Clinical trial NCT03012828
Conditions: QT Effects in Healthy Volunteers
Sponsor: Medicines Development for Global Health
Start date: 2017-01-01; Completion date: 2017-05-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will investigate the effect of a single oral dose of moxidectin on the QT interval associated with moxidectin plasma concentrations.

The effect of moxidectin on other ECG intervals, and on safety, will also be assessed, as will preliminary pharmacokinetics and metabolism

Detailed description:
Moxidectin is being developed as a treatment for Onchocerciasis (river blindness), a serious, debilitating, disease caused by a parasitic worm, Onchocerca volvulus.

Five dose levels of moxidectin will be administered to healthy volunteers and ECG assessments undertaken at pre-specified pharmacokinetic time points to correlate QT interval with moxidectin concentration in plasma.

Arms: arm 1: 10 subjects will receive a single oral dose of moxidectin 4mg arm 2: 10 subjects will receive a single oral dose of moxidectin 8mg arm 3: 10 subjects will receive a single oral dose of moxidectin 16mg arm 4: 10 subjects will receive a single oral dose of moxidectin 24mg arm 5: 10 subjects will receive a single oral dose of moxidectin 36mg arm 6: 10 subjects will receive a single oral dose of placebo
Interventions: intervention 1: Moxidectin intervention 2: Placebo
Intervention descriptions: intervention 1: Moxidectin is a broad spectrum macrocyclic lactone endectocide intervention 2: None

Protocol documents:
Prot_000.pdf: 
Medicines Development for Global Health 
 
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CLINICAL STUDY PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Potential Effect of a Single Oral Dose of 
Moxidectin on the Cardiac QT Interval of Healthy Volunteers 
PROTOCOL NO. MDGH-MOX-1008 
Sponsor: 
Medicines Development for Global Health 
Level 1, 18 Kavanagh Street 
Southbank, Victoria 3006 
Australia 
Site Project Manager: 
Kristin Rittmann 
Clinical Research Coordinator 
Spaulding Clinical Research, LLC 
Telephone: +1 262-306-3093 
United States 
Medical Monitor: 
Jolanta Airey 
Consultant Clinical Development Physician 
SJA Consultancy Services 
Telephone: +61 (0) 409 020 209 
Australia 
Protocol Version: 
2.0 
Protocol Date: 
23 September 2016 
Amendment 1 Date: 
01 March 2017 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed written consent of Medicines Development for Global Health. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice, including the archiving 
of essential documents. 


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Signature Page 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Potential Effect of a 
Single Oral Dose of Moxidectin on the Cardiac QT Interval of 
Healthy Volunteers 
Protocol Number: 
MDGH-MOX-1008 
Version of Protocol: 
2.0 
Date of Protocol: 
23 September 2016 
Date of Amendment 1: 
01 March 2017 
 
Mark Sullivan 
Managing Director 
Medicines Development for Global Health 
 
Date 
Jolanta Airey 
Consultant Clinical Development Physician 
SJA Consultancy Services 
 
Date 
Stephanie Stanworth 
Senior Biostatistician 
Spaulding Clinical Research, LLC 
 
Date 
Meg Robison 
Consultant Medical Writer 
Spaulding Clinical Research, LLC 
 
Date 


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Investigator Signature Page 
I agree to conduct the study as outlined in the protocol entitled “A Randomized, 
Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Potential Effect 
of a Single Oral Dose of Moxidectin on the Cardiac QT Interval of Healthy Volunteers” 
in accordance with the International Council for Harmonisation guidelines and all 
applicable government regulations including United States Title 21 of the Code of 
Federal Regulations Part 54. I have read and understand all sections of the protocol. 
Carlos Sanabria, MD 
Principal Investigator 
 
Date 


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Table of Contents 
1. 
Protocol Synopsis ........................................................................................................ 7 
2. 
List of Abbreviations ................................................................................................ 17 
3. 
Introduction ............................................................................................................... 20 
3.1. 
Background ................................................................................................... 20 
3.2. 
Current Treatment and Unmet Need ............................................................. 20 
3.3. 
Moxidectin .................................................................................................... 21 
3.3.1 
Non-Clinical ...................................................................................... 21 
3.3.2 
Clinical .............................................................................................. 24 
3.4. 
Study Rationale ............................................................................................. 28 
3.4.1 
Rationale for Study Design ............................................................... 28 
3.4.2 
Doses Selected .................................................................................. 30 
4. 
Study Objectives ....................................................................................................... 31 
4.1. 
Primary Objective ......................................................................................... 31 
4.2. 
Secondary Objective ..................................................................................... 31 
4.3. 
Exploratory Objectives ................................................................................. 31 
5. 
Investigational Plan ................................................................................................... 32 
5.1. 
Study Design ................................................................................................. 32 
5.2. 
Study Duration .............................................................................................. 32 
5.3. 
Selection of Study Population ....................................................................... 32 
5.3.1 
Inclusion Criteria .............................................................................. 32 
5.3.2 
Exclusion Criteria ............................................................................. 33 
5.4. 
Withdrawal of Subjects from the Study ........................................................ 35 
5.4.1 
Reasons for Withdrawal .................................................................... 35 
5.4.2 
Handling of Withdrawals .................................................................. 36 
5.4.3 
Replacement Subjects ....................................................................... 36 
5.5. 
Study Procedures .......................................................................................... 36 
5.5.1 
Schedule of Events ............................................................................ 36 
5.5.2 
Study Procedures and Assessment Periods ....................................... 37 
5.5.3 
Period 1 ............................................................................................. 37 
5.5.4 
Period 2 ............................................................................................. 43 
5.6. 
Details of Study Procedures .......................................................................... 43 
5.6.1 
Pharmacodynamic Assessments ....................................................... 43 
5.6.2 
Pharmacokinetic Assessments .......................................................... 44 
5.6.3 
Safety Assessments ........................................................................... 46 
5.6.4 
Demographics, Medical History, and Other Baseline Assessments . 54 
5.6.5 
Documentation of Concomitant Medications ................................... 55 


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5.6.6 
Total Blood Volume ......................................................................... 55 
5.7. 
Study Treatments .......................................................................................... 55 
5.7.1 
Method of Assigning Subjects to Treatment .................................... 55 
5.7.2 
Treatments Administered .................................................................. 56 
5.7.3 
Identity of Study Drug ...................................................................... 56 
5.7.4 
Management of Clinical Supplies ..................................................... 56 
5.7.5 
Blinding............................................................................................. 57 
5.7.6 
Treatment Compliance ...................................................................... 58 
5.7.7 
Prior and Concomitant Medications ................................................. 58 
5.7.8 
Diet, Fluid, Activity Control, and Subject Housing.......................... 59 
5.8. 
Statistical Analysis Plan ................................................................................ 60 
5.8.1 
Pharmacodynamic Endpoints ............................................................ 60 
5.8.2 
Safety and Tolerability Endpoints .................................................... 61 
5.8.3 
Sample Size Calculation ................................................................... 61 
5.8.4 
Analysis Populations ......................................................................... 61 
5.9. 
Statistical Analyses ....................................................................................... 62 
5.9.1 
Pharmacodynamic Analyses ............................................................. 62 
5.9.2 
Pharmacokinetic Analyses ................................................................ 66 
5.9.3 
Safety Analyses ................................................................................. 67 
5.10. Data Quality Assurance ................................................................................ 69 
6. 
Investigator’s Obligations ......................................................................................... 70 
6.1. 
Confidentiality .............................................................................................. 70 
6.2. 
Institutional Review ...................................................................................... 71 
6.3. 
Subject Consent ............................................................................................ 71 
6.4. 
Study Reporting Requirements ..................................................................... 72 
6.5. 
Financial Disclosure and Obligations ........................................................... 72 
6.6. 
Investigator Documentation .......................................................................... 73 
6.7. 
Study Conduct ............................................................................................... 73 
6.8. 
Data Collection ............................................................................................. 73 
6.8.1 
Case Report Forms and Source Documents...................................... 73 
6.9. 
Adherence to the Protocol ............................................................................. 74 
6.10. Reporting Adverse Events ............................................................................ 74 
6.11. Investigator’s Final Report ........................................................................... 74 
6.12. Records Retention ......................................................................................... 75 
6.13. Publications ................................................................................................... 75 
7. 
Study Management ................................................................................................... 77 
7.1. 
Monitoring .................................................................................................... 77 
7.1.1 
Monitoring of the Study .................................................................... 77 


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7.1.2 
Inspection of Records ....................................................................... 77 
7.2. 
Management of Protocol Amendments and Deviations ............................... 77 
7.2.1 
Modification of the Protocol ............................................................. 77 
7.2.2 
Protocol Deviations ........................................................................... 77 
7.3. 
Study Termination ........................................................................................ 78 
7.3.1 
Criteria for Termination of the Study ............................................... 78 
7.3.2 
Criteria for Termination of Investigational Site ................................ 78 
7.4. 
Final Report .................................................................................................. 78 
8. 
Appendices ................................................................................................................ 80 
8.1. 
Appendix A: Responsibilities of the Investigator ......................................... 80 
9. 
Reference List ........................................................................................................... 82 
 
List of Tables 
Table 1-1 
Overall Schedule of Events ........................................................................... 14 
Table 1-2 
Schedule of Events for Period 1 (Day –1 to Day 4)...................................... 15 
Table 5-1 
Clinical Laboratory Tests .............................................................................. 53 
 


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1. 
Protocol Synopsis 
Protocol number: 
MDGH-MOX-1008 
Protocol title: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Potential Effect of a Single Oral Dose of 
Moxidectin on the Cardiac QT Interval of Healthy Volunteers 
Study phase: 
1 
Study site: 
Spaulding Clinical Research, LLC 
525 South Silverbrook Drive 
West Bend, Wisconsin 53095 
United States 
Objectives: 
Primary objective: To analyze the effect of a single oral dose of 
moxidectin on the QT interval associated with moxidectin plasma 
concentrations. 
Secondary objective: To assess the safety and pharmacokinetics (PK) 
of a single oral dose of moxidectin. 
Exploratory objectives: 
 
To gain preliminary information in humans on the metabolism 
and excretion of moxidectin; 
 
To evaluate the baseline-corrected changes in other 
electrocardiogram (ECG) and cardiovascular parameters; and 
 
To evaluate the ECG morphologic changes related to cardiac 
repolarization (ST segment and T waves). 
Subject population: 
The study will enroll at least 60 healthy male subjects who meet all of 
the inclusion criteria and none of the exclusion criteria. 
Inclusion criteria: 
A subject must meet all of the following inclusion criteria to 
participate in this study: 
1. Healthy male between 18 and 50 years of age (inclusive); 
2. Body mass index of 18 to 30 kilograms/meters2 (inclusive) and a 
minimum weight of 50 kilograms (110 pounds); 
3. Biologically or surgically sterile or must commit to using 
2 reliable (in the opinion of the investigator) methods of 
contraception, simultaneously, from Screening through the 
duration of the study period (to Week 12); 
4. Willing and able to give written informed consent. 
Exclusion criteria: 
A subject will be excluded from participation in this study if he meets 
any of the following criteria: 
1. Unwilling to abstain from alcohol, caffeine, xanthine-containing 
products, Seville oranges, grapefruit juices, and fish liver oils 
within 72 hours before Check-in (Day –1) and throughout the 
inpatient period of the study; 
2. Less than 1 bowel movement every 24 hours in the absence of 
any laxative, suppository, or enema use during the month before 
Screening; 
3. Abnormal fecal consistency within 24 hours of Check-in 
(Day –1); 


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4. Clinically relevant abnormal findings on medical history, clinical 
laboratory test results, vital sign measurements, safety 12-lead 
ECG results, or physical examination at Screening or Baseline 
which, in the opinion of the investigator, would interfere with 
dosing, jeopardize the safety of the subject, or impact the validity 
of the study results; 
5. History of clinically significant dermatologic, gastrointestinal, 
renal, hepatic, neurologic, hematologic, endocrine, oncologic, 
pulmonary, immunologic, psychiatric, or cardiovascular disease 
or any other condition which, in the opinion of the investigator, 
would interfere with dosing, jeopardize the safety of the subject, 
or impact the validity of the study results; 
6. History of hypersensitivity or allergic reactions to ivermectin, 
moxidectin, or any of the ingredients in the study drug as 
described in the Investigator’s Brochure; 
7. Any condition that may affect oral drug absorption (e.g., previous 
surgery on the gastrointestinal tract including removal of parts of 
the stomach, bowel, liver, gall bladder, or pancreas); 
8. History of risk factors for torsades de pointes, including 
unexplained syncope, known long QT syndrome, heart failure, 
myocardial infarction, angina, or clinically significant abnormal 
laboratory assessments including hypokalemia, hypercalcemia, or 
hypomagnesemia. Subjects are also excluded if there is a family 
history of long QT syndrome or Brugada syndrome; 
9. A sustained supine systolic blood pressure >150 millimeters of 
mercury (mm Hg) or <90 mm Hg or a sustained supine diastolic 
blood pressure >95 mm Hg or <50 mm Hg at Screening or 
Check-in (Day –1). Blood pressure may be retested twice in the 
supine position. The blood pressure abnormality is considered 
sustained if either the systolic or the diastolic blood pressure 
values are outside of the stated limits for 3 assessments, and the 
subject will not to be randomized; 
10. A resting heart rate of <40 beats per minute or >100 beats per 
minute at Screening or Check-in (Day –1); 
11. An uninterpretable or abnormal screening ECG indicating a 
second- or third-degree atrioventricular block, or 1 or more of the 
following: QRS interval >110 milliseconds (msec); QT interval 
corrected by Fridericia’s formula (QTcF) >450 msec; PR interval 
>200 msec; or any rhythm other than sinus rhythm that is 
interpreted by the investigator to be clinically significant; 
12. Concomitant use of prescription medications, including 
medications known to prolong the corrected QT interval (QTc) or 
herbal preparations, within 14 days or 5 half-lives (whichever is 
longer) before study drug dosing, or use of an over-the-counter 
medication or vitamins within 7 days before study drug dosing; 
13. Received an investigational drug during the 30 days, or 
5 half-lives of the study drug (whichever is longer), before 
Check-in (Day –1), or is planning to receive another 
investigational drug at any time during the study; 


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14. History or presence of alcohol abuse (defined as consumption of 
more than 210 milliliters of alcohol per week, or the equivalent of 
fourteen 4-ounce glasses of wine or fourteen 12-ounce 
cans/bottles of beer or wine coolers per week) within 6 months 
before Screening or a positive alcohol test at Screening or 
Check-in (Day –1); 
15. History or presence of substance abuse within the past 2 years or 
a positive drug screen test at Screening or Check in (Day –1); 
16. Current use or has used tobacco- or nicotine-containing products 
(e.g., cigarettes, e-cigarettes, cigars, chewing tobacco, snuff) 
within 14 days before study drug dosing; 
17. Blood donation or significant blood loss within 30 days before 
Check-in (Day –1) or plasma donation within 7 days before 
Check-in (Day –1); 
18. Presence of hepatitis B surface antigen or antibodies to human 
immunodeficiency virus or hepatitis C virus at Screening; 
19. Poor venous access in both arms; 
20. Clinical signs of active infection and/or a temperature of 
>38.0 degrees Celsius at Screening; 
21. Unable to understand verbal or written English or any other 
language for which a certified translation of the informed consent 
form is available; 
22. For any reason, is deemed by the investigator or medically 
qualified designee to be inappropriate for this study, including a 
subject who is unable to communicate or cooperate with the 
investigator, and/or is unwilling to comply with protocol-defined 
procedures and complete the study. 
Study design: 
This is a randomized, single-center, double-blind, placebo-controlled, 
parallel-group study in which healthy male subjects will be randomly 
assigned to one of the following treatments: 
 
Treatment 1: moxidectin 4 milligrams (mg) (n = 10) 
 
Treatment 2: moxidectin 8 mg (n = 10) 
 
Treatment 3: moxidectin 16 mg (n = 10) 
 
Treatment 4: moxidectin 24 mg (n = 10) 
 
Treatment 5: moxidectin 36 mg (n = 10) 
 
Treatment 6: matching placebo (n = 10) 
Subjects will provide written informed consent before undergoing any 
study-related procedures. Subjects will be screened for eligibility up 
to 28 days before randomization. Subjects who meet all of the 
inclusion and none of the exclusion criteria will be admitted to the 
clinical research unit (CRU) on Day –1 (not less than 12 hours before 
scheduled dosing). Subjects will remain in the CRU for at least 
72 hours after dosing and will return to the CRU for further 
assessment on Days 8, 15, and 22, and Week 12. At Week 8, subjects 
will be contacted via telephone for assessment of adverse events 
(AEs) and concomitant medication use. 
The duration of participation in the study for each subject will be up 
to approximately 112 days, including Screening. 


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Study drug, dosage, and route of 
administration: 
Moxidectin, 2-mg tablets, administered orally as a single dose of 4, 8, 
16, 24, or 36 mg 
Reference drug, dosage, and 
route of administration: 
Placebo matched to moxidectin tablets, administered orally as a single 
dose 
Pharmacodynamic assessments: 
Pharmacodynamics will be assessed via ECGs obtained using a 
Mortara continuous 12-lead digital ECG recorder, which will be 
reviewed and analyzed by the central ECG laboratory. The device will 
remain connected to the subject during the confinement period. The 
ECG data will be transmitted wirelessly to the Surveyor system, 
which will extract triplicate 10-second ECG recordings 
(approximately 1 minute apart) at the following time points: Baseline 
(before dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 
72 hours after dosing. The ECG extractions will be time-matched to 
the PK samples but obtained before the actual sampling time to avoid 
changes in autonomic tone associated with the psychological aspects 
of blood collection as well as the reduction in blood volume 
subsequent to blood collection. 
The continuous ECG data will be sent to the central ECG laboratory 
for a high-resolution measurement of the cardiac intervals and 
morphological assessment. The ECG core laboratory staff will be 
blinded to treatment, time, and study day identifiers. 
Pharmacokinetic assessments: 
Blood samples will be collected to determine the PK of moxidectin 
and metabolites in plasma. Blood samples will be collected for PK 
assessments at Baseline (0 hour; within 15 minutes before dosing) and 
at 0.5, 1, 2, 3, 4*, 5, 6, 8, 12*, 24*, 36*, 48, 60*, and 72 hours after 
dosing, and on Days 8, 15, and 22. 
* Planned time points for analysis of moxidectin metabolite 
concentrations 
Urine and feces samples for PK assessments will be collected from 
each subject as follows:  
 
Urine: Before dosing (single pre-dose collection; first void 
sample in the morning is acceptable and volume recording is not 
required) and for pooled intervals of 0 to 24, 24 to 48, and 48 to 
72 hours after dosing (4 samples) 
 
Feces: Before dosing (single pre-dose collection*) and each 
bowel motion during confinement in the CRU. Samples will be 
pooled at the central laboratory for intervals of 0 to 24, 24 to 48, 
and 48 to 72 hours after dosing (up to 4 samples) 
* Feces specimens (the whole bowel movement) may be collected 
by subjects (at home) within 2 days of submitting them to study 
staff on Day –1. Collection instructions will be provided at 
Screening. 
Specific PK parameters for moxidectin in plasma will include: 
 
AUC0-last: area under the plasma concentration-time curve (AUC) 
from time 0 extrapolated to the last observed concentration  
 
AUC0-inf: AUC from time 0 extrapolated to infinity  
 
cumAUC0-t: cumulative AUC from time 0 extrapolated to time t 
(where t = 24, 48, and 72 hours) 
 
AUC0-24: AUC from time 0 to 24 hours after dosing 
 
AUC24-48: AUC from 24 to 48 hours after dosing 
 
AUC48-72: AUC from 48 to 72 hours after dosing 


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 
Cmax: maximum observed plasma concentration 
 
Tmax: time to maximum observed plasma concentration 
 
t1/2: terminal elimination half-life 
Blood sampling time points will coincide with the ECG time points. 
The blood samples will be collected as close to the scheduled time 
point as possible, within 5 minutes and no later than 10 minutes after 
the ECG, unless otherwise noted. 
Additional PK parameters, including apparent clearance, volume of 
distribution, and others may be determined as appropriate. The PK 
parameters will be expressed in units adjusted for molecular weight 
where appropriate. 
Safety assessments: 
Safety and tolerability will be evaluated in terms of AEs, clinical 
laboratory test results (hematology, serum chemistry, and urinalysis), 
vital sign measurements (blood pressure, heart rate, respiratory rate, 
and oral body temperature), safety 12-lead ECG results, and physical 
examination findings. 
Sample size: 
The sample size of 60 subjects (10 subjects each in 6 treatment 
groups) is considered adequate to explore the effects of moxidectin on 
the QTc interval, as this design will yield 900 QTc-PK pairs in total. 
Additional subjects may be enrolled as alternates in this study should 
a subject choose to withdraw consent before study drug 
administration. Alternate subjects will remain in the CRU from 
Check-in until all subjects due to be dosed have completed dosing. 
Subjects who withdraw after dosing will not be replaced. 
Statistical methods: 
For purposes of statistical analysis, this study is divided into 2 study 
periods:  
 
Period 1: Commences at Screening and will finish on Day 22. 
The study blind will be maintained during this study period. After 
the last subject has completed the study through Period 1, the 
blind will be broken and the data from Period 1 will be analyzed. 
 
Period 2: Period 2 runs from Day 23 to Week 12. Data from 
Period 2 will be analyzed after all subjects have completed the 
study through Week 12. Data for some subjects may be collected 
during Period 2 after the blind has been broken. 
Pharmacodynamics: 
The primary endpoint is the baseline-adjusted QTcF (dQTcF) 
matched to the plasma concentration of moxidectin collected at the 
same time point. 
The relationship between time-matched dQTcF and moxidectin 
concentrations will be investigated by linear mixed-effects modeling. 
The ddQTcF value will be calculated as the placebo-corrected dQTcF 
estimated from the model. 
Before modeling, the concentration-ddQTcF relationship will be 
explored graphically to determine the presence of hysteresis. 
Hysteresis will be assumed if, on average (or median), there are at 
least 3 time points with ddQTcF >5 msec and the time to maximum 
observed plasma concentration (Tmax) and the time of maximal 
ddQTcF (Umax) differ by 30 minutes or more and the 1-sided, 
1-sample Wilcoxon test for the difference between ddQTcF at Tmax 
and at Umax is significant at the 1% level. If hysteresis is present, the 
possibility of fitting a population PK model with an effect 
compartment will be explored. 


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The primary analysis will be provided for the ECG population using a 
mixed-effects model with dQTcF as the dependent variable and 
treatment (active and placebo), time point, and treatment by time 
point interaction as the independent variables with baseline QTcF as a 
covariate and time-matched concentrations of moxidectin (observed if 
hysteresis is not present; predicted from the effect compartment if 
hysteresis is present) as a covariate with random effects of intercept 
and slope. Concentrations of zero will be used for the placebo 
treatment. A spatial power law covariance structure (a time-dependent 
first-order autoregressive covariance designed for unequally-spaced 
time points) will be used. If the model does not converge, then 
unstructured (UN) or compound symmetry (CS) structures will be 
assessed, in that order. The model will be used for predicting 
population average and 90% 2-sided bootstrapped confidence interval 
(CI) of the baseline-adjusted difference (i.e., ddQTcF) between active 
and placebo at each time point bound at clinically relevant 
concentrations. The bootstrap method will be based on percentile CI 
using the 5th and 95th percentiles in the resampling distribution using 
1000 iterations. 
The criterion for negative QT assessment will be the upper bound of 
the 2-sided 90% bootstrapped CI for ddQTcF being below 10 msec at 
the largest geometric mean Cmax value. In addition, the significance 
and magnitude of parameter estimates of the treatment covariate 
(active versus placebo) will be considered. 
Model assumptions will be reviewed with plots of standardized 
residuals versus fitted values and normal Q-Q plots of the 
standardized residuals. If nonlinearity is present, a log linear and/or 
maximum effect (Emax) or other model will be considered. 
Similar analyses will be repeated for HR, PR, and QRS, however, 
bootstrap percentiles will be based on the 2.5th and 97.5th percentiles, 
corresponding to a 2-sided 95% CI rather than the 2-sided 90% CI. 
Pharmacokinetics: 
Non-compartmental analysis will be implemented for the calculation 
of PK parameters. The main PK parameters of interest are the 
cumulative and pre-specified time-window AUCs for moxidectin 
concentrations in plasma. 
Computed PK parameters for moxidectin in plasma will be 
summarized and listed for moxidectin, including mean, geometric 
mean, SD, median, and range, as appropriate. Moxidectin 
concentrations in urine and feces as well as plasma:urine and 
plasma:feces concentration ratios will be summarized. 
Summary statistics describing the time course of concentrations of 
moxidectin metabolites and parent to metabolite ratios in plasma will 
be presented. Metabolite concentrations in urine as well as metabolite 
plasma:urine concentration ratios will be summarized as appropriate. 
Pharmacokinetic/Pharmacodynamic: 
To evaluate the relationship between placebo-corrected mean change 
from Baseline in QTcF (i.e., ddQTcF) versus plasma concentrations 
of moxidectin for all subjects, both graphical and mixed-effects 
analyses of plasma concentration of ddQTcF versus plasma 
concentration of moxidectin will be performed. The mixed-effects 
model will contain ddQTcF as the dependent variable and include the 
corresponding moxidectin plasma concentrations as the independent 
variable. The mixed-effects model will be used to estimate, for all 


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subjects, the predicted population mean ddQTcF and its 
corresponding upper 95% 1-sided CI over a range of observed plasma 
concentrations. A negative result (i.e., the model indicates no plasma 
concentration effect) is a slope of approximately zero. 
Safety: 
All safety assessments, including AEs, clinical laboratory test results, 
vital sign measurements, and safety 12-lead ECG results will be 
summarized using descriptive statistics and presented in data listings. 
Physical examination findings and concomitant medications will be 
presented in data listings. All safety summary tables and figures will 
be generated using SAS®. No inferential statistics will be performed 
on the safety data. 
Date of protocol: 
23 September 2016 
Date of amendment 1: 
01 March 2017 


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Table 1-1 
Overall Schedule of Events 
Assessment 
Period 1 
Period 2 
Screening 
D-28 to D-2 
D-1 
Baseline 
D1 (Pre-dose) 
D1 
D2 
D3 
D4 
D8 
D15 
D22 
W8 
W12f 
Outpatient visit 
X 
 
Refer to Table 1-2: 
Schedule of Events for Period 1 (Day –1 to Day 4) 
X 
X 
X 
 
X 
Informed consent 
X 
 
 
 
 
 
Telephone call 
 
 
 
 
X 
 
Inclusion/exclusion criteria review 
X 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
Medical and medication history 
X 
 
 
 
 
 
Physical examinationa 
X 
X 
X 
X 
 
X 
Vital signsb 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
Calculation of body mass index 
X 
 
 
 
 
 
Hematology, serum chemistry, and 
urinalysisc 
X 
 
 
X 
 
X 
Urine drug screen 
X 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
Safety 12-lead electrocardiogramd 
X 
 
 
X 
 
X 
Continuous 12-lead electrocardiogram 
 
 
 
 
 
 
PK blood sample collectione 
 
X 
X 
X 
 
 
PK feces sample collection 
 
 
 
 
 
 
PK urine sample collection 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
Study drug administration 
 
 
 
 
 
 
Adverse events 
X 
---------------------------X--------------------- 
Concomitant medications 
X 
---------------------------X--------------------- 
Abbreviations: D, day; PK, pharmacokinetic; W, week. 
a. A full physical examination will be performed at Screening. At all subsequent time points, a symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and adverse events reported) will be performed. 
b. Vital signs (supine blood pressure, heart rate, respiratory rate, and oral body temperature) will be measured after the subject has rested for approximately 5 minutes. 
c. Blood samples for hematology and serum chemistry and a urine sample for urinalysis will be collected at Screening, on Days –1, 2, 3, 4, 22, and Week 12. Subjects must fast for 
at least 8 hours before clinical laboratory testing. 
d. Standard 12-lead safety electrocardiograms will be performed after the subject has been supine for approximately 10 minutes. At each relevant time point, safety 12-lead ECGs 
will be performed before blood collection. 
e. Blood samples will be collected for PK assessments at Baseline (0 hour; within 15 minutes before dosing) and at 0.5, 1, 2, 3, 4*, 5, 6, 8, 12*, 24*, 36*, 48, 60*, and 72 hours after 
dosing, and on Days 8, 15, and 22. (* Planned time points for analysis of moxidectin metabolite concentrations, 8-mg cohort only) 
f. If a subject discontinues from the study or is withdrawn, the investigator will notify the sponsor and, when possible, will perform the following procedures: vital sign 
measurements; safety 12-lead electrocardiogram; symptom-based physical examination; collection of adverse events; and clinical laboratory evaluation (including hematology, 
serum chemistry, and urinalysis). 


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Table 1-2 
Schedule of Events for Period 1 (Day –1 to Day 4) 
 
Period 1 
Assessment 
Day –1 
Day 1 
(Pre-dose) 
Day 1 
Day 2 
Day 3 
Day 4 
Hour relative to dosing 
≤-24 
 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
36 
48 
60 
72 
Admission to unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from unit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Confirmation of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, serum chemistry, and 
urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Commence fastingb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administrationb 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consumption of a standardized meal 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Safety 12-lead electrocardiogramc 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Continuous 12-lead electrocardiogramd 
 
------------------------------------------------------------------------- X ---------------------------------------------------------------------- 
Vital signse 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PK blood sample collectionf 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK feces sample collectiong 
 
X 
-----------------------------------------X------------------------------------------ 
--X-- 
--------X------- 
PK urine sample collectionh 
 
X 
-----------------------------------------X------------------------------------------ 
--X-- 
--------X------- 
Adverse events 
X 
X 
---------------------------------------------------------------- X -------------------------------------------------------------- 
Concomitant medications 
X 
X 
---------------------------------------------------------------- X -------------------------------------------------------------- 
Abbreviation: PK, pharmacokinetic. 
a. A full physical examination will be performed at Screening. At all subsequent time points, a symptom-based physical examination (informed by concurrent conditions, signs 
and symptoms, and adverse events reported) will be performed. 
b. On Day –1, subjects will begin fasting as instructed and water can be taken ad libitum. On Day 1, study drug administration (moxidectin or placebo) will occur after an 
overnight fast of at least 10 hours. Study drug will be administered with at least 240 milliliters of water. No food will be allowed for 4 hours after dosing; however, water can 
be taken ad libitum. 
c. Standard 12-lead safety electrocardiograms (ECGs) will be performed after the subject has been supine for approximately 10 minutes. At each relevant time point, safety 
12-lead ECGs will be performed before blood collection. 
d. Continuous 12-lead ECG data will be obtained using a Mortara continuous 12-lead digital ECG recorder, with triplicate 10-second ECG recordings (approximately 1 minute 
apart) extracted at the following time points: Baseline (before dosing on Day 1) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours after dosing. 
e. Vital signs (supine blood pressure, heart rate, respiratory rate, and oral body temperature) will be measured after the subject has rested for approximately 5 minutes. 


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f. Blood samples will be collected for PK assessments at Baseline (0 hour; within 15 minutes before dosing) and at 0.5, 1, 2, 3, 4*, 5, 6, 8, 12*, 24*, 36*, 48, 60*, and 72 hours 
after dosing, and on Days 8, 15, and 22. (* Planned time points for analysis of moxidectin metabolite concentrations, 8-mg cohort only) 
g. Feces samples will be collected for PK assessments before dosing (single pre-dose collection*) and each bowel motion during confinement in the clinical research unit. 
Samples will be pooled at the central laboratory for intervals of 0 to 24, 24 to 48, and 48 to 72 hours after dosing (up to 4 samples). (* Feces specimens [the whole bowel 
movement] may be collected by subjects [at home] within 2 days of submitting them to study staff on Day –1. Collection instructions will be provided at Screening.)  
h. Urine samples will be collected for PK assessments before dosing (single pre-dose collection; first void sample in the morning is acceptable and volume recording is not 
required) and for pooled intervals of 0 to 24, 24 to 48, and 48 to 72 hours after dosing (4 samples). 
 


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2. 
List of Abbreviations 
Abbreviation  Definition  
°C 
degrees Celsius 
°F 
degrees Fahrenheit 
µg 
microgram(s) 
μM 
micromolar 
ADME 
absorption, distribution, metabolism, and excretion 
AE  
adverse event 
AIC 
Akaike’s information criterion 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from time 0 to 24 hours 
after dosing 
AUC0-inf  
area under the plasma concentration-time curve from time 0 extrapolated 
to infinity  
AUC0-last 
area under the plasma concentration-time curve from time 0 extrapolated 
to the last observed concentration  
AUC24-48 
area under the plasma concentration-time curve from 24 to 48 hours after 
dosing 
AUC48-72 
area under the plasma concentration-time curve from 48 to 72 hours after 
dosing 
BMI  
body mass index  
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI  
confidence interval  
CL 
apparent clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
cm 
centimeter(s) 
Cmax  
maximum observed plasma concentration  
CNS 
central nervous system 
Conc 
linear term for plasma concentration 
Conc2 
quadratic term for plasma concentration 
cQT 
concentration QT 
CRU 
clinical research unit 
CS 
compound symmetry 
CSRC 
Cardiac Safety Research Consortium 


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cumAUC0-t 
cumulative AUC from time 0 extrapolated to time t (where t = 24, 48, 
and 72 hours) 
CYP 
cytochrome P450 
D 
day 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
ddQTc  
time-matched, placebo-corrected, baseline-adjusted QTc  
ddQTcF  
time-matched, placebo-corrected, baseline-adjusted QTcF 
dQTcF  
baseline-adjusted QTcF 
ECG  
electrocardiogram  
eCRF  
electronic case report form  
Emax 
maximum effect 
ER 
exposure response 
FDA  
Food and Drug Administration  
GABA 
gamma-aminobutyric acid 
GCP  
Good Clinical Practice  
gm 
gram(s) 
hERG  
human ether-à-go-go  
HIV 
human immunodeficiency virus 
HPLC 
high performance liquid chromatography 
HR  
heart rate  
ICF  
informed consent form  
ICH  
International Council for Harmonisation  
ID 
identification 
IQ 
Innovation and Quality in Pharmaceutical Development 
IRB  
institutional review board  
IV 
intravenous 
kg 
kilogram(s) 
lb 
pound(s) 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantitation of the assay 
m 
meter(s) 
MDGH 
Medicines Development for Global Health 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
mL 
milliliter(s) 
mm Hg 
millimeters of mercury 
msec 
millisecond(s)  
n 
number 
ng 
nanogram(s) 
NOAEL 
no observed adverse effect level 
OTC 
over the counter 


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oz 
ounce 
PD 
pharmacodynamic(s) 
P-gp 
P-glycoprotein 
PK  
pharmacokinetic(s)  
ppm 
parts per million 
PT 
preferred term 
QTc  
corrected QT interval  
QTcB 
QT interval corrected by Bazett’s formula 
QTcF  
QT interval corrected by Fridericia’s formula  
QTcI  
QT interval with individual correction  
SAE  
serious adverse event  
SOC 
system organ class 
SOP  
standard operating procedure  
t1/2  
terminal elimination half-life  
TEAE 
treatment-emergent adverse event 
Tmax  
time to maximum observed plasma concentration  
TQT 
thorough QT 
Umax 
time of maximal ddQTcF  
UN 
unstructured 
US 
United States 
Vd 
volume of distribution 
W 
week 
WHO 
World Health Organization 


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3. 
Introduction 
3.1. 
Background 
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) and United States (US) Food and Drug Administration 
(FDA) as one of the neglected tropical diseases for which new treatments are sought.1 
Onchocerciasis primarily affects individuals living in remote and impoverished areas of 
low-income countries. More than 99% of the 37 million people with onchocerciasis 
globally live in 31 sub-Saharan African countries. It is estimated that 89 million people 
are at risk of infection. The disease also exists in some foci in Latin America and Yemen. 
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 skin nodules, from which they release 
millions of microfilariae that migrate through the skin and eyes, a critical step in the cycle 
of reinfection and disease perpetuation. Macrofilariae persist in the human body and have 
an estimated life span of approximately 10 to 14 years.2 
The O. volvulus microfilariae cause the ocular and clinical manifestations of 
onchocerciasis. Symptoms include pruritus, dermatitis, depigmentation and atrophy of the 
skin, lymphadenitis, and visual impairment leading to blindness. Onchocerciasis is the 
second leading infectious cause of blindness in the world.3 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 
Onchocerciasis Control Program (a WHO/United Nations collaboration that ran from 
1974 to 2002) area in West Africa.4-6 
The public health and socioeconomic importance of this disease in severely affected 
communities is also profound; the disease reduces income-generating capacity, incurs 
substantial health expenditures, and exerts a devastating socioeconomic effect on already 
challenged communities. 
3.2. 
Current Treatment and Unmet Need 
Ivermectin is a broad-spectrum endectocide that was approved by the FDA for the 
treatment of onchocerciasis in 1996 and is the current standard of care. The 
recommended regimen for the treatment of onchocerciasis is a single oral dose of 


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150 micrograms (µg)/kilogram (kg). In international treatment programs, the most 
commonly used dose interval is 12 months. The aim of these international, 
community-directed ivermectin treatment programs is to achieve control in affected 
communities and, ultimately, work towards elimination of onchocerciasis in areas 
currently assessed as meso- or hyper-endemic for O. volvulus infection.7 
Despite the positive impact of 25 years of ivermectin treatment, onchocerciasis is still a 
cause of significant morbidity. It remains both a leading infectious cause of blindness and 
the fourth leading cause of preventable blindness after cataracts, glaucoma, and 
trachoma.8 Suboptimal responses to ivermectin have been observed in onchocerciasis 
populations in Africa over several years, which manifest as either incomplete reduction in 
skin microfilarial counts or a short-lived decline followed by rapid repopulation of skin 
microfilarial levels. This phenomenon has been reported in the literature in both 
ivermectin-naïve and ivermectin-experienced patients8-16 and was also seen among the 
ivermectin treatment-naïve recipients enrolled in the Phase 2 and Phase 3 studies in the 
moxidectin development program.16 
3.3. 
Moxidectin 
Moxidectin is a macrocyclic lactone that is derived from the actinomycete Streptomyces 
cyanogriseus. Moxidectin is licensed and marketed worldwide by a number of companies 
as a veterinary anthelmintic agent for use in cattle, sheep, swine, horses, and dogs. 
Moxidectin is a milbemycin and a potent broad-spectrum endectocide being developed 
for the treatment of onchocerciasis. During the development of moxidectin, extensive 
safety and metabolism studies were conducted in animals. Summaries of those studies 
considered relevant to the proposed clinical development are included in the 
Investigator’s Brochure. 
3.3.1 Non-Clinical 
3.3.1.1 
Pharmacodynamics 
The mechanism of action of moxidectin is multifaceted; studies indicate that moxidectin 
binds to gated chloride channels in the neurons and muscle cells of parasites, including 
glutamate and gamma-aminobutyric acid (GABA)-gated channels. Binding to the ion 
channel results in hyperpolarization of the nerve and muscle fibers, leading to paralysis 
and death of the parasitic organism. Specificity of moxidectin for the parasite versus the 
mammalian host is a result of this compound having low affinity for mammalian chloride 
channels. For more information, please refer to the Investigator’s Brochure. 


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Moxidectin has been found to be 2 to 10 times more potent in nematodes than ivermectin 
on a dose-per-kg basis and to reduce the motility and viability of adult worms in vitro and 
in vivo. Moxidectin is minimally metabolized with a higher lipophilicity leading to 
deposition in adipose tissue, particularly skin subcutaneous fat. This is reflected in its 
terminal elimination half-life (t1/2) of 20 to 43 days as opposed to 18 hours for 
ivermectin.17 The physicochemical differences of moxidectin compared with ivermectin 
result in a different pharmacodynamic (PD) profile for the parasite, and make moxidectin 
an important new potential treatment for onchocerciasis. In O. volvulus infection, 
moxidectin is both microfilaricidal and affects the fecundity of adult worms. 
3.3.1.2 
Metabolism and Excretion 
The non-clinical pharmacokinetic (PK) profile of moxidectin, as profiled in rats and dogs, 
is characterized by low oral absorption (rats), low plasma clearance, and a high volume of 
distribution, leading to a long t1/2. In radiolabeled absorption, distribution, metabolism, 
and excretion (ADME) oral dosing studies in rats, moxidectin radioactivity was primarily 
eliminated in the feces. Most of the radioactivity was comprised of moxidectin, although 
oxidative metabolites were also detected. Urinary excretion was low (<2%) in rats. These 
data indicate that moxidectin is likely cleared by a combination of biliary excretion of 
unchanged drug and oxidative metabolism. 
Moxidectin is not a potent P-glycoprotein (P-gp) substrate or inhibitor and it is unlikely 
that clinical drug-drug interactions involving cytochrome P450 (CYP) enzyme inhibition 
or P-gp will occur. Results of studies in human hepatocytes and using a 
CYP3A4-luciferase reporter gene assay suggest that moxidectin is an inducer of CYP3A4 
at concentrations higher than 0.05 micromolar (μM); therefore, a clinical drug-drug 
interaction study was conducted. Moxidectin did not have an effect on the PK of 
midazolam, a sensitive CYP3A4 probe substrate. Therefore, although moxidectin can 
induce CYP3A4 in vitro, it is not an inducer in vivo at the therapeutic dose. For further 
information, please refer to the Investigator’s Brochure. 
3.3.1.3 
Safety 
In a pivotal single-dose oral (capsule) study in adult and juvenile dogs designed to assess 
the planned clinical dosing regimen (once yearly administration), central nervous system 
(CNS)-related clinical signs were evident in both the adult and juvenile dogs after a 
single dose at the highest dose evaluated (3 milligrams (mg)/kg). In adult dogs (juvenile 
dogs discussed later), these observations included tremors, ataxia, abnormal posture, 
decreased motor activity, salivation, emesis, increased vocalization, mydriasis, and 
retropulsion. These clinical signs were not considered adverse because they were 


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transient, occurring only within 2 days after dosing, and the animals did not require 
medical treatment. There were no moxidectin-related clinical signs at lower doses, and no 
other parameters were affected by moxidectin. Therefore, the no observed adverse effect 
level (NOAEL) in adult dogs was 3 mg/kg. 
In repeat-dose oral (diet) studies in mice, rats, and dogs, moxidectin was well tolerated at 
the NOAELs in each of these studies. The NOAEL was 6.9 mg/kg/day in the 4-week 
mouse study, 12.2 mg/kg/day in the 4-week rat study, 3.9 mg/kg/day in the 13-week rat 
study, and 0.8 mg/kg/day in the 4-week dog study. Findings at the next highest dose 
included mortality in the 4-week studies in mice and rats, decreased body weight and 
food consumption in the rat and dog studies, increased organ weights of the adrenal gland 
and kidney in the 13-week rat study and CNS-related clinical observations in all studies. 
Additional findings in dogs at the next highest dose of 2.4 mg/kg/day included decreased 
colloid in the thyroid and decreased testes weight and spermatogenic activity, which may 
have been related to the degree of maturation of the 5- to 6-month old dogs as they were 
not observed in the 1-year dog study. In the 13-week and 1-year studies in dogs, there 
were no adverse effects; therefore, the NOAELs were the highest doses tested, 1.6 and 
1.1 mg/kg/day, respectively. The CNS-related clinical observations observed in the 
repeat-dose diet studies included tremors observed in all 3 species, ataxia observed in rats 
and dogs, hypersensitivity to touch observed in mice and rats, and mydriasis observed in 
dogs. 
Moxidectin was not genotoxic in a battery of genotoxicity assays, in vitro or in vivo, and 
was not carcinogenic in mice or rats. The reproductive NOAELs were 5 mg/kg/day in 
both the rat and rabbit developmental studies and at 5 parts per million (ppm) 
(0.4 mg/kg/day) in the rat 3-generation study. In female dogs administered a single 
subcutaneous 1.5-mg/kg injection of moxidectin canine sustained-release injectable 
formulation 1 month before mating, 1 day after mating, 28 days after mating, or 5 days 
after whelping, there were no adverse effects on the female animals, breeding behavior, 
reproductive capacity, pup survival, or pup body weight. The adverse fetal effects 
observed in the rat and rabbit toxicity studies occurred only in the presence of maternal 
toxicity. For further information, please refer to the Investigator’s Brochure. 
The results of the non-clinical safety program supported the subsequent implementation 
of 5 healthy volunteer Phase 1 studies using singles doses of moxidectin up to 36 mg. 
Phase 2 and 3 studies have since been conducted in adult and adolescent patients with 
onchocerciasis (see Section 3.3.2). 


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3.3.2 Clinical 
The moxidectin clinical program encompasses 7 completed single oral dose clinical 
studies spanning Phases 1 to 3. The PK and safety data from these studies are 
summarized below. For further information, please refer to the Investigator’s Brochure. 
3.3.2.1 
Pharmacokinetics 
Moxidectin is a biopharmaceutics classification system Class 2 drug with low solubility 
and high permeability. Moxidectin PK data are available from 193 healthy subjects from 
five Phase 1 studies and 98 patients with O. volvulus infection from the Phase 2 study. In 
all studies, subjects received a single moxidectin dose ranging from 2 to 36 mg. 
Following a single dose of moxidectin in humans, plasma concentrations increased until 
approximately 3 to 4 hours and then decayed in a multiphasic manner, with rapid 
distribution resulting in concentrations declining 10-fold during the first 24 to 48 hours 
following drug administration. Thereafter, plasma concentrations declined slowly, in 
accordance with a long terminal half-life, likely due to sequestration in adipose and skin 
tissue. Administration of moxidectin with food resulted in an increase in maximum 
observed plasma concentration (Cmax) and area under the plasma-concentration time 
curve (AUC) of 34% and 39%, respectively. 
High performance liquid chromatography (HPLC) methods with fluorescence detection 
were validated for the quantitation of moxidectin in human plasma and breast milk. 
Based on a 0.5-milliliter (mL) sample volume, the assays were linear from 0.08 to 
120 nanograms (ng)/mL. For further information, please refer to the Investigator’s 
Brochure. 
3.3.2.2 
Clinical Studies of Moxidectin 
Moxidectin has been administered to 194 healthy volunteers in five Phase 1 studies, and 
in 1105 patients with onchocerciasis in one Phase 2 and one Phase 3 study. For further 
information, please refer to the Investigator’s Brochure. 
Phase 1 studies of moxidectin evaluated single oral doses of 3 to 36 mg of moxidectin 
under fasted and fed conditions in healthy men and women. Moxidectin was well 
tolerated across the dose range. All of the adverse events (AEs) reported across all 
5 studies were mild to moderate in intensity, with the exception of one Grade 3 event 
(enteritis) in a subject who received 36 mg (which was deemed unrelated to test article). 
There were no Grade 4 events and no clinically relevant abnormalities observed in vital 
sign measurements, electrocardiograms (ECGs), or safety laboratory tests. None of the 
subjects died or experienced a serious adverse event (SAE) in any study, and there were 


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no discontinuations from the study because of AEs. There was no relationship between 
either the incidence or type of AEs and the dose of moxidectin administered.  
The most commonly reported AEs in all subjects who took moxidectin were headache, 
infection/upper respiratory tract infection/viral infection, nausea, pharyngitis, cough 
increased, rhinitis leukopenia, dizziness, pain, aspartate aminotransferase increased, 
alanine aminotransferase increased, somnolence, rhinitis, flatulence, gastroenteritis, 
myalgia, and asthenia.  
The Phase 2 study was a randomized, single-ascending dose, double-blind, 
parallel-design, active (ivermectin)-controlled, inpatient/outpatient study conducted at a 
single center, the Onchocerciasis Chemotherapy Research Center in Ghana, an 
onchocerciasis endemic region of Africa. Of the 172 subjects in the safety population, 
170 subjects (98.8%) experienced at least one AE. In assessing the safety of 
chemotherapeutics in the treatment of onchocerciasis, a generally universal observation 
among treated patients is the Mazzotti reaction, which is a constellation of symptoms 
caused by an immunologically mediated reaction to the dying microfilariae. Common 
systemic clinical manifestations of the Mazzotti reaction include pruritus, rash, 
lymphadenitis, headache, myalgia, arthralgia, hypotension (including severe symptomatic 
postural hypotension), fever, and swelling of the face and limbs. Ocular events include 
epiphora (excessive lacrimation), photophobia, conjunctival injection, limbitis, anterior 
uveitis, chorioretinitis, and optic neuritis. 
At least 1 AE consistent with the effects of the dying microfilariae was reported for 
38 subjects (86.4%) treated with 2-mg moxidectin, 45 subjects (100%) treated with 4-mg 
moxidectin, 37 subjects (97.4%) treated with 8-mg moxidectin, and 43 subjects (95.6%) 
treated with ivermectin, occurring more commonly in moxidectin recipients. The events 
were not life threatening in either moxidectin or ivermectin recipients. No clinically 
relevant treatment-related non-Mazzotti AEs were observed in any of the treatment 
groups. No subject was withdrawn from the study due to an AE. Eight subjects 
experienced SAEs in the study: 5, 1, and 2 subjects in the moxidectin 2-, 4-, and 8-mg 
treatment groups, respectively. None of the SAEs were considered related to test article 
by the investigator. One subject (moxidectin 2 mg) died on Day 310 from a snakebite. 
All moxidectin doses (except 2 mg at the 18-month time point) resulted in statistically 
significantly lower skin microfilaria levels at all time points after treatment when 
compared with ivermectin. 
A large (n = 1472) multicenter (multinational), double-blind, randomized 
(moxidectin 2:ivermectin 1), stratified (gender, baseline microfilarial load, site), 


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ivermectin-controlled Phase 3 study was conducted in subjects infected with O. volvulus: 
1472 subjects were enrolled across 4 sites and treated with either a single 8-mg dose of 
moxidectin (n = 978) or a single 150-µg/kg dose of ivermectin (n = 494). Subjects 
participated in a 30-day screening period, a minimum 6-day inpatient evaluation period 
following administration of study drug, and follow-up visits at Day 14 and at Months 1, 
3, 6, 12, and (for a subset of subjects) 18 months. Study follow-up of at least 12 months 
was completed for greater than 95% of study subjects. The study met the pre-defined 
primary endpoint of superiority of moxidectin over ivermectin at Month 12 (P <0.0001). 
Furthermore, treatment differences were observed early and persisted to 18 months. 
Similar efficacy was seen across the different level of infection subsets. 
All 978 subjects (100%) in the moxidectin treatment group and 491 subjects (99.4%) in 
the ivermectin treatment group experienced treatment-emergent AEs (TEAEs) during the 
active phase of the study (defined as the date of study drug administration and up to 
180 days after this date). 
A total of 966/978 subjects (98.8%) in the moxidectin treatment group and 
480/494 subjects (95.6%) in the ivermectin treatment group experienced at least 1 AE 
consistent with the effects of the dying microfilariae. Reactions occurring more 
frequently in the moxidectin treated subjects included lymph node pain, lymphadenitis, 
tachycardia, pruritus (skin or eye), edema, rash, urticaria, and orthostatic hypotension; 
this is consistent with a more extensive decrease in skin microfilariae and faster reduction 
in skin microfilariae generally observed with moxidectin treatment as compared with 
ivermectin treatment. A total of 205/978 subjects (21.0%) in the moxidectin treatment 
group and 79/494 subjects (16.0%) in the ivermectin treatment group experienced ocular 
TEAEs, the most common of which were eye pain, eye pruritis, and eyelid edema. 
Only 25 subjects (2.6%) in the moxidectin treatment group and 13 subjects (2.6%) in the 
ivermectin group experienced adverse drug reactions, assessed by the investigator as drug 
related but not associated with efficacy reactions. 
No AEs during the active phase of the study led to withdrawal. 
In total, 57 subjects (3.8%) experienced 77 SAEs during the active phase of the study. In 
the moxidectin treatment group, 39/978 subjects (4.0%) experienced 52 events, and in the 
ivermectin treatment group, 18/494 subjects (3.6%) experienced 25 events. None of the 
SAEs were considered related to test article by the investigator. One subject (moxidectin 
2 mg) died on Day 310 from a snakebite. Four subjects died during the active phase of 
the study, 2 subjects (0.2%) in each group. In the moxidectin group, 1 subject died due to 
peritonitis and cardiac arrest following complications after surgical intervention for a 


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vesico-vaginal fistular surgical repair and a second subject died following an acute 
asthma attack. In the ivermectin group, 1 subject died due to sepsis following falciparum 
malaria infection and a second subject died after experiencing diabetic acidotic coma 
secondary to malaria and meningeal syndrome. 
The full and final analysis of the Phase 3 study data is ongoing and will be concluded in 
the fourth quarter of 2016. 
3.3.2.3 
Cardiovascular Safety 
Non-clinical data supportive of the cardiovascular safety of moxidectin consists of the 
following: 
 A lack of binding to ion channels, including calcium Type L and Type N, 
ATP-sensitive potassium, Ca-activated V1 potassium, IKr (human ether-à-go-go 
[hERG]) potassium and Site 2 sodium channels in a NovaScreen assay; 
 Minimal effect on hERG current in HEK293 cells in vitro at concentrations 
approximately 100-fold higher than Cmax in adult patients in a Phase 2 study; and 
 Lack of effect on corrected QT interval (QTc) monitored over 72 hours in a dog 
cardiovascular-telemetered study at an oral dose of 1 mg/kg, approximately 16.5-fold 
in excess of the proposed human dose on Cmax and 24.7-fold higher on AUC. 
In all clinical studies, participants received a single moxidectin dose, with doses ranging 
from 2 to 36 mg. The review of currently available clinical cardiac safety data, including 
ECGs from the 6 analyzed studies, indicates no identifiable proarrhythmic risk to date. 
Specifically, in the five Phase 1 studies, there were no deaths, SAEs, or premature 
discontinuations due to AEs and there were no clinically meaningful changes in ECGs. In 
the Phase 2 study, which investigated 3 dose levels of moxidectin versus standard-of-care 
ivermectin, there were no SAEs in the system organ class (SOC) of cardiac disorders. 
There was 1 SAE of grand mal convulsion (moxidectin 2 mg), 2 non-serious AEs of 
syncope (moxidectin 2 mg and 4 mg), and 1 non-serious AE of ventricular extrasystole 
(moxidectin 2 mg). There was no evidence of QTc prolongation in these patients. 
Two patients receiving moxidectin (4 mg and 8 mg) who had a post-baseline QT interval 
corrected by Bazett’s formula (QTcB) of >450 milliseconds (msec) with a >10% increase 
from Baseline did not have any AEs in the SOC of cardiac disorders or AEs suggestive of 
delayed repolarization (Medical Dictionary for Regulatory Activities [MedDRA] query 
“Torsade de pointes/QT prolongation”). One subject in the moxidectin 8-mg treatment 
group on Day 1 had a QTc interval >480 msec. This subject, a 59-year-old female with 
history of chloroquine allergy and palpitation and a baseline QTc of 468.55 msec, had a 


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QTc of 495.49 msec on Day 1 after study treatment. There were no associated cardiac 
AEs. Her QTc interval on Day 8 was 475.39 msec. No subject in any of the treatment 
groups had a QTc interval greater than 500 msec. There was no statistically significant 
difference (P >0.05) between moxidectin and ivermectin treatment groups for any QTc 
interval change greater than 30 msec or 60 msec, or with values greater than 450 msec, 
480 msec, or 500 msec during the study. For further information, please refer to the 
current Investigator’s Brochure. 
3.4. 
Study Rationale 
Even though the available non-clinical and clinical data is not suggestive of a QT 
liability, the aim of the current study is to definitively assess the QT prolongation 
potential of moxidectin through a dedicated dose-ranging design with intensive and 
time-matched PK and ECG collections using a concentration QT (cQT) analysis 
approach. 
The study will enroll healthy male volunteers. The rationale for including only males is 
that moxidectin plasma concentration predictions have been derived from PK data from 
the Phase 1 study (3110A1-1005-EU) in which only males 18 to 50 years were enrolled. 
Protocol 3110A1-1005-EU had the largest number of subjects with PK data, and utilized 
the batch of moxidectin tablets that was subsequently administered in the pivotal Phase 3 
clinical trial of male and female patients with onchocerciasis. Therefore, protocol 
MDGH-MOX-1008 seeks to enroll subjects that are concordant in baseline characteristics 
of those enrolled in Protocol 3110A1-1005-EU, enabling informal comparisons of PK 
data from 3110A1-1005-EU and MDGH-MOX-1008. Further, the effects of moxidectin 
during pregnancy are unknown and the inclusion of women of childbearing potential 
would require a particularly long-term commitment to a double-barrier method of 
protection given the relatively long half-life of moxidectin. The equivalent of 
approximately 5 half-lives of moxidectin is 6 months, and this represents an onerous 
obligation in this healthy subject population. 
3.4.1 Rationale for Study Design 
A definitive human QT prolongation risk-assessment study has not been performed with 
moxidectin. The results of this study will provide an understanding of the cardiac safety 
profile of moxidectin that is appropriate for the proposed use, a single oral 8-mg dose. 
Given the PK characteristics of moxidectin (i.e., long half-life), a standard 4-way 
crossover thorough QT (TQT) study cannot be conducted as described in International 
Council for Harmonisation (ICH) E14. ICH E14 suggests conduct of a 4-arm 


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parallel-group study for drugs with a long half-life where a crossover design is not 
feasible.18 
The December 2014 joint meeting between the FDA, the Clinical Pharmacology 
Leadership Group of the Consortium for Innovation and Quality in Pharmaceutical 
Development (IQ), and the Cardiac Safety Research Consortium (CSRC) has provided 
the impetus for using a cQT approach for replacing the TQT study;19,20 most typically by 
adding intensive ECGs into the first-in-human dose-ranging study and utilizing 
exposure-response (ER) analyses to detect QT effects. The experience with ER analyses 
of ECG data has increased over the last decade and ER analyses have become an integral 
part of FDA Interdisciplinary Review Team review of data from QT assessment studies.21 
The ER analyses allow for a wide range of plasma concentrations to be analyzed, which 
improves the power to detect and exclude small QT effects22,23 compared with the 
by-time-point analyses conducted for TQT studies. Experience with QT-prolonging drugs 
demonstrates that the effect on the QT interval is related to plasma levels of the drug or 
main metabolites, which further supports analyses in relation to plasma concentration. In 
contrast, by-time-point analyses as conducted in a standard ICH E14 parallel-group study 
design do not incorporate the concept of ER.21 The results of the prospective IQ-CSRC 
study further support the cQT approach as a sensitive means to detect positive QT 
signals20 and is the reason a cQT study is proposed to assess the QT prolongation 
potential for moxidectin. 
Although the first-in-human dose-ranging study for moxidectin has been completed, 
conducting a QT study similar to a first-in-human dose-ranging study using an ER 
approach, if properly designed, will be at least as sensitive in detecting a QT signal as the 
by-time-point ICH E14-recommended parallel-group study. Furthermore, such an 
approach will require fewer subjects for enrollment. This cQT study is similar in design 
to a first-in-human dose-ranging study; however, there will be no need to stagger 
enrollment into cohorts for safety (which has already been established). 
Subjects will be randomized into 6 treatment groups (5:1 moxidectin:placebo) with 
10 subjects per group. The dose range will provide for a 12-fold dose margin (4.7-fold 
exposure margin at Cmax), exceeding the 4.5-fold range that is typically suggested if there 
is no positive control to diminish the risk of a false negative.21 Triplicate ECGs will be 
assessed at Baseline and at pre-specified time points matched with PK sampling for 
3 days in all subjects (see Section 5.6.1). With 15 sampling time points, this design will 
yield 900 QTc-PK pairs in total. After placebo and baseline subtraction, there will be 
700 time-matched, placebo-corrected, baseline-adjusted QTc (ddQTc)-PK pairs. In 


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contrast, the Ferber design20,24 used in the IQ-CSRC study yielded 315 QTc-PK pairs and 
189 ddQTc-PK pairs per drug. 
3.4.2 Doses Selected 
The proposed human dose for the treatment of onchocerciasis is 8 mg. This study will 
assess moxidectin as a single oral dose at doses up to 36 mg in tablet form and in the 
fasted state. In addition to the non-clinical safety pharmacology and toxicology studies, 
which provided adequate safety margin multiples in reference to the 36-mg dose, 
moxidectin has previously been administered at doses up to 36 mg in healthy human 
subjects and was well tolerated. Specifically, in Study 3110A1-100-EU, there was no 
evidence of clinically relevant safety findings after administration of moxidectin (oral 
liquid). No clinically relevant abnormalities were observed in vital sign measurements, 
ECGs, or laboratory test results during the study. A slightly higher incidence of CNS AEs 
(somnolence and mild dizziness) was observed in the 36-mg fed and fasted treatment 
groups (moxidectin or placebo). As this was prior to study unblinding and the dose was 
well above the predicted therapeutic dose, the decision was made to end the study prior to 
enrollment of a planned 54-mg cohort. There was found to be no major difference in the 
pattern and severity of AEs and the AEs reported during the study were mild to moderate 
in intensity with the exception of one Grade 3 event (enteritis) in the 36-mg group, which 
was deemed unrelated to test article. There were no SAEs and no subjects discontinued 
the study due to an AE. 
Increased exposure to moxidectin has been observed in liquid presentations compared 
with tablets and when moxidectin is given with food. Of the 10 subjects who received 
moxidectin as an oral solution at 36 mg in Study 3110A1-100-EU, the fasted mean (±SE) 
AUC from time 0 extrapolated to infinity (AUC0-inf) was 451 (±48.2) ng*days/mL 
compared with fed AUC0-inf of 624 (±41.6) ng*days/mL. Therefore, moxidectin 
administered in tablet form and in the fasted state should ensure that exposure is less than 
or equal to existing clinical experience.  
Further information on the safety findings and PK of moxidectin are included in the 
Investigator’s Brochure. 


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4. 
Study Objectives 
4.1. 
Primary Objective 
The primary objective of the study is to analyze the effect of a single oral dose of 
moxidectin on the QT interval associated with moxidectin plasma concentrations. 
4.2. 
Secondary Objective 
The secondary objective of the study is to assess the safety and PK of a single oral dose 
of moxidectin. 
4.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
 To gain preliminary information in humans on the metabolism and excretion of 
moxidectin; 
 To evaluate the baseline-corrected changes in other ECG and cardiovascular 
parameters; and 
 To evaluate the ECG morphologic changes related to cardiac repolarization (ST 
segment and T waves). 


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5. 
Investigational Plan 
5.1. 
Study Design 
This is a randomized, single-center, double-blind, placebo-controlled, parallel-group 
study in which healthy male subjects will be randomly assigned to one of the following 
treatments: 
 Treatment 1: moxidectin 4 mg (n = 10) 
 Treatment 2: moxidectin 8 mg (n = 10) 
 Treatment 3: moxidectin 16 mg (n = 10) 
 Treatment 4: moxidectin 24 mg (n = 10) 
 Treatment 5: moxidectin 36 mg (n = 10) 
 Treatment 6: matching placebo (n = 10) 
5.2. 
Study Duration 
Subjects will be screened for eligibility up to 28 days before randomization. Subjects who 
meet all of the inclusion and none of the exclusion criteria will be admitted to the clinical 
research unit (CRU) on Day –1 (not less than 12 hours before scheduled dosing). 
Subjects will remain in the CRU for at least 72 hours after dosing and will return to the 
CRU for further assessment on Days 8, 15, and 22, and Week 12. At Week 8, subjects 
will be contacted via telephone for recording of AEs and concomitant medication use. 
The duration of participation in the study for each subject will be up to approximately 
112 days, including Screening. 
5.3. 
Selection of Study Population 
Eligibility will be determined at Screening and reconfirmed at Check-in on Day –1. The 
investigator or medically qualified designee will be responsible for confirming subject 
eligibility by documenting in the electronic case report form (eCRF) that each subject 
meets all of the inclusion criteria in Section 5.3.1 and does not meet any of the exclusion 
criteria in Section 5.3.2. 
5.3.1 Inclusion Criteria 
A subject must meet all of the following inclusion criteria to participate in this study: 
1. 
Healthy male between 18 and 50 years of age (inclusive); 


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2. 
Body mass index (BMI) of 18 to 30 kg/meters (m)2 (inclusive) and a minimum 
weight of 50 kg (110 pounds [lb]); 
3. 
Biologically or surgically sterile or must commit to using 2 reliable (in the opinion 
of the investigator) methods of contraception, simultaneously, from Screening 
through the duration of the study period (to Week 12); 
4. 
Willing and able to give written informed consent. 
5.3.2 Exclusion Criteria 
A subject will be excluded from participation in this study if he meets any of the 
following criteria: 
1. 
Unwilling to abstain from alcohol, caffeine, xanthine-containing products, Seville 
oranges, grapefruit juices, and fish liver oils within 72 hours before Check-in 
(Day –1) and throughout the inpatient period of the study; 
2. 
Less than 1 bowel movement every 24 hours in the absence of any laxative, 
suppository, or enema use during the month before Screening; 
3. 
Abnormal fecal consistency within 24 hours of Check-in (Day –1); 
4. 
Clinically relevant abnormal findings on medical history, clinical laboratory test 
results, vital sign measurements, safety 12-lead ECG results, or physical 
examination at Screening or Baseline which, in the opinion of the investigator, 
would interfere with dosing, jeopardize the safety of the subject, or impact the 
validity of the study results; 
5. 
History of clinically significant dermatologic, gastrointestinal, renal, hepatic, 
neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, 
psychiatric, or cardiovascular disease or any other condition which, in the opinion 
of the investigator, would interfere with dosing, jeopardize the safety of the subject, 
or impact the validity of the study results; 
6. 
History of hypersensitivity or allergic reactions to ivermectin, moxidectin, or any of 
the ingredients in the study drug as described in the Investigator’s Brochure; 
7. 
Any condition that may affect oral drug absorption (e.g., previous surgery on the 
gastrointestinal tract including removal of parts of the stomach, bowel, liver, gall 
bladder, or pancreas); 
8. 
History of risk factors for torsades de pointes, including unexplained syncope, 
known long QT syndrome, heart failure, myocardial infarction, angina, or clinically 
significant abnormal laboratory assessments including hypokalemia, hypercalcemia, 


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or hypomagnesemia. Subjects are also excluded if there is a family history of long 
QT syndrome or Brugada syndrome; 
9. 
A sustained supine systolic blood pressure >150 millimeters of mercury (mm Hg) 
or <90 mm Hg or a sustained supine diastolic blood pressure >95 mm Hg or 
<50 mm Hg at Screening or Check-in (Day –1). Blood pressure may be retested 
twice in the supine position. The blood pressure abnormality is considered sustained 
if either the systolic or the diastolic blood pressure values are outside of the stated 
limits for 3 assessments, and the subject will not to be randomized; 
10. A resting heart rate (HR) of <40 beats per minute (bpm) or >100 bpm at Screening 
or Check-in (Day –1); 
11. An uninterpretable or abnormal screening ECG indicating a second- or third-degree 
atrioventricular block, or 1 or more of the following: QRS interval >110 msec; QT 
interval corrected by Fridericia’s formula (QTcF) >450 msec; PR interval 
>200 msec; or any rhythm other than sinus rhythm that is interpreted by the 
investigator to be clinically significant; 
12. Concomitant use of prescription medications, including medications known to 
prolong the QTc or herbal preparations, within 14 days or 5 half-lives (whichever is 
longer) before study drug dosing, or use of an over-the-counter (OTC) medication 
or vitamins within 7 days before study drug dosing; 
13. Received an investigational drug during the 30 days, or 5 half-lives of the study 
drug (whichever is longer), before Check-in (Day –1), or is planning to receive 
another investigational drug at any time during the study; 
14. History or presence of alcohol abuse (defined as consumption of more than 210 mL 
of alcohol per week, or the equivalent of fourteen 4-ounce [oz] glasses of wine or 
fourteen 12-oz cans/bottles of beer or wine coolers per week) within 6 months 
before Screening or a positive alcohol test at Screening or Check-in (Day –1); 
15. History or presence of substance abuse within the past 2 years or a positive drug 
screen test at Screening or Check-in (Day –1); 
16. Current use or has used tobacco- or nicotine-containing products (e.g., cigarettes, 
e-cigarettes, cigars, chewing tobacco, snuff) within 14 days before study drug 
dosing; 
17. Blood donation or significant blood loss within 30 days before Check-in (Day –1) 
or plasma donation within 7 days before Check-in (Day –1); 


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18. Presence of hepatitis B surface antigen or antibodies to human immunodeficiency 
virus (HIV) or hepatitis C virus at Screening; 
19. Poor venous access in both arms; 
20. Clinical signs of active infection and/or a temperature of >38.0 degrees Celsius (°C) 
at Screening; 
21. Unable to understand verbal or written English or any other language for which a 
certified translation of the informed consent form is available; 
22. For any reason, is deemed by the investigator or medically qualified designee to be 
inappropriate for this study, including a subject who is unable to communicate or 
cooperate with the investigator, and/or is unwilling to comply with protocol-defined 
procedures and complete the study. 
5.4. 
Withdrawal of Subjects from the Study 
A subject may withdraw from the study for any reason and at any time. 
The investigator must make every reasonable effort to keep each subject in the study 
except where termination or withdrawal is for reasons of safety. The investigator also has 
the right to withdraw subjects from study in the event of concurrent illness, AE, protocol 
violation, administrative reason, or other reason. 
It is understood by all concerned that an excessive rate of withdrawal from the study can 
render the study difficult to interpret. 
5.4.1 Reasons for Withdrawal 
The primary reason for treatment discontinuation will be noted using the following 
categories:  
1. 
AE: The subject experiences an AE that, in the opinion of the investigator, requires 
early termination. If a subject is discontinued from the study due to an AE, the 
investigator or medically qualified designee will be required to follow-up with the 
subject until the event resolves or becomes stable. If a subject death occurs during 
the study, the cause of death will be reported as an SAE, with an outcome of death 
noted in the eCRF.  
A subject will be withdrawn from the study if he has an ECG with a manually 
measured QTcF of >500 msec at any time point after dosing that is confirmed by 
the investigator. It will be recorded as an AE and reported immediately to the 
medical monitor.  


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2. 
Protocol deviation: The subject fails to meet protocol entry criteria or does not 
adhere to protocol requirements, and continued participation will pose an 
unnecessary risk to the subject’s health.  
3. 
Voluntary withdrawal of consent: The subject wishes to withdraw from the study in 
the absence of a medical need.  
4. 
Study termination: The sponsor, institutional review board (IRB), FDA, or other 
regulatory agency terminates the study.  
5. 
Other.  
Note: This category includes withdrawals caused by an accidental or a medical 
emergency, unblinding, or other rare cases. The specific reasons will be recorded in 
the eCRF. 
5.4.2 Handling of Withdrawals 
The investigator may terminate a subject’s study participation at any time during the 
study if the subject meets the withdrawal criteria described in Section 5.4.1. In addition, a 
subject may discontinue his participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary reason for 
termination must be recorded. 
If a subject discontinues from the study or is withdrawn, the investigator will notify the 
sponsor and, when possible, will perform the following procedures: vital sign 
measurements; safety 12-lead ECG; symptom-based physical examination; collection of 
AEs; and clinical laboratory evaluation (including hematology, serum chemistry, and 
urinalysis). 
5.4.3 Replacement Subjects 
Additional subjects may be enrolled as alternates in this study should a subject choose to 
withdraw consent before study drug administration. Alternate subjects will remain in the 
CRU from Check-in until all subjects due to be dosed have completed dosing. Subjects 
who withdraw after dosing will not be replaced. 
5.5. 
Study Procedures 
5.5.1 Schedule of Events 
The schedules of events are presented in Table 1-1 and Table 1-2. 


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5.5.2 Study Procedures and Assessment Periods 
The study procedures to be performed for each subject enrolled in the study are listed in 
the following sections. Additional details of the study procedures are provided in 
Section 5.6. Any deviation from procedures planned in the protocol must be recorded in 
the source documents and the sponsor must be notified. 
All laboratory tests on blood samples will be performed at the selected laboratory. 
Information on collection and shipment of all required study samples will be described in 
the Study Reference Manual. 
Additional visits and/or assessments may be conducted as clinically indicated. For these 
additional assessments, visit-specific data will not be collected in the eCRF, although all 
AEs and concurrent medications must be recorded throughout the study period. 
5.5.3 Period 1 
5.5.3.1 
Screening 
Subjects will be screened up to 28 days before randomization (range: Day –28 to Day –2) 
to determine eligibility for participation in the study. Screening assessments may be 
conducted on different days if required. At Screening, the following procedures will be 
performed and documented: 
 Written informed consent obtained before any study-related procedures (see 
Section 6.3) 
 Review of inclusion/exclusion criteria (see Section 5.3) 
 Recording of demographic information including date of birth, gender, ethnicity, and 
race (see Section 5.6.4) 
 Medical and medication history (see Section 5.6.4) 
 Full physical examination (see Section 5.6.3.6) 
 Vital signs (supine blood pressure, HR, respiratory rate, oral body temperature) (see 
Section 5.6.3.4) 
 Height and body weight measurement and calculation of BMI (see Section 5.6.3.6) 
 Blood samples for hematology and serum chemistry and urine sample for urinalysis 
(see Section 5.6.3.3) 
 Urine drug screen (see Section 5.6.3.3) 


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 Serology (hepatitis B surface antigen, antibodies to HIV and hepatitis C virus) (see 
Section 5.6.3.3) 
 Safety 12-lead ECG (see Section 5.6.3.5) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
Results of all screening tests must be available and reviewed before the subject’s 
Check-in Visit. Subjects meeting all of the inclusion criteria and none of the exclusion 
criteria will return to the CRU for Check-in on Day –1. 
5.5.3.2 
Day –1 
Subjects will be admitted to the CRU on Day –1 (not less than 12 hours before scheduled 
dosing) and continued eligibility will be confirmed through the review of the inclusion 
and exclusion criteria. Subjects will begin fasting as instructed and water can be taken 
ad libitum. On Day –1, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) (see Section 5.6.3.6) 
 Body weight measurement (see Section 5.6.3.6) 
 Blood samples for hematology and serum chemistry and urine sample for urinalysis 
(see Section 5.6.3.3) 
 Urine drug screen (see Section 5.6.3.3) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
5.5.3.3 
Day 1 
5.5.3.3.1 
Pre-Dose 
On Day 1, the following procedures will be performed and documented before dosing: 
 Randomization (see Section 5.7.1). Subjects will have a final assessment of eligibility 
before randomization; those subjects meeting all of the inclusion and none of the 
exclusion criteria will be randomized and will continue fasting until dosing. 
 Vital signs (supine blood pressure, HR, respiratory rate, oral body temperature) 
within 15 minutes before dosing (see Section 5.6.3.4) 


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 Begin continuous 12-lead ECG (see Section 5.6.1.1) 
 Blood sample for PK assessment (collected within 15 minutes before dosing) (see 
Section 5.6.2.1) 
 Pre-dose feces sample collection for PK assessment (see Section 5.6.2.2) 
 Pre-dose urine sample collection for PK assessment (see Section 5.6.2.2) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
5.5.3.3.2 
Dosing 
At Hour 0 on Day 1, the following procedures will be performed and documented: 
 Study drug administration (see Section 5.7.2) 
5.5.3.3.3 
Post-Dose 
After dosing on Day 1, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) at 4 and 12 hours after dosing (see Section 5.6.3.6) 
 Safety 12-lead ECG at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after dosing (see 
Section 5.6.3.5) 
 Continuous 12-lead ECG with extractions at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after 
dosing (see Section 5.6.1.1) 
 Blood samples for PK assessment (collected at 0.5, 1, 2, 3, 4*, 5, 6, 8, and 12* hours 
after dosing on Day 1. (* Planned time points for analysis of moxidectin metabolite 
concentrations) (see Section 5.6.2.1) 
 Standardized meal (lunch) served approximately 4 hours after dosing (see 
Section 5.7.8) 
 Feces sample for PK assessment (collected from 0-24 hours after dosing on Day 1) 
(see Section 5.6.2.2) 
 Urine sample for PK assessment (collected from 0-24 hours after dosing on Day 1) 
(see Section 5.6.2.2) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 


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5.5.3.4 
Day 2 
On Day 2, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) at 24 hours after dosing (see Section 5.6.3.6) 
 Blood samples for hematology and serum chemistry and urine sample for urinalysis at 
24 hours after dosing (see Section 5.6.3.3) 
 Safety 12-lead ECG at 24 hours after dosing (see Section 5.6.3.5) 
 Continuous 12-lead ECG with extractions at 24 and 36 hours after dosing (see 
Section 5.6.1.1) 
 Blood samples for PK assessment (collected at 24* and 36* hours after dosing on 
Day 1. (* Planned time points for analysis of moxidectin metabolite concentrations) 
(see Section 5.6.2.1) 
 Feces sample for PK assessment (collected from 24-48 hours after dosing on Day 1) 
(see Section 5.6.2.2) 
 Urine sample for PK assessment (collected from 24-48 hours after dosing on Day 1) 
(see Section 5.6.2.2) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
5.5.3.5 
Day 3 
On Day 3, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) at 48 hours after dosing (see Section 5.6.3.6) 
 Blood samples for hematology and serum chemistry and urine sample for urinalysis at 
48 hours after dosing (see Section 5.6.3.3) 
 Safety 12-lead ECG at 48 hours after dosing (see Section 5.6.3.5) 
 Continuous 12-lead ECG with extractions at 48 and 60 hours after dosing (see 
Section 5.6.1.1) 
 Blood samples for PK assessment (collected at 48 and 60* hours after dosing on 
Day 1. (* Planned time points for analysis of moxidectin metabolite concentrations) 
(see Section 5.6.2.1) 


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 Feces sample for PK assessment (collected from 24-48 hours after dosing on Day 1) 
(see Section 5.6.2.2) 
 Urine sample for PK assessment (collected from 24-48 hours after dosing on Day 1) 
(see Section 5.6.2.2) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
5.5.3.6 
Day 4 
On Day 4, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) at 72 hours after dosing (see Section 5.6.3.6) 
 Blood samples for hematology and serum chemistry and urine sample for urinalysis at 
72 hours after dosing (see Section 5.6.3.3) 
 Safety 12-lead ECG at 72 hours after dosing (see Section 5.6.3.5) 
 Continuous 12-lead ECG with extraction at 72 hours after dosing (see 
Section 5.6.1.1) 
 Vital signs (supine blood pressure, HR, respiratory rate, oral body temperature) at 
72 hours after dosing (see Section 5.6.3.4) 
 Blood sample for PK assessment (collected at 72 hours after dosing) (see 
Section 5.6.2.1) 
 Feces sample for PK assessment (collected from 48-72 hours after dosing) (see 
Section 5.6.2.2) 
 Urine sample for PK assessment (collected from 48-72 hours after dosing) (see 
Section 5.6.2.2) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
 Discharge from the CRU (after all study procedures are completed at 72 hours after 
moxidectin administration) 


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5.5.3.7 
Day 8 
On Day 8, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) (see Section 5.6.3.6) 
 Blood sample for PK assessment (see Section 5.6.2.1) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
5.5.3.8 
Day 15 
On Day 15, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) (see Section 5.6.3.6) 
 Blood sample for PK assessment (see Section 5.6.2.1) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
5.5.3.9 
Day 22 
On Day 22, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) (see Section 5.6.3.6) 
 Vital signs (supine blood pressure, HR, respiratory rate, oral body temperature) (see 
Section 5.6.3.4) 
 Blood samples for hematology and serum chemistry and urine sample for urinalysis 
(see Section 5.6.3.3) 
 Safety 12-lead ECG (see Section 5.6.3.5) 
 Blood sample for PK assessment (see Section 5.6.2.1) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 


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5.5.4 Period 2 
5.5.4.1 
Week 8 
At Week 8, subjects will be contacted via telephone for recording of AEs and 
concomitant medications. These data will be documented. 
5.5.4.2 
Week 12 
At Week 12, the following procedures will be performed and documented: 
 Symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and AEs reported) (see Section 5.6.3.6) 
 Vital signs (supine blood pressure, HR, respiratory rate, oral body temperature) (see 
Section 5.6.3.4) 
 Blood samples for hematology and serum chemistry and urine sample for urinalysis 
(see Section 5.6.3.3) 
 Safety 12-lead ECG (see Section 5.6.3.5) 
 Recording of AEs (see Section 5.6.3.1) 
 Recording of concomitant medications (see Section 5.6.5) 
5.6. 
Details of Study Procedures 
5.6.1 Pharmacodynamic Assessments 
5.6.1.1 
Continuous 12-Lead Electrocardiogram Acquisition 
Pharmacodynamics will be assessed via ECGs obtained using a Mortara continuous 
12-lead digital ECG recorder, which will be reviewed and analyzed by the central ECG 
laboratory. The device will remain connected to the subject during the confinement 
period. Subjects may be allowed to shower at times that do not conflict with scheduled 
study procedures (i.e., showers will not be permitted on Day 1 due to the frequency of 
scheduled study procedures on that particular day). The ECG data will be transmitted 
wirelessly to the Surveyor system, which will extract triplicate 10-second ECG 
recordings (approximately 1 minute apart) at the following time points: 
 Baseline (before dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours 
after dosing 
A window of ±5 minutes around each time point will be utilized to capture ECGs of 
adequate quality, although every effort should be made to capture them as close to the 


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scheduled time points as possible. The ECG extractions will be time-matched to the PK 
samples but obtained before the actual sampling time to avoid changes in autonomic tone 
associated with the psychological aspects of blood collection as well as the reduction in 
blood volume subsequent to blood collection. 
Subjects will refrain from talking and will be required to be in a supine position in a quiet 
room with no external stimuli (e.g., music or television) for approximately 10 minutes 
before and 5 minutes after the defined ECG collection time points. 
5.6.1.2 
Continuous 12-Lead Electrocardiogram Analysis Methods 
The continuous ECG data will be sent to the central ECG laboratory for a high-resolution 
measurement of the cardiac intervals and morphological assessment. The ECG core 
laboratory staff will be blinded to treatment, time, and study day identifiers. 
The 12-lead continuous digital ECG signal for each subject will be recorded continuously 
during subject confinement. 
Digital ECGs will be transmitted to the central ECG laboratory’s validated data 
management system. If targeted ECG time points are artifactual and of poor quality, the 
central ECG laboratory will extract analyzable 10-second ECGs as close as possible to 
the targeted time points. The cardiologists responsible for interpreting the ECGs will be 
blinded to all study drug identifiers and collection times. 
Lead II is the lead of choice for the over-reads and the baseline and on-treatment ECGs 
will be based on the same lead. All ECGs from a particular subject will be read by a 
single reader. 
If lead II is not analyzable, ECG analysis will be conducted in lead V5. If lead V5 is not 
analyzable, the most appropriate lead (e.g., lead V2) will be used. 
5.6.2 Pharmacokinetic Assessments 
5.6.2.1 
Blood Samples 
Blood samples will be collected to determine the PK of moxidectin and metabolites in 
plasma. Plasma aliquots will be stored frozen at the CRU before being shipped to a 
specialized laboratory for analysis. Blood samples will be collected for PK assessments at 
Baseline (0 hour; within 15 minutes before dosing) and at 0.5, 1, 2, 3, 4*, 5, 6, 8, 12*, 
24*, 36*, 48, 60*, and 72 hours after dosing, and on Days 8, 15, and 22. 
* Planned time points for analysis of moxidectin metabolite concentrations 


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Blood sampling time points will coincide with the ECG time points. The blood samples 
will be collected as close to the scheduled time point as possible, within 5 minutes and no 
later than 10 minutes after the ECG, unless otherwise noted. 
Sample collection, processing, and storage will be described in the Study Reference 
Manual. 
5.6.2.2 
Urine and Feces Samples 
Urine and feces for PK assessments will be collected from each subject at the following 
time points: 
 Urine: Before dosing (single pre-dose collection; first void sample in the morning is 
acceptable and volume recording is not required) and for pooled intervals of 0 to 24, 
24 to 48, and 48 to 72 hours after dosing (4 samples) 
 Feces: Before dosing (single pre-dose collection*) and each bowel motion during 
confinement in the CRU. Samples will be pooled at the central laboratory for 
intervals of 0 to 24, 24 to 48, and 48 to 72 hours after dosing (up to 4 samples) 
* Feces specimens (the whole bowel movement) may be collected by subjects (at 
home) within 2 days of submitting them to study staff on Day –1. Collection 
instructions will be provided at Screening. 
At Screening, subjects will be provided with materials to collect feces so that when the 
subject has a bowel movement on or before Day –1 (-2 days), this can be collected if it 
occurs before admission to the CRU (or up to and including 0.5 hours before dosing as 
necessary to obtain a collection before dosing). A sample may be collected at the CRU on 
Day –1. Subjects will be instructed to refrigerate any feces specimen collected before 
admission to the CRU. 
The weight of each feces specimen will be measured (grams) and recorded to the whole 
number. Urine volumes will be pooled over each interval and the total volume obtained; a 
single sample from the total volume will be obtained for PK assessments. 
Urine and feces samples will be stored frozen at the CRU before being shipped to a 
specialized laboratory for analysis. Sample collection, processing, and storage will be 
described in the Study Reference Manual. 


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5.6.3 Safety Assessments 
5.6.3.1 
Adverse Events 
An AE is defined (per ICH E2A) as any untoward medical occurrence in a patient or 
clinical investigation subject that is administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment. An AE could therefore be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease that is temporally associated with the use of a medicinal (investigational) product, 
whether or not the incident is considered related to the medicinal (investigational) 
product.  
Adverse event monitoring will begin after the subject signs the informed consent form 
(ICF) and will continue until Week 12. Before dosing of the study drug, AEs will be 
assessed for their relationship to study procedure(s) by the investigator. 
At each study visit, the investigator will assess whether any subjective AEs have 
occurred. A neutral question such as, “How have you been feeling since your last visit?” 
will be asked. Subjects may report AEs that occur at any other time during the study.  


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Each AE will be graded for severity using the following guidance: 
Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially Life 
Threatening 
Nausea/vomiting 
No interference 
with activity or 
1-2 episodes/24 
hours 
Some 
interference with 
activity or >2 
episodes/ 
24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
Emergency room visit 
or hospitalization for 
hypotensive shock 
Diarrhea 
2-3 loose stools 
or <400 gm/24 
hours 
4-5 stools or 
400-800 gm/ 
24 hours 
6 or more watery 
stools or >800 gm/ 
24 hours or 
requires outpatient 
IV hydration 
Emergency room visit 
or hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non-narcotic 
pain reliever <24 
hours or some 
interference with 
activity 
Significant; any 
use of narcotic pain 
reliever or prevents 
daily activity 
Emergency room visit 
or hospitalization 
Fatigue 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents daily 
activity 
Emergency room visit 
or hospitalization 
Myalgia 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents daily 
activity 
Emergency room visit 
or hospitalization 
Clinical adverse 
event NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal 
interference with 
usual social and 
functional 
activities with 
intervention not 
indicated 
Moderate 
symptoms 
causing greater 
than minimal 
interference with 
usual social and 
functional 
activities with 
intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual 
social and 
functional 
activities with 
intervention or 
hospitalization 
indicated 
Potentially 
life-threatening 
symptoms causing 
inability to perform 
basic self-care 
functions with 
intervention indicated 
to prevent permanent 
impairment, persistent 
disability, or death 
Abbreviations: gm, gram(s); IV, intravenous. 
Source: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 
(2014) and the Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent volunteers Enrolled in 
Preventive Vaccine Clinical Trials (2007). 
All laboratory values must be reviewed in real time by the investigator. Given that all 
laboratory data are collected and statistically analyzed according to their respective 
toxicity grades, laboratory abnormalities that occur without related clinical symptoms and 
signs should generally not be recorded as an AE unless they represent a clinically 
significant event. Where possible, the overall diagnosis rather than the laboratory 
abnormality should be recorded in the AE eCRF. This will avoid duplication of 
laboratory abnormalities in both the AE and laboratory reports. Abnormal laboratory 
results that are of clinical significance will be reviewed by the medical monitor. 


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Any laboratory test result that meets the criteria for an SAE (refer to Section 5.6.3.1.1) 
should be recorded as an AE, the AE page of the eCRF completed, and an SAE form also 
completed in order for the sponsor to collect additional information about that 
abnormality, including information regarding relationship to study product or other 
causes, any action taken, and resolution. 
Each AE will be assessed for causality using the following criteria:  
 Definitely related: The experience follows a reasonable temporal sequence from 
administration of the study drug or in which the drug level has been established in 
body fluids or tissues; the experience follows a known response pattern to the 
suspected drug and this is confirmed by improvement upon stopping the drug 
(dechallenge) and reappearance of the reaction upon repeated exposure (rechallenge).  
 Probably related: The experience follows a reasonable temporal sequence from 
administration of the study drug; the experience follows a known response pattern to 
the suspected drug and this is confirmed by dechallenge; the experience could not be 
reasonably explained by the known characteristics of the subject’s clinical state.  
 Possibly related: The experience follows a reasonable temporal sequence from 
administration of the study drug; the experience follows a known response pattern to 
the suspected drug; the experience could be produced by the subject’s clinical state or 
other modes of therapy administered to the subject.  
 Not related: The experience occurs before administration of the study drug; the 
experience follows a reasonable temporal sequence from administration of the study 
drug but does not follow a known response pattern to the suspected drug and could be 
reasonably explained by the known characteristics of the subject’s clinical state; the 
experience is proven to be caused by the subject’s disease or condition or another 
drug through rechallenge; the experience does not recur following rechallenge.  
All subjects experiencing AEs, whether considered associated with the use of the study 
drug or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory 
explanation for the changes observed.   
All AEs are documented in the eCRF, whether or not the investigator concludes the event 
to be related to the study drug. The event term, start and stop date, and severity are 
documented, along with the investigator’s opinion of the causal relationship between the 
event and study drug administration (not related, possible, probable, or definite). 


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All AEs will be followed until resolution or until the investigator determines that further 
follow-up is not necessary. The type of follow-up (telephone call or CRU visit) will be 
based on medical judgment and the severity of the event. 
5.6.3.1.1 
Serious Adverse Events 
An SAE is an AE that results in any of the following: 
 Death 
 Is life threatening (i.e., the subject was at risk of death from the event. “Life 
threatening” in the definition of “serious” refers to an event in which the subject was 
at immediate risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe) 
 Inpatient hospitalization or prolongation of existing hospitalization 
Note: Emergency department visits are not considered hospitalizations 
 Persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
An AE may be considered serious (i.e., an important medical event) if based on medical 
and scientific judgment, the event may not be immediately life threatening or result in 
death, but may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the definition above. 
If an SAE occurs, appropriate therapy will be administered based on the investigator’s 
judgment. Subjects will then be monitored closely as appropriate. 
5.6.3.2 
Additional Points to Consider for Adverse Events 
Diagnoses versus signs and symptoms:  
 Each AE will be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms will NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) will be 
recorded as an AE(s).  
Laboratory values and ECG findings:  
 Changes in laboratory values or ECG parameters are only considered to be AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is 
required or if the investigator judges the change to be beyond the range of normal 
physiological fluctuation).  


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 If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis 
only will be reported as an AE.  
Pre-existing conditions:  
 Pre-existing conditions (present before the start of the AE collection period) are 
considered concurrent medical conditions and will NOT be recorded as AEs. 
However, if the subject experiences a worsening (severity or frequency) or 
complication of such a concurrent condition, the worsening or complication will be 
recorded as an AE. The investigator will ensure that the AE term recorded captures 
the change in the condition (e.g., “worsening of…”).  
Pre-planned surgeries or procedures:  
 Procedures (surgeries or therapies) that were planned before the start of AE collection 
are not considered AEs. However, if a pre-planned procedure is performed early 
(e.g., as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition will be captured as an AE.  
Elective surgeries or procedures:  
 Elective procedures planned or performed where there is no change in the subject’s 
medical condition will not be recorded as AEs, but will be documented in the 
subject’s source documents.  
Overdose:  
 Cases of study drug overdose without manifested side effects are NOT considered 
AEs. 
5.6.3.2.1 
Reporting of Serious Adverse Events 
Reports of SAEs require immediate reporting to the sponsor and the medical monitor, 
within 24 hours of the investigator’s knowledge of the event, whether or not the 
investigator believes that the experience is related to study drug.  
An SAE form must be completed, signed by the investigator, and include at a minimum: 
the event term(s), a short description of the AE, the reason why the AE is categorized as 
serious, the investigator’s current opinion of the relationship between the event and the 
study drug (causality assessment), as well as the subject’s identification number, gender, 
age, and relevant medical history.  


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Additional information, as appropriate, will be sent to the sponsor and medical monitor 
when it becomes available (e.g., copies of relevant subject records, autopsy reports, and 
other documents).  
Reporting of a suspected SAE will not be delayed in order to obtain additional 
information.  
Any additional information, if collected, can be reported as a follow-up to the initial 
report.  
For each SAE, a corresponding AE eCRF must also be completed. 
The investigator is responsible for notifying the IRB in writing of any SAE. All SAEs are 
to be documented in the eCRF with the date of onset and resolution, frequency, 
determination of seriousness, severity, action taken, outcome, and relationship to study 
drug. 
Any SAE, including death, occurring while the subject is receiving study drug, 
irrespective of the investigator’s opinion regarding study drug relationship, will be 
reported by telephone immediately to one of the following individuals: 
Name: Nicole Kruger or Sally Kinrade 
Telephone: +61 425 846 036 or +61 419 301 193 
Email: SAE@medicinesdevelopment.com 
Any SAEs that occur within 30 days after the last dose of study drug that come to the 
attention of the investigator, and are thought to be related to study drug, will be reported 
to the sponsor and the medical monitor. 
5.6.3.2.2 
Follow-Up of Serious Adverse Events 
All SAEs will be followed until the outcome is known or the subject’s condition has 
stabilized. 
All follow-up information on SAEs is to be reported within 1 working day of receipt by 
the investigator in the manner described previously. 
The FDA requires that all SAEs that are unexpected and potentially related to the study 
drug must be reported to the FDA in writing within 15 calendar days of notification of 
Medicines Development for Global Health (MDGH). Serious AEs that meet the criterion 
for death or are immediately life threatening require MDGH to notify the FDA by 
telephone, fax, or in writing as soon as possible but no later than 7 calendar days after the 


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first knowledge that the case qualifies, followed up by a complete report within 
8 additional calendar days. 
MDGH or delegate will prepare an expedited report for the FDA based on information 
provided by Spaulding, and copies will be distributed to the investigator. 
Expedited reports, as addenda to the Investigator’s Brochure, will be filed with the 
Investigator’s Brochure by the investigator upon receipt. The investigator also will 
forward a copy of all expedited reports to the IRB as required. 
5.6.3.2.3 
Subject Deaths 
All deaths of subjects, regardless of cause, occurring within 30 days after subject 
termination, and which are known to the investigator, will be reported on the appropriate 
page of the eCRF. 
Documentation of the subject’s cause of death and a copy of the autopsy report, if any, 
will also be provided. MDGH must be notified immediately by telephone of all subject 
deaths; written follow-up must be received within 3 working days of initial notification. 
Death will not be reported as an SAE, but as a clinical outcome. The cause of death on a 
source document, such as the medical record, death certificate or autopsy report, will be 
used as the event term for the SAE. 
For subjects in which concurrent AEs or SAEs are present at the time of death, such AEs 
or SAEs will be marked as resolved with the date of resolution entered as the date of 
death. 
Only the SAE that caused the subject’s death will be marked with an outcome of “Fatal.” 
5.6.3.2.4 
Reporting of Pregnancy 
This study will only enroll male subjects. If their female partner is of childbearing 
potential, male subjects must commit to using 2 reliable (in the opinion of the 
investigator) methods of contraception, simultaneously, from Screening through the 
duration of the study period (to Week 12). 
5.6.3.3 
Clinical Laboratory Tests 
Clinical laboratory samples and the diagnostic screening samples will be collected as 
specified in the schedule of events (Table 1-1 and Table 1-2). All samples will be 
collected in accordance with acceptable laboratory procedures. The tests that will be 
performed are presented in Table 5-1. Subjects must fast for at least 8 hours before 
clinical laboratory testing. 


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Results will be reviewed by the investigator or medically qualified designee. Any values 
outside of the reference range will be evaluated for clinical significance. The investigator 
or medically qualified designee may repeat the laboratory safety tests if deemed 
appropriate. 
Table 5-1 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Complete Blood Count (CBC) 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count  
White blood cell count (with 
automated differential) 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bicarbonate 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Direct bilirubin 
Glucose 
Lactic dehydrogenase (LDH) 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
Appearance 
Bilirubin 
Blood 
Color 
Glucose 
Ketones 
Leukocyte esterase 
Microscopic examination: red 
blood cells; white blood 
cells; epithelial cells; 
bacteria, crystals, casts, etc. 
(if present) 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Diagnostic Screening Tests: 
Serology 
Urine Drug Screen 
Hepatitis panel (hepatitis B surface antigen and 
hepatitis C virus antibody) and human 
immunodeficiency virus antibody (Screening only) 
Urine drug screen will include: amphetamines, 
barbiturates, benzodiazepines, cannabinoids, 
cocaine, ethanol, opiates, phencyclidine, 
propoxyphene, cotinine, and methadone 
(Screening and Check-in [Day –1]) 
Laboratory testing for hematology, serum chemistry, urinalysis, and diagnostic screening 
tests will be performed at a Clinical Laboratory Improvement Amendments 
(CLIA)-credentialed and regulated laboratory. The results of laboratory tests will be 
returned to the investigator or medically qualified designee, who will review the results 
together with the data in the eCRF. The investigator will maintain a copy of the 
laboratory accreditation and the reference ranges used by the laboratory. 
5.6.3.4 
Vital Sign Measurements 
Vital sign measurements will be performed as specified in the schedule of events 
(Table 1-1 and Table 1-2). Vital signs (supine blood pressure, HR, respiratory rate, and 
oral body temperature [°C]) will be measured after the subject has rested for 
approximately 5 minutes. 


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When multiple procedures occur at the same time point, the vital sign measurements will 
be obtained first, followed by the 12-lead ECG conducted at the scheduled time point, 
followed by blood collection (as close to the scheduled time point as possible, within 
5 minutes and no later than 10 minutes after the ECG, unless otherwise noted), followed 
by the physical examination, followed by the meal (if scheduled). A window of 
±5 minutes around each time point will be utilized for vital sign measurements. 
5.6.3.5 
Safety 12-Lead Electrocardiograms and Electrocardiogram 
Discontinuation Criteria 
Standard 12-lead digital safety ECGs will be performed as specified in the schedule of 
events (Table 1-1 and Table 1-2) after the subject has been supine for approximately 
10 minutes. At each relevant time point, safety 12-lead ECGs will be performed before 
blood collection. 
A subject will be withdrawn from the study if he has an ECG with a manually measured 
QTcF of >500 msec at any time point after dosing that is confirmed by the investigator. 
5.6.3.6 
Physical Examinations 
Physical examinations will be performed at the time points specified in the schedule of 
events (Table 1-1 and Table 1-2). A full physical examination will be performed at 
Screening. At all subsequent time points, a symptom-based physical examination 
(informed by concurrent conditions, signs and symptoms, and AEs reported) will be 
performed. The screening physical examination will consist of the following body 
systems: eyes, ears, nose, and throat; cardiovascular system; respiratory system; 
gastrointestinal system; dermatological system; extremities; musculoskeletal system; 
nervous system; and lymph nodes. 
The subject’s weight (kg) and height (centimeters [cm]) will be measured using a 
calibrated scale while the subject is wearing light street clothing and no shoes. The 
subject’s BMI will be calculated using metric units and rounded to the nearest whole 
number according to the following formula: BMI = weight (kg)/height (m)2. 
5.6.4 Demographics, Medical History, and Other Baseline Assessments 
A complete medical history will include a review of all major body systems. Medical 
history will include conditions and diseases that have a stop date before or on the 
screening date. Conditions and diseases that are ongoing at Screening or start between 
Screening and the start of study drug will be recorded on the Concurrent Conditions page 
of the eCRF. The history of smoking (tobacco and/or nicotine use), alcohol and caffeine 
use, and all medications taken for 28 days before Check-in will also be recorded in the 


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source documents only. Demographics will include the date of birth, gender, ethnicity, 
and race as described by the subject. 
5.6.5 Documentation of Concomitant Medications 
Beginning at Screening, all medication use, including vitamins, oral herbal preparations, 
and weight-loss preparations will be documented. Relevant information (i.e., name of 
medication, dose, units, frequency of administration, dates, and reasons for use) will be 
recorded in the source documents and in the eCRF. All changes in medication will be 
noted. If the reason for use meets the definition of an AE, the AE will be recorded on the 
appropriate page of the eCRF and in the source documents for that subject. All 
medications taken before the signing of the ICF will be recorded as prior medications. 
5.6.6 Total Blood Volume 
The approximate total blood volume to be collected per subject, including all safety 
clinical laboratory and PK evaluations for the entire study, will be specified in the ICF. 
Additional blood samples may be collected at the investigator’s discretion if required for 
appropriate medical management or follow-up. 
5.7. 
Study Treatments 
5.7.1 Method of Assigning Subjects to Treatment 
A statistician unblinded to treatment allocation and otherwise independent of study 
conduct will generate the randomization schedule. All randomization information will be 
secured and housed in a locked storage area, accessible only by the randomization 
personnel, the assigned pharmacist, and his or her verifier(s). 
Randomized subjects will be assigned unique subject numbers in sequential order based 
on their order of qualification. Randomization will take place before dosing on Day 1, 
with equal random assignment to one of the following treatments: 
 Treatment 1: moxidectin 4 mg (n = 10) 
 Treatment 2: moxidectin 8 mg (n = 10) 
 Treatment 3: moxidectin 16 mg (n = 10) 
 Treatment 4: moxidectin 24 mg (n = 10) 
 Treatment 5: moxidectin 36 mg (n = 10) 
 Treatment 6: matching placebo (n = 10) 


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5.7.2 Treatments Administered 
Study drug administration (moxidectin or placebo) will occur after an overnight fast of at 
least 10 hours. On the morning of Day 1, subjects will receive either moxidectin 
(Treatments 1 through 5) or placebo matched to moxidectin (Treatment 6) according to 
the randomization schedule. Study drug will be administered orally in a double-blind 
manner (Section 5.7.5). To maintain the blind, each subject will receive 18 matching 
tablets. Study drug will be administered with at least 240 mL of water. No food will be 
allowed for 4 hours after dosing; however, water can be taken ad libitum. Thereafter, 
meals (lunch, dinner, and evening snack) will be served as regularly scheduled. Meal 
timing and components, activity levels, and general conditions in the CRU will be as 
similar as possible for all treatment groups. 
5.7.3 Identity of Study Drug 
Moxidectin has a white or pale yellow powder appearance. For the current study, 
moxidectin will be provided as tablets containing 2-mg moxidectin with microcrystalline 
cellulose, anhydrous lactose, sodium lauryl sulfate, colloidal silicon dioxide, 
croscarmellose sodium, and magnesium stearate. 
The placebo tablets will be matched in appearance to the active study drug, and will 
contain the same excipients but will not contain moxidectin. 
5.7.4 Management of Clinical Supplies 
5.7.4.1 
Study Drug Packaging and Storage 
Study drug will be kept in a secure cabinet or room with access restricted to necessary 
study site personnel. Moxidectin and placebo tablets will be stored at 15°C to 25°C 
(59 degrees Fahrenheit [°F] to 77°F), protected from light and moisture, and must not be 
frozen. Temperature excursions are permitted up to 30°C (86°F). 
5.7.4.2 
Study Drug Accountability 
In accordance with federal regulations (21 Code of Federal Regulations [CFR] 312.62), 
the investigator is required to keep accurate records showing final disposition of all 
investigational drugs. 
THE INVESTIGATOR MUST NOT USE MATERIAL PROVIDED FOR THIS 
PARTICULAR STUDY IN ANOTHER STUDY WITHOUT PRIOR WRITTEN 
APPROVAL FROM MDGH. 
The Investigator or his/her designee will record: 


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 Person Responsible: If the same individual signs the forms from day to day, his/her 
title need not be recorded after the first time. 
 Lot Number: The lot number may be indicated on the label applied to each container 
of the product. 
 Manufacture/Expiration Date: The manufacture and expiration date may be listed on 
the label of the product and should be recorded in the accountability logs. 
 Date Used: Date administered or dispensed to the subject. 
 Disposition of Material: Indicate if administered, destroyed, damaged in transit and 
destroyed, or other final disposition of material. Material cannot be transferred for 
pre-clinical or other use without prior written approval from MDGH. 
 Date Returned to MDGH or Destroyed: At the termination of the study, unused and 
opened and partially used containers may be returned to MDGH or designee. 
However, the investigator or medically qualified designee will not destroy the 
supplies without immediate prior consultation with MDGH. Indicate date when 
unused containers are returned (day/mo/yr-Ret.) or destroyed (day/mo/yr-Des.). 
Ultimate accountability for receiving, dispensing, and inventory of the test material lies 
with the investigator or medically qualified designee. Federal regulation requires that 
storage of the substance be in a secure enclosure, access to which is limited, to prevent 
theft or diversion, and in accordance with the labeling and storage guidelines. 
Material remaining at the completion of the study will be returned to MDGH or will be 
handled otherwise according to written instructions from MDGH. 
5.7.5 Blinding 
The study will be double-blind and the blind will be maintained through the use of 
blinding envelopes held by the dispensing pharmacist. All randomization information 
will be secured and housed in a locked storage area, accessible only by the randomization 
personnel, the assigned pharmacist, and his or her verifier(s). Neither the subjects nor 
CRU staff administering the study drug will know the study drug being administered. To 
maintain the blind, each subject will receive 18 matching tablets. The placebo tablets will 
be matched in appearance to the active study drug, and will contain the same excipients 
as moxidectin tablets but will not contain moxidectin. 
For Period 1, which commences at Screening, the study blind will be maintained for all 
personnel through Day 22. Once all subjects complete Period 1, the database will be 
locked for all data to Day 22. The database will not yet include study data from Week 8 


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or 12. To allow primary analysis after completion of Day 22, the study blind will be 
broken for data management, the study statistician, primary and validation programmers, 
the Cardiac Safety Expert (Mason Cardiatric Safety Consultation), the PK vendor 
(Nuventra Pharma Sciences, Inc), medical writers, and the sponsor for purposes of data 
analysis and review. All other personnel, including those conducting subject procedures 
and assessments will remain blinded. 
The study will then be unblinded for all other personnel including the clinic and other 
biometrics roles after all subjects complete the Week 12 assessments and the data 
collected in Period 2 is locked. 
5.7.5.1 
Breaking the Blind 
The study drug blind will not be broken by the investigator or designee unless 
information concerning the study drug is necessary for the medical treatment of the 
subject. The blinding envelopes containing randomization information for each subject 
will be sent to the CRU. The sponsor or medical monitor must be notified immediately if 
the study drug blind is broken. The date, time, and reason that the blind was broken will 
be recorded in the source documents. 
5.7.6 Treatment Compliance 
Study drug will be administered in the CRU under direct observation of study personnel 
and recorded in the eCRF. The CRU personnel will confirm that the subject has ingested 
the entire dose of study drug. 
5.7.7 Prior and Concomitant Medications 
Subjects may not have received an investigational drug during the 30 days, or 5 half-lives 
of the study drug (whichever is longer), before Check-in (Day –1) and cannot be planning 
to receive another investigational drug at any time during the study period. 
Prescription medications, including medications known to prolong the QTc interval or 
herbal preparations, will be prohibited within 14 days or 5 half-lives (whichever is 
longer) before study drug dosing. In addition, tobacco- or nicotine containing products 
(e.g., cigarettes, e-cigarettes, cigars, chewing tobacco, snuff) are also prohibited within 
14 days before study drug dosing and throughout the course of the study. 
Any OTC medication or vitamins are prohibited within 7 days before study drug dosing 
and throughout the course of the study (except medication approved by the sponsor on a 
case-by-case basis). 


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The following are prohibited for 72 hours before Check-in (Day –1) and during 
participation in the inpatient period of the study: 
 Alcohol, caffeine, and xanthine-containing products (e.g., tea, coffee, chocolate, cola) 
 Seville oranges and grapefruit juices 
 Fish liver oils 
Medications and supplements taken before study enrollment and throughout the study 
will be recorded in the eCRF. 
5.7.8 Diet, Fluid, Activity Control, and Subject Housing 
Subjects will be confined in the CRU from the day of Check-in (Day –1) until all study 
procedures are completed at 72 hours after moxidectin administration (Day 4). Subjects 
will return to the CRU for outpatient visits on Days 8, 15, and 22, and Week 12. 
In this study, subjects will receive a menu for the dosing period to include 3 meals and an 
evening snack. Breakfast will be served on nonfasting days (Days 2, 3, and 4). On Day 1, 
lunch will be served approximately 4 hours after dosing, dinner will be served 
approximately 9 to 10 hours after dosing, and if needed a light snack will be served 
beginning approximately 13 hours after dosing. 
On Day –1, subjects will begin fasting as instructed and water can be taken ad libitum. 
On Day 1, study drug administration (moxidectin or placebo) will occur after an 
overnight fast of at least 10 hours. Study drug will be administered with at least 240 mL 
of water. No food will be allowed for 4 hours after dosing; however, water can be taken 
ad libitum. Thereafter, meals (lunch, dinner, and evening snack) will be served as 
regularly scheduled. Meal timing and components, activity levels, and general conditions 
in the CRU will be as similar as possible for all treatment groups. 
When multiple procedures occur at the same time point, the vital sign measurements will 
be obtained first, followed by the 12-lead ECG conducted at the scheduled time point, 
followed by blood collection (as close to the scheduled time point as possible, within 
5 minutes and no later than 10 minutes after the ECG, unless otherwise noted), followed 
by the physical examination, followed by the meal (if scheduled).  
Subjects will not be allowed to engage in strenuous exercise (defined at the investigator’s 
discretion) throughout the course of the study. Subjects will not be allowed to sleep 
during ECG conduction or recording since the QT-RR relationship is different during 
sleep. The subject’s body position will be controlled to maintain supine positioning 
before and during the ECG extraction time points. 


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5.8. 
Statistical Analysis Plan 
Details of all planned statistical analyses will be described in a separate statistical 
analysis plan. 
For purposes of statistical analysis, this study is divided into 2 study periods:  
 Period 1: Commences at Screening and will finish on Day 22. The study blind will be 
maintained during this study period. After the last subject has completed the study 
through Period 1, the blind will be broken and the data from Period 1 will be 
analyzed. 
 Period 2: Period 2 runs from Day 23 to Week 12. Data from Period 2 will be analyzed 
after all subjects have completed the study through Week 12. Data for some subjects 
may be collected during Period 2 after the blind has been broken. 
All data collected will be presented in data listings. Missing data will not be imputed. 
Measurements that are excluded from the descriptive and inferential analyses will be 
included in the subject data listings. This will include those measurements from excluded 
subjects, or measurements from unscheduled collections, or extra measurements that may 
arise from 2 or more analyses of the plasma sample from the same time point. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, arithmetic 
mean, SD, median, minimum, and maximum). 
Demographic and background characteristics will be summarized overall for all subjects. 
The number of subjects who enroll in the study and the number and percentage of 
subjects who discontinue and reasons for discontinuation will be presented. 
5.8.1 Pharmacodynamic Endpoints 
The PD endpoints are calculated from the mean of the triplicate continuous 12-lead ECG 
data as: 
1. 
dQTcF –baseline-adjusted QTcF; 
2. 
ddQTcF – time-matched, placebo-corrected, baseline-adjusted QTcF, which is 
calculated as the dQTcF minus the time-matched mean dQTcF of all placebo 
subjects at each post-dose time point (ddQTcF = [dQTcF (active dose groups) – 
mean dQTcF (placebo)]); 
The primary study endpoint is the dQTcF matched to the plasma concentration of 
moxidectin collected at the same time point. 


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Analogous derived exploratory endpoints are also calculated for HR and duration of PR, 
RR, and QRS interval parameters. 
The ECG morphologic changes data are also considered an exploratory endpoint. 
5.8.2 Safety and Tolerability Endpoints 
The safety endpoints are: 
1. 
Monitoring and reporting of AEs; 
2. 
Vital sign measurements; 
3. 
Clinical laboratory test results (hematology, serum chemistry, and urinalysis); 
4. 
Safety 12-lead ECG results; 
5. 
Physical examination findings. 
Secondary study endpoints include AEs, clinical laboratory test results, vital sign 
measurements, safety 12-lead ECG results, and physical examination findings. 
5.8.3 Sample Size Calculation 
The sample size of 60 subjects (10 subjects each in 6 treatment groups) is considered 
adequate to explore the effects of moxidectin on the QTc interval, as this design will 
yield 900 QTc-PK pairs in total. Additional subjects may be enrolled as alternates in this 
study should a subject choose to withdraw consent before study drug administration. 
Alternate subjects will remain in the CRU from Check-in until all subjects due to be 
dosed have completed dosing. Subjects who withdraw after dosing will not be replaced. 
5.8.4 Analysis Populations 
For this study, 4 study populations will be defined:  
 The ECG population will include all subjects who receive at least 1 dose of study 
drug and have at least 1 pair of pre-dose and post-dose QTc data for at least 1 time 
point. Subjects in this population will be used for all digital ECG summaries and 
analyses. Subjects in this population will be analyzed as randomized. 
 The PK population will include all subjects who receive at least 1 dose of moxidectin 
and provide an adequate number of blood samples for the determination of plasma 
PK parameters. Subjects in this population will be used for all PK summaries. 
Subjects in this population will be analyzed according to the drug received (actual 
drug concentration). 


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 The PK/PD population will include all subjects in the ECG population who have 
time-matched plasma concentrations. Subjects in this population will be analyzed 
according to the drug received (actual drug concentration). 
 The safety population will include all subjects who receive at least 1 dose of study 
drug. Subjects in this population will be used for demographic and safety summaries. 
Subjects in this population will be analyzed according to the drug received (actual 
drug concentration).   
5.9. 
Statistical Analyses 
5.9.1 Pharmacodynamic Analyses 
All continuous 12-lead ECG data collected will be presented in data listings. Data from 
subjects excluded from the analysis populations will be presented in the data listings, but 
not included in the calculation of summary statistics. For categorical variables, 
frequencies and percentages will be presented. Continuous variables will be summarized 
using descriptive statistics (n, mean, SD, 2-sided confidence bounds [90% for the QTcF 
interval or 95% for other parameters], median, 25th percentile, 75th percentile, minimum, 
and maximum). The mean of the triplicate 0-hour time point on Day 1 will be used as the 
baseline. The continuous 12-lead ECG parameters (QTcF, HR, PR, RR, and QRS) and 
the corresponding changes from Baseline (denoted as dQTcF, dHR, dPR, dRR, and 
dQRS) and placebo-adjusted endpoints (denoted as ddQTcF, ddHR, ddPR, ddRR, and 
ddQRS) will be summarized by treatment and time point. 
The means and 90% confidence intervals (CIs) for the dQTcF and placebo-adjusted 
(algebraic) ddQTcF will be calculated across all subjects for each time point and each 
active treatment and displayed graphically. Secondary endpoints will also be displayed 
using 95% CI, if applicable. 
5.9.1.1 
Primary Analysis of the Primary Pharmacodynamic Endpoint 
The relationship between time-matched dQTcF and moxidectin concentrations will be 
investigated by linear mixed-effects modeling. The ddQTcF value will be calculated as 
the placebo-corrected dQTcF estimated from the model. 
Before modeling, the concentration-ddQTcF relationship will be explored graphically to 
determine the presence of hysteresis. Hysteresis will be assumed if, on average (or 
median), there are at least 3 time points with ddQTcF >5 msec and the time to maximum 
observed plasma concentration (Tmax) and the time of maximal ddQTcF (Umax) differ by 
30 minutes or more and the 1-sided, 1-sample Wilcoxon test for the difference between 


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ddQTcF at Tmax and at Umax is significant at the 1% level. If hysteresis is present, the 
possibility of fitting a population PK model with an effect compartment will be explored. 
The primary analysis will be provided for the ECG population using a mixed-effects 
model with dQTcF as the dependent variable and treatment (active and placebo), time 
point, and treatment by time point interaction as the independent variables with baseline 
QTcF as a covariate and time-matched concentrations of moxidectin (observed if 
hysteresis is not present; predicted from the effect compartment if hysteresis is present) 
as a covariate with random effects of intercept and slope. Concentrations of zero will be 
used for the placebo treatment. A spatial power law covariance structure (a 
time-dependent first-order autoregressive covariance designed for unequally-spaced time 
points) will be used. If the model does not converge, then unstructured (UN) or 
compound symmetry (CS) structures will be assessed, in that order. The model will be 
used for predicting population average and 90% 2-sided bootstrapped CI of the 
baseline-adjusted difference (i.e., ddQTcF) between active and placebo at each time point 
bound at clinically relevant concentrations. The bootstrap method will be based on 
percentile CI using the 5th and 95th percentiles in the resampling distribution using 
1000 iterations. 
The criterion for negative QT assessment will be the upper bound of the 2-sided 90% 
bootstrapped CI for ddQTcF being below 10 msec at the largest geometric mean Cmax 
value. In addition, the significance and magnitude of parameter estimates of the treatment 
covariate (active versus placebo) will be considered. 
At the request of the FDA, the primary endpoint in the study has been updated to dQTcF 
and this is the dependent variable in the primary analysis, which includes plasma 
concentrations as covariates with random slope and intercept as well as treatment and 
time point as categorical independent variables. However, in addition to obtaining the 
plasma concentration intercept and slope estimates, the estimated dQTcF values from the 
primary analysis will be compared by calculating the differences overall and at each time 
point between the active treatment and placebo, resulting in estimates of ddQTcF, which 
will be presented. In addition, a secondary analysis with ddQTcF as the dependent 
variable will be performed, as is typical and well understood, to assess correlation and 
overall profile of ddQTcF and plasma concentrations. The sponsor believes it is 
important to do these analyses in addition to the primary analysis, because the dQTcF 
analysis could yield a spuriously positive or negative regression slope based on the 
relationship between the well-known spontaneous circadian change in dQTcF and the 
concentration-time profile of the investigational drug. For example, if the early to midday 
circadian increase in dQTcF concurred with a rise in plasma concentration of moxidectin, 


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this could create the appearance of a positive relationship that might exceed the upper 
confidence boundary of 10 msec within the drug’s clinically expected concentration 
range. Converse timing between circadian change and plasma concentration change could 
produce the opposite effect. In the ddQTcF analysis, the placebo group’s circadian 
change largely eliminates this type of spurious observation. Thus, in addition to 
examining the dQTcF model, if the primary analysis produces a significantly positive or 
negative regression slope, the relationship between the investigational drug’s plasma 
concentration-time course in relationship to the circadian change of dQTcF in the placebo 
group will also be examined, to determine if a positive or negative correlation could have 
affected the dQTcF-plasma concentration relationship. 
Model assumptions will be reviewed with plots of standardized residuals versus fitted 
values and normal Q-Q plots of the standardized residuals. If nonlinearity is present, a log 
linear and/or maximum effect (Emax) or other model will be considered. 
Similar analyses will be repeated for HR, PR, and QRS, however, bootstrap percentiles 
will be based on the 2.5th and 97.5th percentiles, corresponding to a 2-sided 95% CI 
rather than the 2-sided 90% CI. 
5.9.1.2 
Secondary Analysis: Pharmacokinetic/Pharmacodynamic 
Analyses 
To evaluate the relationship between placebo-corrected mean change from Baseline in 
QTcF (i.e., ddQTcF) versus plasma concentrations of moxidectin for all subjects in the 
PK/PD population, both graphical and mixed-effects analyses of plasma concentration of 
ddQTcF versus plasma concentration of moxidectin will be performed. The mixed-effects 
model will be used to account for the clustering effects within each subject at different 
time points. The mixed-effects model will contain ddQTcF as the dependent variable and 
include the corresponding time-matched plasma moxidectin concentrations as the 
independent variable. The mixed-effects model will be used to estimate, for all subjects, 
the predicted population mean ddQTcF and its corresponding upper 95% 1-sided 
(equivalent to the upper 90% 2-sided) CI over a range of observed plasma concentrations. 
A negative result (i.e., the model indicates no plasma concentration effect) is a slope of 
approximately zero. 
The adequacy of the linear assumption between ddQTcF and plasma concentrations will 
be determined by adding a quadratic term to the mixed-effects model. If the quadratic 
term is different than zero, having P<0.05, and Akaike's information criterion (AIC) is 
smaller in comparison with the linear model’s AIC, then a quadratic term may be added. 
In addition, a transformation of the concentrations (e.g., log[C/LLOQ], where LLOQ is 


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the lower limit of quantitation of the assay and all values below the LLOQ are replaced 
with the LLOQ) may also be assessed. The best model fit will be determined by the 
lowest AIC. 
The predicted mean expected ddQTcF and the 90% 2-sided CI will be calculated using 
the estimates of the slopes from the mixed-effect models, for all subjects, at relevant 
concentration levels (i.e., the mean maximum plasma concentration under each dose 
level). 
A plot of the observed median-decile drug concentrations and associated mean ddQTcF 
(90% CI) together with the mean model-predicted ddQTcF will be used to evaluate the 
adequacy of the model fit to the assumption of linearity and the impact on quantifying the 
concentration response relationship. 
5.9.1.3 
Categorical QTc Findings 
Categorical summaries using the largest postdose QTcF and largest dQTcF will be 
performed to determine the number and percentage of subjects, by treatment, who meet 
each of the following criteria: 
 Result ≤450 msec; 
 Result >450 and ≤480 msec; 
 Result >480 and ≤500 msec; 
 Result >500 msec; 
 dQTcF ≤30 msec; 
 dQTcF >30 and ≤60 msec; 
 dQTcF >60 msec. 
5.9.1.4 
Categorical Analysis of Other Electrocardiogram Intervals 
Categorical summaries of outliers will be provided for other ECG variables (PR, QRS, 
and HR) as follows: 
 PR outliers postdose (PR >200 msec and a 25% or greater increase from Baseline); 
 QRS outliers postdose (QRS >100 msec and a 25% or greater increase from 
Baseline); 
 HR outliers postdose (HR <50 beats/minute and a 25% or greater decrease from 
Baseline); 


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 HR outliers postdose (HR >100 beats/minute and a 25% or greater increase from 
Baseline). 
Any instance in 1, 2, or 3 of the triplicate ECGs of any subject overall and at each time 
point will be counted as 1 outlier event. 
5.9.1.5 
Electrocardiogram Diagnostic Statement Analysis 
Abnormal diagnostic statements will be tallied and tabulated for each treatment and time 
point. The variety of diagnostic statements with the same meaning will be aggregated into 
defined categories. For example, T wave inversion and lead V2 and T wave flattening in 
lead II will both be categorized as nonspecific T wave abnormality. The incidence rate of 
diagnostic statements will be tabulated for both pre-dose and post-dose assessments, and 
also tabulated with diagnostic statements categorized as treatment-emergent diagnostic 
statements (i.e., diagnostic statements not present on any baseline assessment). All 
abnormal ECG diagnostic findings will be listed. 
5.9.1.6 
Adequacy of Heart Rate Correction 
The adequacy of the correction formula will be assessed by determining the linear 
relationship of QTcF to RR. Adequacy is defined as a population QTcF:RR slope of 
<|0.045|, and a slope of <|0.045| in at least 50% of individual subjects. 
The QT interval with individual correction (QTcI) is mentioned in the ICH E14 Guidance 
as an ancillary correction method. 
The QTcI, if needed, will be calculated for each subject, using all available QT/RR 
pre-dose pairs by first determining the slope of each subject’s QT:RR relationship using 
all available pre-dose data. Then QTcI will be calculated from each subject’s individual 
ECG time point QT and RR interval values with the formula: QTcI = QT + slope (1000 – 
RR). 
5.9.2 Pharmacokinetic Analyses 
5.9.2.1 
Moxidectin Concentrations 
Moxidectin concentrations in urine and feces as well as plasma:urine and plasma:feces 
concentration ratios will be summarized. 
Summary statistics describing the time course of concentrations of moxidectin 
metabolites and parent to metabolite ratios in plasma will be presented. Metabolite 
concentrations in urine as well as metabolite plasma:urine concentration ratios will be 
summarized as appropriate. 


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5.9.2.2 
Pharmacokinetic Parameters 
Non-compartmental analysis, using Phoenix WinNonlin version 6.4, will be implemented 
for the calculation of PK parameters. The Cmax will be excluded from all estimations of 
elimination rate constants for non-compartmental analysis. The elimination rate constant 
will be estimated if a given subject has more than 2 concentration values in the terminal 
portion of the curve and R-square greater than 0.95. Computed PK parameters for 
moxidectin in plasma will be summarized and listed for moxidectin, including mean, 
geometric mean, SD, median, and range, as appropriate. 
Specific PK parameters for moxidectin in plasma will include: 
 AUC0-last: AUC from time 0 extrapolated to the last observed concentration  
 AUC0-inf: AUC from time 0 extrapolated to infinity  
 cumAUC0-t: cumulative AUC from time 0 extrapolated to time t (where t = 24, 48, 
and 72 hours) 
 AUC0-24: AUC from time 0 to 24 hours after dosing 
 AUC24-48: AUC from 24 to 48 hours after dosing 
 AUC48-72: AUC from 48 to 72 hours after dosing 
 Cmax: maximum observed plasma concentration 
 Tmax: time to maximum observed plasma concentration 
 t1/2: terminal elimination half-life 
Additional PK parameters, including apparent clearance (CL), volume of distribution 
(Vd), and others may be determined as appropriate. The PK parameters will be expressed 
in units adjusted for molecular weight where appropriate. 
5.9.3 Safety Analyses 
All safety assessments, including AEs, clinical laboratory test results, vital sign 
measurements, and safety 12-lead ECG results will be summarized using descriptive 
statistics and presented in data listings. Physical examination findings and concomitant 
medications will be presented in data listings. All safety summary tables and figures will 
be generated using SAS®. No inferential statistics will be performed on the safety data. 
5.9.3.1 
Adverse Events 
Summary tables for TEAEs will include numbers and percentages of subjects 
experiencing TEAEs by SOC and preferred term (PT). If a subject has more than 1 TEAE 


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that codes to the same PT, the subject will be counted only once for that PT. Similarly, if 
a subject has more than 1 TEAE within a SOC category, the subject will be counted only 
once in that SOC category. The following summary tables will be included in the clinical 
study report for each treatment and overall: summary of TEAEs, relationship of TEAEs 
to study drug, severity of TEAEs, TEAEs leading to study discontinuation, and SAEs. 
Data listings will be provided for all AEs, AEs leading to study discontinuation, and 
SAEs. 
5.9.3.2 
Clinical Laboratory Tests 
Individual results of clinical laboratory tests (hematology, serum chemistry, and 
urinalysis) that are outside of the reference range will be flagged in the data listings. 
Clinical laboratory data will be presented in data listings and summarized by treatment 
and by toxicity grade. 
5.9.3.3 
Vital Sign Measurements 
Descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum) 
of each vital sign measurement and change from Baseline will be summarized for each 
treatment. All vital sign data will be presented in data listings. 
5.9.3.4 
Safety 12-Lead Electrocardiograms 
Individual results of safety 12-lead ECGs, which meet pre-defined very high or very low 
criteria, will be flagged and displayed in a summary table. Descriptive statistics (number 
of subjects, mean, SD, CV, median, minimum, and maximum) of each vital sign 
measurement will be summarized for each treatment. All ECG data will be listed in the 
data listings. 
5.9.3.5 
Other Safety Data 
The physical examination findings will be presented in the data listings. Clinically 
significant changes from Baseline in physical examination findings will be recorded as 
AEs. 
5.9.3.6 
Interim Analyses 
The primary analysis will be performed once all subjects have completed Day 22. An 
additional safety supplement will be provided once all subjects complete Week 12. In 
addition, concentrations of moxidectin in urine and feces and moxidectin metabolites in 
plasma and urine and associated PK parameters will not be included in the primary 
analyses after Day 22; however, those data will be analyzed after Period 2 and included 


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in the safety supplement. No interim analysis and early termination is planned. However, 
the overall safety pattern will be monitored closely and the study may be discontinued for 
valid scientific or administrative reasons. 
Only 1 set of datasets, tables, listings, and graphs are outlined in this SAP. The intent is 
to summarize all available data after Period 1, and then, rather than producing 2 sets of 
datasets and tables (1 for each period), the datasets and tables will be reproduced with the 
additional data added from Period 2 to replace the existing datasets and TLFs from 
Period 1. 
5.10. Data Quality Assurance 
The sponsor or designee will perform the quality assurance and quality control activities 
of this study; however, responsibility for the accuracy, completeness, and reliability of 
the study data presented to the sponsor lies with the principal investigator generating the 
data. Before subjects are enrolled, the sponsor or designee will explain the protocol, 
Investigator’s Brochure, and eCRFs to the investigator. In addition, the clinical monitor 
will be available to explain applicable regulations and to answer any questions regarding 
the conduct of the study. 
At its discretion, the sponsor may conduct audits as part of the implementation of quality 
assurance to ensure that the study is being conducted in compliance with the ICH 
harmonised tripartite guideline E6(R1): Good Clinical Practice (GCP), the protocol, 
standard operating procedures (SOPs), and all applicable regulatory requirements. Audits 
will be independent of, and separate from, the routine monitoring and quality control 
functions. The CRU may also be compelled to undergo an inspection by a regulatory 
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6. 
Investigator’s Obligations 
The following administrative items are meant to guide the principal investigator or 
sub-investigator in the conduct of the study but may be subject to change based on 
industry and government SOPs, working practice documents, or guidelines. Changes will 
be reported to the IRB but will not necessarily result in protocol amendments. 
The investigator will permit study-related monitoring, audit(s), IRB review(s), and 
regulatory inspection(s) with direct access to all of the required source documents and 
associated records. Source documents and records must be preserved for at least 15 years 
after the completion, discontinuation of, or withdrawal from the study or 2 years after the 
last approval of a marketing application by the sponsor in an ICH region, whichever is 
the longest. 
6.1. 
Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, a subject’s source data will 
only be linked to the sponsor’s clinical study database or documentation via a unique 
identification (ID) number. As permitted by all applicable laws and regulations, limited 
subject attributes such as sex, age or date of birth, and subject initials may be used to 
verify the subject and accuracy of the subject’s unique ID number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires that the investigator permit its monitor or designee’s monitor, 
representatives from any regulatory authority (e.g., FDA), the sponsor’s designated 
auditors, and the appropriate IRB to review the subject’s original medical records (source 
data or documents), including, but not limited to, clinical laboratory test result reports, 
ECG reports, admission and discharge summaries for hospital admissions occurring 
during a subject’s study participation, and autopsy reports. Access to a subject’s original 
medical records requires the specific authorization by the subject as part of the informed 
consent process (Section 6.3). 
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (i.e., subject name, address, and other 
identifier fields not collected in the subject’s eCRF). 
All information concerning the study treatment, MDGH, and its operations, such as 
patent applications, formulae, manufacturing processes, basic scientific data, and material 
not previously published are considered confidential and shall remain the sole property of 
the sponsor. The investigator agrees to use this information only in accomplishing the 


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current study and will not use it for any other purposes without written consent from the 
sponsor. 
6.2. 
Institutional Review 
The IRB must be constituted according to the applicable state and federal requirements of 
the participating region. The sponsor or designee will require documentation noting the 
constitution of the respective IRB. If any member of the IRB has direct participation in 
this study, written notification regarding his or her abstinence from voting must also be 
obtained. Any IRB unwilling to provide names and titles of all members due to privacy 
and conflict of interest concerns will instead provide a Federal Wide Assurance Number 
or comparable number assigned by the Department of Health and Human Services. 
The sponsor or designee will supply relevant documents for submission to the respective 
IRB for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a 
copy of the ICF, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations must be submitted to 
the IRB for approval. Written approval by the IRB of the protocol and ICF must be 
obtained and submitted to the sponsor or designee before commencement of the study 
(i.e., before shipment of the study drug). The IRB approval must refer to the study by 
exact protocol title, number, and version date; identify versions of other documents 
(e.g., ICF) reviewed; and state the approval date. 
The site must adhere to all requirements stipulated by their respective IRB. This may 
include notification to the IRB regarding protocol amendments, updates to the ICF, 
recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports, and updates regarding the ongoing review of the study at intervals 
specified by the respective IRB, and submission of the investigator’s final status report to 
the IRB. All IRB approvals and relevant documentation for these items must be provided 
to the sponsor or designee. 
6.3. 
Subject Consent 
Written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki and the ICH Guidelines for GCP and in accordance with all 
applicable laws and regulations. The ICF will describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The ICF will explain the nature of the study, its 
objectives, and potential risks and benefits, and documents the date that informed consent 
is given. The ICF will detail the requirements of the participant and the fact that he is free 


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to withdraw at any time without giving a reason and without prejudice to his further 
medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the ICF. 
The ICF must be approved by both the IRB and the sponsor before use. 
The ICF must be written in a language fully comprehensible to the prospective subject. It 
is the responsibility of the investigator to explain the detailed elements of the ICF to the 
subject. Information will be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB. In the event that the subject is not capable of 
rendering adequate written informed consent, the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable 
laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample 
opportunity to: 1) inquire about details of the study, and 2) decide whether or not to 
participate in the study. If the subject, or subject’s legally acceptable representative, 
determines that he will participate in the study, then the ICF must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and 
before the subject enters into the study. The subject will be instructed to sign using his 
legal name, using blue or black ballpoint ink. The investigator must also sign and date the 
ICF at the time of consent and before the subject enters into the study. 
Once signed, the original ICF will be stored in the investigator’s site file. The investigator 
must document the date that the subject signs the ICF in the subject’s medical or unit 
record. A copy of the signed ICF will be given to the subject. 
All revised ICFs must be reviewed and signed in the same manner as the original ICF. 
The date that the revised consent was obtained will be recorded in the subject’s medical 
or unit record and the subject will receive a copy of the revised ICF. 
6.4. 
Study Reporting Requirements 
The investigator is obliged to provide the sponsor with complete test results and all data 
derived by the investigator from the study. During the study, only the sponsor may make 
study information available to the investigator or to regulatory agencies, except as 
required by law or regulation. In addition, the principal investigator or sub-investigator 
agrees to submit annual reports to his IRB as appropriate. 
6.5. 
Financial Disclosure and Obligations 
The principal investigator or sub-investigators are required to provide financial disclosure 
information to allow the sponsor to submit the complete and accurate certification or 


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disclosure statements required under 21 CFR 54. In addition, the principal investigator or 
sub-investigators must provide to the sponsor a commitment to update this information 
promptly if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
Neither the sponsor nor Spaulding is financially responsible for further testing or 
treatment of any medical condition that may be detected during the screening process. In 
addition, in the absence of specific arrangements, neither the sponsor nor Spaulding is 
financially responsible for further treatment of the subject’s disease. 
6.6. 
Investigator Documentation 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subjects’ health information, including, but not 
limited to, the Standards for Individually Identifiable Health Information, 45 CFR Parts 
160 and 164 (the Health Insurance Portability and Accountability Act of 1996 privacy 
regulation). The investigator shall ensure that study subjects authorize the use and 
disclosure of protected health information in accordance with the privacy regulations of 
the Health Insurance Portability and Accountability Act and in a form satisfactory to the 
sponsor. 
6.7. 
Study Conduct 
The principal investigator agrees that the study will be conducted according to the 
principles of the ICH E6(R1). The principal investigator will conduct all aspects of this 
study in accordance with US FDA regulations, the ICH E6(R1) GCP, and applicable 
local, state, and federal laws. 
6.8. 
Data Collection 
The full details of procedures for data handling will be documented in the Data 
Management Plan. Adverse events, medical history, and concurrent conditions will be 
coded using the current version of MedDRA. Concomitant medications will be coded 
using the WHO Drug Dictionary. 
6.8.1 Case Report Forms and Source Documents 
Completed eCRFs are required for each subject randomly assigned to study drug. 
Electronic data entry is accomplished through the ClinSpark® (Foundry Health) remote 
data capture application, which allows for on-site data entry and data management. This 
provides immediate, direct data transfer to the database, as well as immediate detection of 
discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 


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manner. Each person involved with the study will have an individual ID code and 
password that allows for record traceability. Thus, the system, and subsequently any 
investigative reviews, can identify coordinators, investigators, and individuals who have 
entered or modified records. Furthermore, the investigator retains full responsibility for 
the accuracy and authenticity of all data entered into the electronic data capture system. 
The completed dataset and associated files are the sole property of the sponsor and will 
not be made available in any form to third parties, except for authorized business 
representatives or appropriate governmental health or regulatory authorities, without 
written permission of the sponsor. 
Monitoring visits to the study site will be made periodically during the study to ensure 
that all aspects of the protocol are followed. Source documents will be reviewed for 
verification of data recorded in the eCRFs. Source documents are defined as original 
documents, data, and records. The investigator and institution guarantee access to source 
documents by the sponsor or designee and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the 
investigator’s binder, study drug, subject medical records, informed consent 
documentation, documentation of subject authorization to use personal health information 
(if separate from the ICFs), and review of eCRFs and associated source documents. It is 
important that the investigator and other study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. 
6.9. 
Adherence to the Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance 
with the ICH E6(R1) and all applicable guidelines and regulations. 
6.10. Reporting Adverse Events 
By participating in this study, the principal investigator or sub-investigator agrees to 
submit reports of SAEs according to the timeline and method outlined in this protocol. 
6.11. Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, will inform the 
institution; the investigator or institution will provide the IRB with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any required reports. 


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6.12. Records Retention 
The investigator agrees to keep the records stipulated in Section 6.8.1 and those 
documents that include (but are not limited to) the study-specific documents, ID log of all 
participating subjects, medical records, source worksheets, all original signed and dated 
ICFs, subject authorization forms regarding the use of personal health information (if 
separate from the ICFs), copies of all eCRFs, query responses, and detailed records of 
drug disposition, to enable evaluations or audits from regulatory authorities, the sponsor, 
or designees. Furthermore, ICH 4.9.5 requires the investigator to retain essential 
documents specified in ICH E6 until at least 2 years after the approval of a marketing 
application for a specified drug indication being investigated or, if an application is not 
approved, until at least 2 years after the investigation is discontinued and regulatory 
authorities are notified. In addition, ICH 4.9.5 states that the study records will be 
retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record 
retention. The investigator will contact and receive written approval from the sponsor 
before disposing of any such documents. 
6.13. Publications 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 
Manuscript authorship for any peer-reviewed publication will appropriately reflect 
contributions to the production and review of the document. All publications and 
presentations must be prepared in accordance with this section and the Clinical Study Site 
Agreement. In the event of any discrepancy between the protocol and the Clinical Study 
Site Agreement, the Clinical Study Site Agreement will prevail. The publication of the 
study in its entirety will be the first data to be published; any subset of the study data may 
be published only after the primary study publication has been made. 
The investigator will provide the sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days before such presentation or 
submission for publication. The sponsor shall inform the investigator in writing of any 
changes or deletions in such presentation or publication required to protect the sponsor’s 
confidential and proprietary technical information and to address inaccurate data or 
inappropriate interpretations in the context of any pooled multicenter results. At the 
expiration of such 60-day period, the investigator may proceed with the presentation or 
submission for publication unless the sponsor has notified the institution or the 


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investigator in writing that such proposed publication or presentation discloses the 
sponsor’s confidential and proprietary technical information. Further, upon the request of 
the sponsor, the investigator will delay the publication or presentation for an additional 
90 days to permit the sponsor to take necessary actions to protect its intellectual property 
interests. 


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7. 
Study Management 
7.1. 
Monitoring 
7.1.1 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the 
study closely. In doing so, the monitor will visit the investigator and study facility at 
periodic intervals, in addition to maintaining necessary contact through telephone, email, 
and letter. The monitor will maintain current personal knowledge of the study through 
observation, review of study records and source documentation, and discussion of the 
conduct of the study with the investigator and staff. All aspects of the study will be 
carefully monitored by the sponsor or designee for compliance with applicable 
government regulation with respect to GCP and current SOPs. 
7.1.2 Inspection of Records 
The investigator involved in the study will permit study-related monitoring, audits, IRB 
review, and regulatory inspection(s). In the event of an audit or inspection, the 
investigator agrees to allow the sponsor, representatives of the sponsor, the competent 
authority, or other regulatory agency access to all study records. The investigator will 
promptly notify the sponsor of any audits scheduled by any regulatory authorities and 
promptly forward copies of any audit reports received to the sponsor. 
7.2. 
Management of Protocol Amendments and Deviations 
7.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or 
designee. Amendments to the protocol must be submitted in writing to the principal 
investigator’s or sub-investigator’s IRB for approval before subjects can be enrolled into 
an amended protocol. 
7.2.2 Protocol Deviations 
The investigator will not implement any deviations from or change to the protocol 
without agreement by the sponsor except where necessary to eliminate an immediate 
hazard to study subjects. Protocol deviations fall into 2 categories: those with approval 
before the event (protocol exemptions) and those occurring during the course of the study 
without prior approval (protocol violations). If an exemption from the protocol design 
(e.g., a missed study visit) is desired for an individual subject, other than those to 


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eliminate immediate hazard, the investigator must request an exemption from the sponsor 
or designee. If an exemption is granted, the investigator must notify the IRB, if required. 
The exemption and rationale will be documented at the site and in the sponsor files. 
Exemptions will not be granted for eligibility criteria. 
For any protocol violation, the site will document the protocol violation in the subject’s 
source documents. In the event of a significant violation, the site will notify the sponsor 
or designee. Significant violations include, but are not limited to, those that involve fraud 
or misconduct, increase the health risk to the subject, or confound interpretation of 
primary study assessments. 
7.3. 
Study Termination 
The study will be completed as planned unless the following criteria are satisfied that 
require early termination of the study. 
 New information regarding the safety or efficacy of the study drug that indicates a 
change in the known risk/benefit profile for the investigational medicinal product, 
such that the risk/benefit is no longer acceptable for subjects participating in the 
study; 
 Significant violation of GCP that compromises the ability to achieve the primary 
study objective or compromises subject safety. 
7.3.1 Criteria for Termination of the Study 
The study site may be terminated if the site (including the investigator) is found in 
significant violation of GCP, protocol, or contractual agreement, or is unable to ensure 
adequate performance of the study. 
7.3.2 Criteria for Termination of Investigational Site 
In the event that the sponsor elects to terminate the study or the investigational site, a 
study-specific procedure for early termination will be provided by the sponsor; the 
procedure will be followed by the investigational site during the course of termination. 
7.4. 
Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure 
preparation of the clinical study reports and provision of them to the regulatory 
agency(ies) as required by the applicable regulatory requirement(s). They or their 
designee will also ensure that the clinical study reports in marketing applications meet the 
standards of the ICH guideline E3: Structure and Content of Clinical Study Reports. 


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Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 


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8. 
Appendices 
8.1. 
Appendix A: Responsibilities of the Investigator 
Sponsored clinical research studies are subject to the regulations of the FDA. The 
responsibilities imposed on an investigator by the FDA are summarized in the “Statement 
of Investigator” (Form FDA 1572), which must be completed and signed before the 
investigator may participate in this study. 
In signing a Form FDA 1572, the investigator agrees to assume the following 
responsibilities: 
1. 
Conduct the study in accordance with the protocol. 
2. 
Personally conduct or supervise the staff who will assist in this protocol. 
3. 
Ensure that all colleagues and employees assisting in the conduct of the study are 
informed of these obligations. 
4. 
Secure prior approval of the study and any changes by an appropriate IRB that 
conform to FDA requirements. 
5. 
Ensure that the IRB will be responsible for initial, continuing review, and approval 
of the protocol. Promptly report to the IRB all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the 
study to the IRB and issue a final report within 3 months of study completion. 
6. 
Ensure that requirements for informed consent as outlined in 21 CFR Part 50 are 
met. 
7. 
Obtain valid informed consent from each subject who participates in the study, and 
document the date of consent in the subject’s medical chart. Each ICF will contain 
a subject authorization section that describes the uses and disclosures of a subject’s 
personal information (including personal health information) that will take place in 
connection with the study. If an ICF does not include such a subject authorization, 
then the investigator must obtain a separate subject authorization form from each 
subject or the subject’s legally acceptable representative. 
8. 
Prepare and maintain adequate case histories of all persons entered into the study, 
including eCRFs, hospital records, laboratory results, etc., and maintain this data 
for a minimum of 2 years following notification by the sponsor that all 
investigations have been discontinued or that the FDA has approved the New Drug 
Application. Before disposing of any records, the sponsor must be contacted. 


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9. 
Allow possible inspection and copying by the FDA of eCRFs and records of drug 
distribution. 
10. 
Maintain current records of the receipt, administration, and disposition of study 
drug, and return all unused study drug to the sponsor. 
11. 
Report adverse reactions to the sponsor promptly. In the event of an SAE, notify 
the sponsor within 24 hours. 


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9. 
Reference List 
1. 
Henry J. Kaiser Family Foundation. Fact Sheet - The U.S. Government and 
Global Neglected Tropical Diseases. 2015. 
2. 
Hopkins A, Boatin B. Chapter 11, Onchocerciasis. In: Selendy J, ed. Water and 
Sanitation-Related Diseases and the Environment. Hoboken, New Jersey: John 
Wiley & Sons, Inc.; 2011. 
3. 
WHO. Prevention of Blindness and Visual Impariment Onchocerciasis. (Accessed 
15 December 2015, at 
http://www.who.int/blindness/partnerships/onchocerciasis_home/en/.) 
4. 
Prost A, Vaugelade J. Excess mortality among blind persons in the West African 
savannah zone. Bull World Health Organ. 1981;59:773-6. 
5. 
Pion SD, Kamgno J, Demanga N, Boussinesq M. Excess mortality associated 
with blindness in the onchocerciasis focus of the Mbam Valley, Cameroon. 
Ann Trop Med Parasitol. 2002;96:181-9. 
6. 
Little MP, Breitling LP, Basáñez MG, Alley ES, Boatin BA. Association between 
microfilarial load and excess mortality in onchocerciasis: an epidemiological 
study. Lancet. 2004;363:1514-21. 
7. 
London Declaration on Neglected Tropical Diseases. Ending the neglect and 
reaching 2020 goals. 2012. (Accessed 6 November 2013, at 
http://unitingtocombatntds.org/downloads/press/ntd_event_london_declaration_o
n_ntds.pdf.) 
8. 
African Program for Onchocerciasis Control. Onchocerciasis - The Disease and 
its impact. (Accessed 15 December 2015, at 
http://www.who.int/apoc/onchocerciasis/disease/en/.) 
9. 
Basáñez MG, Pion SD, Boakes E, Filipe JA, Churcher TS, Boussinesq M. Effect 
of single-dose ivermectin on Onchocerca volvulus: a systematic review and 
metaanalysis. Lancet Infect Dis. 2008;8:310-22. 
10. 
Coffeng LE, Stolk WA, Zoure HG, et al. African Programme For Onchocerciasis 
Control 1995-2015: model-estimated health impact and cost. PLoS Negl Trop 
Dis. 2013;7:e2032. 
11. 
Awadzi K, Boakye DA, Edwards G, et al. An investigation of persistent 
microfilaridermias despite multiple treatments with ivermectin, in two 
onchocerciasis-endemic foci in Ghana. Ann Trop Med Parasitol. 2004;98:231-49. 
12. 
Awadzi K, Attah SK, Addy ET, et al. Thirty-month follow-up of sub-optimal 
responders to multiple treatments with ivermectin, in two onchocerciasis-endemic 
foci in Ghana. Ann Trop Med Parasitol. 2004;98:359-70. 
13. 
Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK. 
Prevalence and intensity of Onchocerca volvulus infection and efficacy of 
ivermectin in endemic communities in Ghana: a two-phase epidemiological study. 
Lancet. 2007;369:2021-9. 
14. 
Pion SD, Grout L, Kamgno J, Nana-Djeunga H, Boussinesq M. Individual host 
factors associated with Onchocerca volvulus microfilarial densities 15, 80 and 
180 days after a first dose of ivermectin. Acta Trop. 2011;120 Suppl 1:S91-9. 
15. 
Ardelli BF, Guerriero SB, Prichard RK. Genomic organization and effects of 
ivermectin selection on Onchocerca volvulus P-glycoprotein. Mol Biochem 
Parasitol. 2005;143:58-66. 


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Protocol No. MDGH-MOX-1008 
 
Confidential 
 
01 March 2017 
Page 83 of 83 
Version 2.0 
16. 
Bakajika D, Kanza E, Howard H, et al. Is O. volvulus suboptimal response to 
ivermectin a result of selection under ivermectin pressure? Insights from a study 
comparing ivermectin and moxidectin in areas without prior ivermectin mass 
treatment. 62nd Annual Meeting of the American Society of Tropical Medicine 
and Hygiene (ASHTM 2013). Washington DC, USA. 2013. 
17. 
Stromectol (ivermectin) [package insert] Merck & Co. Inc. Whitehouse Station 
(NJ); 2007. 
18. 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use. E14 The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for 
Non-Antiarrhythmic Drugs. 2005. 
19. 
Cardiac Safety Research Consortium. (Accessed 08 August 2016, at 
http://cardiac-safety.org/.) 
20. 
Darpo B, Benson C, Dota C, et al. Results from the IQ-CSRC prospective study 
support replacement of the thorough QT study by QT assessment in the early 
clinical phase. Clin Pharmacol Ther. 2015;97:326-35. 
21. 
Darpo B, Garnett C, Keirns J, Stockbridge N. Implications of the IQ-CSRC 
Prospective Study: Time to Revise ICH E14. Drug Saf. 2015;38:773-80. 
22. 
Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play 
a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin 
Pharmacol. 2008;48:13-8. 
23. 
Ferber G, Zhou M, Darpo B. Detection of QTc Effects in Small Studies—
Implications for Replacing the Thorough QT Study. Ann Noninvasive 
Electrocardiol. 2015;20:368-77. 
24. 
Darpo B, Sarapa N, Garnett C, et al. The IQ-CSRC prospective clinical Phase 1 
study: "Can early QT assessment using exposure response analysis replace the 
thorough QT study?". Ann Noninvasive Electrocardiol. 2014;19:70-81. 
 

SAP_001.pdf: 
 
Confidential and Proprietary, Medicines Development for Global Health 
 
 
 
 
 
CLINICAL STUDY PROTOCOL: MDGH-MOX-1008 
 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Potential Effect of a Single Oral Dose of 
Moxidectin on the Cardiac QT Interval of Healthy Volunteers 
 
Statistical Analysis Plan 
 
 
 
Version 1: 01 March 2017 
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


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Statistical Analysis Plan Signature Page 
 
 
 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Potential Effect 
of a Single Oral Dose of Moxidectin on the Cardiac 
QT Interval of Healthy Volunteers 
 
 
Investigational Product: 
Moxidectin  
Sponsor:                                            Medicines Development for Global Health 
 
Level 1, 18 Kavanagh Street 
 
Southbank, Victoria 3006 
 
Australia  
 
Protocol Number: 
MDGH-MOX-1008 
 
Protocol Version/Issue Date: 
Version 2.0 / 01 March 2017 
Analysis Plan Version/Date:  
Version 1 / 01 March 2017 
 
 
Signature: _____________________________________ Date: __________________ 
Sally Kinrade 
Director of Clinical 
Medicines Development for Global Health 
 
 
Signature: _____________________________________ Date: __________________ 
Stephanie Stanworth, MS 
Biostatistics, Spaulding Clinical Research, LLC 


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Table of Contents 
LIST OF ABBREVIATIONS ..............................................................................................5 
1 
Introduction ...................................................................................................................7 
2 
Objectives and Endpoints ..............................................................................................8 
2.1 Primary Objective ................................................................................................8 
2.2 Secondary Objective ............................................................................................8 
2.3 Exploratory Objectives ........................................................................................8 
2.4 Endpoints 
....................................................................................................8 
2.4.1 Pharmacokinetic Endpoints .....................................................................8 
2.4.2 Pharmacodynamic Endpoints ..................................................................9 
2.4.3 Safety and Tolerability Endpoints .........................................................10 
3 
Study Design ...............................................................................................................11 
3.1 Number of Subjects ...........................................................................................11 
3.2 Sample Size Considerations ..............................................................................11 
3.3 Study Design ..................................................................................................11 
3.4 Unblinding Procedures ......................................................................................16 
3.5 Interim Analyses ................................................................................................16 
4 
General Statistical Considerations ..............................................................................18 
5 
Analysis Populations ...................................................................................................19 
5.1 Safety Population ..............................................................................................19 
5.2 Pharmacokinetic Population ..............................................................................19 
5.3 Electrocardiogram Population ...........................................................................19 
5.4 Pharmacokinetic/Pharmacodynamic Population ...............................................19 
5.5 Handling of Missing Data .................................................................................19 
5.6 Key Definitions .................................................................................................20 
6 
Subject Disposition and Baseline Characteristics .......................................................21 
6.1 Subject Discontinuation ....................................................................................21 
6.2 Protocol Deviations ...........................................................................................21 
6.3 Demographics and Baseline Characteristics .....................................................21 
6.4 Medical History .................................................................................................21 
6.5 Inclusion and Exclusion Criteria .......................................................................21 
7 
Pharmacokinetic Analyses ..........................................................................................22 
7.1 Moxidectin and Metabolite Concentrations ......................................................22 
7.2 Pharmacokinetic Parameters .............................................................................22 
8 
Pharmacodynamic Analyses .......................................................................................25 
8.1 Continuous 12-Lead Electrocardiogram Assessments ......................................25 
8.2 General Summaries ...........................................................................................25 
8.3 Statistical Analyses ............................................................................................26 


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9 
Safety Analysis ............................................................................................................31 
9.1 Adverse Events ..................................................................................................31 
9.2 Clinical Laboratory Evaluations (Serum Chemistry, Hematology, Urinalysis) 32 
9.3 Vital Signs 
..................................................................................................32 
9.4 Safety 12-Lead Electrocardiogram ....................................................................32 
9.5 Concomitant Medications ..................................................................................33 
9.6 Extent of Exposure ............................................................................................33 
9.7 Other Safety Assessments .................................................................................33 
10 References ...................................................................................................................34 
APPENDIX A: LIST OF TABLES, LISTINGS, AND FIGURES ...................................35 
 


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LIST OF ABBREVIATIONS 
λz 
terminal elimination rate constant 
Aeurine(0-24) 
urinary recovery between 0 and 24 hours 
Aeurine(0-72) 
urinary recovery between 0 and 72 hours 
Aeurine(24-48) 
urinary recovery between 24 and 48 hours 
Aeurine(48-72) 
urinary recovery between 48 and 72 hours 
Aefeces(0-24) 
fecal recovery between 0 and 24 hours 
Aefeces(0-72) 
fecal recovery between 0 and 72 hours 
Aefeces(24-48) 
fecal recovery between 24 and 48 hours 
Aefeces(48-72) 
fecal recovery between 48 and 72 hours 
AE 
adverse event 
AIC 
Akaike's information criterion 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from time 0 to 24 hours 
AUC0-48 
area under the plasma concentration-time curve from time 0 to 48 hours 
AUC0-72 
area under the plasma concentration-time curve from time 0 to 72 hours 
AUC0-inf 
area under the plasma concentration-time curve from time 0 extrapolated 
to infinity 
AUC0-last 
area under the plasma concentration-time curve from time 0 extrapolated 
to the last observed concentration 
AUC24-48 
area under the plasma concentration-time curve from time 24 to 48 hours 
AUC48-72 
area under the plasma concentration-time curve from time 48 to 72 hours 
AUCext 
percentage of AUC0-inf obtained by extrapolation 
BQL 
below the quantitation limit 
CI 
confidence interval 
CL/F 
apparent clearance following extravascular administration 
CLr(0-24) 
renal clearance from time 0 to 24 hours 
CLr(0-72) 
renal clearance from time 0 to 72 hours 
CLr(24-48) 
renal clearance from 24 to 48 hours 
CLr(48-72) 
renal clearance from 48 to 72 hours 
Cmax 
maximum observed plasma concentration 
CRU 
clinical research unit 
Cfeces 
concentration of drug in feces 
Curine 
concentration of drug in urine 
CV% 
percent coefficient of variation 
ddQTcF 
time-matched, placebo-corrected, baseline-adjusted QTcF 


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dQTcF 
baseline-adjusted QTcF 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
Emax 
maximum effect 
HR 
heart rate 
LLOQ 
lower limit of quantitation 
MDGH 
Medicines Development for Global Health 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
millisecond(s) 
n 
number 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QTc 
corrected QT interval 
QTcB 
QT interval corrected by Bazett’s formula 
QTcF 
QT interval corrected by Fridericia’s formula 
QTcI 
QT interval with individual correction 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to the maximum observed plasma concentration 
Umax 
time of maximal ddQTcF 
Vd/F 
apparent volume of distribution following extravascular administration 
Vurine 
urine volume  
Wfeces 
fecal mass  


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentation to be used for the analysis and summarization of pharmacokinetic (PK) and 
safety data from Protocol MDGH-MOX-1008 with Spaulding Clinical Research, LLC 
responsible for the analysis and presentation of the PK and safety data. In addition, the 
primary and exploratory endpoints detailing the pharmacodynamic (PD) analysis of 
electrocardiograms (ECGs) will be described in this analysis plan, with Mason Cardiac 
Safety Consultation responsible for the analysis and presentation of these data.  
 
The analysis plan will be finalized prior to database lock. Any changes made after 
finalization of the analysis plan will be documented. Related documents are the study 
protocol and electronic case report forms (eCRFs).  


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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective is to analyze the effect of a single oral dose of moxidectin on the QT 
interval associated with plasma moxidectin concentrations. 
2.2 
Secondary Objective 
The secondary objective is to assess the safety and PK of a single oral dose of moxidectin. 
2.3 
Exploratory Objectives 
The exploratory objectives are: 
 To gain preliminary information in humans on the metabolism and excretion of 
moxidectin; 
 To evaluate the baseline-corrected changes in other ECG and cardiovascular 
parameters; and 
 To evaluate the ECG morphologic changes related to cardiac repolarization (ST 
segment and T waves). 
2.4 
Endpoints 
2.4.1 
Pharmacokinetic Endpoints 
The plasma PK parameters of moxidectin will be determined from the concentration-time 
profiles for all evaluable subjects. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. The following plasma PK 
parameters will be estimated using noncompartmental parameters, unless otherwise 
specified: 
1. AUC0-last – area under the plasma concentration-time curve (AUC) from time 0 
extrapolated to the last observed concentration; 
2. AUC0-inf – AUC from time 0 extrapolated to infinity; 
3. AUCext – percentage of AUC0-inf obtained by extrapolation (a diagnostic parameter 
calculated and listed in the data listing, but not included in the descriptive statistics); 
4. AUC0-24 – AUC from time 0 to 24 hours; 
5. AUC0-48 –AUC from time 0 to 48 hours; 
6. AUC0-72 –AUC from time 0 to 72 hours; 
7. AUC24-48 – AUC from time 24 to 48 hours; 
8. AUC48-72 – AUC from time 48 to 72 hours; 
9. Cmax – maximum observed plasma concentration; 
10. Tmax – time to Cmax; 
11. t1/2 – terminal elimination half-life; 
12. λz – terminal elimination rate constant; 
13. CL/F – apparent clearance following extravascular administration; 


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14. Vd/F – apparent volume of distribution following extravascular administration. 
In addition, exploratory endpoints include descriptions of metabolite concentrations over 
time for analytes in plasma, urine, and feces and metabolite to parent (molar equivalents) 
ratios over time for analytes in plasma and urine. The following parameters will be 
calculated for urine: 
1. Aeurine(0-72) – urinary recovery between 0 and 72 hours; 
2. Aeurine(0-24) – urinary recovery between 0 and 24 hours; 
3. Aeurine(24-48) – urinary recovery between 24 and 48 hours; 
4. Aeurine(48-72) – urinary recovery between 48 and 72 hours; 
5. CLr(0-72) – renal clearance from time 0 to 72 hours; 
6. CLr(0-24) – renal clearance from time 0 to 24 hours; 
7. CLr(24-48) – renal clearance from 24 to 48 hours; 
8. CLr(48-72) – renal clearance from 48 to 72 hours. 
The following parameters will be calculated for feces: 
1. Aefeces(0-72) – fecal recovery between 0 and 72 hours; 
2. Aefeces(0-24) – fecal recovery between 0 and 24 hours; 
3. Aefeces(24-48) – fecal recovery between 24 and 48 hours; 
4. Aefeces(48-72) – fecal recovery between 48 and 72 hours. 
The PK endpoints are considered secondary study endpoints. The main PK parameters of 
interest in this study are the cumulative and pre-specified time-window AUCs for 
moxidectin concentrations in plasma. 
2.4.2 
Pharmacodynamic Endpoints 
The PD endpoints are calculated from the mean of the triplicate continuous 12-lead ECG 
data as: 
1. dQTcF – baseline-adjusted QT interval corrected by Fridericia’s formula (QTcF);  
2. ddQTcF – time-matched, placebo-corrected, baseline-adjusted QTcF, which is calculated 
as the dQTcF minus the time-matched mean dQTcF of all placebo subjects at each 
postdose time point (ddQTcF=[dQTcF(active dose groups)-mean dQTcF(placebo)]); 
The primary study endpoint is the dQTcF matched to the plasma concentration of 
moxidectin collected at the same time point. 
Analogous-derived exploratory endpoints are also calculated for heart rate (HR), and 
duration of PR, RR, and QRS interval parameters. 
The ECG morphologic changes data are also considered an exploratory endpoint.  


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2.4.3 
Safety and Tolerability Endpoints 
The safety endpoints are: 
1. Monitoring and reporting of adverse events (AEs);  
2. Vital sign measurements; 
3. Clinical laboratory test results (hematology, serum chemistry, urinalysis); 
4. 12-lead safety ECG results; 
5. Physical examination findings.  
Secondary study endpoints include AEs, clinical laboratory test results, vital sign 
measurement, safety 12-lead ECG results, and physical examination findings. 


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3 
STUDY DESIGN 
3.1 
Number of Subjects 
There will be 60 generally healthy male subjects between 18 and 50 years old enrolled in 
the study. 
3.2 
Sample Size Considerations 
The sample size of 60 subjects (10 subjects each in 6 treatment groups) is considered 
adequate to explore the effects of moxidectin on the corrected QT interval (QTc), as this 
design will yield 900 QTc-PK pairs in total. Additional subjects may be enrolled as 
alternates in this study should a subject choose to withdraw consent before study drug 
administration. Alternate subjects will remain in the clinical research unit (CRU) from 
Check-in until all subjects due to be dosed have completed dosing. Subjects who withdraw 
after dosing will not be replaced. 
3.3 
Study Design 
This is a randomized, single-center, double-blind, placebo-controlled, parallel-group study 
in which healthy male subjects will be randomly assigned to one of the following 
treatments: 
 Treatment 1: moxidectin 4 mg (n = 10) 
 Treatment 2: moxidectin 8 mg (n = 10) 
 Treatment 3: moxidectin 16 mg (n = 10) 
 Treatment 4: moxidectin 24 mg (n = 10) 
 Treatment 5: moxidectin 36 mg (n = 10) 
 Treatment 6: matching placebo (n = 10) 
 
Subjects will be screened for eligibility up to 28 days before randomization. Subjects who 
meet all of the inclusion and none of the exclusion criteria will be admitted to the CRU on 
Day –1 (not less than 12 hours before scheduled dosing). Subjects will remain in the CRU 
for at least 72 hours after dosing and will return to the CRU for further assessment on Days 
8, 15, and 22, and Week 12. At Week 8, subjects will be contacted via telephone for 
recording of AEs and concomitant medication use. 
Randomized subjects will be assigned unique subject numbers in sequential order based on 
their order of qualification. Randomization will take place before dosing on Day 1, with 
equal random assignment to each treatment. Subjects are considered as enrolled once 
randomized. 
The duration of participation in the study for each subject will be up to approximately 
112 days, including Screening. 
For purposes of statistical analysis, this study is divided into 2 study periods:  


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 Period 1: Commences at Screening and will finish on Day 22. The study blind will 
be maintained during this study period. After the last subject has completed the 
study through Period 1, the blind will be broken and the data from Period 1 will be 
analyzed. 
 Period 2: Runs from Day 23 to Week 12. Data from Period 2 will be analyzed after 
all subjects have completed the study through Week 12. Data for some subjects may 
be collected during Period 2 after the blind has been broken. 
The overall schedule of events is provided in Table 1 and the Period 1, Day –1 to Day 4 
schedule of events is provided in Table 2. 


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Table 1. Overall Schedule of Events 
Assessment 
Period 1 
Period 2 
Screening 
D-28 to D-2 
D-1 
Baseline 
D1 (Predose) 
D1 
D2 
D3 
D4 
D8 
D15 
D22 
W8 
W12f 
Outpatient visit 
X 
 
Refer to Table 2: 
Schedule of Events for Period 1 (Day –1 to Day 4) 
X 
X 
X 
 
X 
Informed consent 
X 
 
 
 
 
 
Telephone call 
 
 
 
 
X 
 
Inclusion/exclusion criteria review 
X 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
Medical and medication history 
X 
 
 
 
 
 
Physical examinationa 
X 
X 
X 
X 
 
X 
Vital signsb 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
Calculation of body mass index 
X 
 
 
 
 
 
Hematology, serum chemistry, and 
urinalysisc 
X 
 
 
X 
 
X 
Urine drug screen 
X 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
Safety 12-lead electrocardiogramd 
X 
 
 
X 
 
X 
Continuous 12-lead electrocardiogram 
 
 
 
 
 
 
PK blood sample collectione 
 
X 
X 
X 
 
 
PK feces sample collection 
 
 
 
 
 
 
PK urine sample collection 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
Study drug administration 
 
 
 
 
 
 
Adverse events 
X 
---------------------------X--------------------- 
Concomitant medications 
X 
---------------------------X--------------------- 
Abbreviations: D, day; PK, pharmacokinetic; W, week. 
a. A full physical examination will be performed at Screening. At all subsequent time points, a symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and adverse events reported) will be performed. 
b. Vital signs (supine blood pressure, heart rate, respiratory rate, and oral body temperature) will be measured after the subject has rested for approximately 5 minutes. 
c. Blood samples for hematology and serum chemistry and a urine sample for urinalysis will be collected at Screening, on Days –1, 2, 3, 4, 22, and Week 12. Subjects must fast for at 
least 8 hours before clinical laboratory testing. 
d. Standard 12-lead safety electrocardiograms will be performed after the subject has been supine for approximately 10 minutes. At each relevant time point, safety 12-lead 
electrocardiograms will be performed before blood collection. 
e. Blood samples will be collected for PK assessments at Baseline (0 hour; within 15 minutes before dosing) and at 0.5, 1, 2, 3, 4*, 5, 6, 8, 12*, 24*, 36*, 48, 60*, and 72 hours after 
dosing, and on Days 8, 15, and 22. (* Planned time points for analysis of moxidectin metabolite concentrations, 8-mg cohort only) 
f. If a subject discontinues from the study or is withdrawn, the investigator will notify the sponsor and, when possible, will perform the following procedures: vital sign 
measurements; safety 12-lead electrocardiogram; symptom-based physical examination; collection of adverse events; and clinical laboratory evaluation (including hematology, 
serum chemistry, and urinalysis). 


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Table 2. Schedule of Events for Period 1 (Day –1 to Day 4) 
 
Period 1 
Assessment 
Day –1 
Day 1 
(Predose) 
Day 1 
Day 2 
Day 3 
Day 4 
Hour relative to dosing 
≤-24 
 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
36 
48 
60 
72 
Admission to unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from unit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Confirmation of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, serum chemistry, and 
urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Commence fastingb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administrationb 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consumption of a standardized meal 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Safety 12-lead electrocardiogramc 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Continuous 12-lead electrocardiogramd 
 
------------------------------------------------------------------------- X ----------------------------------------------------------------------
 
Vital signse 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PK blood sample collectionf 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK feces sample collectiong 
 
X 
-----------------------------------------X------------------------------------------
--X-- 
--------X------- 
PK urine sample collectionh 
 
X 
-----------------------------------------X------------------------------------------
--X-- 
--------X------- 
Adverse events 
X 
X 
---------------------------------------------------------------- X ----------------------------------------------------------- 
Concomitant medications 
X 
X 
---------------------------------------------------------------- X ----------------------------------------------------------- 
Abbreviation: PK, pharmacokinetic. 
a. A full physical examination will be performed at Screening. At all subsequent time points, a symptom-based physical examination (informed by concurrent conditions, signs and 
symptoms, and adverse events reported) will be performed. 
b. On Day –1, subjects will begin fasting as instructed and water can be taken ad libitum. On Day 1, study drug administration (moxidectin or placebo) will occur after an overnight 
fast of at least 10 hours. Study drug will be administered with at least 240 milliliters of water. No food will be allowed for 4 hours after dosing; however, water can be taken 
ad libitum. 
c. Standard 12-lead safety electrocardiograms (ECGs) will be performed after the subject has been supine for approximately 10 minutes. At each relevant time point, safety 12-lead 
ECGs will be performed before blood collection. 
d. Continuous 12-lead ECG data will be obtained using a Mortara continuous 12-lead digital ECG recorder, with triplicate 10-second ECG recordings (approximately 1 minute 
apart) extracted at the following time points: Baseline (before dosing on Day 1) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours after dosing. 
e. Vital signs (supine blood pressure, heart rate, respiratory rate, and oral body temperature) will be measured after the subject has rested for approximately 5 minutes. 
f. Blood samples will be collected for PK assessments at Baseline (0 hour; within 15 minutes before dosing) and at 0.5, 1, 2, 3, 4*, 5, 6, 8, 12*, 24*, 36*, 48, 60*, and 72 hours 
after dosing, and on Days 8, 15, and 22. (* Planned time points for analysis of moxidectin metabolite concentrations, 8-mg cohort only) 


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g. Feces samples will be collected for PK assessments before dosing (single predose collection*) and each bowel motion during confinement in the clinical research unit. Samples 
will be pooled at the central laboratory for intervals of 0 to 24, 24 to 48, and 48 to 72 hours after dosing (up to 4 samples). (* Feces specimens [the whole bowel movement] may 
be collected by subjects [at home] within 2 days of submitting them to study staff on Day –1. Collection instructions will be provided at Screening.)  
h. Urine samples will be collected for PK assessments before dosing (single predose collection; first void sample in the morning is acceptable and volume recording is not required) 
and for pooled intervals of 0 to 24, 24 to 48, and 48 to 72 hours after dosing (4 samples).  


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3.4 
Unblinding Procedures 
The study will be double-blind and the blind will be maintained through the use of 
blinding envelopes held by the dispensing pharmacist. All randomization information 
will be secured and housed in a locked storage area, accessible only by the randomization 
personnel, the assigned pharmacist, and his or her verifier(s). Neither the subjects nor 
CRU staff administering the study drug will know the study drug being administered. To 
maintain the blind, each subject will receive 18 matching tablets. The placebo tablets will 
be matched in appearance to the active study drug, and will contain the same excipients 
as moxidectin tablets but will not contain moxidectin.  
The study drug blind will not be broken by the investigator or designee unless 
information concerning the study drug is necessary for the medical treatment of the 
subject. The blinding envelopes containing randomization information for each subject 
will be sent to the CRU. The sponsor or medical monitor must be notified immediately if 
the study drug blind is broken. The date, time, and reason that the blind was broken will 
be recorded in the source documents. 
For Period 1, which commences at Screening, the study blind will be maintained for all 
personnel through Day 22. Once all subjects complete Period 1, the database will be 
locked for all data to Day 22. The database will not yet include study data from Week 8 
or 12. To allow primary analysis after completion of Day 22, the study blind will be 
broken for data management, the study statistician, primary and validation programmers, 
the Cardiac Safety Expert (Mason Cardiatric Safety Consultation), the PK vendor 
(Nuventra Pharma Sciences, Inc), medical writers, and the sponsor for purposes of data 
analysis and review. All other personnel, including those conducting subject procedures 
and assessments, will remain blinded.  
The study will then be unblinded for all other personnel including the clinic and other 
biometrics roles after all subjects complete the Week 12 assessments and the data 
collected in Period 2 is locked.  
3.5 
Interim Analyses 
The primary analysis will be performed once all subjects have completed Day 22. An 
additional safety supplement will be provided once all subjects complete Week 12. In 
addition, concentrations of moxidectin in urine and feces and moxidectin metabolites in 
plasma and urine and associated PK parameters will not be included in the primary 
analyses after Day 22; however, those data will be analyzed after Period 2 and included 
in the safety supplement. No interim analysis and early termination is planned. However, 
the overall safety pattern will be monitored closely and the study may be discontinued for 
valid scientific or administrative reasons. 
Only 1 set of datasets, tables, listings, and graphs are outlined in this SAP. The intent is 
to summarize all available data after Period 1, and then, rather than producing 2 sets of 
datasets and tables (1 for each period), the datasets and tables will be reproduced with the 


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additional data added from Period 2 to replace the existing datasets and TLFs from Period 
1.  
 


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4 
GENERAL STATISTICAL CONSIDERATIONS 
All analyses described in this plan are considered a priori analyses in that they have been 
defined prior to breaking the blind. All other analyses, if any, designed subsequent to 
breaking the blind will be considered post hoc analyses and will be applied as exploratory 
methodology. All post hoc analyses will be identified as such in the clinical study report. 
All statistical tests will be tested at α=0.05, 2-sided significance level, unless otherwise 
stated. Descriptive statistics for continuous variables will include number of subjects (n), 
mean, standard deviation (SD), median, minimum, and maximum, unless otherwise 
noted. Confidence intervals (CIs) will be presented where appropriate. Descriptive 
statistics for categorical variables will consist of frequency and percentage.  
All analyses will be conducted with SAS Version 9.4 or later using procedures 
appropriate for the particular analysis. 
 


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5 
ANALYSIS POPULATIONS 
5.1 
Safety Population 
The safety population will include all subjects who receive at least 1 dose of study drug. 
Subjects in this population will be used for demographic and safety summaries. Subjects 
in this population will be analyzed according to the drug received (actual drug 
concentration). 
5.2 
Pharmacokinetic Population 
The PK population will include all subjects who receive at least 1 dose of moxidectin and 
provide an adequate number of blood samples for the determination of plasma PK 
parameters. Subjects in this population will be used for all PK summaries. Subjects in this 
population will be analyzed according to the drug received (actual drug concentration). 
5.3 
Electrocardiogram Population 
The ECG population will include all subjects who receive at least 1 dose of study drug 
and have at least 1 pair of predose and postdose QTc data for at least 1 time point. 
Subjects in this population will be used for all digital ECG summaries and analyses. 
Subjects in this population will be analyzed as randomized. 
5.4 
Pharmacokinetic/Pharmacodynamic Population 
The PK/PD population will include all subjects in the ECG population who have 
time-matched plasma concentrations for the active moxidectin treatments. Subjects in this 
population will be analyzed according to the drug received (actual drug concentration). 
5.5 
Handling of Missing Data 
Missing data will not be imputed, except in the case of missing dates or times, for which 
values will be imputed if needed for analysis (ie, use of nominal time point value if 
elapsed time is missing). Data that are excluded from the descriptive or inferential 
analyses will be included in the data listings. This will include those measurements from 
excluded subjects, or measurements from unscheduled collections or extra measurements 
that may arise from 2 or more analyses of the plasma sample from the same time point.    
In calculation of the concentration summaries and display in graphs, if values are below 
the quantitation limit (BQL) they will be set to zero; however, they will be presented as 
BQL in data listings. If all concentrations at a given time point are BQL, the mean will be 
presented as zero and the SD and percent coefficient of variation (CV%) will be reported 
as not applicable. If a mean concentration is BQL, it will be flagged in the summary 
table. For the calculation of PK parameters, BQL values that occur before dose 
administration will be set to zero. The BQL values that occur after dose administration, 
but before the first measurable concentration will be set to zero. If a BQL value occurs at 
the end of the collection interval (after the last quantifiable concentration) it will be 
treated as missing data. If 2 BQL values occur in succession after Cmax, the profile will be 
deemed to have terminated at the first BQL value and any subsequent concentrations will 


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be omitted from the PK calculations. 
5.6 
Key Definitions 
Baseline value is defined as the last available off-treatment value collected prior to the 
time of the first dose. 
Relative study day is defined as number of days from the first dose date and will be 
presented on all listings where a complete date is presented. 
  


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6 
SUBJECT DISPOSITION AND BASELINE 
CHARACTERISTICS 
6.1 
Subject Discontinuation 
The number of subjects who enroll in the study and the number and percentage of 
subjects who complete the study will be presented by treatment. The frequency and 
percentage of subjects who withdraw or discontinue from the study and the primary 
reason for withdrawal or discontinuation will be summarized. 
 
A data listing of subject disposition including study completion status and reason for 
study discontinuation will be provided. In addition, subject populations and reasons for 
exclusion from the population will be provided in a data listing. 
6.2 
Protocol Deviations 
Protocol deviations will be captured as a log from clinical monitoring and presented in a 
data listing. 
6.3 
Demographics and Baseline Characteristics 
Descriptive statistics (ie, mean, SD, median, minimum, and maximum) will be calculated 
for continuous demographic and baseline characteristics variables (age, weight at 
Screening, height, and body mass index at Screening) and frequency counts and 
percentages will be tabulated for categorical demographic variables (sex, race, and 
ethnicity) for each treatment and overall.  
A data listing will be provided for all demographic data. In addition, the baseline 
characteristics of weight, height, and body mass index will be included in the vital sign 
data listing. 
6.4 
Medical History 
Medical history data will be mapped using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA) to system organ class (SOC) and preferred term (PT) 
and will be listed by subject identification number, medical condition reported term, 
onset date, and ongoing status/resolution date. 
6.5 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria not met will be provided in a data listing. 
 


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7 
PHARMACOKINETIC ANALYSES 
7.1 
Moxidectin and Metabolite Concentrations 
Moxidectin concentrations in plasma will be collected and analyzed for all subjects. 
Moxidectin concentrations in urine and feces and metabolite concentrations in plasma 
and urine will be analyzed for the subset of subjects who receive the 8-mg dose  (See 
Table 3). 
Table 3. Analyses for Each Matrix 
Matrix 
Analysis for moxidectin 
Analysis for moxidectin metabolites 
Plasma 
a 
b 
Urine 
b 
b 
Feces 
b 
not analyzed 
a All subjects 
b 8-mg cohort 
For plasma, the time course of concentrations of moxidectin will be presented and 
summarized using descriptive statistics (n, mean, SD, CV%, median, minimum, 
maximum, geometric mean, and geometric CV%) by time point and treatment. For urine 
and feces, the amount of moxidectin excreted by collection interval will be presented and 
summarized using descriptive statistics (n, mean, SD, CV%, median, minimum, 
maximum, geometric mean, and geometric CV%) by time point and treatment.   
For plasma and urine, amount of metabolite by collection interval and metabolite to 
parent (molar equivalents) ratios will be presented and summarized using descriptive 
statistics (n, mean, SD, CV%, median, minimum, maximum, geometric mean, and 
geometric CV%) by collection interval and treatment.   
Concentrations that are BQL will be treated as outlined in Section 5.5. Mean plasma 
concentration-time profiles will be plotted by treatment on linear and semilogarithmic 
scales using nominal times. Individual concentration-time plots and spaghetti plots with 
subject concentration-time profiles overlaid by respective treatments will be included in 
the appendices using linear and semilogarithmic scales.  
7.2 
Pharmacokinetic Parameters 
All PK analyses will be performed according to applicable standard operating procedures 
and protocol specifications. Pharmacokinetic parameters will be calculated for the PK 
population using Phoenix® WinNonlin® version 6.3 or later (Certara, Princeton, New 
Jersey) using actual sampling times. If actual times are missing, nominal times may be 
used and will be noted in the appropriate data listing. 
The PK parameters for plasma moxidectin will be estimated as follows (data permitting): 


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AUC0-last: 
AUC from time 0 extrapolated to the last observed concentration, 
calculated by a combination of linear and logarithmic trapezoidal 
methods (linear up/log down method). 
AUC0-inf: 
AUC from time 0 extrapolated to infinity, calculated as AUC0-last + 
Clast/λz where, Clast is the last measurable concentration. 
AUCext: 
Percentage of AUC0-inf obtained by extrapolation, calculated as 
([AUC0-inf – AUC0-last]/AUC0-inf) * 100 (a diagnostic parameter 
calculated and listed in the data listing, but not included in the 
descriptive statistics). 
AUC0-24: 
AUC from time 0 to 24 hours. 
AUC0-48: 
AUC from time 0 to 48 hours. 
AUC0-72: 
AUC from time 0 to 72 hours. 
AUC24-48: 
AUC from time 24 to 48 hours. 
AUC48-72: 
AUC from time 48 to 72 hours. 
Cmax: 
Maximum observed plasma concentration, observed by inspection of 
individual study participant plasma concentration-time plots. 
Tmax: 
Time to Cmax, obtained directly from the observed concentration-time 
data. 
t1/2: 
Terminal elimination half-life, calculated using the equation (ln[2]/λz). 
λz: 
Terminal elimination rate constant, estimated by linear regression of 
logarithmically transformed concentration-time data. Calculation of λz 
requires a minimum of 3 data points after (and not including) Cmax. The 
coefficient of determination (R2), for the linear regression must be at 
least 0.95. 
CL/F: 
Apparent clearance following extravascular administration, calculated 
as Dose/AUC0-inf. 
Vd/F 
Apparent volume of distribution following extravascular administration, 
calculated as Dose/(λz * AUC0-inf). 
 
All subjects in the PK population will be included in the descriptive statistics for the PK 
parameters. No value for λz, AUC0-inf, AUCext, CL/F, Vd/F, or t1/2 will be reported for 
cases that do not exhibit a terminal log-linear phase in the concentration-time profile. No 
PK parameters will be calculated for subjects with fewer than 4 quantifiable 
concentrations following BQL imputation. Additional PK parameters may be calculated, 
as necessary, to fully characterize the PK profile of moxidectin. 


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The PK parameters for urine moxidectin will be estimated as follows (data permitting): 
Aeurine(0-72): 
Urinary recovery between 0 and 72 hours, where  
Ae(0-t)
, where Curine,i represents the 
concentration of drug in urine during collection interval i, and Vurine,i 
represents the cumulative urine volume during collection interval i. 
Aeurine(0-24): 
Urinary recovery between 0 and 24 hours, where Ae(0-24) = Curine(0-24) * 
Vurine(0-24). 
Aeurine(24-48): 
Urinary recovery between 24 and 48 hours, where Ae(24-48) = 
Curine(24-48) * Vurine(24-48). 
Aeurine(48-72): 
Urinary recovery between 48 and 72 hours, where Ae(48-72) = 
Curine(48-72) * Vurine(48-72). 
CLr(0-72): 
Renal clearance from 0 to 72 hours, where Ae(0-72)/AUC(0-72). 
CLr(0-24): 
Renal clearance from 0 to 24 hours, where Ae(0-24)/AUC(0-24). 
CLr(24-48): 
Renal clearance from 24 to 48 hours, where Ae(24-48)/AUC(24-48). 
CLr(48-72): 
Renal clearance from 48 to 72 hours, where Ae(48-72)/AUC(48-72). 
 
The PK parameters for feces moxidectin will be estimated as follows (data permitting): 
Aefeces(0-72): 
Fecal recovery between 0 and 72 hours, where  
Ae(0-t)
, where Cfeces,i represents the 
concentration of drug in feces (ng/g) during collection interval i, and 
Wfeces,i represents the total fecal mass during collection interval i. 
Aefeces(0-24): 
Fecal recovery between 0 and 24 hours, where Ae(0-24) = Cfeces(0-24) * 
Wfeces(0-24). 
Aefeces(24-48): 
Fecal recovery between 24 and 48 hours, where Ae(24-48) = Cfeces(24-48) * 
Wfeces(24-48). 
Aefeces(48-72): 
Fecal recovery between 48 and 72 hours, where Ae(48-72) = Cfeces(48-72) * 
Wfeces(48-72). 
 
Descriptive statistics of PK parameters for moxidectin will be provided for the PK 
population by treatment and will include n, mean, SD, CV%, median, minimum, 
maximum, geometric mean, and geometric CV% (where applicable). 


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8 
PHARMACODYNAMIC ANALYSES 
The PD analyses for the continuous 12-lead ECG data is outlined in this section, but will 
be the responsibility of Mason Cardiac Safety Consultation. 
8.1 
Continuous 12-Lead Electrocardiogram Assessments 
Pharmacodynamics will be assessed via ECGs obtained using a Mortara continuous 
12-lead digital ECG recorder, which will be reviewed and analyzed by the central ECG 
laboratory. The device will remain connected to the subject during the confinement 
period. The ECG data will be transmitted wirelessly to the Surveyor system, which will 
extract triplicate 10-second ECG recordings (approximately 1 minute apart) at baseline 
(before dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours after dosing. 
A window of ±5 minutes around each time point will be utilized to capture ECGs of 
adequate quality, although every effort should be made to capture them as close to the 
scheduled time points as possible. The ECG extractions will be time-matched to the PK 
samples but obtained before the actual sampling time to avoid changes in autonomic tone 
associated with the psychological aspects of blood collection as well as the reduction in 
blood volume subsequent to blood collection. 
The continuous ECG data will be sent to the central ECG laboratory for a high-resolution 
measurement of the cardiac intervals and morphological assessment. The ECG core 
laboratory staff will be blinded to treatment, time, and study day identifiers. 
The 12-lead continuous digital ECG signal for each subject will be recorded continuously 
during subject confinement. 
Digital ECGs will be transmitted to the central ECG laboratory’s validated data 
management system. If targeted ECG time points are artifactual and of poor quality, the 
central ECG laboratory will extract analyzable 10-second ECGs as close as possible to 
the targeted time points. The cardiologists responsible for interpreting the ECGs will be 
blinded to all study drug identifiers and collection times. 
Lead II is the lead of choice for the over-reads and the baseline and on-treatment ECGs 
will be based on the same lead. All ECGs from a particular subject will be read by a 
single reader. 
If lead II is not analyzable, ECG analysis will be conducted in lead V5. If lead V5 is not 
analyzable, the most appropriate lead will be used (eg, lead V2). 
8.2 
General Summaries 
All continuous 12-lead ECG data collected will be presented in data listings. Data from 
subjects excluded from the analysis populations will be presented in the data listings, but 
not included in the calculation of summary statistics. For categorical variables, 
frequencies and percentages will be presented. Continuous variables will be summarized 
using descriptive statistics (n, mean, SD, 2-sided confidence bounds [90% for the QTcF 
interval or 95% for other parameters], median, 25th percentile, 75th percentile, minimum, 
and maximum). The mean of the triplicate 0-hour time point on Day 1 will be used as the 


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baseline. The continuous 12-lead ECG parameters (QTcF, HR, PR, RR, and QRS) and 
the corresponding changes from Baseline (denoted as dQTcF, dHR, dPR, dRR, and 
dQRS) and placebo-adjusted endpoints (denoted as ddQTcF, ddHR, ddPR, ddRR, and 
ddQRS) will be summarized by treatment and time point.  
The means and 90% CIs for the dQTcF and placebo-adjusted (algebraic) ddQTcF will be 
calculated across all subjects for each time point and each active treatment and displayed 
graphically. Secondary endpoints will also be displayed using 95% CI, if applicable. 
8.3 
Statistical Analyses 
Primary Analysis  
The relationship between time-matched, baseline-adjusted QTcF (dQTcF) and 
moxidectin concentrations will be investigated by linear mixed-effects modeling. The 
ddQTcF value will be calculated as the placebo-corrected dQTcF estimated from the 
model. 
Before modeling, the concentration-ddQTcF relationship will be explored graphically to 
determine the presence of hysteresis. Hysteresis will be assumed if, on average (or 
median), there are at least 3 time points with ddQTcF >5 msec and the time to maximum 
observed plasma concentration (Tmax) and the time of maximal ddQTcF (Umax) differ by 
30 minutes or more and the 1-sided, 1-sample Wilcoxon test for the difference between 
ddQTcF at Tmax and at Umax is significant at the 1% level. If hysteresis is present, the 
possibility of fitting a population PK model with an effect compartment will be explored. 
The primary analysis will be provided for the ECG population using a mixed-effects 
model with dQTcF as the dependent variable and treatment (active and placebo), time 
point, and treatment by time point interaction as the independent variables with baseline 
QTcF as a covariate and time-matched concentrations of moxidectin (observed if 
hysteresis is not present; predicted from the effect compartment if hysteresis is present) 
as a covariate with random effects of intercept and slope. Concentrations of zero will be 
used for the placebo treatment. A spatial power law covariance structure (a time-
dependent first-order autoregressive covariance designed for unequally-spaced time 
points) will be used. If the model does not converge then unstructured (UN) or compound 
symmetry (CS) structures will be assessed, in that order. The model will be used for 
predicting population average and 90% 2-sided bootstrapped CI of the baseline-adjusted 
difference (ie, ddQTcF) between active and placebo at each time point bound at clinically 
relevant concentrations. The bootstrap method will be based on percentile CI using the 
5th and 95th percentiles in the resampling distribution using 1000 iterations.  
The criterion for negative QT assessment will be the upper bound of the 2-sided 90% 
bootstrapped CI for ddQTcF being below 10 msec at the largest geometric mean Cmax 
value. In addition, the significance and magnitude of parameter estimates of the treatment 
covariate (active vs. placebo) will be considered. 
 


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At the request of the United States Food and Drug Administration, the primary endpoint 
in the study has been updated to dQTcF and this is the dependent variable in the primary 
analysis, which includes plasma concentrations as covariates with random slope and 
intercept as well as treatment and time point as categorical independent variables. 
However, in addition to obtaining the plasma concentration intercept and slope estimates, 
the estimated dQTcF values from the primary analysis will be compared by calculating 
the differences overall and at each time point between the active treatment and placebo, 
resulting in estimates of ddQTcF, which will be presented. In addition, a secondary 
analysis with ddQTcF as the dependent variable will be performed, as is typical and well 
understood, to assess correlation and overall profile of ddQTcF and plasma 
concentrations. We believe it is important to do these analyses in addition to the primary 
analysis, because the dQTcF analysis could yield a spuriously positive or negative 
regression slope based on the relationship between the well-known spontaneous circadian 
change in dQTcF and the concentration-time profile of the investigational drug. For 
example, if the early to midday circadian increase in dQTcF concurred with a rise in 
plasma concentration of moxidectin, this could create the appearance of a positive 
relationship that might exceed the upper confidence boundary of 10 msec within the 
drug’s clinically-expected concentration range. Converse timing between circadian 
change and plasma concentration change could produce the opposite effect. In the 
ddQTcF analysis, the placebo group’s circadian change largely eliminates this type of 
spurious observation. Thus, in addition to examining the dQTcF model, if the primary 
analysis produces a significantly positive or negative regression slope, we will also 
examine the relationship between the investigational drug’s plasma concentration-time 
course in relationship to the circadian change of dQTcF in the placebo group, to 
determine if a positive or negative correlation could have affected the dQTcF-plasma 
concentration relationship. 
The relevant SAS code statements are:  
PROC MIXED DATA = DATA; 
   CLASS SUBJID TRT ATPTN; 
   MODEL dQTcF = BASE TRT ATPTN TRT*ATPTN CONC /SOLUTION 
RESIDUAL OUTP=PRED; 
   RANDOM INTERCEPT CONC / SUBJECT = SUBJID; 
   REPEATED ATPTN / type=SP(POW) (ATPTN) SUBJECT=SUBJID; 
   LSMEANS TRT TRT*ATPTN /DIFF ALPHA=0.1 CL at CONC=xx.x;  
   LSMEANS TRT TRT*ATPTN /DIFF ALPHA=0.1 CL;  
RUN; 
In the above statements: 
 TRT represents the treatment (active or placebo); 
 ATPTN represents the postdose nominal time point; 
 BASE represents the baseline value for QTcF; 
 CONC represents measured plasma concentrations of moxidectin; 


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 SP(POW) is a spatial power law covariance structure (a time-dependent 
first-order autoregressive covariance designed for unequally-spaced time points), 
if the model does not converge then unstructured or compound symmetry 
structures will be assessed, in that order; 
 LSMEAN differences between the treatments at the Geometric Cmax value and at 
the average concentration value, where xx.x represents the largest geometric mean 
Cmax value among the doses, most likely for the 36-mg dose, will be provided. 
Model assumptions will be reviewed with plots of standardized residuals versus fitted 
values and normal Q-Q plots of the standardized residuals. If nonlinearity is present, a log 
linear and/or maximum effect (Emax) or other model will be considered. 
Similar analyses will be repeated for HR, PR, and QRS, however, bootstrap percentiles 
will be based on the 2.5th and 97.5th percentiles, corresponding to a 2-sided 95% CI 
rather than the 2-sided 90% CI. 
Secondary Analysis: Pharmacokinetic/Pharmacodynamic Analyses 
To evaluate the relationship between placebo-corrected mean change from Baseline in 
QTcF (ie, ddQTcF) versus plasma concentrations of moxidectin for all subjects in the 
PK/PD population, both graphical and mixed-effects analyses of plasma concentration of 
ddQTcF versus plasma concentration of moxidectin will be performed. The mixed-effects 
model will be used to account for the clustering effects within each subject at different 
time points. The mixed-effects model will contain ddQTcF as the dependent variable and 
include the corresponding time-matched plasma moxidectin concentrations as the 
independent variable. The mixed-effects model will be used to estimate, for all subjects, 
the predicted population mean ddQTcF and its corresponding upper 95% 1-sided 
(equivalent to the upper 90% 2-sided) CI over a range of observed plasma concentrations. 
A negative result (ie, the model indicates no plasma concentration effect) is a slope of 
approximately zero.  
The adequacy of the linear assumption between ddQTcF and plasma concentrations will 
be determined by adding a quadratic term to the mixed-effects model. If the quadratic 
term is different than zero, having P<0.05, and Akaike's information criterion (AIC) is 
smaller in comparison with the linear model’s AIC, then a quadratic term may be added. 
In addition, a transformation of the concentrations (eg, log[C/LLOQ], where LLOQ is the 
lower limit of quantitation of the assay and all values below the LLOQ are replaced with 
the LLOQ) may also be assessed. The best model fit will be determined by the lowest 
AIC. 
The predicted mean expected ddQTcF and the 90% 2-sided CI will be calculated using 
the estimates of the slopes from the mixed-effect models, for all subjects, at relevant 
concentration levels (ie, the mean maximum plasma concentration under each dose 
level). 


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The relevant SAS code statements are:  
PROC MIXED DATA = DATA; 
   CLASS SUBJID; 
   MODEL ddQTcF = CONC /SOLUTION OUTPM=PRED ALPHA=0.05; 
   RANDOM INTERCEPT CONC / TYPE=UN SUBJECT = SUBJID; 
RUN; 
In the above statements: 
 CONC represents the measured plasma concentrations of moxidectin; 
 Type=UN means an unstructured covariance matrix, which is used for the 
correlated random effects (INTERCEPT and CONC). If the model does not 
converge other covariance structures will be investigated. 
A plot will be provided to show CI of each treatment using the following model, adding 
in the treatment variable as follows: 
PROC MIXED DATA = DATA; 
   CLASS SUBJID TRT; 
   MODEL ddQTcF = CONC TRT/SOLUTION OUTP=PRED; 
   RANDOM INTERCEPT CONC /TYPE=UN SUBJECT = SUBJID; 
RUN; 
Where TRT represents the individual treatments (moxidectin 4 mg, moxidectin 8 mg, 
moxidectin 16 mg, moxidectin 24 mg, and moxidectin 36 mg). 
A plot of the observed median-decile drug concentrations and associated mean ddQTcF 
(90% CI) together with the mean model-predicted ddQTcF will be used to evaluate the 
adequacy of the model fit to the assumption of linearity and the impact on quantifying the 
concentration response relationship. 
Categorical QTc Findings 
Categorical summaries using the largest postdose QTcF and largest change from Baseline 
(dQTcF) will be performed to determine the number and percentage of subjects, by 
treatment, who meet each of the following criteria: 
 Result ≤450 msec; 
 Result >450 and ≤480 msec; 
 Result >480 and ≤500 msec; 
 Result >500 msec; 
 dQTcF ≤30 msec; 
 dQTcF >30 and ≤60 msec; 
 dQTcF >60 msec. 
 
 


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Categorical Analysis of Other ECG Intervals 
Categorical summaries of outliers will be provided for other ECG variables (PR, QRS, 
and HR) as follows: 
 PR outliers postdose (PR >200 msec and a 25% or greater increase from 
Baseline); 
 QRS outliers postdose (QRS >100 msec and a 25% or greater increase from 
Baseline); 
 HR outliers postdose (HR <50 beats/minute and a 25% or greater decrease from 
Baseline); 
 HR outliers postdose (HR >100 beats/minute and a 25% or greater increase from 
Baseline). 
Any instance in 1, 2, or 3 of the triplicate ECGs of any subject overall and at each time 
point will be counted as 1 outlier event.  
ECG Diagnostic Statement Analysis 
Abnormal diagnostic statements will be tallied and tabulated for each treatment and time 
point. The variety of diagnostic statements with the same meaning will be aggregated into 
defined categories. For example, T wave inversion and lead V2 and T wave flattening in 
lead II will both be categorized as nonspecific T wave abnormality. The incidence rate of 
diagnostic statements will be tabulated for both predose and postdose assessments, and 
also tabulated with diagnostic statements categorized as treatment-emergent diagnostic 
statements (ie, diagnostic statements not present on any baseline assessment). All 
abnormal ECG diagnostic findings will be listed. 
Adequacy of HR Correction 
The adequacy of the correction formula will be assessed by determining the linear 
relationship of QTcF to RR. Adequacy is defined as a population QTcF:RR slope of 
<|0.045|, and a slope of <|0.045| in at least 50% of individual subjects. 
The QT interval with individual correction (QTcI) is mentioned in the International 
Council for Harmonisation E14 Guidance as an ancillary correction method. 
The QTcI, if needed, will be calculated for each subject, using all available QT/RR 
predose pairs by first determining the slope of each subject’s QT:RR relationship using 
all available predose data. Then QTcI will be calculated from each subject’s individual 
ECG time point QT and RR interval values with the formula: QTcI = QT + slope (1000 – 
RR). 


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9 
SAFETY ANALYSIS 
9.1 
Adverse Events 
Adverse events will be coded using the current version of MedDRA. Each verbatim term 
will be mapped to SOC and PT. 
A treatment-emergent AE (TEAE) is defined as any AE that began or worsened 
following the start of study drug. 
An overall summary of TEAEs will be provided summarizing subjects with at least 1 of 
the following: TEAE, related TEAE, Grade 3 or 4 TEAE, serious TEAE, related serious 
TEAE, TEAE leading to study discontinuation, and related TEAE leading to study 
discontinuation as well as the number of events with each of the previously mentioned 
categories by treatment and overall.  
In addition, summaries of unique TEAEs will be presented by SOC, PT, and by treatment 
and overall and will include number and percentage of subjects who experienced the 
unique event for:   
1. All TEAEs, 
2. All TEAEs by relationship, 
3. All TEAEs by severity grade, 
4. All TEAEs leading to study discontinuation. 
 
Related TEAEs include all those classified by the investigator as possibly, probably, or 
definitely related. Unrelated TEAEs are those events classified as not related.  
For summaries by relationship, the most related event will be selected. For summaries by 
severity grade, the most severe grade will be selected. 
Multiple events will be counted once only per subject and treatment in each of the 
previously mentioned summaries by treatment and overall. In the presentation, SOC and 
PT will be sorted in alphabetical order.  
 
All AEs captured in the database will be listed in by-subject data listings; however, only 
TEAEs will be summarized. 
MedDRA version will be footnoted in both tables and data listings.   


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9.2 
Clinical Laboratory Evaluations (Serum Chemistry, 
Hematology, Urinalysis) 
Clinical laboratory evaluations of serum chemistry, hematology, and urinalysis will be 
performed. Results and change from Baseline will be summarized by treatment and 
scheduled visit/time point using descriptive statistics for numeric parameters and using 
counts and percentages for categorical parameters. Baseline is defined as stated in 
Section 5.6. Values reported with a “<” or “>” sign will be converted to numeric values 
and summarized.  
Shifts from Baseline to values outside of the normal range will be presented using the 
worst-case result by parameter and treatment that occurred postdose and summarized 
using the number and percentage of subjects with laboratory test results below, within, 
and above normal ranges for numeric parameters and normal, abnormal for categorical 
parameters. The denominators for calculating the percentages will be based on the 
number of subjects with nonmissing assessments for each parameter. 
Clinically significant laboratory values (as determined by the investigator) will be 
provided in a data listing including all values for a given parameter for subjects who had 
at least 1 postbaseline clinically significant value.  
All clinical laboratory data will also be presented in data listings in chronological order 
by date if unscheduled or repeated values.  
9.3 
Vital Signs 
Descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum) 
for vital sign measurements collected at Baseline and each scheduled postbaseline time 
point will be summarized by treatment. In addition, change from Baseline will be 
calculated, where baseline is defined as stated in Section 5.6.  
Vital sign measurements will be presented in a data listing.  
9.4 
Safety 12-Lead Electrocardiogram 
Results and changes from Baseline will be presented for each safety ECG parameter and 
summarized by treatment at Baseline and scheduled postdose time point using descriptive 
statistics (number of subjects, mean, SD, median, minimum, and maximum). Baseline is 
defined as stated in Section 5.6. The results will be interpreted as normal, abnormal not 
clinically significant, or abnormal clinically significant, and the interpretation will be 
summarized for each treatment and scheduled time point using counts and percentages. 
The denominators for calculating the percentages will be based on the number of subjects 
with nonmissing assessments at each time point. 
A categorical summary of QTcF interval and QT interval corrected by Bazett’s formula 
(QTcB) will be provided using counts and percentages at Baseline and maximum 
postbaseline by treatment for the following categories:  
 Result ≤450 msec; 


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 Result >450 and ≤480 msec; 
 Result >480 and ≤500 msec; 
 Result >500 msec; 
 Change from Baseline ≤30 msec; 
 Change from Baseline >30 and ≤60 msec; 
 Change from Baseline >60 msec. 
Safety 12-lead ECG data will be provided in a data listing. 
9.5 
Concomitant Medications 
Prior and concomitant medications will be classified according to the World Health 
Organization Drug dictionary and presented in a data listing by anatomical therapeutic 
chemical class level 3 and preferred drug name. 
Medications with a start and end date occurring before the first dose date/time date will 
be identified as prior medications. Medications with an end date occurring on or after the 
first dose date/time or that have unknown or ongoing end dates will be identified as 
concomitant medications. In the event of a partial date, it will be compared to the first 
dose date/time and if year and or month is clearly prior to the first dose date, and the 
medication’s end date is partial, but clearly prior to the first dose date/time then the 
medication will be classified as prior medication. However, if the partial date overlaps 
with the first dose/date as having the same year and/or month then the medication will be 
classified as concomitant medication.  
9.6 
Extent of Exposure 
Study drug administration dates and times will be presented in a data listing. 
9.7 
Other Safety Assessments 
The physical examination findings and other safety assessments will be presented in data 
listings. 
 
 
 


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10 
REFERENCES 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (US). Guidance for Industry: E14 Clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
non-antiarrhythmic drugs. October 2005.  
E14 Implementation Working Group ICH E14 Guideline: The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic Drugs Questions & Answers (R3). 10 December 2015 Available 
at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ 
Efficacy/E14/E14_Q_As_R3__Step4.pdf 
 
 


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APPENDIX A: LIST OF TABLES, LISTINGS, AND FIGURES 
Shells of the tables, listings, and graphs will be provided as a separate document. Titles 
may change slightly from what is presented here in this appendix, where this appendix is 
designed to give the reader an understanding of what is intended to be presented, in 
creating the shells, the tables may need to be presented differently to adhere to the actual 
data collected. 


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14 
TABLES, LISTINGS AND GRAPHS REFERRED TO BUT 
NOT PRESENTED IN THE TEXT 
14.1 
Disposition and Demographic Data Summary Tables 
Table 14.1.1 
Subject Disposition (All Randomized Subjects) 
Table 14.1.2 
Demographic and Baseline Characteristics (Safety Population) 
Table 14.1.3 
Demographic and Baseline Characteristics (PK Population) 
Table 14.1.4 
Demographic and Baseline Characteristics (ECG Population) 
Table 14.1.5 
Demographic and Baseline Characteristics (PK/PD Population) 
14.2 
Pharmacokinetic and Pharmacodynamic Summary Tables 
14.2.1 
Concentration and Pharmacokinetic Summaries, Analyses, and 
Figures  
Table 14.2.1.1 
Summary of Plasma Concentrations Over Time (PK Population) 
Table 14.2.1.2 
Summary of Plasma Pharmacokinetic Parameters (PK Population) 
Table 14.2.1.3 
Summary of Urine Pharmacokinetic Parameters (PK Population) 
Table 14.2.1.4 
Summary of Feces Pharmacokinetic Parameters (PK Population) 
Figure 14.2.1.1 
Mean ± SD Plasma Moxidectin Concentration (ng/mL)-Time Profile, 
Linear Scale (PK Population) 
Figure 14.2.1.2 
Mean Plasma Moxidectin Concentration (ng/mL)-Time Profile, 
Semilogarithmic Scale (PK Population) 
Figure 14.2.1.3 
Mean ± SD Plasma Moxidectin Metabolite Concentration (ng/mL)-
Time Profile, Linear Scale (PK Population) 
Figure 14.2.1.4 
Mean Plasma Moxidectin Metabolite Concentration (ng/mL)-Time 
Profile, Semilogarithmic Scale (PK Population) 
Figure 14.2.1.5 
Mean ± SD Plasma Moxidectin Metabolite to Parent (molar 
equivalents) Ratios Over Time (PK Population) 
Figure 14.2.1.6 
Mean ± SD Urine Moxidectin Amount Excreted Over Time (PK 
Population) 
Figure 14.2.1.7 
Mean ± SD Urine Moxidectin Metabolite Amount Excreted Over 
Time (PK Population) 
Figure 14.2.1.8 
Mean ± SD Urine Moxidectin Metabolite to Parent Amount Excreted 
(molar equivalents) Ratios Over Time (PK Population) 
Figure 14.2.1.9 
Mean ± SD Feces Moxidectin Amount Excreted Over Time (PK 
Population) 
14.2.2 
Pharmacodynamic Summaries, Analyses, and Figures 
Table 14.2.2.1 
Summary of Continuous ECG Parameter Results and Change From 
Baseline (ECG Population) 
Table 14.2.2.2 
Summary of Simple/Unadjusted Continuous ECG Parameters (ECG 
Population) 
Table 14.2.2.3 
Summary of Primary Analysis Mixed-Effects Model Parameters 
(ECG Population) 


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Table 14.2.2.4 
Summary of Primary Analysis Mixed-Effects Model Predicted 
ddECG and Predicted Interval at Geometric Mean Maximum Plasma 
Concentration (ECG Population) 
Table 14.2.2.5 
Summary of Secondary Analyses Mixed-Effects Model Predicted 
Regression Slope Estimates and Predictions (PK/PD Population) 
Table 14.2.2.6 
Summary of Continuous QTcF Interval Categories (ECG Population) 
Table 14.2.2.7 
Summary of Continuous PR, QRS, and HR Outliers (ECG 
Population) 
Table 14.2.2.8 
Summary of Continuous ECG Diagnostic Statements (ECG 
Population) 
Table 14.2.2.9 
Summary of Treatment-Emergent Continuous ECG Diagnostic 
Statements (ECG Population) 
Figure 14.2.2.1 
dQTcF Interval vs. Time Showing Mean and 2-sided 90% Confidence 
Bounds (ECG Population) 
Figure 14.2.2.2 
dHR vs. Time Showing Mean and 2-sided 95% Confidence Bounds 
(ECG Population) 
Figure 14.2.2.3 
dPR Interval vs. Time Showing Mean and 2-sided 95% Confidence 
Bounds (ECG Population) 
Figure 14.2.2.4 
dQRS Interval vs. Time Showing Mean and 2-sided 95% Confidence 
Bounds (ECG Population) 
Figure 14.2.2.5 
dRR Interval vs. Time Showing Mean and 2-sided 95% Confidence 
Bounds (ECG Population) 
Figure 14.2.2.6 
ddQTcF Interval vs. Time Showing Mean and 2-sided 90% 
Confidence Bounds (ECG Population) 
Figure 14.2.2.7 
ddHR vs. Time Showing Mean and 2-sided 95% Confidence Bounds 
(ECG Population) 
Figure 14.2.2.8 
ddPR Interval vs. Time Showing Mean and 2-sided 95% Confidence 
Bounds (ECG Population) 
Figure 14.2.2.9 
ddQRS Interval vs. Time Showing Mean and 2-sided 95% 
Confidence Bounds (ECG Population) 
Figure 14.2.2.10 
ddRR Interval vs. Time Showing Mean and 2-sided 95% Confidence 
Bounds (ECG Population) 
Figure 14.2.2.11 
Residual Plots From Primary Analyses by Parameter (ECG 
Population)  
Figure 14.2.2.12 
ddQTcF Interval vs. Plasma Moxidectin Concentrations (PK/PD 
Population)  
Figure 14.2.2.13 
ddQTcF Interval vs. Plasma Moxidectin Concentration by Treatment 
(PK/PD Population)  
Figure 14.2.2.14 
Observed Median-decile Plasma Moxidectin Concentrations and 
Associated Mean ddQTcF Interval (90% CI) Together With the Mean 
(90% CI) Predicted ddQTcF Interval (PK/PD Population)  
Figure 14.2.2.15 
Residual Plots From Secondary Analysis (PK/PD Population)  
Figure 14.2.2.16 
Scatter Plot and Linear Regression for QTcF Interval vs. RR Interval 
(ECG Population)   


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14.3 
Safety Data Summary Tables 
14.3.1 
Adverse Events 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events (Safety 
Population) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug (Safety Population) 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity Grade (Safety Population) 
Table 14.3.1.5 
Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class, Preferred Term, and 
Relationship (Safety Population) 
14.3.2 
Listing of Deaths, Other Serious and Significant Adverse Events 
Listing 14.3.2.1 
Serious Adverse Events and Deaths (Safety Population) 
14.3.3 
Narratives of Deaths, Other Serious and Certain Other 
 
Significant Adverse Events 
Provided by Clinical, if applicable. 
14.3.4 
Abnormal Laboratory Value Listings 
Listing 14.3.4.1 
Clinically Significant Laboratory Results (Safety Population) 
14.3.5 
Other Observations Related to Safety 
Table 14.3.5.1 
Vital Sign Results and Change From Baseline (Safety Population) 
Table 14.3.5.2 
Hematology Parameter Results and Change From Baseline (Safety 
Population) 
Table 14.3.5.3 
Hematology Parameter Shifts From Baseline (Safety Population) 
Table 14.3.5.4 
Serum Chemistry Parameter Results and Change From Baseline 
(Safety Population) 
Table 14.3.5.5 
Serum Chemistry Parameter Shifts From Baseline (Safety Population) 
Table 14.3.5.6 
Urinalysis Parameter Results and Change From Baseline (Safety 
Population) 
Table 14.3.5.7 
Urinalysis Parameter Shifts From Baseline (Safety Population) 
Table 14.3.5.8 
Safety ECG Parameter Results and Change From Baseline (Safety 
Population) 
Table 14.3.5.9 
Safety ECG Interpretation (Safety Population) 
Table 14.3.5.10 
Safety ECG Categorical Results (Safety Population) 
 
 


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16.1      Study Information 
Appendix 16.1.7.1 Randomization Schedule 
Appendix 16.1.10.1 Clinical Laboratory Reference Ranges 
16.2 
Subject Data Listings 
16.2.1 
Subject Discontinuation 
Appendix 16.2.1.1  Subject Disposition  
16.2.2 
Protocol Deviations 
Appendix 16.2.2.1  Protocol Deviations  
16.2.3 
Subject Populations and Excluded Reasons 
Appendix 16.2.3.1  Subjects in the Safety, PK, ECG, and PK/PD Populations and 
Excluded Reasons 
16.2.4 
Demographic Data 
Appendix 16.2.4.1  Demographic and Baseline Characteristics  
Appendix 16.2.4.2  Inclusion/Exclusion Criteria Not Met  
Appendix 16.2.4.3  Medical History 
16.2.5 
Compliance and Drug Concentration Data 
Appendix 16.2.5.1 
Study Drug Administration 
Appendix 16.2.5.2 
Plasma Concentrations and Sampling Times 
Appendix 16.2.5.3 
Urine Concentrations, Volume, and Sampling Times 
Appendix 16.2.5.4 
Feces Concentrations, Stool Weight, and Sampling Times 
16.2.6 
Pharmacokinetic and Pharmacodynamic Data 
Appendix 16.2.6.1  Plasma Pharmacokinetic Parameters 
Appendix 16.2.6.2  Urine Pharmacokinetic Parameters 
Appendix 16.2.6.3  Feces Pharmacokinetic Parameters 
Appendix 16.2.6.4  Continuous ECG Parameter Results 
Appendix 16.2.6.5  Continuous ECG Parameter Change From Baseline (dECG) Results 
Appendix 16.2.6.6  Continuous ECG Parameter Adjusted for Placebo (ddECG) Results 
Appendix 16.2.6.7  Continuous Abnormal ECG Diagnostic Statements  
Appendix 16.2.6.8  Figures for Plasma Moxidectin Individual Concentration-Time 
Profiles, Linear Scale 
Appendix 16.2.6.9  Figures for Plasma Moxidectin Individual Concentration-Time 
Profiles, Semilogarithmic Scale 
Appendix 16.2.6.10 Spaghetti Plots for Plasma Moxidectin Individual Concentration-
Time Profiles, Linear Scale 
Appendix 16.2.6.11 Spaghetti Plots for Plasma Moxidectin Individual Concentration-
Time Profiles, Semilogarithmic Scale 
16.2.7 
Adverse Events and Other Safety Data 
Appendix 16.2.7.1  Adverse Events  
Appendix 16.2.7.2  Adverse Events Leading to Study Discontinuation  


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Appendix 16.2.7.3  Prior and Concomitant Medications 
Appendix 16.2.7.4  Vital Sign Measurements 
Appendix 16.2.7.5  Safety 12-Lead Electrocardiogram 
Appendix 16.2.7.6  Physical Examination 
16.2.8  Individual Laboratory Safety Response Data 
Appendix 16.2.8.1    Clinical Laboratory Results for Hematology 
Appendix 16.2.8.2    Clinical Laboratory Results for Serum Chemistry 
Appendix 16.2.8.3   Clinical Laboratory Results for Urinalysis 
Appendix 16.2.8.4  Urine Drug and Alcohol Screen Results 
Appendix 16.2.8.5  HIV and Hepatitis Screen Results