), the Investigator, the RA and/or the responsible EC; and/or 
• Significant violation of GCP that compromises the rights and safety of the study 
participants or the ability to achieve the primary study objective. 
Conduct of the study may also be terminated if the Investigator or site staff are found in 
significant violation of contractual agreements, or are unable to ensure adequate 
performance of the study. 
The Investigator has the right to request termination of the study if it is considered in the best 
interest of current and potential future study participants’ safety or the investigator finds it 
impossible to complete the study as required by the protocol and GCP.   
Sponsor and Investigator need to consult with each other before the decision to terminate the 
study prematurely and agree on a termination procedure to ensure that, for example, 
participant safety is protected (follow up of ongoing AEs), investigational product is 
disposed in a manner consistent with the regulatory requirements and all study 
documentation stored in a manner that safeguards participant confidentiality.  
 

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14 
STATISTICAL ANALYSIS 
This trial is a randomized, double blind, parallel group, active control study design 
comparing the safety and efficacy of annual or biannual doses of moxidectin (8 mg) or 
ivermectin (approximately 150 µg/kg) for the treatment of onchocerciasis. Participants 
meeting all inclusion and no exclusion criteria will be randomized to one of four treatment 
groups (as described in Section 4.2), stratified by their baseline microfilariae skin density 
(<20 mf/mg versus ≥ 20 mf/mg) and Aire de Santé of residence (Section 4.2 and 
Section 8.1). 
Following Baseline assessments and randomization, participants will be followed for 
36 months.  
For the purpose of the analysis, the term Baseline will refer to the last assessment taken prior 
to administration of the first dose of investigational product and therefore includes 
assessments taken during Screening per the schedule in Table 1 or if scheduled Day -1 to 0 
(pre-dose) assessments are missing.  
 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of participants in the Full Analysis Set 
(FAS) (Section 14.8.1) who achieve a sustained skin microfilariae response (SMR) at 
Month 12 (SMR12) defined as an undetectable (zero) O. volvulus skin microfilariae count 
for each skin snip at both Months 6 and 12.  
For each FAS participant, the calculation of zero O. volvulus skin microfilariae at a given 
time point will use all available, non-missing, skin snips. Participants with a zero count for 
each non-missing skin snip at both Months 6 and 12 will be categorized as a SMR12 
responder. Participants with a non-zero count at either Month 6 or 12 will be categorized as a 
SMR12 non-responder. Participants with no available skin snip data at either Month 6 or 12 
will be imputed as a non-responder for their SMR12 status. See Section 14.11.6 for further 
information on handling of missing data for this endpoint. 
 
Secondary Efficacy Endpoints  
14.2.1 
Sustained Skin Microfilariae Response (SMR) 
SMR is defined as zero O. volvulus skin microfilariae detected in all skin snips at all relevant 
post-Baseline assessments:  
• SMR12 is defined as above but for pairwise comparisons other than annual or 
biannual moxidectin treatment (Section 14.11.2.1) 
• SMR18 is defined as zero O. volvulus skin microfilariae counts at all of 
Months 6, 12, and 18;  
• SMR24 is defined as zero O. volvulus skin microfilariae counts at all of 
Months 6, 12, 18 and 24;  
• SMR30 is defined as zero O. volvulus skin microfilariae counts at all of 
Months 6, 12, 18, 24, and 30; and  
• SMR36 is defined as zero O. volvulus skin microfilariae counts at all of 
Months 6, 12, 18, 24, 30, and 36.  
The calculation of these SMR endpoints will follow the same algorithm defined above for 
the SMR12 primary endpoint as relevant.  
14.2.2 
Mean Skin Microfilariae Density 
The mean skin microfilariae density (mf/mg skin) at a given time point will be the arithmetic 
average of the skin microfilariae densities across FAS participants.  

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For an individual participant the skin microfilariae density value is defined as the average 
skin microfilariae density among the non-missing skin snips at each time point. For some 
analyses the skin microfilariae density for a given participant may be transformed using a 
log transformation (log(x + 1)).  
See Section 14.11.6 for further details of how missing data will be handled for this endpoint. 
14.2.3 
Mean and Median Percent Change (Reduction) from Screening 
(Baseline) in Skin Microfilariae Density 
The mean percent change from Screening (Baseline) in skin microfilariae density (as defined 
above) at a given time point is defined as the arithmetic mean of the individual percentage 
change from Screening per participant. The median percent change from Screening 
(Baseline) in skin microfilariae density at a given time point is defined as the median of the 
individual percentage change from Screening per participant. 
See Section 14.11.6 for further details of how missing data will be handled for this endpoint.    
14.2.4 
Proportion of Participants with Zero Skin Microfilariae at Each 
6 Monthly Assessment 
This endpoint will provide the cross-sectional proportion of FAS participants with zero skin 
microfilariae detected in each skin snip at each distinct 6 month assessment. The proportion 
at each 6 month assessment will be cross-sectional without regard to the participant’s skin 
count status at other time points. There will be no imputation for missing data. 
14.2.5 
Endpoints for Live Microfilariae in the Anterior Chambers 
For live microfilariae in the anterior chambers of the eyes, the endpoints will be calculated 
as follows:  
• Sustained ocular microfilariae response defined as zero live O. volvulus microfilariae 
in the anterior chambers of the eyes at all post-Baseline assessments up to and 
including each of Months 12, 18, 24, 30, and 36, respectively.   
• Mean, and mean change from baseline, with respect to the number of live 
microfilariae in the anterior chambers of the eyes at each post-Screening assessment. 
• Mean and median percent reduction (from pre-treatment) of live microfilariae 
defined as the arithmetic mean and median of the individual percentage change from 
Screening per participant with respect to the number of live microfilariae in the 
anterior chambers of the eyes at each post-Screening assessment. 
• Proportion of participants with zero live microfilariae in the anterior chambers of the 
eyes at each post-Screening assessment. 
For these endpoints, only FAS participants with at least one live microfilaria in the anterior 
chambers across both eyes at Screening (Baseline) will be eligible for these analyses. If 
sufficient participants have a Screening count of ≥ 10 live microfilariae in the anterior 
chambers of the eyes, this group will be analyzed separately.  
Since the mean and median endpoints are calculated using the total live microfilariae count 
per participant only participants with non-missing data from both eyes will be eligible for 
those endpoints.  To maintain comparability across the ocular endpoints, the requirement for 
non-missing data in both eyes will be used for all the ocular endpoints.  Data for these 
endpoints will not be imputed.  See Section 14.11.6 for further details of how missing data 
will be handled for this endpoint. 

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Exploratory Endpoints 
14.3.1 
Signs and Symptoms of Onchocerciasis 
Presence and severity of reactive skin lesions and pruritus will be analyzed descriptively for 
each 6 monthly visit. Only participants in the safety analysis set with these signs and 
symptoms at Screening (Baseline) will be included in follow-up and eligible for these 
analyses.  
14.3.2 
Viability and Fertility of Male and Female Macrofilariae 
Provided the number of individuals with palpable nodules and who agree to nodule excision 
is sufficiently high to support conclusions on the relative effect of the treatment regimens, 
histopathology of nodules may be performed. Viability endpoints will be descriptive only 
and include the proportion of live, moribund, dead, or dead and calcified male and female 
macrofilariae, per participant averaged across all participants by treatment and overall.   
Fertility endpoints will be descriptive only and include: 
• The proportion of female worms by absence or presence of oocytes or embryos 
overall and by developmental stage (oocytes, morula, coiled, stretched, pretzel) per 
participant averaged across all participants by treatment and overall, and  
• The proportion of male worms by absence or presence of spermatogenic stages and 
type of spermatogenic stages per participant averaged across all participants by 
treatment and overall.  
Depending on the histopathological stains available at the time of histopathology, additional 
endpoints may be defined.  
 
Safety Endpoints 
Safety endpoints will be AEs, vital signs, concomitant medications and liver function tests 
and use the safety analysis set. 
If applicable, the outcomes of pregnancies and health-related findings on the neonates to 1 
year of age will be included.  
 
Primary Efficacy Hypothesis 
The primary efficacy hypothesis is a test of the average treatment effect with respect to 
achieving SMR at Month 12 (SMR12) when comparing the biannual versus the annual 
moxidectin treatment arms. The average treatment effect will be estimated by the 
standardized risk difference (RD) using the methodology outlined by Steingrimsson and 
colleagues (Steingrimsson et al. 2017), see Section 14.11.1. The null (Ho) and alternative 
(Ha) hypotheses for a two-tailed test are depicted below: 
 
 
 
 
 
Ho:  πbiann_moxi   - πann_moxi  = 0 
 
Ha:  πbiann_moxi  - πann_moxi   ≠ 0 
Where:    

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πbiann_moxi = the proportion in the target population achieving a SMR12 when assigned 
treatment with biannual moxidectin, and 
πann_moxi = the proportion in the target population achieving a SMR12 when assigned 
treatment with annual moxidectin. 
A statistically significant result, p < 0.05 two-tailed, with a RD favoring biannual moxidectin 
treatment, will confirm the superior efficacy of two 6-monthly moxidectin treatments over a 
single moxidectin treatment with respect to the proportion of the target population achieving 
a sustained microfilariae response at Month 12 (SMR12). The primary analysis will use the 
full analysis set (FAS, Section 14.8.1). 
 
Sample Size 
The sample sizes per randomized treatment group are shown in Table 9 and reflect the 
allocation ratios for each of the four treatment groups. 
Table 9: Sample Size by Randomized Treatment Group 
Dosing Schedule  
Randomized Treatment Group 
(N = number) 
Moxidectin 
Ivermectin 
Annual 
N = 120 
N = 40 
Biannual 
N = 120 
N = 40 
The sample sizes between the moxidectin and ivermectin groups reflecting a 3:1 
randomization ratio (Section 14.7) will provide safety data for up to a total of at least 960 
exposures to moxidectin and 320 exposures to ivermectin, providing a probability of around 
0.99 and 0.80 to detect at least 1 AE with a true background rate of 0.005, respectively, 
assuming exposures are independent.  
The estimated treatment effects were calculated from the large single dose Phase III trial 
with similar inclusion/exclusion criteria (Section 2.3.2.3). In that trial, an 'annual moxidectin 
group' (N = 977; as-randomized set) was included in the study design; however, there was no 
'biannual moxidectin group' included in that trial or elsewhere. Hence, hypothetical SMR12 
rates for a biannual moxidectin group using the previous Phase III data were calculated 
assuming that participants with zero microfilariae at Month 6 would continue to have zero 
microfilariae at Month 12 with biannual treatment. The hypothetical SMR12 rate for the 
annual moxidectin group was estimated from the Phase III data for all moxidectin 
participants with zero microfilariae at Months 6 and 12. For both estimates, calculations 
were derived imputing non-response for participants with missing skin snip data. Given 
these assumptions, the hypothetical SMR12 rates for the biannual and annual moxidectin 
groups were estimated to be 90% and 43%, respectively. For these hypothetical SMR12 rates 
and 120 participants meeting the FAS criteria (all randomized participants exposed to at least 
one dose of investigational product) within each of the two moxidectin groups, the power of 
the primary efficacy hypothesis, comparison of the biannual versus the annual moxidectin 
arm with respect to SMR12, was estimated to be > 95% via a z-test for two independent 
proportions at a two-tailed alpha level of 0.05. 
Assuming the possibility of a lesser treatment effect than that derived from the Phase III 
study outlined above, the statistical power was also calculated for hypothetical SMR12 rates 
of 70% and 50% for the biannual and annual moxidectin groups, respectively.  Given these 
hypothetical SMR12 rates, a sample size of 120 participants per group yields a power of 
approximately 90%. Although these power calculations do not account for adjustment of 
covariates which will be incorporated into the primary analysis of the SMR12 endpoint, they 
should provide reasonable power estimates. 

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Randomization and Randomization Ratio 
Participants will be randomized using an algorithm stratified by Baseline microfilariae 
density (< 20 mf/mg versus ≥ 20 mf/mg) and Aire de Santé.  
The randomization algorithm will yield the following allocation ratios among the 4 treatment 
groups: 1:1 allocation ratio for the moxidectin biannual vs moxidectin annual treatment 
arms, 1:1 allocation ratio for the ivermectin biannual vs ivermectin annual treatment arms, 
3:1 allocation ratio for moxidectin vs ivermectin for both the biannual and annual treatment 
arms. 
The 3:1 randomization ratio for the moxidectin and ivermectin treatment arms was chosen to 
maximize the safety data base after exposure to moxidectin while preserving the ability to 
compare the type, frequency and severity of AEs after moxidectin with those after 
ivermectin in the same population within the same time period.   
The randomization lists will be generated by an independent statistician not otherwise 
participating in the study. The randomization algorithm implemented will be documented, 
remain secured by the independent statistician, and provided in the clinical study report. 
 
Analysis Populations 
14.8.1 
Full Analysis Set 
The FAS is defined as all randomized participants exposed to at least one dose of 
investigational product. Participants in the FAS will be analyzed as randomized regardless of 
the actual treatment received.  
14.8.2 
Safety Analysis Set 
The safety analysis set is defined as all participants exposed to investigational product. For 
the safety analysis set, participants will be analyzed according to the actual investigational 
product received regardless of their randomized treatment group. 
14.8.3 
Per Protocol Analysis Set 
The per protocol analysis will be used for selected sensitivity analyses. The per protocol 
analysis set will include participants with no major protocol violations which will be 
specified a priori before database lock and analysis. 
 
Group Comparability 
Since the study is randomized and stratified by Baseline microfilariae density and Aire de 
Santé it is expected that the treatment arms will, on average, be balanced with respect to 
known and unknown prognostic factors.  
Statistical tests to assess group comparability with respect to baseline characteristics will not 
be conducted.  
Exploratory subgroup analyses and/or statistical models adjusting for baseline covariates 
suspected as being prognostic factors, other than those pre-specified, may be conducted for 
descriptive and supportive purposes. 
 Data Analysis Methods 
The FAS and safety analysis sets will be used for the analysis of efficacy and safety, 
respectively, unless otherwise stated.  
Aggregate data summaries will be provided by treatment arm and overall. If relevant, data 
summaries will also be provided by study time point. Line listings of study data will also be 

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included. Unless otherwise stated, all p-values will be two-tailed. Adjustment for multiple 
comparisons for secondary and exploratory endpoints will not be conducted.  
Further analysis details will be provided in the Statistical Analysis Plan (SAP). The SAP will 
be finalized prior to unblinding and the undertaking of any analysis. Any changes to the 
finalized SAP during the study will be documented. Deviations from the planned statistical 
analyses outlined in the SAP will be identified and described in the clinical study report. 
 Statistical and Analytical Plan 
14.11.1 
Statistical Analysis of the Primary Efficacy Hypothesis 
Following the methodology of Steingrimsson and colleagues (Steingrimsson et al. 2017), a 
logistic regression model with SMR12 as the dependent variable and main effects for 
Baseline microfilariae density (< 20 mf/mg density vs. ≥ 20 mf/mg density), the continuous 
metric for Baseline microfilariae density, village, and randomized treatment groups 
(moxidectin biannual versus moxidectin annual) will be fitted using the FAS. The predicted 
probabilities from the resulting logistic regression model will be calculated for each 
participant for each of these two treatments, regardless of the participant’s actual randomized 
treatment group. In essence, for each FAS participant two predicted probabilities will be 
calculated: one reflecting the probability of a SMR12 if the participant were assigned to 
biannual moxidectin treatment, and a second reflecting the probability of a SMR12 if the 
participant were assigned to annual treatment. The average of the predicted probabilities for 
each treatment across all FAS participants are the estimates corresponding to the target 
population proportions denoted in the null and alternative hypotheses above. Their 
difference is the standardized RD of Steingrimsson and colleagues (Steingrimsson et al. 
2017) and an estimate of the average treatment effect. The standard error (SE) of the 
standardized RD is obtained via a bootstrap from 1000 samples. The statistical test of the 
null hypothesis above is a Wald test obtained by dividing the standardized RD by its 
bootstrapped SE and comparing the result to the inverse of the standard normal cumulative 
distribution function appropriate for a two-sided test at alpha = 0.05. The 95% CIs will also 
be calculated using the bootstrapped SE. 
Participants in the FAS with no available data at any post-Baseline time point included in the 
calculation of the SMR12 will be categorized as a SMR12 non-responder. Participants 
missing Baseline microfilariae density will have their Baseline value imputed using the 
mean of their Aire de Santé. For the standardized RD, the point estimate, SE, the 95% CI, 
Wald statistic, and p-value will be provided along with the estimated treatment proportions. 
Standardized odds ratios (ORs) and relative risk will also be calculated using the same 
methodology.  
Should the logit model fail to converge with the inclusion of both the continuous and 
dichotomous covariates for Baseline microfilariae density, the dichotomous Baseline 
microfilariae density will be removed from the model. 
Sensitivity analyses supportive of the primary efficacy analyses will include comparison of 
the SMR12 in the biannual and annual moxidectin groups for each stratum used in the 
randomization and re-running the primary analysis using the per-protocol and safety analysis 
set. Additionally, sensitivity analyses for the primary efficacy endpoint will explore various 
imputation algorithms for participants with missing data. Further details will be outlined in 
the SAP. 

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14.11.2 
Statistical Analysis of Secondary and Exploratory Efficacy 
Endpoints 
14.11.2.1 
SMR12 Additional Pairwise Group Comparisons 
The SMR12 endpoint for additional pairwise group comparisons will be analyzed similar to 
that described above for the primary efficacy analysis using the FAS. These pairwise 
comparisons include: 
• Annual moxidectin versus annual ivermectin; 
• Biannual moxidectin versus biannual ivermectin; and/or 
• Annual moxidectin versus biannual ivermectin. 
As the secondary analyses will be supportive to the primary analysis, no adjustment for 
multiple comparisons will be made. 
14.11.2.2 
SMR18, SMR24, SMR30, and SMR36 
The analysis of the SMR endpoints at Months 18, 24, 30 and 36 and the pairwise 
comparisons will be conducted in a manner similar to that described for the SMR12 
endpoint. 
14.11.2.3 
Mean Skin Microfilariae Density 
The mean skin microfilariae density will be analyzed using an Analysis of Covariance 
(ANCOVA) model separately for each time-point and pairwise comparison noted in 
Section 14.11.2.1 and the annual vs biannual moxidectin comparison. Randomized treatment 
group, Baseline mean skin microfilariae density (continuous), and the two randomized 
stratification factors will be included as main effect covariates in the ANCOVA model. The 
analysis will include robust (sandwich) standard error estimates for statistical assessment of 
the regression coefficients and CIs. Prior to analysis, for each participant, the skin 
microfilariae density will be log transformed (natural log) with a 1 added, (log(x + 1)). 
Summary statistics will be transformed back for presentation. Should the ANCOVA model 
fail to converge with the inclusion of both the continuous and dichotomous covariates for 
Baseline microfilariae density, the dichotomous Baseline microfilariae density will be 
removed from the model. 
Additional sensitivity analyses may include nonparametric tests via permutation methods.  
In addition to the adjusted means, summary descriptive statistics including the mean and 
median for the raw and raw change from baseline values will also be provided by timepoint 
and randomized treatment arm. 
See Section 14.11.6 for further details of how missing data will be handled for this endpoint. 
14.11.2.4 
Mean and Median Percent Change (Reduction) from Baseline in 
Skin Microfilariae Density 
The percent change from Baseline in skin microfilariae density will be analyzed 
descriptively using the raw skin microfilariae density data. Both the mean and median 
percent change will be provided. Analyses will be provided by treatment group, time point, 
and overall. FAS  
See Section 14.11.6 for further details of how missing data will be handled for this endpoint. 
14.11.2.5 
Proportion of FAS Participants with 0 Skin Microfilariae at Each 
6 Monthly Assessment 
This analysis will consist of descriptive summary statistics providing the cross-sectional 
results. The proportion will be calculated on the number of FAS participants with non-

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missing data at each time point. As such, no imputation for missing data will be done. For 
each time point the number of participants with non-missing data and the 95% CI will be 
provided. The summary tables will be categorized by randomized treatment group and 
overall as well as by time point and skin microfilariae density stratum at randomization. 
As a sensitivity analysis, these data may also be analyzed imputing a non-response (i.e. 
assuming detectable skin microfilariae levels) for participants with missing data at each 
relevant time point. 
14.11.2.6 
Live microfilariae in the Anterior Chambers of the Eye  
Analysis of live microfilariae in the anterior chambers of the eyes in FAS participants with 
live microfilariae in the anterior chambers of the eyes at Baseline will be descriptive, as the 
number of participants in this subgroup is likely to be small. For each time point, descriptive 
summary statistics will be calculated for each endpoint.  For continuous endpoints, 
summaries will include the mean, median, standard deviation (SD), min, max, and the 
number of FAS participants contributing to the statistics. For sustained ocular microfilariae 
response endpoints, the SMR proportion, the number of responders, the 95% CI, and the 
number of FAS participants contributing to the statistics will be calculated. 
Missing data will not be imputed for the descriptive analyses described above and only 
participants with non-missing data for both eyes will be included. If the sample size is not 
unreasonably small, a sensitivity analysis imputing a non-zero outcome for participants with 
missing data may be conducted for the sustained ocular response endpoint. 
If sufficient participants have a Screening count of ≥ 10 live microfilariae in the anterior 
chambers of the eyes, this group may be analyzed separately.   
14.11.2.7 
Signs and Symptoms of Onchocerciasis 
Descriptive summary statistics will be provided for these endpoints. Only participants in the 
safety analysis set with these signs and symptoms at Screening (Baseline) will be included in 
follow-up and eligible for these analyses. Missing data will not be imputed.  
14.11.2.8 
Viability and Fertility of Male and Female Macrofilariae as 
Determined by Histopathology of Nodules Excised at Month 36 
Provided the number of individuals with palpable nodules and who agree to excision of 
nodules is sufficiently high to support conclusions on the relative effect of the treatment 
regimens, histopathology of nodules may be performed. Descriptive summary statistics will 
be calculated for these endpoints including only participants with histological evaluation 
data. Missing data will not be imputed.    
14.11.3 
Description of Subgroups to Be Analyzed 
The SMR endpoints and the mean skin microfilariae density endpoints for the FAS will be 
descriptively summarized and analyzed by treatment group for the following subgroups:  
• Baseline skin microfilariae density (< 20 mf/mg versus ≥ 20 mf/mg skin);  
• Age categories (specified in the SAP);  
• Sex; and 
• Aire de Santé. 
14.11.4 
Analysis of Participant Disposition, Demographics, and Baseline 
Characteristics 
Descriptive summary tables will be provided summarizing participant disposition by 
randomized treatment arm for each analysis set, including all participants randomized 

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regardless of exposure to investigational product along with reasons for early withdrawal 
from investigational product and early withdrawal from the study. Demographic and medical 
history summary statistics will also be provided by randomized treatment group and overall. 
14.11.5 
Analysis of Safety 
Safety will be assessed using the safety analysis set and will include TEAEs, vital signs, 
liver function, concomitant medications and pregnancy outcomes. 
Imputation of partial AE and concomitant medication dates will be done in order to 
categorize an event or medication as treatment emergent or as having started or been taken 
after the first treatment and subsequent treatments, respectively. Details of the date 
imputation algorithm will be provided in the SAP. 
14.11.5.1 
Adverse Events 
TEAE participant incidence will be summarized by body system and preferred term. Data 
will be tabulated by severity, investigator assessment of relationship to investigational 
product, serious TEAEs and TEAEs leading to death or study withdrawal. They will be 
summarized as follows: 
• Overall 
• TEAEs will be summarized overall and by 6 month time period after each 
investigational product administration.  
An additional analysis of TEAEs starting, or worsening, after the nodulectomies will be 
conducted separately for those participants in the safety analysis set which underwent 
nodulectomies. 
Key TEAEs of interest may be further analyzed by skin microfilariae density before each 
investigational product administration and, using Kaplan-Meier methods, assessed for time-
to-first events and/or time-to-resolution. Additionally, for key TEAEs exposure adjusted 
rates may be provided along with the timing of TEAEs relative to each dose of 
investigational product.  
TEAEs may also be summarized by age and sex and by pre-treatment skin microfilariae 
density. 
Line listings of all TEAEs will be provided.  
For participants in the safety analysis set, events occurring after signing of informed 
consent/assent but prior to the first exposure to investigational product will be provided in 
separate line listings.  
14.11.5.2 
Vital Signs 
Aggregate summary data for vital signs will be provided at Screening and post-Screening 
time points along with changes from Baseline and the subsequent applicable pre-treatment 
time points. Means, medians, standard deviations, minimum and maximum values will be 
provided. 
14.11.5.3 
Liver Function Tests 
Aggregate summary data for liver function test results will be provided for pre- and five day 
post-dose assessments associated with Day 0, Month 6 and Month 12 investigational product 
administration. Means, medians, standard deviations, minimums and maximum values will 
be provided. Change from Baseline, and from the pre- Month 6 and Month 12 
investigational product administration values, as relevant, may also be provided. 

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14.11.5.4 
Concomitant medications 
Concomitant medications for TEAEs will be summarized overall and by 6 month time 
period after each investigational product administration specified in Section 14.11.5.1. 
14.11.5.5 
Pregnancy Outcomes 
Narratives will be provided for each pregnancy and baby born for the first year of its life. 
14.11.6 
Handling of Missing Data 
For the SMR endpoints FAS participants with missing data at a given time point for a SMR 
endpoint will be imputed with a non-response value at that timepoint. Participants who died 
on-study will be imputed as a non-responder for all time points subsequent to their death.   
Additionally, participants who took a medication prohibited because of the potential impact 
on O. volvulus identified by the clinical team prior to any unblinding and data analysis will 
be categorized as a non-responder for any subsequent time points post prohibited-medication 
exposure.   
For the ANCOVA analyses of the mean skin microfilariae densities participants with 
missing data at a given time point will have their Baseline value imputed, including missing 
data for participants who died on study. For exposure to prohibited medication as defined 
above, the timepoints subsequent to exposure will also be imputed with the participants 
baseline value.  Participants missing Baseline microfilariae density will have their Baseline 
value imputed using the mean of their Aire de Santé. 
The descriptive analyses for the mean and median percent reduction endpoints will impute 
missing data in a similar manner.   
The same principles apply for the analysis of the relevant ocular endpoints if inferential 
analyses are conducted for those endpoints. 
Partial start/end dates for TEAEs and concomitant medications will be imputed as outlined 
in Section 14.11.5.1. 
Further details including sensitivity analyses conducted to assess the impact of missing data 
will be described in the SAP. 
14.11.7 
Interim Analysis 
A DSMB will review safety data for the duration of the study (Section 12).  
With respect to efficacy, no interim analyses are expected to be conducted.   
However, after the last participant has completed their Month 12 assessment, the Month 12 
data entered into the database will be cleaned and locked (frozen) to support a final analysis 
of the Month 12 data prior to the study’s completion. The rationale for conducting early 
analysis of the primary endpoint is to provide timely information to the WHO, policymakers, 
regulators and the onchocerciasis research and control community necessary for planning 
efforts toward future inclusion of moxidectin in national control programs.   
The Investigator and study staff, participants, and Sponsor will remain blinded to individual 
treatment assignments. An independent statistical group will conduct the analysis, thus 
maintaining the blind to individual data for personnel responsible for final analysis of the 
study upon completion of the study. The primary efficacy endpoint (proportion of 
participants achieving SMR12 for moxidectin biannual compared with moxidectin annual 
treatment arms), mean skin microfilariae density, and aggregate safety data through Month 
12 will be reported. Individual participant and minimum or maximum for aggregate mean 
microfilariae density data will not be reported at this time.  

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The results included in any report provided to the Sponsor will be submitted to regulatory 
authorities (RA, US FDA) and ECs.  
The unblinded treatment allocations will be applied to secured analysis data model (ADaM) 
files and not entered into the trials database. Operating details will be provided in the SAP or 
an additional document provided prior to undertaking an analysis.   
14.11.8 
Supplemental Analyses for Informing Guidelines and Policies 
The types of analyses required by regulatory agencies do not always meet the requirements 
for decisions on inclusion of an intervention in guidelines and policies.  A separate SAP will 
be written for supplemental analyses addressing these requirements.  The analyses will not 
be executed until the Study’s conclusion.   
14.11.9 
Update of Statistical Analysis Plans in View of Potential Impact of 
COVID-19 Pandemic on Study Conduct and Data 
Before unblinding, the data will be reviewed to assess which protocol deviations such as 
treatments, efficacy assessments or safety assessments that were missed or conducted 
outside the protocol prescribed window are attributable to the COVID-19 pandemic.  The 
Statistical Analysis Plans will then be updated to reflect complementary or appropriately 
modified approaches to the analyses.  
 

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15 
ETHICAL ASPECTS 
 
Declaration of Helsinki and Applicable Regulations 
The Investigator will ensure that this study is conducted in full conformance with the 
protocol, the latest version of the “Declaration of Helsinki”, the International Ethical 
Guidelines for Health-related Research Involving Humans of the Council of International 
Organizations of Medical Sciences (CIOMS), the ICH-GCP Guideline and all applicable 
regulations.  
 
Approval of Study Conduct by the Regulatory Authority 
This protocol, material used to inform potential study participants about the study 
(participant information document and informed consent and assent forms, PICF), the 
Investigator's Brochure and a dossier in the investigational medicinal products will be 
submitted by the Sponsor through the Investigator to the RA. Approval of study conduct by 
the RA is required before the study can be started. 
Protocol amendments as well as memoranda summarizing administrative changes of the 
protocol (Section 15.5) will be submitted to the RA as specified in the letter of approval of 
study conduct. 
 
Ethics Committee Approval 
This protocol, PICFs and the Investigator's Brochure, will be submitted by the Investigator 
to the EC assigned to the study by the MdSP. Furthermore, they will be submitted to the 
WHO Ethics Review Committee.  
Approval from the ECs must be obtained before starting the study and should specify the 
protocol number and/or title and protocol version, PICF version number and/or date and the 
date on which the EC met and the date the EC granted the approval and/or the date of 
signature on the approval. 
Any protocol amendments (Section 15.5) after receipt of the original EC approval must also 
be submitted to the ECs and approved by the ECs before the amendment can be 
implemented (except where required to ensure participant safety). The ECs will be notified 
of changes to the protocol that are purely administrative (Section 15.5).  
Documents to be used for informing participants of any early termination of the 
study (Section 13.5), new data that might impact their decision on continued study 
participation (Section 15.10) and the results of the study (Section 15.22) will also be 
submitted for EC approval prior to use. 
 
Reports to RA and ECs 
Reports to the RA and the ECs will be submitted as requested by the RA and ECs in their 
decision/approval letters. In the absence of specific requests, a progress report summarizing 
the number of individuals screened and treated in the past year and the number and type of 
SAEs reported since the last report will be submitted to the ECs annually. 
 
Protocol Amendments 
Administrative changes of the protocol are defined as corrections and/or clarifications that 
have no effect on the safety of the participant, scope, design, assessments or scientific 
validity of the study. These administrative changes will be agreed upon by the Sponsor and 
the Investigator, and will be documented in a memorandum. The Investigator will then 
notify the EC and the RA of these administrative changes. 

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Other modifications of the protocol (protocol amendments) must be prepared in consultation 
between the Sponsor and the Investigator and must be reviewed and approved by the 
Sponsor-designated Medical Monitor and the Statistician before sign-off by the Sponsor and 
the Investigator. Investigator and Sponsor-approved protocol amendments will be submitted 
to the ECs, to the RA as well as to the US FDA IND 126876 (Section 18). They must be 
approved by the RA (if indicated in the RA study approval letter) and/or ECs prior to the 
amendment being implemented. 
In the event of an emergency, the Investigator may institute any medical procedures deemed 
appropriate. However, all such procedures must be promptly reported to the Sponsor Clinical 
Development Manager for this study and the Medical Monitor, and the ECs. 
 
Study Site Capacity 
CRMT was one of the research centers established for the moxidectin Phase III study 
(protocol ONCBL60801). It is located at Referral Hospital (Hôpital de Réference) at Rethy, 
Ituri Province, and managed by the 20th Communauté Evangélique au Centre de l’Afrique 
(CECA/20), Bunia, member of the Église du Christ au Congo, in the DRC. 
Establishment of the CRMT in preparation for the Phase III study included renovation of 
buildings not used by the Hôpital de Réference to provide rooms and facilities required for 
that study. These facilities, including laboratories, locked storage facilities for study 
documentation, locked and temperature controlled room for the storage and preparation of 
investigational product, a meeting room and staff offices will be used for this study.   
Clinical, ophthalmological and laboratory equipment and material and other infrastructure 
elements such as cars, motorcycles, back-up generators, fuel reservoirs and communications 
means (satellite dish for internet connectivity) were also provided for the Phase III study and 
will be utilized for this study as needed. Additional and/or replacement equipment and 
material needed for this study will be purchased by CECA/20 from the grant obtained from 
the European and Developing Countries Clinical Trials Partnership (EDCTP) by the 
Sponsor, the Investigator (Dr. T. Ukety, CECA/20) and Co-Investigator (Dr. M. Mandro, 
DPS Ituri) and other researchers.  
 
Study Team 
The study will be led by Dr. T. Ukety, who is an ophthalmologist from Ituri, has conducted 
onchocerciasis-related studies in Ituri prior to joining WHO and was involved in the 
Phase III study as a technical advisor.  
The co-investigator up to June 2022, Dr. M. Mandro, is also from Ituri and has conducted 
onchocerciasis-related studies in Ituri and was a clinical monitor of the moxidectin Phase III 
study, in particular the site in Ituri.  He has been seconded to this study from the DPS Ituri. 
In June 2022, Dr. M. Mandro moved to Kinshasa to pursue other professional opportunities 
and was replaced by another qualified sub-investigator.  
Some staff who conducted the Phase III study in Ituri will be involved in this study as well. 
These staff, as well as additional staff hired for this study, will undergo (re)training on the 
ethical requirements for study conduct, the requirements for study conduct as outlined in the 
ICH-GCP, the protocol, protocol required procedures and protocol required documentation.   
The SOPs established for the Phase III study will be adapted or complemented for the study 
procedures required in this study.  

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Study Initiation 
The study can only be started after approval by the RA and the assigned ECs and after the 
Sponsor has approved study start following the study initiation visit. 
The objective of the initiation visit is to verify that the Investigator and study team have the 
means and knowledge to conduct the study. During the initiation visit, the Sponsor 
representative(s) will review with the Investigator and study team all Declaration of 
Helsinki, CIOMS and ICH-GCP requirements, the profile of AEs occurring after ivermectin 
and moxidectin treatment, all protocol requirements, study required equipment, material and 
consumables, study implementation plans including plans for study participant recruitment, 
SOPs, study documentation requirements including source records and eCRFs (Section 16), 
SAE reporting requirements and forms (Section 10.3.3), pregnancy reporting and follow 
requirements and forms (Section 10.6), study team training records and the study 
Authorization and Delegation Log. This verification will include the review of study team 
member curricula vitae and copies of qualification or licensure documents to confirm that 
study team members have the qualifications DRC law requires for the activities delegated to 
them on the study Authorization and Delegation Log, as well as records of training on study 
procedures delegated to them and which are not part of routine health care (e.g. skin 
snipping, counting of microfilariae, procedures for liver function tests).  
Furthermore, team members will be trained on the use of the eCRF and data management 
processes (Section 16.2). The Sponsor will ensure that its representatives are fluent in both 
English and French. 
Any deficiencies found will be discussed with the Investigator and need to be addressed 
before the Sponsor will approve study start.   
 
Informed Consent and Assent with Parental/Guardian Consent 
It is the responsibility of the Investigator to obtain written informed consent (or informed 
assent from minors with parental/guardian informed consent) from each individual 
participating in this study after explanation of the aims, methods, objectives and anticipated 
benefits and risks of the study in the local language(s) (Section 5.5.1) and wording they can 
understand. The Investigator must also explain to the potential study participants that they 
are completely free to refuse to enter the study or to withdraw from it at any time for any 
reason.  
The Investigator must utilize the EC-approved PICFs for informing potential study 
participants and for documenting written informed consent/assent. 
Information about the study will be provided and written informed consent or assent with 
parental/guardian consent obtained by a physician. Should the physician not speak the local 
language, another member of the study team who speaks the local language must be present 
to act as interpreter. The study team members authorized to inform study participants of the 
study and obtain written informed consent/assent with parental/guardian consent will be 
documented on the Authorization and Delegation Log. 
The appropriate consent or assent with parental/guardian consent must be obtained before 
any Screening or other study procedures are initiated (Section 6.1). 
The information and consent/assent forms in French and the local language(s) (see 
Sections 5.5.1.1 and 5.5.1.2) will be included separately in the RA and EC submissions. A 
final approved version of these documents will be retained in the study files and must be 
used in the informed consent/assent discussions with potential study participants. 

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15.9.1 
Considerations during the Development of the Participant 
Information Documents 
The Participant Information documents were written and the wording chosen to fit:  
• The planned step-wise process (Section 5.5.2) for informing communities and 
interested individuals about all aspects of the study required for the community to 
advise on study implementation and for individuals to decide upon their own or their 
child/ward’s participation; 
• The full age range for study eligibility so that adolescents and their parents/guardian 
can be informed simultaneously; 
• The step-wise consent/assent (to screening, to study participation, to nodulectomies, 
Section 6.2); 
• The decision to run the single dose safety study concurrently, so that individuals not 
eligible for this study (or not wanting to commit to a 3 three year study with repeated 
skin snips and 27 months requirement for contraception) can be immediately offered 
participation in a study with less stringent eligibility criteria, fewer evaluations and 
lasting only 3 months (Section 4.7); 
• The notions in the population in the recruitment areas to ensure that they are familiar 
with specific concepts (e.g. currency exchange rates) or that unfamiliar concepts are 
explained (e.g. blinding) or presented in terms meaningful to the potential 
participants (e.g. randomization as ‘decided by chance’, insurance as ‘Sponsor 
having put money aside’, password-protected as ‘in a locked and secure area’).  
15.9.2 
Provisions for Informed Consent and Assent with Parental/Guardian 
Consent by Illiterate Individuals 
A high percentage of the population in the recruitment areas is illiterate (Section 5.5.1).  
Furthermore, the ‘literacy’ criteria from the Informed Consent/Assent perspective are much 
higher than the criteria used locally.  To avoid these different literacy criteria and different 
provisions for informed consent/assent from illiterate and literate individuals being 
perceived as insulting or lacking respect, it was decided that a literate witness will be 
required for all participants. 
Consequently, all adults and minors will confirm their consent or assent with 
parental/guardian consent via signature, mark or finger print (as per their preference) on the 
consent form in the presence of a literate witness they have chosen.  The literate witness will 
confirm through their dated signature that they were present when the information was 
provided and that they witnessed that any questions asked were answered to the satisfaction 
of the potential participant and their parent/guardian, if applicable, and that voluntary 
informed consent or assent with parental/guardian consent was given.   
15.9.3 
Provisions for Informed Assent for Minors with Parental/Guardian 
Informed Consent 
Informed assent with written parental/guardian consent will be obtained for minors aged 12 
to 17 years old.  
Refusal of the parent(s)/guardian or minor constitutes dissent and precludes the minor's 
participation in the research. Every effort should be made to obtain, if possible, the consent 
of both parent(s).  
In order to respect local culture and unless otherwise advised by the RA or the EC, for 
orphans living with relatives, the head of the household (guardian) will be providing 
informed consent to complement the minors informed assent as the guardian.  

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Minors living with family members other than their parents, will require parental consent.  
If an adolescent turns 18 years during their participation in screening or the study, he or she 
will be asked to provide written informed consent as soon as practically reasonable on the 
same form the minor signed for assent. 
 Information to Study Participants in Case of New Data Emerging 
During the Course of Their Study Participation 
Should new data emerge during the course of this study that may affect the willingness of 
study participants to continue in the study, the data will be submitted to the ECs together 
with a PICF for informing the study participants about these data as a basis for their decision 
to continue study participation. 
Upon approval of the PICF by the EC, study participants will be contacted to provide and 
discuss with them this information and ask them about their decision or not to reconsent (or 
re-assent with parental/guardian re-consent). The Investigator will seek guidance from the 
chiefs and elders of the villages where the participants live on how to provide the 
information (e.g. participant meeting, visit to each individual participant). 
At the time these data emerge, the PICFs for use during continued recruitment of new 
participants will be updated accordingly and submitted to the EC for approval. 
 Information to Study Participants about ‘Incidental Findings’ 
Health problems identified during Screening or a study that are not related to the health 
problem being studied (in this case onchocerciasis and the response to the administration of 
moxidectin or ivermectin) are these days sometimes referred to as ‘incidental findings’. 
Plans for informing participants need to distinguish ‘anticipatable’ findings (i.e. health 
problems known to be diagnosed with the examinations and tests used) and ‘unanticipatable’ 
findings (i.e. health problems that cannot be expected to be identified based on current state 
of scientific knowledge).  
All examinations and tests used in this study are long established and not undergoing further 
scientific/methodological development (in contrast to, for example, imaging methods). 
Consequently, all health problems identified at each visit are ‘anticipatable’. All of them will 
be discussed with the participant and treatment will either be provided by the study team or 
the participant will be referred to the health system for appropriate care.   
‘Unanticipatable’ findings could only emerge from the use of the O. volvulus microfilariae 
or macrofilariae or left-over serum or left-over urine during research for improved tools and 
strategies for control and elimination of onchocerciasis and other Neglected Tropical 
Diseases (Sections 15.19, 15.20, 15.20.2, 15.20.3). The Sponsor has developed a process that 
provides for the scientists who conduct the research on the left over O. volvulus parasites and 
left-over serum and left-over urine to report to the Sponsor any findings that they consider of 
possible interest for the health of a participant. The Sponsor will convene a meeting of 
members of the DSMB, clinicians specializing in the discipline(s) indicated by the nature of 
the unanticipated finding and the Investigator (or delegate) to discuss the possible clinical 
significance of the unanticipated finding.  This process also ensures that the participant 
anonymity will be preserved.  Unanticipated findings will be provided to the participant only 
if approved by the ECs based on a dossier submitted that details the unanticipatable finding, 
the process and outcome for validating its health significance and the actions that can be 
taken for the benefit of the participant.  In the Participant Information document, potential 
participants are told that it is unlikely that the research on their O. volvulus parasites or on 
their left-over serum (referred to as ‘left-over blood’) or left-over urine will reveal any 
information relevant for their health, but that if this is the case, they will be informed.  

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 Risks due to Study Procedures 
Information on risks associated with study procedures which are not used during routine 
health care is provided in Section 10.7. 
 Risks associated with Investigational Products 
Information on risks associated with moxidectin and ivermectin are provided in 
Section 10.5. 
 Compensation of Study Participants for Time Spent on the Study and 
Costs Incurred for Treatment of an AE in a Local Health Facility 
As study participants will be recruited among villagers who are continuing to pursue their 
usual daily activities, the time participants spend on study activities will be time they are 
unable to pursue gainful work. To compensate study participants for the resulting loss of 
earnings, participants will be compensated for time spent undergoing assessments with the 
average daily earning of the population from which the study participants are being 
recruited, estimated by the Investigator at 5 US Dollars (US$). This is the equivalent of 
approximately 8500 Congolese francs and approximately 20 000 Uganda Shillings, the 
currency commonly used in both the primary and back-up recruitment area. The exchanges 
rates vary over time and the local population is very familiar with the impact of these 
variations.  To minimize participants suffering financially from exchange rates becoming 
unfavorable to them, the compensation is set based on the US$ and will be provided at the 
up-to-date exchange rate and in the currency the individual participant choses. 
The time spent prior to Screening (i.e. for informing the potential participants and obtaining 
informed consent to Screening) will not be compensated for. 
On Day 1 to Day 5 after investigational product administration, when the reactions to the 
microfilaricidal effect of moxidectin or ivermectin typically start and resolve (Section 10.5), 
an appropriately trained study team member will visit each participant daily (Section 7.3.5). 
If after that period study participants chose to visit a local health facility rather than contact 
the study team (directly or via the SFP (Section 5.2.4)) because of an AE, study participants 
will be compensated for any costs incurred for visiting the local health facility and for the 
treatment of an AE in the facility if that AE could possibly, probably or definitely be related 
to treatment with ivermectin or moxidectin.   
Study participants will not be compensated for costs incurred for treatment at health facilities 
of AEs unambiguously not related to investigational product or study conduct (e.g. malaria, 
appendicitis, snake bites, respiratory infections, intestinal infections and parasitosis, 
epilepsy, trauma) or related to treatments they obtained from traditional healers.   
 Safety of Study Participants Withdrawing Prematurely from Further 
Treatment or the Study 
For provisions to ensure follow up of study participants withdrawing or withdrawn from 
further treatment or the study, see Section 13.2. 
 Volume of Blood Sampled 
Blood will be drawn for liver function tests (3.0 mL/draw) and for infection with Loa loa 
(0.06 ml), if applicable. Liver function tests conducted before and five days after 
investigational product administration on Day 0, Month 6 and Month 12 will require a total 
of 18.0 mL and a maximum of 6.0 mL within a 4 week period.  These volumes are below the 
acceptable maximum volumes for single blood draws and blood draws over a four week 
period in paediatric studies of 1% and 3% of the total blood volume, respectively 

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(2001/20/EC 2008, Zisowsky et al. 2010). These would be 24 ml and 72 ml, respectively, 
assuming a weight of 30 kg and 80 ml of blood/kg, consistent with weights in the range to be 
expected for 12 year old girls in the population from which participants will be recruited.  
 Confidentiality of Trial Documents and Participant Records 
The Investigator must ensure that the participants’ anonymity will be maintained and that 
their identities are protected from unauthorized parties. On eCRFs or other documents 
submitted to the Sponsor, participants will not be identified by their names, but by the 
participant’s code assigned to each participant (Section 7.4).  
The Investigator will keep a participant screening log showing the names and addresses as 
well as participant codes. This log, as well as other documents not for submission to the 
Sponsor (e.g. participant’s signed informed consent/assent forms), will be maintained by the 
Investigator in strict confidence. 
All documents with results of the examinations conducted during this study, including, but 
not limited to the documents identifying study participants by name, will be stored in a 
locked cabinet or room with access restricted to authorized study team members and 
electronic records will be password protected (Sections 16.1 and 16.2). 
 Clinical Trial Insurance 
Clinical trial insurance equivalent to at least US$10,000,000 has been secured by the 
Sponsor to provide appropriate compensation to the participants should they suffer harm as a 
result of their participation in this study. This will also provide financial protection for those 
responsible for review and approval of the study protocol and for its conduct.   
The insurance policy will be provided to the RA and the MdSP designated EC at the time of 
protocol submission.  
 Ownership and Future Use of Biological Specimen Remaining After 
Completion of the Protocol Required Examinations 
Biological specimens left over and not destroyed after all tests have been completed (serum 
left over from liver function tests, urine left over from pregnancy tests, O. volvulus 
microfilariae and macrofilariae) will be owned jointly by CECA/20 and the Sponsor who 
agree to make these available for other research, in the interest of developing new tools and 
strategies primarily for onchocerciasis and secondarily for other NTDs prevalent in Africa.  
This intended use and the duration of the sample storage (20 years) is included in the PICF 
for potential participants.   
Should specimens be requested by for-profit organizations, CECA20 and the Sponsor will 
negotiate with the potential specimen users provisions for access to resulting products for the 
public health systems in the African countries at cost with no more than a minimum profit 
margin. A dossier summarizing the intended use and commitments of potential for-profit 
users will be submitted to an EC and the RA for approval before specimens are provided.   
In all cases, specimen-accompanying information collected during this study needed for the 
research will be anonymized and the transfer covered by a Material Transfer Agreement. 
The Material Transfer Agreement will also specify that the researchers have to inform the 
Sponsor should they identify ‘unanticipatable findings’ (Section 15.11).   
For further information on identified recipients of the parasites, left over serum and urine, 
see Sections 15.20.2 and 15.20.3, respectively.  

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 Maximization of Study Outputs for Improved Tools and Strategies for 
Control/Elimination of Onchocerciasis and other Neglected Tropical 
Diseases 
This research requires a significant investment of time (by the study participants, study team 
members, Sponsor and review committee members) and financial investment (EDCTP, 
Sponsor). Consequently, consideration has been given to how this investment can contribute 
to advance research for other improved tools and strategies for control and elimination of 
onchocerciasis and other NTDs without unacceptable increase in risk for study participants.   
15.20.1 
Modelling of Time to Onchocerciasis Elimination and Cost-
Effectiveness of Ivermectin vs Moxidectin-Based Elimination 
Policies 
For countries to decide whether to include moxidectin in their onchocerciasis elimination 
policies, they need not only efficacy and safety data, but also estimates of 
(a) epidemiological impact/time to onchocerciasis elimination and (b) cost-effectiveness of 
annual and biannual treatment with moxidectin relative to annual and biannual treatment 
with ivermectin. The skin microfilariae data and, if obtained (see Section 6.2), the data from 
the histopathological examinations of excised nodules from this study will be combined with 
the data from other studies of moxidectin and of ivermectin and used to model both (a) and 
(b). 
15.20.2 
Use of Skin Microfilariae and Macrofilariae  
The challenges African onchocerciasis endemic countries face for elimination of 
onchocerciasis transmission include that onchocerciasis is endemic across large contiguous 
areas which cross administrative boundaries within countries and borders between countries. 
Furthermore, different areas and countries initiated mass drug administration at different 
times and implementation has encountered different challenges. This is particularly so for 
countries suffering from past or current conflict, such as DRC. It results in different areas 
reaching the criteria for stopping treatment at different times. The recent WHO 'Guidelines 
for stopping mass drug administration and verifying elimination of human onchocerciasis' 
provide criteria for when transmission can be considered interrupted within a transmission 
zone so that mass drug administration can be stopped, but does not provide criteria for 
delineating transmission zones (World Health Organization 2016).  
To ensure that treatment is stopped in one area only when stopping criteria are met across 
the total geographic area of a 'transmission zone', and to minimize the risk that new 
infections are introduced from neighboring areas where transmission is still ongoing into 
areas where mass drug administration was stopped, countries need tools to delineate 
transmission zones. 
Furthermore, in several areas in Africa with long-term ivermectin mass drug administration, 
individuals with ‘suboptimal’ response to ivermectin have been identified.  Serial skin 
snipping or nodulectomies and histological examination of macrofilariae are currently the 
only methods available for monitoring the prevalence of suboptimal response to ivermectin. 
This makes it impossible for control and elimination programs to monitor O. volvulus 
susceptibility to ivermectin.  Countries need tools suitable for large scale monitoring. 
Research for such tools is currently ongoing through WHO/TDR (Hedtke et al. 2020). The 
research also targets a tool to allow control/elimination programs to quantify the number of 
reproductively active male and female O. volvulus that contributed to a sample of parasites 
obtained from skin snips or infected/infective vectors and to monitor the prevalence of 
suboptimal response to ivermectin. One of the WHO/TDR funded investigators (Dr. W. 

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Grant) at La Trobe University, Melbourne, Australia, has received a grant from United 
States of America National Institute of Health which allows significantly accelerated 
progress towards the WHO/TDR targeted tools and includes funding for the preservation and 
shipment of parasites for this research. Following completion of skin microfilariae counts, 
the microfilariae will be preserved in alcohol and shipped to that investigator (Sections 7.4.8 
and 7.4.12.2). Furthermore, following excision of onchocercal nodules, some nodule 
material will be preserved in alcohol and shipped to Dr. Grant. Samples will be shipped 
anonymized and under a Material Transfer Agreement which specifies 20 year maximum 
storage time and that all parasite genetic sequences obtained during this research will be 
deposited in a publicly available repository (Sections 15.19).  
Parasites not needed for this research will be shipped anonymized under a Material Transfer 
Agreement to the ‘Molecular Resources Division’ of the NIH-NIAID Filariasis Research 
Reagent Resource Center (FRRRC, or FR3, http://www.filariasiscenter.org/, 
http://www.filariasiscenter.org/resources/molecular-resources) to ensure that they can be 
used world-wide for research in support of control and elimination of NTDs.   
FR3 was established in 1969 and has a long history of partnership with (and at times funding 
from) WHO and supporting WHO funded researchers (including WHO/TDR funded 
research which led to development of moxidectin for onchocerciasis) (Michalski et al. 
2011). FR3 not only provides material to researchers world-wide but also offers free 
protocols and technical support to researchers. Over the past 7 years, FR3 has made 741 
shipments to recipients in 61 countries, including 33 countries in Africa (Benin, Botswana, 
Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Comoros, Democratic 
Republic of the Congo, Ethiopia, Gabon, Gambia, Ghana, Kenya, Liberia, Madagascar, 
Malawi, Mali, Mauritania, Mauritius, Namibia, Niger, Nigeria, Sao Tome and Principe, 
Senegal, Sierra Leone, South Africa, South Sudan, Sri Lanka, Swaziland, Tanzania, Togo, 
Uganda) (personal communication to Annette C. Kuesel, WHO/TDR, by Dr. Steven A. 
Williams, Director of Molecular Resources FRRRC (FR3), Director of the River Blindness 
Genome Project (1997-2005), Coordinator of the World Health Organization Filarial 
Genome Project (1994-2005), http://www.filariasiscenter.org/resources/molecular-
resources). Prerequisite for receipt of material by researchers is signature of a Material 
Transfer Agreement.   
15.20.3 
Use of Left-over Serum and Urine  
Left-over serum (see Section 7.4.10) and urine (see Section 7.4.7) will be frozen and 
preserved for biomarker, drug and vaccine research conducted by academic researchers or 
developers of diagnostics, drugs and vaccines for control and elimination of onchocerciasis 
or other NTDs (Section 15.19).  
For this purpose, the samples will be shipped to the ‘Molecular Resources Division’ of FR3 
(for further information on FR3, see Section 15.20.2). 
After minors who have agreed to participate in the study become adults, they will be asked 
whether they continue to agree to study participation (see Section 15.9.3) and, if applicable, 
to the use of the left-over serum and urine for future research. In case they change their 
mind, the Material Transfer Agreement between the Sponsor and CECA/20 and FR3 
includes the following provisions: 
• Samples identified as coming from minors will be put ‘in quarantine’ at FR3, i.e. will 
not be shipped to any requesters. They will be moved out of quarantine only after 
confirmation from the Sponsor or CECA/20 that the minor has confirmed agreement 
to future use of the left-over samples upon becoming an adult. 

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• Upon receipt of information from the Sponsor or CECA/20 that the minor has not 
maintained agreement to future use of left-over samples when becoming an adult or 
that further follow up of the minor for consent to future use of the left over serum is 
not possible, FR3 will retrieve and destroy the samples.   
Retrieval of samples for ‘moving them out of quarantine’ or for destruction is made possible 
through the bar code system based sample management in place at FR3 and the fact that FR3 
will provide bar-code labelled vials to CECA/20 for shipment of the samples.  
For provisions for specimen anonymity and Material Transfer Agreement see Section 15.19. 
 Complaints Process 
During the consultation with village communities during study preparation (Section 5.1), 
paths for study participants to convey complaints or suggestions to the study team will be 
discussed. Independent of whether they choose to provide these via intermediates (e.g. 
village chief, SFP) or directly to a study team member, feedback will be provided by a study 
team member. The study team member providing the feedback will be selected by the 
Investigator depending on the type of feedback/complaint. 
 Ownership of Study Data 
The data generated during the study will be owned by MDGH as per the agreement for the 
EDCTP grant concluded by MDGH and CECA/20. MDGH has committed to providing 
anonymized study data to the US FDA in support of a request to expand the moxidectin US 
Prescribing Information.  
In addition, MDGH will provide the anonymized data and reports to the WHO and country 
policy makers at their request.  
 Post-Study Activities 
15.23.1 
Post-Study Reports to RA and EC 
Following completion of the data analysis, a summary report will be provided to the RA and 
the ECs. 
15.23.2 
Post-Study Information about the Study to Study Participants 
The summary report to the ECs will be accompanied by an Information Document 
containing the information to be conveyed to study participants about the results of the study 
and planned future activities. This EC-approved Information Document will be the basis for 
informing the study participants (and interested other inhabitants of their villages) about the 
study. 
At that time participants will also be informed about the treatment regimen they were 
randomized to.  
15.23.3 
Post-Study Reports to Other Stakeholders 
Summary reports will be provided to and discussed with other relevant stakeholders, 
including those involved in the preparation of this study (Section 5.1) and presented to the 
Comité d'Experts Independants pour l'Elimination de l'Onchocercose de la RDC, the 
WHO/AFRO Expanded Special Project for Elimination of Neglected Tropical Diseases and 
relevant departments in WHO Headquarters.  
 Post-Study Access to Moxidectin 
Moxidectin has been approved in the US for the treatment of onchocerciasis due to 
O. volvulus in patients aged 12 years and older, but is not yet registered in DRC. 

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Consequently, moxidectin cannot be provided post-study to the population in the study area 
or anywhere else in DRC without approval by the RA via registration of moxidectin in DRC, 
another type of authorization, or in a RA and EC approved clinical trial. 
At the request of the RA, the Sponsor will submit the dossier that formed the basis of the 
US FDA registration to the RA.   
Given that the dossier is in English and includes >400 000 pages, the Sponsor is exploring 
the possibility for registration via the 'Collaborative Procedure for Accelerated Registration' 
of drugs approved by stringent regulatory authorities such as the US FDA currently being 
piloted by WHO in a number of countries, including DRC 
(https://extranet.who.int/prequal/content/faster-registration-fpps-approved-sras) (World 
Health Organization 2018). 
Until moxidectin has been integrated into WHO guidelines and/or DRC onchocerciasis 
control/elimination policies, the Sponsor will ensure access to treatment with moxidectin to 
clinical trial participants and their communities, provided the Sponsor receives the 
appropriate request with authorization and implementation and pharmacovigilance plans 
from the RA. 
 Provisions for the implementation of the Study during the COVID-19 
Pandemic 
All activities required for successful implementation of the study, ranging from community 
mobilization and information (Section 5), over obtaining informed consent/assent (Section 
15.19) to screening, treatment and follow up (Sections 7.3 and 7.4) were reviewed in 
conjunction with the relevant national and local guidance on management of the COVID-19 
pandemic.  
The objective of this review was to determine whether the study can be conducted during the 
pandemic in a way that minimizes risk of transmission of SARS-CoV-2 and could have an 
overall positive benefit-risk ratio through re-enforcement of the education of the population 
in the villages in the recruitment area on COVID-19 measures and contribution to screening 
for COVID-19 cases.   
Specifically, the review of the activities determined: 
• the extent to which they can be conducted with physical distancing and the 
operational measures to be taken, 
• the extent to which those involved will have already undergone education on 
COVID-19 and required pre-cautions to minimize SARS-CoV-2 transmission, 
• the need for the study team to provide the initial education on COVID-19 (based on 
Information, Education and Communication material provided by the local COVID-
19 task force) vs. re-enforcing previous education about COVID-19 provided by the 
local COVID-19 task force,  
• how screening for suspected COVID-19 cases through temperature measurement, 
questioning for symptoms defining individuals as suspected COVID-19 cases, advice 
to such cases to self-isolate and information to the responsible public health system 
units can be incorporated and take place at the beginning of all other protocol 
planned activities,  
• additional measures that need to be taken to minimize the risk of SARS-CoV-2 
transmission during all activities where physical distancing is not possible.   

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The details of the measures to be taken during the different activities are provided in 
Appendix 21.2.  As national or local health system directives evolve during the course of the 
pandemic, the measures described in the Appendix will be adapted accordingly. 
Furthermore, in view of possible outbreaks of potentially life threatening diseases (such as 
Ebola or COVID-19), treatment with investigational drugs or vaccines for such diseases 
have been included among permitted investigational products in Section 9.3. 
All measures to minimize risk of transmission of COVID-19 will be implemented in 
coordination and collaboration with the national/local COVID-19 response team which will 
also ensure that the study will adapt its measures as required by changing government/health 
system guidance. All communication and community engagement about COVID-19 will be 
done in coordination and collaboration with the national/local COVID-19 response team and 
based on their communication material.  
 

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16 
STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING 
 
Source records 
Data collection is the responsibility of the clinical trial site staff, under the supervision of the 
site Investigator. It is the Investigator's responsibility to ensure the accuracy, completeness, 
legibility and veracity of the reported data.  
The data will be documented either on paper (written records, print outs of analytical 
devices, retinal/disc photographs) or onto a tablet equipped with the CliniOps App Suite 
developed by CliniOps (a Mobile, Cloud-based, Digital Solutions company based in 
Freemont, CA, USA) that allows storage and backup of all data entered as well as uploading 
of selected data into the eCRF.  Data documented with this Direct Data Capture system are 
referred to as electronic source data (eSource). 
All paper source records should be typed or filled out using a black or blue pen, and must be 
legible. Errors should be crossed out with a single strike line and not obliterated (e.g. via use 
of correction fluid), the correction inserted, and the change initialed and dated by the 
Investigator or his/her authorized delegate. Printouts and photos that might fade overtime 
should be copied and/or digitized to ensure long-term availability.  
The data to be captured manually or as eSource will be agreed between the study team and 
the Sponsor and documented prior to initiation of the study. 
 
Electronic Case Report Forms and Data Management 
For each participant screened, an eCRF must be completed and signed electronically by the 
Investigator or delegated co-Investigator. For requirements for eCRFs for participants who 
withdraw from treatment or from the study or are withdrawn from treatment or the study by 
the Investigator, see Section 13. 
In view of the possible impact of the COVID-19 pandemic on study conduct, the eCRF will 
include fields allowing to capture which protocol deviations are attributable to the COVID-
19 pandemic (including, but not limited to, study participants cannot be treated or assessed 
within the protocol specified time frame because they are self-isolating, or they or their 
family are under quarantine, or study team members are under quarantine). 
The eCRF software developed by CliniOps is compliant with the US Code of Federal 
Regulations for Electronic Records and Electronic Signatures (21 CFR Part 11) and the US 
Health Insurance Portability and Accountability Act and is validated to meet data security, 
data quality and data monitoring requirements in accordance with ICH GCP guidelines. The 
data system includes password protection and internal quality controls, such as automatic 
range checks, to identify data that appears inconsistent, incomplete or inaccurate.  
Participants will be identified in the eCRF only via their participant code, not by name or 
any other information that might allow identification of the participant (see Section 15.17). 
Data management will be conducted by Sponsor-trained study team members at the site and 
by CliniOps, contracted by the Sponsor. The data manager at CliniOps will implement 
integrated testing and verification controls to ensure data completeness and internal 
consistency. Each operation performed is tracked by an audit trail. Each person at CliniOps 
is subject to professional secrecy.  
 
 Investigator’s Files/Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 

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documents should be classified into two separate categories: (i) Investigator’s Study File, 
and (ii) participant source records (Section 16.1). 
The Investigator’s Study File will contain essential documents such as the 
protocol/amendments, EC and RA approvals with correspondence, approved PICF and 
signed consent/assent forms, screening logs, randomization lists, investigational product 
records, staff curricula vitae and authorization forms and other documents and 
correspondence. The eCRFs with data queries and audit trails will also be retained in an 
archive acceptable format. 
Participant source records may include physician’s and nurse’s notes, original laboratory 
reports, and any other records generated during and for this study.  
The storage system used during the trial and for archiving (irrespective of the type of media 
used) will allow for document identification, version history, search, and retrieval. The 
Sponsor will ensure that the Investigator has control of and continuous access to the data 
reported to the Sponsor. The Investigator will have control of all essential documents and 
records generated by the investigator and the study team before, during, and after the trial. 
All essential documents should be retained for at least 25 years after the end of the clinical 
trial. These documents should be retained for a longer period however if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. The Sponsor will 
inform the investigator/institution as to when these documents no longer need to be retained. 
The Investigator must notify the Sponsor prior to destroying any clinical study records. 
Should the Investigator wish to assign the study records to another party (due to retirement 
or leaving the site organization) or to move them to another location, the Sponsor must be 
notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the Investigator and the 
Sponsor to store these in (a) sealed container(s) outside of the site so that they can be 
returned sealed to the Investigator in case of a regulatory audit. Where source records are 
required for the continued care of the participant, appropriate copies should be made, or 
extracted from the Direct Data Capture system in the case of eSource, as applicable, for 
storage outside of the site. 
 

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MONITORING, AUDITING AND INSPECTION OF THE STUDY 
 
Access to Source Records 
The Investigator shall supply the Sponsor, on request, with any required study 
documentation and records generated during examination of participants or analysis of the 
biological samples obtained during the study. This is particularly important for source data 
verification or when errors in data transcription are suspected.  
In case of governmental or regulatory queries or requests for audits and inspections, it is also 
necessary to have access to the complete study records.  Individuals authorized by 
governmental and regulatory agencies to audit or inspect studies have the obligation to 
respect participant confidentiality. 
 
Monitoring of the Study 
The study will be monitored by an unblinded monitor to review randomization and 
investigational product dispensing and a blinded monitor to review all other activities. 
Monitoring will occur by on-site visits and/or remotely at a frequency specified in the 
Monitoring Plan or more frequently, if triggered by observations made during a visit, remote 
monitoring or as requested by the DSMB. 
It is understood that the responsible monitors, as a Sponsor representative, will be fluent in 
English and French and contact and visit the Investigator in person or electronically 
regularly and that he/she will be allowed, on request, direct access to the source records as 
per ICH-GCP guidelines to inspect the various records of the trial (eCRFs, signed 
consent/assent forms, laboratory test reports, participant records in local health facilities the 
study participant might contact and other pertinent data, randomization and investigational 
product dispensing records) provided that participant confidentiality is maintained as 
required by ICH-GCP.  
It will be the monitor’s responsibility to inspect such documents to verify the adherence of 
study conduct to ICH-GCP requirements and the protocol and to verify the completeness, 
consistency and accuracy of the data entered on the eCRF.  
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
in the course of these monitoring visits are resolved. 
 
Audits and Inspections 
The Investigator/Institution will also permit trial-related audits, EC review, and regulatory 
inspection(s), providing direct access to source records to appropriately qualified personnel 
from the Sponsor or its representative who speak English and French, or to RA or health 
authority inspectors or EC representatives after appropriate notification. The verification of 
the eCRF data may be by direct inspection of source records (where permitted by law) or 
through an interview technique. 
Sponsor quality assurance audit(s) may be conducted during the study and/or preceding a 
planned regulatory inspection. 
Inspections by regulatory authorities are at their discretion and cannot be foreseen. It is usual 
practice for regulatory authorities of foreign countries (e.g. US FDA or the regulatory 
authorities of other countries considering approval of moxidectin) to contact their 
counterparts in the RA of the country where the study is conducted when considering an 
inspection. 

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CONDUCT OF THE STUDY UNDER US FDA INVESTIGATIONAL NEW 
DRUG APPLICATION  
MDGH is conducting Study 3001 under US FDA Investigational New Drug (IND) 
application 126876. This IND application was opened as part of MDGH’s interactions with 
the US FDA which resulted in the 2018 US marketing approval of moxidectin for the 
treatment of onchocerciasis due to O. volvulus in patients aged 12 years and older (US FDA 
NDA 210867). Study 3001 is a MDGH NDA 210867 post marketing commitment study.  
Consequently, this protocol was submitted to the US FDA by the Sponsor and the Sponsor 
will ensure all requirements under Title 21 Part 56 of the US Code of Federal Regulations 
(Institutional Review Boards) are satisfied, or applicable US FDA waiver approved prior to 
study commencement.  
As required by US law, a description of this clinical trial has been made available on 
http://www.ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03876262). This 
website will not include information that can identify participants.  
US FDA regulations include the following requirement: when seeking informed consent for 
applicable clinical trials, as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall 
be provided to each clinical trial subject in informed consent documents and processes. This 
will notify the clinical trial subject that clinical trial information has been or will be 
submitted for inclusion in the clinical trial registry databank under paragraph (j) of section 
402 of the Public Health Service Act. The statement is: "A description of this clinical trial 
will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site 
will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time." 
While this requirement is applicable to this study, this statement has not been included in the 
Participant Information Documents for the following reasons:  
• The population that will be recruited (e.g. Section 5.5.1) does not know what a Web 
site is, has no access to the web and is thus not able to access 
http://www.ClinicalTrials.gov. A study team member could access this for them, but 
they would not be able to read the entries. Furthermore, since the text on the Web 
site is not phrased in lay language appropriate for the participant population, a 
translation of the entries into the local language (see Sections 5.5.1.1 and 5.5.1.2) by 
a study team member would have no informative value to (potential) participants.  
Consequently, inclusion of this statement in the Participant Information Document 
would not have the informative value for the target population intended by the US 
FDA.   
• Elements in this statement intended to inform participants about the confidentiality 
and deidentification of their data in any reporting of the study results are included in 
the Information Documents for the (potential) participants. 
• All elements of the description of the trial on http://www.ClinicalTrials.gov which 
are not technical (i.e. not referring to statistical analysis of the data) are included in 
the Information Documents for the (potential) participants. 
 
Reporting to US FDA During the Study 
As required under the post-marketing commitment, MDGH will provide annual updates on 
this study to the US FDA. These will describe the study status (e.g. ongoing, delayed), and 
include information such as the number of participants screened, treated, withdrawn and 
safety data and any changes to the expected study completion date (noting encountered 
difficulties if applicable).  

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Additionally, MDGH will submit the report of the Month 12 analysis of the primary 
endpoint and associated safety data to the IND (Section 14.11.7).  
 
Reporting to US FDA After the Study 
Upon completion of this study, MDGH intends to submit the final clinical study report to the 
US FDA in support of a request to update the moxidectin US Prescribing Information with 
comparative data on the efficacy and safety of moxidectin and ivermectin when given at 
annual and biannual re-treatment frequencies. If approved, this will provide a US 
Prescribing Information for moxidectin that is more closely aligned with the anticipated use 
of moxidectin in the field. 
 

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19 
PUBLICATIONS 
MDGH will update the study entry on www.ClinicalTrials.gov with significant study status 
updates and to include a summary of the study results when available, which will not contain 
information that could identify participants. 
The Sponsor has also listed the study on the Pan African Clinical Trials Registry 
(https://pactr.samrc.ac.za/). 
Once approved by the RA and the ECs, the protocol will be made publicly available.  
The results of this study will be published in peer-reviewed open access journals and 
presented at scientific meetings. Sponsor-initiated publications and/or presentations will be 
agreed upon between the Investigator and Sponsor. Investigator-initiated publications and/or 
presentations will be provided for review by the Sponsor at least 30 days before the 
submission deadline for the manuscript and/or presentation abstract to enable relevant input 
based on information from other studies that may not yet be available to the Investigator. 
Any formal publication of the study in which input of the Sponsor personnel exceeded that 
of conventional monitoring will be considered as a joint publication by the Investigator and 
the appropriate Sponsor personnel. Authorship will be determined by mutual agreement in 
accordance with International Committee of Medical Journal Editors recommendations. 
Additional authors will be agreed prior to journal submission.  
Oral or written presentations or publications will mention "this research is part of the 
EDCTP2 Programme supported by the European Union (grant NUMBER RIA2017NCT-
1843)". 
 

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20 
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21 
APPENDICES 
 
Appendix 1: Adverse Events Toxicity Grading Scale 
 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Major Clinical 
Conditions: 
Cardiovascular 
Arrhythmia 
(by ECG or 
physical 
examination) 
Specify 
type, if 
applicabl
e 
No symptoms AND 
No intervention 
indicated 
No symptoms 
AND Non-urgent 
intervention 
indicated 
Non-life-
threatening 
symptoms AND 
Non-urgent 
intervention 
indicated 
Life-threatening 
arrhythmia OR 
Urgent intervention 
indicated 
Blood Pressure 
Abnormalities 0F0F1 
Hypertension 
(with the lowest 
reading taken 
after repeat 
testing during a 
visit) 
≥ 18 years of 
age 
140 to < 160 
mmHg systolic 
OR 
90 to < 100 
mmHg diastolic 
≥ 160 to < 180 
mmHg 
systolic OR 
≥ 100 to < 110 
mmHg 
diastolic 
≥ 180 mmHg 
systolic OR 
≥ 110 
mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously 
diagnosed with 
hypertension (e.g., 
malignant 
hypertension) OR 
Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
≥ 99th percentile 
+ 5 mmHg 
adjusted for age, 
height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously 
diagnosed with 
hypertension (e.g., 
malignant 
hypertension) OR 
Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms 
corrected with oral 
fluid replacement 
Symptoms AND 
IV fluids indicated 
Shock requiring 
use of 
vasopressors or 
mechanical 
assistance to 
maintain blood 
pressure 
Cardiac Ischemia 
or Infarction 
Report only one 
NA 
NA 
New symptoms 
with ischemia 
(stable angina) OR 
New testing 
consistent with 
ischemia 
Unstable angina 
OR Acute 
myocardial 
infarction 
 
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines 
for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; 
originally published online November 14, 2011; DOI: 10.1542/peds.2009-2107C 
 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 107 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with 
mild to moderate 
activity or exertion 
Symptoms at rest 
or with minimal 
activity or exertion 
(e.g., hypoxemia) 
OR Intervention 
indicated (e.g., 
oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive 
medications, 
ventricular assist 
device, heart 
transplant) 
Hemorrhage 
(with significant 
acute blood loss) 
NA 
Symptoms AND 
No transfusion 
indicated 
Symptoms AND 
Transfusion of ≤ 
2 units packed 
RBCs indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 
units packed RBCs 
(for children, 
packed RBCs 
> 10 cc/kg) 
indicated 
Prolonged PR 
Interval or AV 
Block 
Report only one 
> 16 years of age 
PR interval 0.21 to 
< 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type 
I 2nd degree AV 
block 
Type II 2nd 
degree AV block 
OR Ventricular 
pause ≥ 
3.0 seconds 
Complete AV block 
≤ 16 years of age 
1st degree AV 
block (PR interval 
> normal for age 
and rate) 
Type I 2nd 
degree AV 
block 
Type II 2nd 
degree AV block 
OR Ventricular 
pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged 
QTc 
Interval1F1F2 
0.45 to 0.47 
seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds 
above baseline 
Life-threatening 
consequences 
(e.g., Torsade de 
pointes, other 
associated serious 
ventricular 
dysrhythmia) 
Thrombo
sis or 
Embolism 
Report only one 
NA 
Symptoms AND 
No intervention 
indicated 
Symptoms 
AND 
Intervention 
indicated 
Life-threatening 
embolic event 
(e.g., pulmonary 
embolism, 
thrombus) 
Dermatologic 
 
 
 
 
Alopecia (scalp 
only) 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to 
more than one 
area 
Generalized 
NA 
 
2 As per Bazett’s formula. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 108 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral 
antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals) 
Life-threatening 
consequences 
(e.g., sepsis, 
tissue necrosis) 
Hyperpigmentation Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to 
more than one 
area 
Generalized 
NA 
Pruritus2F2F3 3 
(without skin 
lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify 
type, if 
applicabl
e 
Localized rash 
Diffuse rash 
OR Target 
lesions 
Diffuse rash AND 
Vesicles or 
limited number of 
bullae or 
superficial 
ulcerations of 
mucous 
membrane limited 
to one site 
Extensive or 
generalized bullous 
lesions OR 
Ulceration of 
mucous 
membrane 
involving two or 
more distinct 
mucosal sites OR 
Stevens-Johnson 
syndrome OR 
Toxic epidermal 
necrolysis 
Endocrine and 
Metabolic 
 
 
 
 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled 
despite treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences 
(e.g., ketoacidosis, 
hyperosmolar non- 
ketotic coma, end 
organ failure) 
 
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 109 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Gynecomastia 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Disfiguring 
changes AND 
Symptoms 
requiring 
intervention or 
causing inability to 
perform usual 
social & functional 
activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy3F3F4 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy4F4F5 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
Gastrointestinal 
 
 
 
 
Anorexia 
Loss of appetite 
without 
decreased oral 
intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total 
parenteral nutrition) 
 
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and 
abdomen. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 110 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis) 
Symptoms recur 
or persist despite 
intervention 
Life-threatening 
consequences 
Bloating or 
Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical 
intervention 
indicated 
Radiologic, 
endoscopic, or 
operative 
intervention 
indicated 
Life-threatening 
consequences 
(e.g., sepsis, 
perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with 
manual 
evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 3 
stools over 
baseline per 24-
hour period 
Persistent 
episodes of 
unformed to 
watery stools OR 
Increase of 4 to 6 
stools over 
baseline per 24-
hour period 
Increase of ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number 
of stools OR Mild 
dehydration 
Liquid stools with 
moderate 
dehydration 
Life-threatening 
consequences 
(e.g., liquid stools 
resulting in severe 
dehydration, 
hypotensive shock) 
Dysphag
ia or 
Odynoph
agia 
Report only 
one and 
specify 
location 
Symptoms but 
able to eat usual 
diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention 
indicated 
Life-threatening 
reduction in oral 
intake 
Gastrointesti
nal Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopi
c 
interventio
n indicated 
Transfusion 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or 
Stomatitis 
Report only 
one and 
specify 
location 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
OR Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 111 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in 
minimal oral 
intake for > 48 
hours OR 
Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization 
not indicated 
Symptoms with 
hospitalization 
indicated 
Life-
threatening 
consequences 
(e.g., 
circulatory 
failure, 
hemorrhage, 
sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Interventio
n indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge 
requiring the use 
of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent 
episodes with 
no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Musculoskeletal 
 
 
 
 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-
care functions 
Arthritis 
Stiffness or joint 
swelling causing 
no or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint 
stiffness or 
swelling causing 
inability to perform 
basic self-care 
functions 
Myalgia 
(generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Muscle pain 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle 
pain causing 
inability to perform 
basic self-care 
functions 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 112 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Osteonecrosis 
NA 
No symptoms 
but with 
radiographic 
findings AND 
No operative 
intervention 
indicated 
Bone pain with 
radiographic 
findings OR 
Operative 
intervention 
indicated 
Disabling bone 
pain with 
radiographic 
findings causing 
inability to perform 
basic self-care 
functions 
Osteopenia6 
≥ 30 years of age 
BMD t-score 
-2.5 to -1 
NA 
NA 
NA 
< 30 years of age 
BMD z-score 
-2 to -1 
NA 
NA 
NA 
Osteoporosis5F5F66 
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing 
loss of vertebral 
height) 
Pathologic fracture 
causing life-
threatening 
consequences 
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing 
loss of vertebral 
height) 
Pathologic fracture 
causing life-
threatening 
consequences 
Neurologic 
 
 
 
 
Acute CNS 
Ischemia 
NA 
NA 
Transient 
ischemic attack 
Cerebral vascular 
accident (e.g., 
stroke with 
neurological 
deficit) 
Altered Mental 
Status (for 
Dementia, see 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance below) 
Changes causing 
no or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Confusion, 
memory 
impairment, 
lethargy, or 
somnolence 
causing inability to 
perform usual 
social & functional 
activities 
Delirium OR 
Obtundation 
OR Coma 
Ataxia 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia 
detected on 
examination 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling 
symptoms causing 
inability to perform 
basic self-care 
functions 
 
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific 
Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World 
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 
2007: Printed by the University of Sheffield. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 113 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention deficit 
disorder) 
Specify type, if 
applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part- 
time basis 
indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full- 
time basis 
indicated 
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated 
Developmental 
Delay 
< 18 years of age 
Specify type, if 
applicable 
Mild developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either 
motor or cognitive, 
as determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated OR 
Headache with 
significant 
impairment of 
alertness or other 
neurologic function 
Neuromuscul
ar Weakness 
(includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual 
social & functional 
activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness 
impairing 
ventilation 
Neurosensory 
Alteration 
(includes 
paresthesia and 
painful 
neuropathy) 
Specify type, if 
applicable 
Minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration 
or paresthesia 
causing inability to 
perform usual 
social & functional 
activities 
Disabling sensory 
alteration or 
paresthesia 
causing inability to 
perform basic self-
care functions 
Seizures 
New Onset 
Seizure 
≥ 18 years of 
age 
NA 
NA 
1 to 3 seizures 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 114 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
< 18 years of 
age (includes 
new or pre- 
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal 
state 
Seizure lasting 5 to 
< 20 minutes with 
< 24 hours 
postictal state 
Seizure lasting ≥ 
20 minutes OR > 
24 hours postictal 
state 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Pre-existing 
Seizure 
NA 
Increased 
frequency from 
previous level of 
control without 
change in seizure 
character 
Change in 
seizure character 
either in duration 
or quality (e.g., 
severity or 
focality) 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness 
(e.g., pre-syncope) 
Loss of 
consciousness 
with no 
intervention 
indicated 
Loss of 
consciousness 
AND 
Hospitalization or 
intervention 
required 
NA 
Pregnancy, 
Puerperium, and 
Perinatal 
 
 
 
 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal death 
occurring at ≥ 20 
weeks gestation 
NA 
Preterm Birth 
(report using 
mother’s 
participant ID) 
Live birth at 34 to 
< 37 weeks 
gestational age 
Live birth at 28 to 
< 34 weeks 
gestational age 
Live birth at 24 to 
< 28 weeks 
gestational age 
Live birth at < 24 
weeks gestational 
age 
Spontaneous 
Abortion or 
Miscarriage6F6F7 
(report using 
mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous 
abortion or 
miscarriage 
NA 
Psychiatric 
 
 
 
 
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing more than 
minimal 
interference with 
usual social & 
functional activities 
Severe difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing inability to 
perform usual 
social & functional 
activities requiring 
intervention or 
hospitalization 
NA 
Psychiatric 
Disorders 
(includes anxiety, 
depression, 
mania, and 
psychosis) 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to 
self or others OR 
Acute psychosis 
OR Behavior 
causing inability to 
perform basic self-
care functions 
 
7 Definition: A pregnancy loss occurring at < 20 weeks gestational age. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 115 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Specify disorder 
functional activities 
usual social & 
functional activities 
Suicidal Ideation 
or Attempt 
Report only one 
Preoccupied 
with thoughts of 
death AND No 
wish 
to 
kill 
oneself 
Preoccupied 
with thoughts of 
death AND 
Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial 
or complete plans 
but no attempt to 
do so OR 
Hospitalization 
indicated 
Suicide attempted 
Respiratory  
 
 
 
 
Acute 
Bronchospasm 
Forced expiratory 
volume in 1 
second or peak 
flow reduced to 
≥ 70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 
second or peak 
flow 50 to 
< 70% OR 
Symptoms with 
intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 
second or peak 
flow 25 to 
< 50% OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Forced 
expiratory 
volume in 1 
second or peak 
flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase 
in respiratory rate 
for age 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Nasal flaring 
OR Intercostal 
retractions OR 
Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual 
social & functional 
activities OR 
Pulse oximetry < 
90% 
Respiratory failure 
with ventilator 
support indicated 
(e.g., CPAP, BPAP, 
intubation) 
Sensory 
 
 
 
 
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention 
not indicated 
Hearing aid or 
intervention 
indicated 
Profound bilateral 
hearing loss (> 80 
dB at 2 kHz and 
above) OR Non-
serviceable hearing 
(i.e., >50 dB 
audiogram and 
<50% speech 
discrimination) 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 116 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
< 12 years of 
age (based on a 
1, 2, 3, 4, 
6 and 8 
kHz 
audiogr
am) 
> 20 dB hearing 
loss at ≤ 4 kHz 
> 20 dB hearing 
loss at > 4 kHz 
> 20 dB hearing 
loss at ≥ 3 kHz in 
one ear with 
additional speech 
language related 
services indicated 
(where available) 
OR Hearing loss 
sufficient to 
indicate 
therapeutic 
intervention, 
including hearing 
aids 
Audiologic 
indication for 
cochlear implant 
and additional 
speech- language 
related services 
indicated (where 
available) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis 
with symptoms OR 
Medical 
intervention 
indicated 
Posterior or pan- 
uveitis OR 
Operative 
intervention 
indicated 
Disabling visual loss 
in affected eye(s) 
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-
care functions 
Visual Changes 
(assessed from 
baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual 
social & functional 
activities 
Disabling visual loss 
in affected eye(s) 
Systemic 
 
 
 
 
Acute 
Allergic 
Reaction 
Localized 
urticaria (wheals) 
with no medical 
intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized 
urticaria OR 
Angioedema with 
intervention 
indicated OR 
Symptoms of mild 
bronchospasm 
Acute 
anaphylaxis OR 
Life-threatening 
bronchospasm 
OR Laryngeal 
edema 
Chills 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 117 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Cytokine 
Release 
Syndrome7F7F8 
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody 
infusion) 
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and 
symptoms OR 
Recurrence of 
symptoms 
following initial 
improvement 
Life-
threatening 
consequence
s (e.g., 
requiring 
pressor or 
ventilator 
support) 
Fatigue or Malaise 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating 
symptoms of 
fatigue or malaise 
causing inability to 
perform basic self-
care functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C 
or 100.4 to < 
101.5°F 
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to 
< 102.7°F 
≥ 39.3 to < 40.0°C 
or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 
104.0°F 
Pain8F8F9 (not 
associated with 
study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal 
interference with 
usual social & 
functional activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Pain causing 
inability to perform 
usual social & 
functional activities 
Disabling pain 
causing inability to 
perform basic self-
care functions OR 
Hospitalization 
indicated 
Serum Sickness9F9F10 Mild signs 
and 
symptoms 
Moderate signs 
and symptoms 
AND Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention 
indicated (e.g., 
steroids or IV fluids) 
Life-
threatening 
consequence
s (e.g., 
requiring 
pressor or 
ventilator 
support) 
Underweight10F10F11 
> 5 to 19 years 
of age 
WHO BMI z-score 
< -1 to -2 
WHO BMI z-score 
< -2 to -3 
WHO BMI z-score 
< -3 
WHO BMI z-score 
< -3 with life-
threatening 
consequences 
2 to 5 years of age WHO Weight-for- 
height z-score 
< -1 to -2 
WHO Weight-for- 
height z-score 
< -2 to -3 
WHO Weight-for- 
height z-score < -3 
WHO Weight-for-
height z-score < -3 
with life- 
threatening 
consequences 
< 2 years of age 
WHO Weight-for- 
length z-score 
< -1 to -2 
WHO Weight-for- 
length z-score 
< -2 to -3 
WHO Weight-for- 
length z-score < -3 
WHO Weight-for-
length z-score < -3 
with life- 
threatening 
 
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of 
breath. 
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section 
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea. 
11 WHO reference tables may be accessed by clicking the desired age range or by accessing the following 
URLs: http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 118 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
consequences 
Unintentional 
Weight Loss 
(excludes 
postpartum weight 
loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss 
in body weight 
from baseline 
≥ 20% loss in body 
weight from 
baseline OR 
Aggressive 
intervention 
indicated (e.g., 
tube feeding, total 
parenteral 
nutrition) 
Urinary 
 
 
 
 
Urinary Tract 
Obstruction 
NA 
Signs or 
symptoms of 
urinary tract 
obstruction 
without 
hydronephrosis 
or renal 
dysfunction 
Signs or symptoms 
of urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction 
causing life-
threatening 
consequences 
Site Reactions to 
Injections and 
Infusions 
 
 
 
 
Injection Site Pain 
or Tenderness 
Report only one 
Pain or 
tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater 
than minimal 
limitation of use of 
limb 
Pain or 
tenderness 
causing inability to 
perform usual 
social & functional 
activities 
Pain or 
tenderness 
causing inability to 
perform basic self-
care function OR 
Hospitalization 
indicated 
Injection Site 
Erythema or 
Redness1F1F12 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 
to 
< 100 cm2 surface 
area OR 
Symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
≥ 10 cm in 
diameter OR ≥ 
100 cm2 surface 
area OR 
Ulceration OR 
Secondary 
infection OR 
Phlebitis OR 
Sterile abscess 
OR Drainage OR 
Symptoms 
causing inability 
to perform usual 
social & functional 
activities 
Potentially life- 
threatening 
consequences 
(e.g., abscess, 
exfoliative 
dermatitis, 
necrosis 
involving 
dermis or 
deeper tissue) 
 
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or 
measured surface area. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 119 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
≤ 15 years of age 
≤ 2.5 cm in 
diameter 
> 2.5 cm in 
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface 
area of the 
extremity segment 
involved (e.g., 
upper arm or 
thigh) OR 
Ulceration OR 
Secondary 
infection OR 
Phlebitis OR 
Sterile abscess 
OR Drainage 
Potentially life- 
threatening 
consequences 
(e.g., abscess, 
exfoliative 
dermatitis, 
necrosis 
involving 
dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 
15 years of 
age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Injection Site 
Pruritus 
Itching localized to 
the injection site 
that is relieved 
spontaneously or 
in 
< 48 hours of 
treatment 
Itching beyond the 
injection site that 
is not generalized 
OR Itching 
localized to the 
injection site 
requiring ≥ 48 
hours treatment 
Generalized 
itching causing 
inability to perform 
usual social & 
functional 
activities 
NA 
Laboratory Values 
 
 
 
 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without 
life- threatening 
consequences 
pH < 7.3 with life- 
threatening 
consequences 
Albumin, 
Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0 
≥ 20  to < 30 
< 2.0 
< 20 
NA 
Alkaline 
Phosphatase, 
High 
1.25 to < 2.5 
x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without 
life- threatening 
consequences 
pH > 7.5 with life- 
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 
x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase 
(Pancreatic) or 
Amylase (Total), 
High 
Report only one 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, 
High 
Report only one 
1.25 to < 2.5 
x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 120 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Bicarbonate, 
Low 
(mEq/L; 
mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0  to < 16.0 
11.0  to < 16.0 
8.0  to < 11.0 
8.0  to < 11.0 
< 8.0 
< 8.0 
Bilirubin 
Direct 
Bilirubin12F12F13, 
High 
> 28 days of 
age 
NA 
NA 
> ULN with other 
signs and 
symptoms of 
hepatotoxicity. 
> ULN with life- 
threatening 
consequences 
(e.g., signs and 
symptoms of liver 
failure) 
≤ 28 days of 
age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, 
High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
≤ 28 days of 
age 
See Appendix A. 
Total Bilirubin for 
Term and 
Preterm 
Neonates 
See Appendix A. 
Total Bilirubin 
for Term and 
Preterm 
Neonates 
See Appendix 
A. Total Bilirubin 
for Term and 
Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5 
2.65 to < 2.88 
11.5  to < 12.5 
2.88  to < 3.13 
12.5 to < 13.5 
3.13 to < 3.38 
≥ 13.5 
≥  3.38 
< 7 days of age 
11.5  to < 12.4 
2.88  to < 3.10 
12.4  to < 12.9 
3.10  to < 3.23 
12.9  to < 13.5 
3.23  to < 3.38 
≥ 13.5 
≥  3.38 
Calcium (Ionized), 
High 
(mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4 
1.95 to < 2.10 
7.0 to < 7.8 
1.75 to < 1.95 
6.1 to < 7.0 
1.53 to < 1.75 
< 6.1 
< 1.53 
< 7 days of age 
6.5 to < 7.5 
1.63 to < 1.88 
6.0 to < 6.5 
1.50 to < 1.63 
5.50 to < 6.0 
1.38 to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), 
Low 
(mg/dL; mmol/L) 
< LLN  to 4.0 
< LLN  to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
Cardiac Troponin 
I, High 
NA 
NA 
NA 
Levels consistent 
with myocardial 
infarction or 
unstable angina as 
defined by the 
local laboratory 
Creatine Kinase, 
High 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase to 1.3 
to < 1.5 x 
participant’s 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase to 1.5 
to < 2.0 x 
participant’s 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 
x participant’s 
baseline 
 
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the 
total bilirubin. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 121 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Creatinine 
Clearance13F13F14 
or eGFR, Low 
*Report only one 
NA 
< 90 to 60 ml/min 
or ml/min/1.73 m2 
OR 
10 to < 30% 
decrease from 
participant’s 
baseline 
< 60 to 30 ml/min 
or ml/min/1.73 m2 
OR 
30 to < 50% 
decrease from 
participant’s 
baseline 
< 30 ml/min 
or 
ml/min/1.73 
m2 OR 
≥ 50% decrease 
from participant’s 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
≥ 500 
≥ 27.75 
Nonfasting, High 116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
≥ 500 
≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64 
3.05 to <3.55 
40 to < 55 
2.22 to < 3.05 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
< 1 month of age 
50 to 54 
2.78 to < 3.00 
40 to < 50 
2.22 to < 2.78 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to < 2.0 
x ULN without 
acidosis 
≥ 2.0 x ULN 
without acidosis 
Increased lactate 
with pH < 7.3 
without life- 
threatening 
consequences 
Increased lactate 
with pH < 7.3 with 
life- threatening 
consequences 
Lipase, High 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, 
Fasting, High 
≥ 18 years of 
age 
200 to < 240 
5.18 to < 6.19 
240 to < 300 
6.19 to < 7.77 
≥ 300 
≥ 7.77 
NA 
< 18 years of age 
170 to < 200 
4.40 to < 5.15 
200 to < 300 
5.15 to < 7.77 
≥ 300 
≥ 7.77 
NA 
LDL, Fasting, 
High 
≥ 18 years of age 
130 to < 160 
3.37 to < 4.12 
160 to < 190 
4.12 to < 4.90 
≥ 190 
≥ 4.90 
NA 
> 2 to < 18 
years of age 
110 to < 130 
2.85 to < 3.34 
130 to < 190 
3.34 to < 4.90 
≥ 190 
≥ 4.90 
NA 
Triglycerides, 
Fasting, High 
150 to 300 
1.71 to 3.42 
>300  to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium14F14F15 
Low 
(mEq/L; 
mmol/L) 
1.2 to < 1.4 
0.60 to < 0.70 
0.9 to < 1.2 
0.45 to < 0.60 
0.6 to < 0.9 
0.30 to < 0.45 
< 0.6 
< 0.30 
 
14 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in 
mL/min/1.73m2). Sites should choose the method defined in their study and when not specified, use the method 
most relevant to the study population. 
15 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 122 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.65 to < LLN 
1.4 to < 2.0 
0.45 to < 0.65 
1.0 to < 1.4 
0.32 to < 0.45 
< 1.0 
< 0.32 
1 to 14 years of 
age 
3.0 to < 3.5 
0.97 to < 1.13 
2.5 to < 3.0 
0.81 to < 0.97 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5 to < 4.5 
1.13 to < 1.45 
2.5 to < 3.5 
0.81 to < 1.13 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6  to < 6.0 
5.6  to < 6.0 
6.0  to < 6.5 
6.0  to < 6.5 
6.5  to < 7.0 
6.5  to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0  to < 3.4 
3.0  to < 3.4 
2.5  to < 3.0 
2.5  to < 3.0 
2.0  to < 2.5 
2.0  to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146  to < 150 
146  to < 150 
150  to < 154 
150  to < 154 
154  to < 160 
154  to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130  to < 135 
130  to < 135 
125  to < 130 
125  to < 130 
121  to < 125 
121  to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0  to < 12.0 
0.59  to < 0.71 
12.0  to < 15.0 
0.71  to < 0.89 
≥ 15.0 
≥ 0.89 
Absolute CD4+ 
Count, 
Low 
(cell/mm3; cells/L) 
> 5 years 
of age (not 
HIV 
infected) 
300 to < 400 
300 to < 400 
200 to < 300 
200 to < 300 
100 to < 200 
100 to < 200 
< 100 
< 100 
Absolute 
Lymphocyte 
Count, Low 
(cell/mm3; 
cells/L) 
> 5 years of 
age (not HIV 
infected) 
600 to < 650 
0.600 x 109 to 
< 0.650 x 109 
500 to < 600 
0.500 x 109 to 
< 0.600 x 109 
350 to < 500 
0.350 x 109 to 
< 0.500 x 109 
< 350 
< 0.350 x 109 
Absolute 
Neutrophil Count 
(ANC), Low 
(cells/mm3; 
cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 
1.000 
x 109 
600 to 799 
0.600 x 109 to 0.799 
x 109 
400 to 599 
0.400 x 109 to 
0.599 
x 109 
< 400 
< 0.400 x 109 
2 to 7 days of 
age 
1,250 to 1,500 
1.250 x 109 to 
1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109 
750 to 999 
0.750 x 109 to 
0.999 
x 109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109 
1,500 to 2,999 
1.500 x 109 to 
2.999 
x 109 
< 1,500 
< 1.500 x 109 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 123 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Fibrinogen, 
Decreased 
(mg/dL; g/L) 
100 to < 200 
1.00 to < 2.00 
OR 
0.75 to < 1.00 
x LLN 
75 to < 100 
0.75 to < 1.00 
OR 
≥ 0.50 to < 
0.75 x LLN 
50 to < 75 
0.50 to < 0.75 
OR 
0.25 to < 
0.50 x LLN 
< 50 
< 0.50 
OR 
< 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin15F15F16
, Low 
(g/dL; 
mmol/L)16F16F17 
≥ 13 years 
of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years 
of age 
(female 
only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age 
to < 13 years of 
age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days 
of age (male 
and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days 
of age (male 
and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days 
of age (male 
and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of 
age (male 
and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.5 x ULN 
1.5 to < 2.0 x ULN 
2.0 to < 3.0 x ULN 
≥ 3.0 x ULN 
Methemoglobin 
(% hemoglobin) 
5.0 to < 10.0% 
10.0 to < 15.0% 
15.0 to < 20.0% 
≥ 20.0% 
PTT, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.66 
x ULN 
1.66 to < 
2.33 x ULN 
2.33 to < 
3.00 x ULN 
≥ 3.00 x ULN 
Platelets, 
Decreased 
(cells/mm3; 
cells/L) 
100,000 to 
< 125,000 
100.000 x 109 to 
< 125.000 x 109 
50,000 to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000 to 
< 50,000 
25.000 x 109 to 
< 50.000 x 109 
< 25,000 
< 25.000 x 109 
 
16 Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been 
on hormone therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which 
they identify (i.e., a transgender female should be graded using the female sex at birth hemoglobin laboratory 
values). 
17 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin 
results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted 
to g/dL using appropriate conversion factor for the particular laboratory. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 124 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
PARAMETER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
PT, High 
(not on 
anticoagulation 
therapy 
1.1 to < 1.25 
x ULN 
1.25 to < 
1.50 x ULN 
1.50 to < 
3.00 x ULN 
≥ 3.00 x ULN 
WBC, Decreased 
(cells/mm3; 
cells/L) 
> 7 days of 
age 
2,000 to 2,499 
2.000 x 109 to 
2.499 
x 109 
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109 
1,000 to 1,499 
1.000 x 109 to 
1.499 
x 109 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 
6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109 
2,500 to 3,999 
2.500 x 109 to 
3.999 
x 109 
< 2,500 
< 2.500 x 109 
Glycosuria 
(random 
collection 
tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not 
to be reported 
based on 
dipstick findings 
or on blood 
believed to be of 
menstrual origin) 
6 to < 10 RBCs 
per high power 
field 
≥ 10 RBCs per 
high power field 
Gross, with or 
without clots OR 
With RBC casts 
OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria 
(random 
collection 
tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 125 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
 
Appendix 2: Overview of Measures to Minimize Risk of Transmission of 
SARS-CoV-2 virus during study conduct based on national/local guidance 
as of 30 June 2020 
Principal 
objective 
(protocol 
section) 
Target 
Population’ 
Physical 
Distancing 
possible 
Information on physical distancing or measures 
to be taken to reduce risk of transmission  
Across all 
Across all 
 
• All measures to minimize risk of transmission of 
COVID-19 will be implemented in coordination 
and collaboration with the DPS “Equipe 
d’Intervention Rapide COVID-19 & Maladie de 
Virus Ebola (MVE)” 
• All communication about and community 
engagement regarding COVID-19 
(Communication des risques et engagement 
communautaire en réponse à la COVID-19) will 
occur in coordination and collaboration with the 
DPS “Equipe d’Intervention Rapide COVID-19 & 
MVE” and use their communication material. 
Community 
mobilization 
(Sections 
5.1, 5.2.1, 
5.2.2, 5.2.3, 
5.3) 
Government 
authorities; 
Provincial and 
national 
parliament 
members; 
Provincial and 
Territory and 
Health Zone 
authorities and 
staff 
Yes 
• By the time community mobilization is initiated, all 
members of this ‘target population’ will have 
already undergone education on COVID-19, and 
procedures for screening for COVID-19 
symptoms before entering their buildings will have 
been put in place and everybody will wear masks. 
• Meetings will be arranged to include not more 
than a total of 20 participants (including study 
team members). 
• The offices/meeting rooms of the ‘target 
population’ will have already been set up for 
physical distancing and procedures will have 
been put in place to refer anybody with COVID-19 
symptoms to the designated local health 
facility/COVID-19 team.  
• Documents distributed will be left with meeting 
participants. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 126 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
Principal 
objective 
(protocol 
section) 
Target 
Population’ 
Physical 
Distancing 
possible 
Information on physical distancing or measures 
to be taken to reduce risk of transmission  
Community 
mobilization 
(Sections 
5.1, 5.2.1, 
5.2.2, 5.2.3, 
5.3) 
Civil society (e.g. 
associations of 
different 
professional, 
religious groups, 
non-
governmental 
organizations), 
Local staff of  
Local media staff 
Yes 
• By the time community mobilization is initiated, all 
meeting participants will have undergone 
education on COVID-19.   
• Meetings will be arranged to include not more 
than a total of 20 participants (including study 
team members).  
• Study team will bring thermometers for 
temperature measurements and inform, as 
necessary, participants about COVID-19 related 
requirements.  
• Study team will ask all meeting participants about 
symptoms of suspected COVID-19 cases and 
advise those meeting suspected case definition to 
self-isolate and to call the responsible health 
/COVID-19 team. They will be excluded from the 
meeting.  
• Study team will ensure that all passing this 
screening will wash hands before entering the 
room and wear masks throughout the meeting. 
• Study team will ensure meeting space is set up to 
allow physical distancing.  
• The study team will initiate the meeting with a 
demonstration on how to properly use and clean 
cloth masks and an overview of government 
guidance on minimizing the risk of SARS-CoV-2 
transmission, early detection, self-isolation, 
COVID-19 designated health facilities and contact 
tracing.  
• Documents distributed will be left with meeting 
participants. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 127 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
Principal 
objective 
(protocol 
section) 
Target 
Population’ 
Physical 
Distancing 
possible 
Information on physical distancing or measures 
to be taken to reduce risk of transmission  
Community 
mobilization 
(Sections 
5.2.4, 5.4) 
Religious 
Leaders, Village/ 
Community 
Leaders,  
Elders,  
Relais 
Communautaires 
(RECOs) 
Yes 
• By the time community mobilization is initiated, all 
meeting participants will have undergone 
education on COVID-19. 
• Meetings will be arranged per village, and include 
not more than 20 participants, including not more 
than 10 chiefs and elders (typically 5), 5-7 
RECOs and approximately 3 study team 
members.  
• Meetings will be set up in open spaces, a church 
or a school with study team ensuring seating is 
arranged for physical distancing.  
• Study team will bring thermometers for 
temperature measurements. 
• Study team will ask all meeting participants about 
symptoms of suspected COVID-19 cases and 
advise those meeting suspected case definition to 
self-isolate and to call the responsible health 
facility (or the study team will call the health 
facility/COVID-19 team on their behalf). They will 
be excluded from the meeting.  
• Study team will be bringing megaphones and 
cloth masks for all meeting participants, and 
ensure availability of soap and water (or hand 
sanitizers) for handwashing at the beginning and 
the end of the meeting. 
• Study team will ensure that all meeting 
participants wash hands before entering the 
meeting space, wear masks all along the meeting 
and wash hands at the end of the meeting. 
• The study team will initiate the meeting with a 
demonstration on how to properly use and clean 
cloth masks and an overview of government 
guidance on minimizing the risk of SARS-CoV-2 
transmission, early detection, self-isolation, 
COVID-19 designated health facilities and contact 
tracing. 
• Documents and cloth masks distributed will be left 
with meeting participants who will be advised to 
bring the mask to subsequent meetings. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 128 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
Principal 
objective 
(protocol 
section) 
Target 
Population’ 
Physical 
Distancing 
possible 
Information on physical distancing or measures 
to be taken to reduce risk of transmission  
Consultation 
with village 
communities 
and 
providing 
information 
required for 
village 
members to 
decide on 
participation 
in the study 
(Section 
5.2.2) 
Village 
inhabitants 
Yes 
• By the time community mobilization is initiated, 
the communities will have undergone education 
on COVID-19. 
• While the pandemic is ongoing, the community 
meetings as per protocol section 5.2.2 will be 
preceded by a meeting with heads of families to 
provide them with a short overview of government 
guidance on minimizing the risk of SARS-CoV-2 
transmission, early detection, self-isolation, 
COVID-19 designated health facilities and contact 
tracing, demonstration on proper use and 
cleaning of cloth masks and the arrangements for 
further meetings with their family members about 
the study.  
• For further information, see provisions for 
meetings with religious, village, community 
leaders, elders and RECOs. 
• The 1st and 2nd meeting as per Section 5.2.2 will 
be arranged to take place with no more than 20 
meeting participants including 1 RECO, 1 
potential (or selected) literate witness, and up to 
16 members of 3-4 families (and two or three 
study team members).   
• For further information, see provisions for 
meetings with religious, village, community 
leaders, elders and RECOs. 
Provision of 
informed 
consent / 
assent 
(Sections 
5.2.2, 15.9) 
Village 
inhabitants 
interested in 
study 
participation 
Yes 
• Meetings between 1 study team member (or 1 
study team member plus 1 translator) and an 
individual wanting to provide informed consent (or 
a minor with their parent(s)/guardian wanting to 
provide informed assent and consent) and the 
literate witness will take place in a setting that will 
allow physical distancing.   
• For further information, see provisions for 
meetings with religious, village, community 
leaders, elders and RECOs. 
• All will be asked to bring the cloth masks provided 
to them to the next meeting (study visits). 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 129 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
Principal 
objective 
(protocol 
section) 
Target 
Population’ 
Physical 
Distancing 
possible 
Information on physical distancing or measures 
to be taken to reduce risk of transmission  
All study 
visits 
(Section 7.3) 
Screening/study 
participants 
Yes/No 
• All study team members will wear masks and 
gloves during all interactions with study 
participants. 
• (Potential) participants will be asked to bring and 
wear the cloth masks they were provided with 
during the meetings in which they were informed 
about the study.   
• Soap and water (or hand sanitizers) will be 
brought so that each visit can be initiated and end 
with hand washing/sanitizing.  
• Staff members will wash/sanitize hands and 
change gloves between interactions with different 
participants.   
• Areas where screening/study participants can 
wait will be set up with physical distancing. 
• At the beginning of each study visit a study team 
member will measure the temperature of all 
participants and ask them about COVID-19 
symptoms, will advise them to self-isolate and 
either ask them to call the designated health 
facility/COVID-19 team or call that health 
facility/COVID-19 team on their behalf. If they are 
identified by the health facility/COVID-19 team as 
not COVID-19 infected, the relevant study visit 
will be rescheduled.  If they are identified as 
COVID-19 infected, study visits will be arranged 
to take place after they have been confirmed as 
recovered by the designated public health staff.  
• All equipment will be sanitized between use on 
different participants.  

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 130 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
 
 
Appendix 3: Summary of Protocol Amendments 
The Summary of Protocol Amendments for Amendment 3 is provided below. The Summary 
of Protocol Amendments for Amendments 1 and 2 is provided as a separate document and 
maintained in the Trial Master File. 
 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 131 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
RATIONALE FOR PROTOCOL AMENDMENT No. 3 
This amendment reduces the sample size for MDGH-MOX-3001 to mitigate recruitment issues and enable timely completion of the study. The 
original sample size was selected to meet secondary study outcomes and gather additional safety data to support inclusion of moxidectin in 
World Health Organization treatment guidelines, and was much larger than required to achieve adequate power for efficacy. Assuming the 
original hypothesized treatment effect, the reduced sample size retains a power of > 0.95 and the reduction of the sample size to 320 participants 
will not impact the primary objective of the study. 
The following sections of the protocol have been amended to reflect the reduction in sample size and consequential changes in study procedures. 
1. 
Administrative Protocol Amendments 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Cover page and 
footers 
Version 03 200630 (incorporating 
Amendments 1 and 2) 
30 June 2020 
Final Version 04 230112 (incorporating 
Amendments 1, 2 and 3) 
12 January 2023 
Version details updated to indicate 
protocol amendment 
Throughout 
Not applicable 
Correction of minor typographical and 
grammatical errors.  Definition of 
abbreviations on first use, replacement 
of the term with acronym upon second or 
subsequent use and update of 
abbreviations table as needed. Update of 
references and table of contents as 
required. 
Corrections and updates to text to 
improve document readability and 
ensure consistency and accuracy. 
 
2. 
Formal Protocol Amendments 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Synopsis Exploratory 
Endpoints 
Section 3.2.3 
Exploratory Endpoints 
• 
The viability and fertility of male and 
female macrofilariae as determined 
by histopathology after nodulectomy 
12 months after the last treatment. 
• 
The viability and fertility of male and 
female macrofilariae as determined 
by histopathology after nodulectomy 
12 months after the last treatment. 
Nodulectomies will be performed 
only if the number of individuals with 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 
nodulectomies for histopathology will 
only be conducted if the number of 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 132 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
palpable nodules and who may 
agree to nodule excision is 
considered sufficiently high to 
support conclusions on the relative 
effect of the four treatment regimens. 
participants with palpable nodules is 
considered sufficient to support 
conclusions on the relative effect of the 
four treatment regimens. Approximately 
4% of participants to-date have had 
palpable nodules and not all may agree 
to nodule removal at Month 36. 
Synopsis Number of 
Participants 
4.3 Number of 
Participants and 
Randomization 
Approximately 1000 
At least 320 
Text revised to reflect the reduction of 
sample size to mitigate recruitment 
issues and enable timely completion of 
the study. Assuming the original 
hypothesized treatment effect, the 
reduction of the sample size will not 
impact the primary objective of the study. 
Synopsis Specialized 
Analyses 
Viability and fertility of macrofilariae in 
the excised nodules will be determined 
via histopathology. 
Viability and fertility of macrofilariae in 
the excised nodules will be determined 
via histopathology, provided 
nodulectomies are performed because 
the number of individuals with palpable 
nodules and who may agree to nodule 
excision is considered sufficiently high to 
support conclusions on the relative effect 
of the treatment regimens. 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 
nodulectomies for histopathology will 
only be conducted if the number of 
participants with palpable nodules is 
considered sufficient to support 
conclusions on the relative effect of the 
four treatment regimens. Approximately 
4% of participants to-date have had 
palpable nodules and not all may agree 
to nodule removal at Month 36. 
Synopsis Sample size 
The sample size and randomization ratio 
will provide safety data for up to a total of 
3000 exposures to moxidectin and 1000 
exposures to ivermectin, providing a 
probability of around 0.95 and 0.63 to 
detect at least 1 or more AEs with a true 
background rate of 0.001, respectively, 
The total sample size of 320 participants 
and randomization ratio will provide 
safety data for up to a total of 960 
exposures to moxidectin and 320 
exposures to ivermectin, providing a 
probability of around 0.99 and 0.80 to 
detect at least 1 or more AEs with a true 
Text revised to reflect the reduction of 
sample size to mitigate recruitment 
issues and enable timely completion of 
the study. Assuming the original 
hypothesized treatment effect, the 
reduction of the sample size will not 
impact the primary objective of the study. 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
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Page 133 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
assuming exposures are independent. 
This is considered to provide sufficient 
data for assessment of safety of repeat 
doses of moxidectin compared with 
ivermectin. 
This sample size provides greater than 
95% statistical power at a two-tailed 
alpha level of 0.05 for the comparison of 
the primary outcome, SMR at Month 12 
(SMR12) in the biannual versus annual 
moxidectin treatment arms. 
background rate of 0.005, respectively, 
assuming exposures are independent. 
This is considered to provide sufficient 
data for assessment of safety. 
The sample size of 120 subjects per 
moxidectin group provides an 
approximate power of 90% at a two-
tailed alpha level of 0.05 for the 
comparison of the primary outcome, 
SMR at Month 12 (SMR12) in the 
biannual versus annual moxidectin 
treatment arms. 
Synopsis Data Safety 
Monitoring Board 
Review: 
A data safety monitoring board (DSMB) 
will undertake a review of serious 
adverse events (SAEs) reported during 
the first month after each round of 
treatment to advise the Sponsor on 
initiation of the next treatment round. 
A data safety monitoring board (DSMB) 
will undertake a review of serious 
adverse events (SAEs) reported during 
the first month after each round of 
treatment to advise the Sponsor on 
continuation of the study. 
Text revised to align with section 12, 
Data Safety Monitoring Board Review. 
Table 1 Schedule of 
Assessments 
Not applicable 
Addition of footnote: 
j If the number of individuals with 
palpable nodules is sufficiently high to 
support conclusions of histopathological 
evaluation on the relative effect of the 
treatment regimens, or if requested by 
participants 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 
nodulectomies for histopathology will 
only be conducted if the number of 
participants with palpable nodules is 
considered sufficient to support 
conclusions on the relative effect of the 
four treatment regimens, but that 
nodulectomies may also be performed at 
the request of participants. 
2.4.3 Rationale for 
Efficacy Assessments 
The effect on macrofilariae viability and 
reproductive activity will be explored via 
histopathology, the standard method 
The effect on macrofilariae viability and 
reproductive activity will be explored via 
histopathology, the standard method 
used in clinical studies examining this 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 

Medicines Development for Global Health 
Protocol Number: MDGH-MOX-3001 
 
CONFIDENTIAL 
MDGH-MOX-3001 Protocol Final v04 230112 
Page 134 of 140 
12 January 2023 
(incorporating Amendments 1, 2 and 3) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
used in clinical studies examining this 
effect. 
effect, provided the number of individuals 
with palpable nodules and who agree to 
nodule excision is sufficiently high to 
support conclusions on the relative effect 
of the treatment regimens. 
nodulectomies for histopathology will 
only be conducted if the number of 
participants with palpable nodules is 
considered sufficient to support 
conclusions on the relative effect of the 
four treatment regimens. Approximately 
4% of participants to-date have had 
palpable nodules and not all may agree 
to nodule removal at Month 36. 
4.6 Estimated Duration 
of the Study 
It is anticipated that the total duration of 
the study from initiation to completion will 
be approximately 50 months, comprised 
of approximately 5 months for 
recruitment, 36 months treatment and 
post-treatment follow up, and 9 months 
for data analysis and reporting. 
It was originally anticipated that the total 
duration of the study from initiation to 
completion would be approximately 
50 months, comprised of approximately 
5 months for recruitment, 36 months 
treatment and post-treatment follow up, 
and 9 months for data analysis and 
reporting. Based on recruitment rates to 
date, the duration of recruitment has 
been extended to approximately 24 
months resulting in a total estimated 
study duration of approximately 69 
months. 
Text revised to reflect changes to 
anticipated study durations due to 
slower-than-anticipated recruitment 
rates.  

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6.2 Informed Consent 
and Assent with 
Parental/Guardian 
Consent 
In addition, at Month 36, participants with 
palpable onchocercal nodules will be 
asked whether they will consent/assent 
to nodulectomy (Section 6.2.3). 
In addition, at Month 36, and provided 
the number of participants with palpable 
nodules is sufficiently high to support 
conclusions from histopathological 
evaluation of the excised nodules 
(Section 7.4.12), participants with 
palpable onchocercal nodules will be 
asked whether they will consent/assent 
to nodulectomy (Section 6.2.3). Should 
that not be the case, participants with 
palpable nodules will be asked whether 
they wish to have their nodules removed 
and, if yes, to document their 
consent/assent. 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 
nodulectomies for histopathology will 
only be conducted if the number of 
participants with palpable nodules is 
considered sufficient to support 
conclusions on the relative effect of the 
four treatment regimens, but that nodule 
excision may also be performed at the 
request of participants. 
6.2.3 Informed 
Consent and Assent 
with Parental/Guardian 
Consent to 
Nodulectomies 
However, considering that the time 
between informed consent to study 
participation and the nodulectomies is 
36 months, detailed information on the 
nodulectomy procedure, its risks and 
benefits, and that it is voluntary, will be 
provided to those with palpable 
onchocercal nodules and written 
consent/assent sought at the Month 36 
visit. 
However, considering that the time 
between informed consent to study 
participation and the nodulectomies is 
36 months, detailed information on the 
nodulectomy procedure, its risks and 
benefits, and that it is voluntary, will be 
provided to those with palpable 
onchocercal nodules and written 
consent/assent sought at the Month 36 
visit as appropriate for the objectives of 
the nodulectomies (see Section 12). 
Text added to clarify that participant 
information and consent procedures will 
be appropriate for the objectives of the 
nodulectomy, whether conducted for 
histopathology or for other reasons at the 
participant’s request. 
7.3.9 End of Study 
Visit (Month 36) 
Discussion will be held with participants 
with palpable nodules considered 
onchocercal about the procedure, risks 
and potential benefits of voluntary 
nodulectomies. 
Discussion will be held with participants 
with palpable nodules considered 
onchocercal about the procedure, risks 
and potential benefits of voluntary 
nodulectomies and their objectives 
(Section 6.2). 
Text added to clarify that information 
provided to participants will be 
appropriate for the objectives of the 
nodulectomy, whether conducted for 
histopathology or for other reasons at the 
participant’s request. 
7.4.12.1 Nodulectomy 
When consenting/assenting to 
nodulectomy, participants can designate 
When consenting/assenting to 
nodulectomy, participants can designate 
nodules they wish to have removed.  
Text revised to clarify that participants 
will be asked to nominate nodules for 
excision. 

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nodules they do not wish to have 
removed. 
7.4.12.2 
Histopathological 
Examination of 
Excised Nodules 
The excised nodules will be processed 
for histopathology and slices stained with 
hematoxylin-eosin or specific stains 
available at that time. 
Excised nodules will be processed for 
histopathology and slices stained with 
hematoxylin-eosin or specific stains 
available at that time, provided 
nodulectomies are performed to compare 
the effect of the study drugs (Section 
6.2). 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 
histopathology will only be conducted if 
nodulectomies are performed for the 
purpose of comparison of the effect of 
the four treatment regimens. 
12 Data Safety 
Monitoring Board 
Review 
The first DSMB data review for this study 
will be convened after completion of a 
one month period after the first round of 
investigational product administration. 
The first DSMB data review for this study 
will be convened after approximately 150 
participants have completed a one month 
period after the first round of 
investigational product administration. 
Timing of initial DSMB meeting revised 
as a consequence of slower-than-
expected recruitment rates. 
14.3.2 Viability and 
Fertility of Male and 
Female Macrofilariae 
14.11.2.8 Viability and 
Fertility of Male and 
Female Macrofilariae 
as Determined by 
Histopathology of 
Nodules Excised at 
Month 36 
Not applicable 
Provided the number of individuals with 
palpable nodules and who agree to 
nodule excision is sufficiently high to 
support conclusions on the relative effect 
of the treatment regimens, 
histopathology of nodules may be 
performed. 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 
histopathology will only be conducted if 
nodulectomies are performed for the 
purpose of comparison of the effect of 
the four treatment regimens. 
14.6 Sample Size 
The sample sizes per randomized 
treatment group are shown in Table 9 
and reflect the allocation ratios for each 
of the four treatment groups. 
 
The sample sizes per randomized 
treatment group are shown in Table 9 
and reflect the allocation ratios for each 
of the four treatment groups. 
 
Text revised to reflect the reduction of 
sample size to mitigate recruitment 
issues and enable timely completion of 
the study. Assuming the original 
hypothesized treatment effect, the 
reduction of the sample size will not 
impact the primary objective of the study. 

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Section 
Original Text 
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Table 9: Sample Size by Randomized 
Treatment Group 
Dosing 
Schedule  
Randomized Treatment 
Group 
(N = number) 
Moxidectin 
Ivermectin 
Annual 
N = 375 
N = 125 
Biannual 
N = 375 
N = 125 
The sample sizes between the 
moxidectin and ivermectin groups 
reflecting a 3:1 randomization ratio 
(Section 14.7) will provide safety data for 
up to a total of 3000 exposures to 
moxidectin and 1000 exposures to 
ivermectin, providing a probability of 
around 0.95 and 0.63 to detect at least 1 
AE with a true background rate of 0.001, 
respectively, assuming exposures are 
independent. 
The estimated treatment effects were 
calculated from the large single dose 
Phase III trial with similar 
inclusion/exclusion criteria (Section 
2.3.2.3). In that trial, an 'annual 
moxidectin group' (N = 977; as-
randomized set) was included in the 
study design; however, there was no 
'biannual moxidectin group' included in 
that trial or elsewhere. Hence, 
hypothetical SMR12 rates for a biannual 
moxidectin group using the previous 
Phase III data were calculated assuming 
Table 9: Sample Size by Randomized 
Treatment Group 
Dosing 
Schedule  
Randomized Treatment 
Group 
(N = number) 
Moxidectin 
Ivermectin 
Annual 
N = 120 
N = 40 
Biannual 
N = 120 
N = 40 
The sample sizes between the 
moxidectin and ivermectin groups 
reflecting a 3:1 randomization ratio 
(Section 14.7) will provide safety data for 
up to a total of at least 960 exposures to 
moxidectin and 320 exposures to 
ivermectin, providing a probability of 
around 0.99 and 0.80 to detect at least 1 
AE with a true background rate of 0.005, 
respectively, assuming exposures are 
independent. 
The estimated treatment effects were 
calculated from the large single dose 
Phase III trial with similar 
inclusion/exclusion criteria (Section 
2.3.2.3). In that trial, an 'annual 
moxidectin group' (N = 977; as-
randomized set) was included in the 
study design; however, there was no 
'biannual moxidectin group' included in 
that trial or elsewhere. Hence, 
hypothetical SMR12 rates for a biannual 
moxidectin group using the previous 
Phase III data were calculated assuming 

Medicines Development for Global Health 
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Section 
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Revised to Read 
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that participants with zero microfilariae at 
Month 6 would continue to have zero 
microfilariae at Month 12 with biannual 
treatment. The hypothetical SMR12 rate 
for the annual moxidectin group was 
estimated from the Phase III data for all 
moxidectin participants with zero 
microfilariae at Months 6 and 12. For 
both estimates, calculations were derived 
imputing non-response for participants 
with missing skin snip data. Given these 
assumptions, the hypothetical SMR12 
rates for the biannual and annual 
moxidectin groups were estimated to be 
90% and 43%, respectively. 
Given these hypothetical SMR12 rates 
and assuming 375 participants meeting 
the FAS criteria (all randomized 
participants exposed to at least one dose 
of investigational product) within each of 
the two moxidectin groups, the power of 
the primary efficacy hypothesis, 
comparison of the biannual versus the 
annual moxidectin arm with respect to 
SMR12, was estimated to be greater 
than 95% via a z-test for two 
independent proportions at a two-tailed 
alpha level of 0.05. A sensitivity analysis 
using the lower limit of the 95% CI for the 
biannual SMR12 estimate and the upper 
limit of the 95% CI for the annual SMR12 
estimate also yielded a power greater 
than 95%. Although these power 
calculations do not account for 
adjustment of covariates which will be 
incorporated into the primary analysis of 
that participants with zero microfilariae at 
Month 6 would continue to have zero 
microfilariae at Month 12 with biannual 
treatment. The hypothetical SMR12 rate 
for the annual moxidectin group was 
estimated from the Phase III data for all 
moxidectin participants with zero 
microfilariae at Months 6 and 12. For 
both estimates, calculations were derived 
imputing non-response for participants 
with missing skin snip data. Given these 
assumptions, the hypothetical SMR12 
rates for the biannual and annual 
moxidectin groups were estimated to be 
90% and 43%, respectively. For these 
hypothetical SMR12 rates and 
120 participants meeting the FAS criteria 
(all randomized participants exposed to 
at least one dose of investigational 
product) within each of the two 
moxidectin groups, the power of the 
primary efficacy hypothesis, comparison 
of the biannual versus the annual 
moxidectin arm with respect to SMR12, 
was estimated to be > 95% via a z-test 
for two independent proportions at a two-
tailed alpha level of 0.05. 
Assuming the possibility of a lesser 
treatment effect than that derived from 
the Phase III study outlined above, the 
statistical power was also calculated for 
hypothetical SMR12 rates of 70% and 
50% for the biannual and annual 
moxidectin groups, respectively.  Given 
these hypothetical SMR12 rates, a 
sample size of 120 participants per group 
yields a power of approximately 90%. 

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the SMR12 endpoint, they should provide 
reasonable power estimates. 
Although these power calculations do not 
account for adjustment of covariates 
which will be incorporated into the 
primary analysis of the SMR12 endpoint, 
they should provide reasonable power 
estimates. 
14.11.2.8 Viability and 
Fertility of Male and 
Female Macrofilariae 
as Determined by 
Histopathology of 
Nodules Excised at 
Month 36 
Descriptive summary statistics will be 
calculated for these endpoints including 
only participants with histological 
evaluation data. Missing data will not be 
imputed. 
Provided the number of individuals with 
palpable nodules and who agree to 
excision of nodules is sufficiently high to 
support conclusions on the relative effect 
of the treatment regimens, 
histopathology of nodules may be 
performed. Descriptive summary 
statistics will be calculated for these 
endpoints including only participants with 
histological evaluation data. Missing data 
will not be imputed. 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 
histopathology will only be conducted if 
nodulectomies are performed for the 
purpose of comparison of the effect of 
the four treatment regimens. 
15.7 Study Team 
The co-investigator, Dr. M. Mandro, is 
also from Ituri and has conducted 
onchocerciasis-related studies in Ituri 
and was a clinical monitor of the 
moxidectin Phase III study, in particular 
the site in Ituri.  He has been seconded 
to this study from the DPS Ituri. 
The co-investigator up to June 2022, Dr. 
M. Mandro, is also from Ituri and has 
conducted onchocerciasis-related studies 
in Ituri and was a clinical monitor of the 
moxidectin Phase III study, in particular 
the site in Ituri.  He has been seconded 
to this study from the DPS Ituri. 
In June 2022, Dr. M. Mandro moved to 
Kinshasa to pursue other professional 
opportunities and was replaced by 
another qualified sub-investigator.  
Text revised to reflect a change in Co-
investigator. 
15.20.1 Modelling of 
Time to 
Onchocerciasis 
Elimination and Cost-
Effectiveness of 
Ivermectin vs 
The skin microfilariae data and the data 
from the histopathological examinations 
of excised nodules from this study will be 
combined with the data from other 
studies of moxidectin and of ivermectin 
and used to model both (a) and (b). 
The skin microfilariae data and, if 
obtained (see Section 6.2), the data from 
the histopathological examinations of 
excised nodules from this study will be 
combined with the data from other 
Text added to clarify that as a 
consequence of the reduction in sample 
size and lower-than-expected numbers of 
participants with palpable nodules, 
histopathology will only be conducted if 
nodulectomies are performed for the 

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12 January 2023 
(incorporating Amendments 1, 2 and 3) 
Section 
Original Text 
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Moxidectin-Based 
Elimination Policies 
studies of moxidectin and of ivermectin 
and used to model both (a) and (b). 
purpose of comparison of the effect of 
the four treatment regimens.