Conditions: Onchocerciasis
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 36
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to determine a dose of moxidectin for children 4 to 11 years that is equivalent to an 8 mg dose administered for treatment of onchocerciasis in people 12 years and over. The secondary purpose is to evaluate the safety and pharmacokinetics of a single dose of moxidectin in children and adolescents aged 4 to 17 years.

Detailed description:

Arms:
arm 1: Moxidectin 8mg per oral, single dose arm 2: Moxidectin 8mg (or lower dose) per oral, single dose arm 3: Moxidectin single dose, determined by population pharmacokinetic modelling including data from Cohorts 1 and 2

Interventions: intervention 1: Moxidectin
Intervention descriptions: intervention 1: 2 mg tablets

Protocol document:
Prot_SAP_ICF_001.pdf: 
Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
CONFIDENTIAL 
MDGH-MOX-1006 Protocol Final v1.5 200703 
Page 1 
03 Jul 2020 
(incorporating Amendments 1, 2, 3, 4 and 5) 
Clinical Study Protocol 
 
Study Title: 
An open-label study of the pharmacokinetics and safety of a single 
dose of moxidectin per oral in subjects aged 4 to 17 years with (or at 
risk of) onchocerciasis to identify an optimal dose for treatment of 
children 4 to 11 years. 
Sponsor: 
Medicines Development for Global Health 
Investigational New Drug 
(IND) No (If applicable): 
IND 126876 
Protocol Number: 
MDGH-MOX-1006 
Medical Monitor: 
Dr Jolanta Airey  
Consultant Clinical Development Physician 
SJA Consulting Services, Australia 
Telephone: 
 
Protocol Version/Date: 
Current: 
Final v1.5 (incorporating 
Amendments 1, 2, 3, 4 and 
5) 
Date: 
03 Jul 2020 
 
Prior 
version: 
Final v1.4 (incorporating 
Amendments 1, 2, 3 and 4) 
Date: 
21 Jan 2020 
 
CONFIDENTIALITY STATEMENT 
This study is being performed in compliance with the guidelines of Good Clinical Practice 
(GCP) and all essential documents are being archived. 
Until publication of this protocol following approval by applicable Regulatory Authorities and 
Ethics Committees, any unpublished information contained in this document is the property 
of, or under the control of Medicines Development for Global Health and is provided to you 
in confidence as an Investigator, potential Investigator, or consultant, for review by you, your 
staff, and any applicable Regulatory Authority or Ethics Committee. The information is only 
to be used by you in connection with authorized clinical studies of the investigational product 
described in the protocol. Prior to publication, you will not disclose any of the information to 
others without written authorization from Medicines Development for Global Health, except 
to the extent necessary to obtain informed consent from those persons to whom the drug 
may be administered. 
 
 






Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
CONFIDENTIAL 
MDGH-MOX-1006 Protocol Final v1.5 200703 
Page 4 
03 Jul 2020 
(incorporating Amendments 1, 2, 3, 4 and 5) 
STUDY SYNOPSIS (Project Summary) 
Protocol Number: 
MDGH-MOX-1006 
Study Title: 
An open-label study of the safety and pharmacokinetics of a single dose of moxidectin 
per oral in subjects aged 4 to 17 years with (or at risk of) onchocerciasis to identify an 
optimal dose for treatment of children 4 to 11 years. 
Investigational 
Product: 
Moxidectin 
Indication: 
Treatment of onchocerciasis 
Development Phase: 
Phase I 
Background: 
Moxidectin, a macrocyclic lactone of the milbemycin class, has broad activity against 
filarial and ectoparasitic diseases. Moxidectin has been shown in clinical trials to be well 
tolerated when administered as a single dose of between 2 and 36 milligrams (mg). A 
Phase III clinical trial completed in adults and adolescents (aged 12 years and over) with 
onchocerciasis demonstrated that moxidectin 8 mg provided superior skin microfilariae 
suppression compared to ivermectin (Mectizan®; Merck & Co., Inc.), the current 
standard of care for onchocerciasis. Moxidectin 8 mg as a single oral dose is approved 
by the United States Food and Drug Administration (US FDA) for the treatment of 
onchocerciasis due to Onchocerca (O.) volvulus in patients aged 12 years and over. 
The optimal dose of moxidectin to treat onchocerciasis in children less than 12 years of 
age is not known. The pharmacokinetics of moxidectin in children and adolescents aged 
4 to 17 years is also not known. 
This study minimizes the number of children and the number of invasive procedures for 
each child. In-center stays with a parent or guardian will be implemented to reduce the 
travel required and maximize their access to support during study procedures. Efficacy 
has been demonstrated in the Phase III study and does not form an objective of this 
study. As such, skin snipping to determine skin microfilariae density is not included in 
this study. To balance risks in study participation with potential individual benefit from 
treatment, participants will be recruited from an area where onchocerciasis is endemic. 
Pharmacokinetic results are not anticipated to be affected by infection status. Potential 
adverse events (AEs) associated with effective treatment of onchocerciasis are 
expected to be manageable and transient. 


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
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Page 5 
03 Jul 2020 
(incorporating Amendments 1, 2, 3, 4 and 5) 
Rationale: 
To characterize the pharmacokinetics and safety of moxidectin in children (aged 4 to 
11 years) and adolescents (aged 12 to 17 years) and to enable determination of an 
optimal dose for treatment of children 4 to 11 years. 
Design: 
Prospective, age-stratified, adaptive, open-label, single-dose pharmacokinetic and 
safety study of moxidectin in children and adolescents aged 4 to 17 years with, or at risk 
of, infection with O. volvulus. 
Number of Subjects: 
Approximately 27 with approximately 9 subjects per cohort (to a maximum of 63, 
depending on pharmacokinetic outcomes).  
Number of Centers: 
One site – School of Public Health, University of Health and Allied Sciences (UHAS) 
Research Centre, formerly the Onchocerciasis Chemotherapy Research Centre (OCRC) 
research facility, Volta Region, Ghana. 
Primary Objective: 
Identify an optimal dose of moxidectin for the treatment of children aged 4 to 11 years 
with onchocerciasis. 
Secondary 
Objectives: 
Evaluate the safety and pharmacokinetics of a single dose of moxidectin in children and 
adolescents aged 4 to 17 years.  
Primary Endpoints:  
Dose(s) for children aged 4 to 11 years will be selected based on non-compartmental 
exposure metrics including area under the concentration time curve (AUC) assessed up 
to and including Day 28 and a population pharmacokinetic model.  
Secondary 
Endpoints: 
Safety endpoints include the incidence and severity of AEs, physical examination 
findings, changes in vital signs, and laboratory safety parameters at all time points in the 
study.  
Pharmacokinetic parameters of moxidectin in children and adolescents aged 4 to 
17 years, including maximum observed plasma concentration (Cmax), time to maximum 
observed plasma concentration (Tmax), and other pharmacokinetic parameters will be 
determined by non-compartmental analysis or other methods, as appropriate. 


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
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Page 6 
03 Jul 2020 
(incorporating Amendments 1, 2, 3, 4 and 5) 
Inclusion Criteria: 
1. 
Aged 4 to 17 years, inclusive: 
Cohort I: 12 to 17 years;  
Cohort II: 8 to 11 years;  
Cohort III: 4 to 7 years.  
2. 
Live in a region designated by the World Health Organization (WHO) as endemic 
for O. volvulus infection (World Health Organization 2019). Specifically, participants 
will be recruited from the Kpassa sub-district of the Nkwanta North district. The 
specific communities will include Wii, Jagri-Do, and Azua, where mass drug 
administration with ivermectin for onchocerciasis commenced in October 2017; 
3. 
Willing and able to remain at the research center from Screening up to Day 7; 
4. 
Provision of parental or guardian written informed consent and child assent / lack of 
expression of ‘deliberate objection’ (as appropriate for age); 
5. 
Females of childbearing potential must commit to using a highly effective method of 
contraception as per local family planning guidelines from Baseline (pre-treatment 
on Day 0) until approximately 6 months (Week 24) after treatment with study drug. 
Exclusion Criteria: 
1. 
History of serious medical or psychiatric condition which, in the opinion of the 
investigator, would put the subject at increased risk by participating in the study or 
jeopardize study outcomes; 
2. 
Known or suspected concurrent clinically significant renal, cardiac, pulmonary, 
vascular, metabolic (thyroid disorders, adrenal disease), immunological disorders or 
malignancy, congenital heart disease, chronic lung disease; 
3. 
Has received an investigational product within 28 days, or 5 half-lives, of Baseline, 
whichever is longer; 
4. 
Has received ivermectin or any other anti-helminthic treatments within 28 days of 
Baseline; 
5. 
Has received a vaccination within 7 days of Baseline; 
6. 
Known or suspected hypersensitivity to macrocyclic lactones or excipients used in 
the formulation of moxidectin; 
7. 
Poor venous access; 
8. 
Unable to swallow tablets (flat oval, 8.0 millimeters (mm) x 4.5 mm x 3.0 mm); 
9. 
Weight: 
Cohort I (12 to 17 years): < 30 kg 
Cohort II (8 to 11 years): < 18 kg 
Cohort III (4 to 7 years): < 12 kg 
10. Clinically relevant laboratory abnormalities at Screening, including: 
o 
Hemoglobin < 9.5 grams per deciliter (g/dL) 
o 
Neutrophil (granulocyte) count < 1.5 x 109/L  
o 
Platelet count < 110 x 109/L  
o 
Alanine aminotransferase (ALT) > 1.5 times the upper limit of normal 
range (ULN) 


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
CONFIDENTIAL 
MDGH-MOX-1006 Protocol Final v1.5 200703 
Page 7 
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(incorporating Amendments 1, 2, 3, 4 and 5) 
o 
Total bilirubin > 1.5 times ULN 
11. Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV) positive; 
12. Known or suspected malaria or other ongoing viral, bacterial, or plasmodium 
infection at Screening and/or Baseline; 
13. Loa loa co-infection; 
14. Unwilling, unlikely or unable to comply with all protocol specified assessments; 
15. For females of child-bearing potential, pregnant or breastfeeding, or planning to 
become pregnant; 
16. Previous enrolment in this study; 
17. Is a sibling of another child already enrolled in this study. 
Investigational 
Product: 
Moxidectin oral tablets 2 mg.  
Comparator: 
None 
Design Details and 
Dose Regimens:  
Each subject will receive a single oral dose of moxidectin. 
Three age-defined cohorts will be recruited: 
i. 
Cohort I (12 to 17 years, n = 9) will receive moxidectin 8 mg (4 x 2 mg tablets) 
ii. 
Cohort II: (8 to 11 years, n = 9) will receive moxidectin 8 mg (4 x 2 mg tablets)  
A sentinel group of three subjects will be enrolled in Cohort II. If safety up to 
and including Day 3 in these subjects is acceptable, the additional 6 subjects 
will be enrolled.  
Once all Cohort I and II subjects complete Day 28, a Data and Safety Monitoring 
Board (DSMB) will review safety and pharmacokinetic data to recommend if Cohort III is 
enrolled, and if so, the dose of moxidectin to be administered.  
iii. 
Cohort III: children 4 to 7 years, inclusive (n = 9) will receive a single oral dose 
of moxidectin at a dose to be determined from analyses of Cohorts I and II. 
Initially, a sentinel group of 3 subjects will be enrolled. If safety up to and 
including Day 3 in these subjects is acceptable, the additional 6 subjects will be 
enrolled.  
If for Cohorts II and III, the starting dose results in at least 3 of the subjects having 
moxidectin exposures above the target range, a revised dose will be determined in 
decrements of 2 mg and the Cohort will be repeated with at least 9 new subjects 
enrolled at the new dose. If for Cohort III, the starting dose results in at least 3 subjects 
having moxidectin exposures below the target range, a revised dose will be determined 
in increments of 2 mg to a maximum dose of 8 mg. 


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
CONFIDENTIAL 
MDGH-MOX-1006 Protocol Final v1.5 200703 
Page 8 
03 Jul 2020 
(incorporating Amendments 1, 2, 3, 4 and 5) 
Duration of 
Treatment Per 
Subject: 
Approximately 28 weeks total: up to 30 days prior to Day 0 for consent and pre-
screening, up to 7 days prior to Day 0 for Screening, 7 days in-center and 23 weeks 
outpatient follow up post-treatment. 
Study Procedures: 
Consent and assent (or lack of expression of ‘deliberate objection’, as appropriate for 
age) will be obtained in the village setting and may be obtained up to 30 days prior to 
Baseline. After obtaining written informed consent from the parent(s)/guardian(s) and 
assent (or determining lack of expression of ‘deliberate objection’) from the child (see 
Section 14.1.2 for details), children meeting eligibility criteria that are able to be 
evaluated in the village, will be invited to attend the research center for further 
screening, together with one parent or guardian. Transport by car to and from the 
research center will be provided. Screening procedures will be completed at the 
research center from Day -7 to Day -1 to determine eligibility to participate. On the 
morning of Day 0 the Baseline assessment and confirmation of eligibility will be 
completed. Subjects meeting all of the inclusion and none of the exclusion criteria will 
receive treatment and be monitored post-treatment throughout the day. They will remain 
in the research center until Day 7, and then return to the center at Days 14 and 28, and 
at Week 12 for pharmacokinetic sample collection and safety review and at Week 24 for 
a final safety review. For further details of clinical study procedures, please refer to 
schedule of assessments as presented in Table 1. 
Additional visits and/or assessments may be conducted as clinically indicated. These 
data will be captured in the Case Report Form (CRF) as unscheduled visits, as 
appropriate. 
Contraindications to 
Further Dosing: 
Not applicable on an individual subject basis as all subjects will receive a single dose 
only. 
Dosing of additional subjects in the study will be guided by the DSMB. 
Safety Parameters: 
Physical examinations. 
Vital signs: Respiratory rate, pulse rate, temperature, blood pressure. 
Hematology: Hemoglobin, hematocrit, red blood cell (RBC) count and RBC morphology 
(if abnormal), white blood cell and differential white blood cell count, platelet count. 
Clinical chemistry: aspartate aminotransferase (AST), ALT, gamma-glutamyl 
transferase (GGT), amylase, creatine kinase, total protein, albumin, direct and total 
bilirubin, sodium, potassium, chloride, bicarbonate, phosphorus, blood urea nitrogen 
(BUN), creatinine. 


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
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Page 9 
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(incorporating Amendments 1, 2, 3, 4 and 5) 
Specialized Tests 
and Analyses: 
Plasma pharmacokinetic samples will be collected at Screening (to avoid an extra blood 
collection time point pre-dose) then at Hours 1, 2, 4, 8, 24 and 72 and Days 7, 14 
and 28 and Week 12 post dose. 
Testing for HIV, hepatitis B surface antigen and hepatitis C virus will be conducted at 
Screening. Loiasis will be assessed by daytime blood smear, if required. 
Sample Size 
Determination: 
No formal sample size determination has been undertaken. 
Approximately 9 subjects in each Cohort at a given dose is considered to be an 
adequate sample size for full characterization of the pharmacokinetics of a single dose 
of moxidectin.  
Statistical Analyses: 
No formal hypothesis testing will be performed in this study. Analyses will be descriptive. 
All planned analyses, including non-compartmental pharmacokinetics, population 
pharmacokinetic modelling and safety analyses, will be described in a Statistical 
Analysis Plan (SAP) that will be finalized prior to commencing data analysis.  
At the conclusion of analysis of data for Cohorts I and II, the existing population 
pharmacokinetic model will be updated with these data and formal simulations of AUC 
from time 0 extrapolated to infinity (0-inf) and Cmax will be performed by age, and other 
possible covariates to support ongoing dose decisions and initiation of Cohort III. At the 
end of the study, the population pharmacokinetic model will be updated with data from 
all cohorts to support the dose rationale for children. 
Data and Safety 
Monitoring Board 
(DSMB): 
A DSMB of independent experts has been established, with a charter that defines in 
detail its roles and responsibilities. 
The DSMB will review the safety and pharmacokinetic data following completion of 
enrolment and pharmacokinetic data analysis for both Cohorts I and II and advise the 
sponsor on the dose with which Cohort III will be initiated. The DSMB will also meet as 
required during the study. The DSMB will receive any reported Serious Adverse Events 
(SAEs) throughout the study. 
The DSMB will recommend to the Sponsor whether the trial may continue as planned or 
if the trial should be modified or stopped. Any decision to modify or stop the study will be 
communicated to investigators, and regulatory agencies by the Sponsor. Ethics 
Committees will be notified by the investigator according to their requirements. 


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
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Page 10 
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(incorporating Amendments 1, 2, 3, 4 and 5) 
Special Protocol 
Requirements or 
Issues: 
The study will be conducted in an area(s) endemic for O. volvulus and currently 
participating in implementation of ivermectin treatment.  
The study will recruit subjects in communities in the Volta Region of Ghana familiar with 
clinical research and the research center in Hohoe where the in-center period of the 
study will be conducted, since participants in the Phase III study of moxidectin were 
recruited from these villages. This will facilitate understanding of the study and enable 
parents/guardians, as well as children, to provide appropriate informed consent and 
assent for study participation.  


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
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Page 11 
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(incorporating Amendments 1, 2, 3, 4 and 5) 
Table 1: Table of Assessments 
Assessment 
Consent & 
Pre-
screening 
Screening 
On-Study Period 
Exit 
Evaluation 
In-center 
Outpatient 
D-30 to 
D-1 
D-7 to D-1 
D0 
D1 
(H24) 
D2 
(H48) 
D3 
(H72) 
D7 
D14 
D28 
W12 
W24 
(or Unscheduled 
/ Early 
Withdrawal visit) 
Pre- 
Dose 
/ BL 
H0 
H1 
H2 
H4 
H8 
Allowable assessment window 
 
 
 
 
±10M ±10M ±30M ±1H 
±2H 
±2H 
±2H 
±1D 
±2D 
±4D 
±14D 
±28D 
Informed consent / assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination a 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examination a 
 
 
X 
 
(X) 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals signs b 
 
X 
X 
 
X 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Xi 
Arm circumference 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
X 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Hematology c,g 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
(X) 
Clinical chemistry c,g 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
(X) 
Pregnancy test d 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Xi 
Pharmacokinetic blood sampling g 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Screening for co-infections f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moxidectin administration h 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X<------------------------------------------------------------------------------------------------------------------------------------------------------------------->X 
Concurrent medications 
X<------------------------------------------------------------------------------------------------------------------------------------------------------------------->X 
Abbreviations: X = required; (X) = as clinically indicated; M = minutes; H = hour; D = day; W = Week; ECG = electrocardiogram; BL = Baseline. 
a. A full physical examination at Screening, a targeted physical examination (informed by concurrent conditions, signs, symptoms and adverse events) at all subsequent time points. 
b. Blood pressure, pulse, temperature and respiratory rate will be measured lying semi-supine for 5 mins. Unscheduled recordings will be performed if clinically indicated.  
c. Blood samples (approx. 2 milliliter (mL) total) for hematology and biochemistry testing will be drawn within 3 days prior to the Baseline visit (Day 0) and results available prior to dosing.  
d. Serum pregnancy testing will be conducted at Screening and urine pregnancy testing for all other time points for female subjects who are of child-bearing potential (may be conducted at 
unscheduled visits as clinically indicated). 
f. Testing for Human Immunodeficiency Virus (HIV), hepatitis B, and hepatitis C. Loa loa testing only for subjects who have a history of residence in an endemic area.  
g. Application of topical local anesthetic is recommended prior to obtaining blood samples via cannula or needle.  
h. Study drug dosing will be after an overnight fast. Breakfast may be given 2 hours after dosing (and following the H2 blood sample collection). 
i. Not required at unscheduled visits unless clinically indicated. 


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS .................................................................................................................... 12 
2 
STUDY CONTACTS ......................................................................................................................... 21 
3 
INTRODUCTION ............................................................................................................................... 22 
3.1 
Onchocerciasis .......................................................................................................................... 22 
3.2 
Current Treatment and Unmet Need ......................................................................................... 22 
3.3 
Moxidectin ................................................................................................................................. 23 
3.3.1 
Nonclinical ......................................................................................................................... 24 
3.3.1.1 
Pharmacology ................................................................................................................ 24 
3.3.1.2 
Nonclinical Safety .......................................................................................................... 24 
3.3.1.3 
Absorption, Distribution, Metabolism and Excretion ...................................................... 26 
3.3.2 
Clinical ............................................................................................................................... 27 
3.3.2.1 
Clinical Pharmacology ................................................................................................... 28 
3.3.2.2 
Clinical Safety & Efficacy ............................................................................................... 29 
3.4 
Background Rationale ............................................................................................................... 32 
3.4.1 
Study Rationale (Study Goals and Objectives) ................................................................. 32 
3.4.2 
Age Rationale .................................................................................................................... 32 
3.4.3 
Design Rationale ............................................................................................................... 33 
3.4.4 
Dose Rationale .................................................................................................................. 36 
3.4.4.1 
Nonclinical Dose Rationale ........................................................................................... 36 
3.4.4.2 
Population Pharmacokinetic Modelling ......................................................................... 37 
3.4.4.3 
Consideration of Dose Format (Ability of Children to Swallow Dose) ........................... 39 
4 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 40 
4.1 
Objectives .................................................................................................................................. 40 
4.2 
Endpoints ................................................................................................................................... 40 
5 
STUDY DESIGN................................................................................................................................ 41 
5.1 
Study Design ............................................................................................................................. 41 
5.2 
Number of Subjects ................................................................................................................... 41 
5.3 
Cohorts and Dosing Regimens (Methodology) ......................................................................... 41 
5.4 
Study Sites ................................................................................................................................ 43 
5.5 
Estimated Duration of the Study ................................................................................................ 43 
5.6 
Expansion in Children 4 to 11 years, Inclusive ......................................................................... 43 
6 
STUDY POPULATION ...................................................................................................................... 45 
6.1 
Selection of Subjects ................................................................................................................. 45 
6.2 
Inclusion Criteria ........................................................................................................................ 45 
6.3 
Exclusion Criteria ....................................................................................................................... 46 
6.4 
Other Study Eligibility Criteria Considerations .......................................................................... 47 


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6.4.1 
Contraception .................................................................................................................... 47 
6.4.2 
Rescreening ...................................................................................................................... 48 
7 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ................................................................. 49 
7.1 
Study Schedule of Evaluations .................................................................................................. 49 
7.2 
Visit Windows ............................................................................................................................ 49 
7.3 
Study Procedures / Assessment Periods .................................................................................. 49 
7.3.1 
Consent/Assent ................................................................................................................. 49 
7.3.2 
Pre-Screening (Screening Conducted in the Community) ................................................ 50 
7.3.3 
Screening .......................................................................................................................... 50 
7.3.4 
Day -1 ................................................................................................................................ 51 
7.3.5 
Day 0 (Baseline, Dosing and Post-Dose Assessment) ..................................................... 51 
7.3.5.1 
Pre-dose ........................................................................................................................ 51 
7.3.5.2 
Dosing............................................................................................................................ 52 
7.3.5.3 
Post-Dose ...................................................................................................................... 52 
7.3.6 
Day 1 (24 hours) ................................................................................................................ 52 
7.3.7 
Day 2 (48 hours) ................................................................................................................ 53 
7.3.8 
Day 3 (72 hours) ................................................................................................................ 53 
7.3.9 
Day 7 ................................................................................................................................. 53 
7.3.10 
Day 14 Visit ....................................................................................................................... 54 
7.3.11 
Day 28 Visit ....................................................................................................................... 54 
7.3.12 
Week 12 Visit ..................................................................................................................... 54 
7.3.13 
Week 24, Exit Evaluation .................................................................................................. 55 
7.3.14 
Unscheduled Visits ............................................................................................................ 55 
7.4 
Details of Scheduled Assessments ........................................................................................... 56 
7.4.1 
Demographic Data, Medical History, Physical Examination, Vital Signs .......................... 56 
7.4.2 
Electrocardiograms ............................................................................................................ 57 
7.4.3 
Blood and Urine Samples .................................................................................................. 57 
7.4.3.1 
Safety Laboratory Tests ................................................................................................ 58 
7.4.3.2 
Pharmacokinetic Samples ............................................................................................. 58 
7.4.3.3 
Testing for Other Infections ........................................................................................... 59 
7.4.3.4 
Pregnancy Test ............................................................................................................. 59 
7.4.3.5 
Handling and Processing of Biological Specimens ....................................................... 59 
8 
INVESTIGATIONAL PRODUCT ....................................................................................................... 61 
8.1 
Randomization Process ............................................................................................................ 61 
8.2 
Blinding ...................................................................................................................................... 61 
8.3 
Treatment Allocation .................................................................................................................. 61 
8.4 
Supply, Packaging and Labelling .............................................................................................. 61 


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8.5 
Storage and Handling ................................................................................................................ 62 
8.5.1 
Dosage and Administration of Moxidectin Tablets ............................................................ 62 
8.5.2 
Dispensing and Accountability .......................................................................................... 63 
9 
CONCURRENT MEDICATIONS AND TREATMENTS .................................................................... 64 
10 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ................................................................ 65 
10.1 
Safety Parameters ..................................................................................................................... 65 
10.2 
Adverse Events ......................................................................................................................... 65 
10.2.1 
Assessment of Adverse Events ......................................................................................... 65 
10.2.2 
Adverse Event Reporting Period ....................................................................................... 66 
10.3 
Serious Adverse Events ............................................................................................................ 66 
10.3.1 
Clarification of (Serious) Adverse Events .......................................................................... 67 
10.3.2 
Serious Adverse Event Reporting Requirements .............................................................. 68 
10.3.2.1 
All Serious Adverse Events ....................................................................................... 68 
10.3.2.2 
Investigator Reporting Requirements for SAEs ........................................................ 68 
10.4 
Follow Up of Serious and Non-Serious Adverse Events ........................................................... 69 
10.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs or SAEs ........... 69 
10.6 
Toxicity Management ................................................................................................................ 69 
10.7 
Guidance for Dose Modification or Discontinuation of Treatment ............................................. 69 
10.8 
Warnings and Precautions ........................................................................................................ 70 
10.9 
Risks for Women of Childbearing Potential or During Pregnancy ............................................ 70 
10.10 
Procedures to be Followed in the Event of Pregnancy ......................................................... 70 
11 
DATA AND SAFETY MONITORING BOARD (DSMB) ................................................................ 72 
12 
SUBJECT COMPLETION / WITHDRAWAL ................................................................................ 73 
12.1 
Subject Completion ................................................................................................................... 73 
12.2 
Criteria for Premature Withdrawal from Treatment or the Study ............................................... 73 
12.3 
Withdrawal of Subjects from Moxidectin ................................................................................... 73 
12.4 
Withdrawal of Subjects from the Study ..................................................................................... 74 
12.5 
Replacement of Withdrawn Subjects ........................................................................................ 74 
12.6 
Premature Termination of the Study ......................................................................................... 74 
13 
DATA MANAGEMENT CONSIDERATIONS AND STATISTICAL ANALYSIS ........................... 76 
13.1 
Hypothesis ................................................................................................................................. 76 
13.2 
Sample Size Determination ....................................................................................................... 76 
13.3 
Enrolment and Randomization .................................................................................................. 76 
13.4 
Analysis Populations ................................................................................................................. 76 
13.4.1 
Demographic and Baseline Characteristics ...................................................................... 77 
13.4.2 
Data Analysis Methods ...................................................................................................... 77 
13.5 
Statistical and Analytical Plan ................................................................................................... 77 


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13.5.1 
Analysis of Demographics ................................................................................................. 77 
13.5.2 
Analysis of Pharmacokinetics ............................................................................................ 77 
13.5.3 
Population Pharmacokinetics ............................................................................................ 78 
13.5.4 
Analysis of Safety .............................................................................................................. 79 
13.6 
Pharmacokinetic Assessments for Dose Determinations ......................................................... 80 
14 
GENERAL STUDY ADMINISTRATION ....................................................................................... 81 
14.1 
Ethical Aspects (Ethical and Safety Considerations) ................................................................ 81 
14.1.1 
Local Regulations/Declaration of Helsinki ......................................................................... 81 
14.1.2 
Informed Consent .............................................................................................................. 81 
14.1.2.1 
Informing Communities about the Study ................................................................... 82 
14.1.2.2 
Informing Potential Subjects and their Parents/Guardians ....................................... 82 
14.1.2.3 
Informing Children Too Young/Immature to Give Assent. ......................................... 85 
14.1.3 
Compensation ................................................................................................................... 85 
14.1.4 
Provision for Study Visits During School Time .................................................................. 86 
14.1.5 
Ethics Committees ............................................................................................................. 86 
14.1.6 
Conditions for Modifying the Protocol ................................................................................ 86 
14.1.7 
Conditions for Terminating the Study ................................................................................ 87 
14.1.8 
Blood Volumes Sampled Relative to Maximum Recommended Volumes ........................ 87 
14.1.9 
Informing Study Subjects and Communities about the Study Results .............................. 87 
14.1.10 
Implementation of the Study in the context of the COVID-19 Pandemic ...................... 87 
14.1.10.1 
Informing Communities About the Study ................................................................... 89 
14.1.10.2 
Obtaining Informed Consent/Assent ......................................................................... 91 
14.1.10.3 
Pre-screening in Villages ........................................................................................... 91 
14.1.10.4 
Transport Between Villages and the UHAS Research Center .................................. 92 
14.1.10.5 
Accommodation in the UHAS Research Center ....................................................... 92 
14.1.10.6 
Protocol-Planned Examinations ................................................................................ 93 
14.2 
Study Documentation, Case Report Forms and Record Keeping ............................................ 93 
14.2.1 
Investigator Files and Retention of Documents ................................................................ 93 
14.2.2 
Background Data ............................................................................................................... 94 
14.2.3 
Audits and Inspections ...................................................................................................... 95 
14.2.4 
Case Report Forms ........................................................................................................... 95 
14.3 
Monitoring the Study .................................................................................................................. 95 
14.4 
Confidentiality of Trial Documents and Subject Records .......................................................... 96 
14.5 
Publication of Data (Dissemination of Results) ......................................................................... 96 
14.6 
Anticipated Subject Accrual and Duration of the Study ............................................................. 97 
15 
REFERENCES .............................................................................................................................. 98 
16 
APPENDICES ............................................................................................................................. 102 


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16.1 
World Health Organization Designation of Onchocerciasis Endemicity .................................. 102 
16.2 
Population Pharmacokinetic Simulation of Moxidectin to Determine Initial Dosing 
Recommendations for Subjects in Study MDGH-MOX-1006 (d3 Medicine Report, 9 Dec 2016, and 
Statistical Appendix, 26 Nov 2019) ..................................................................................................... 103 
16.3 
Vital Signs Reference Values for Children .............................................................................. 134 
16.4 
Laboratory Reference Values for Ghanaian Children ............................................................. 135 
16.5 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.1, July 2017 ............................................................................................................ 136 
16.6 
Model Adolescent (12 to 17 years) and Parent/Guardian Information Sheet and Assent and 
Consent Form ...................................................................................................................................... 171 
16.7 
Model Information Sheet and Consent Form for Parents/Guardians of Children 4 to 11 Years, 
Including Assent Form for Children 7 to 11 Years .............................................................................. 190 
16.8 
Model Information Sheet for Children 7 to 11 Years ............................................................... 209 
16.9 
Model Information Sheet for Children 4 to 6 Years and Older Children Considered Not Mature 
Enough to Provide Assent ................................................................................................................... 215 
16.10 
Summary of Protocol Amendments ..................................................................................... 219 
16.10.1 
Rationale for Protocol Amendment No. 1 .................................................................... 219 
16.10.2 
Rationale for Protocol Amendment No. 2 .................................................................... 224 
16.10.3 
Rationale for Protocol Amendment No. 3 .................................................................... 237 
16.10.4 
Rationale for Protocol Amendment No. 4 .................................................................... 269 
16.10.5 
Rationale for Protocol Amendment No. 5 .................................................................... 271 
 
LIST OF FIGURES 
Figure 1: Enrolment and Dosing Decision Tree ..................................................................................... 42 
Figure 2: Capacity and Utilization of Participant and Parent/guardian Wards and Recreational Areas 
During the COVID-19 Pandemic ............................................................................................................ 93 
Figure 3: Onchocerciasis Endemicity (2017) and Status of Onchocerciasis Therapeutic Mass Drug 
Administration Coverage (2016) in Ghana ........................................................................................... 102 
 
LIST OF TABLES 
Table 1: Table of Assessments .............................................................................................................. 11 
Table 2: Treatment-emergent Adverse Events Occurring in > 10% of Moxidectin-treated Patients with 
Onchocerciasis in ONCBL60801 (Phase III) .......................................................................................... 30 
Table 3: Number (%) of Subjects Reporting Treatment-Emergent Serious Adverse Events 
(ONCBL60801) ....................................................................................................................................... 31 


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Table 4: Summaries of Cmax and AUC inf for Children 4 to 11 years (8 mg), Adolescents 12 to 17 years 
(8 mg) and  Adult O. volvulus-infected Individuals and Healthy Volunteers (8 mg, 16 mg, 36 mg) 
Emerging from the Population Pharmacokinetic Model Used to Determine the Starting Dose for Children 
8 to 11 Years .......................................................................................................................................... 38 
Table 5: Allowable Visit Windows ........................................................................................................... 49 
Table 6: Relationship to Investigational Product Assessment Terms .................................................... 66 
Table 7: Vital Signs Reference Ranges for Children ............................................................................ 134 
Table 8: Laboratory Reference Ranges for Children ........................................................................... 135 
Table 9: Details of Administrative Protocol Amendments (Amendment 1) .......................................... 219 
Table 10: Details of Non-Administrative Protocol Amendments (Amendment 1) ................................ 220 
Table 11: Details of Administrative Protocol Amendments (Amendment 2) ........................................ 224 
Table 12: Details of Non-Administrative Protocol Amendments (Amendment 2) ................................ 225 
Table 13: Details of Administrative Protocol Amendments (Amendment 3) ........................................ 237 
Table 14: Details of Non-Administrative Protocol Amendments (Amendment 3) ................................ 261 
Table 15: Details of Administrative Protocol Amendments (Amendment 4) ........................................ 269 
Table 16: Details of Administrative Protocol Amendments (Amendment 5) ........................................ 271 
Table 17: Details of Non-Administrative Protocol Amendments (Amendment 5) ................................ 272 
 
 
 


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ABBREVIATIONS 
Abbreviation  
Definition  
% 
percent/percentage 
< 
less than 
> 
greater than 
≤ 
less than or equal to 
≥ 
equal or greater to 
°C 
degrees Celsius 
°F 
degrees Fahrenheit 
g 
microgram(s) 
L 
microliter(s) 
mol 
micromole(s) 
M 
micromolar 
AE  
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-inf 
AUC from time 0 extrapolated to infinity 
AUC0-last 
AUC from time 0 extrapolated to the last observed concentration 
BL 
Baseline 
BUN 
blood urea nitrogen 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
apparent plasma clearance 
CL/F 
apparent plasma clearance, fasting 
CLd2 
clearance from the second compartment 
cm 
centimeter(s) 
Cmax  
maximum observed plasma concentration  
CNS 
central nervous system 
CRF 
case report form 
cumAUC0-t 
cumulative AUC from time 0 extrapolated to time t (where t = 24, 48, and 
72 hours) 
CYP 
cytochrome 
D 
day 
DAIDS 
Division of AIDS 
dL 
deciliter 
DSMB 
Data and Safety Monitoring Board 
ECG  
electrocardiogram  
eCRF  
electronic case report form  
ESPEN 
Expanded Special Project for Elimination of Neglected Tropical Diseases 
fL 
femtoliter(s) 
g/dL 
grams per deciliter 


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Abbreviation  
Definition  
GABA 
gamma-aminobutyric acid 
GCP  
Good Clinical Practice  
GGT 
gamma-glutamyl transferase 
GHS 
Ghana Health Service 
H or h 
hour 
HIV 
human immunodeficiency virus 
HV 
healthy volunteers 
IC50 
half maximal inhibitory concentration 
ICH  
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ID 
identification 
IND 
Investigational New Drug 
IQR 
interquartile range 
IU 
international units 
kg 
kilogram(s) 
L 
liter(s) 
LAR 
legally acceptable representative 
LC 
liquid chromatography 
LD50 
lethal dose, 50% fatalities in test sample 
M 
minute 
MDGH 
Medicines Development for Global Health 
mg 
milligram(s) 
mL 
milliliter(s) 
mm 
millimeter(s) 
mmHg 
millimeters of mercury 
mmol/L 
millimoles per liter 
MS 
mass spectrometry 
N or n 
number 
ng 
nanogram(s) 
NOAEL 
no observed adverse effect level 
O. volvulus 
Onchocerca volvulus 
OCRC 
Onchocerciasis Chemotherapy Research Centre 
OV16 IgG4 
Onchocerca volvulus 16 antigen immunoglobulin G4 
pg 
picogram(s) 
P-gp 
P-glycoprotein 
PI 
Principal Investigator 
QTc 
corrected QT (interval) 
QTcB 
QTc – Bazett's correction formula 
QTcF 
QTc – Fridericia's correction formula 
RBC 
red blood cell 
SAE  
serious adverse event  


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Abbreviation  
Definition  
SAP 
statistical analysis plan 
SD 
standard deviation 
SOP  
standard operating procedure  
SRM 
study reference manual 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life  
Tmax  
time to maximum observed plasma concentration  
UHAS 
University of Health and Allied Sciences 
ULN 
upper limit of normal range 
US 
United States 
US FDA 
United States Food and Drug Administration 
Vc 
central volume of distribution 
Vp2 
volume of distribution of the second peripheral compartment 
W 
week 
WHO 
World Health Organization 


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2 
STUDY CONTACTS 
The study will be conducted at the School of Public Health, University of Health and Allied 
Sciences (UHAS) Research Centre, formerly the Onchocerciasis Chemotherapy Research 
Centre (OCRC) research facility, Volta Region, Ghana. 
Refer to the Study Reference Manual (SRM) for full study contacts. 


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3 
INTRODUCTION 
3.1 Onchocerciasis 
Onchocerciasis (river blindness) is a serious, debilitating, and stigmatizing parasitic disease 
caused by the helminth O. volvulus. It is recognized as an important public health issue by 
health authorities worldwide and is listed by the WHO (African Programme for Onchocerciasis 
Control 2015) and US FDA (The Henry J. Kaiser Family Foundation 2015) as one of the 
neglected tropical diseases for which new treatments are sought.  
Onchocerciasis is endemic in sub-Saharan Africa (Zoure et al. 2014). More than 200 million 
people are considered to be at risk of infection (World Health Organization 2018). 
Onchocerciasis is the second leading cause of infectious blindness (after trachoma) and the 
fourth leading cause of preventable blindness worldwide. In addition to substantial ocular and 
cutaneous morbidity, excess mortality of visually impaired and non-impaired individuals with 
heavy onchocercal infection accounted for 5% of deaths in the Onchocerciasis Control Program 
(a WHO-managed international collaboration that ran from 1974 to 2002) area in West Africa 
(Prost and Vaugelade 1981, Pion et al. 2002, Little et al. 2004). 
O. volvulus larvae are transmitted to humans by the bite of black flies (genus Simulium), which 
breed in fast-flowing rivers and streams. The larvae develop into mature adult worms 
(macrofilariae) and become encapsulated in nodules, from which they release millions of 
microfilariae that migrate through the skin and 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. The O. volvulus microfilariae are the cause of the clinical 
manifestations of onchocerciasis which include pruritus, dermatitis, depigmentation and atrophy 
of the skin, lymphadenitis, and visual impairment leading to blindness.  
The 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 approved by the US FDA for the treatment of 
onchocerciasis in 1996 and is the current standard of care. The recommended regimen for the 


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treatment of onchocerciasis is a single oral dose of ivermectin 150 micrograms (μg) per 
kilogram (kg). In Africa, the most commonly used retreatment interval is during mass drug 
administration is 12 months. The aim of these community-directed ivermectin treatment 
programs is to achieve control of the disease as a public health problem in affected communities 
(Uniting to Combat Neglected Tropical Diseases 2012). Ultimately, the WHO and 
onchocerciasis endemic countries are working towards elimination of onchocerciasis where 
feasible. 
Despite the positive impact of ivermectin treatment, onchocerciasis is still a cause of significant 
morbidity. Suboptimal responses to ivermectin have been observed in several populations in 
Africa over several years and have been reported in the literature in both ivermectin-naïve and 
ivermectin-experienced patients (African Programme for Onchocerciasis Control 2015, Awadzi 
et al. 2004a, Awadzi et al. 2004b, Ardelli et al. 2005, Osei-Atweneboana et al. 2007, Basanez et al. 
2008, Pion et al. 2011, Bakajika et al. 2013, Coffeng et al. 2013, Awadzi et al. 2014). 
Ivermectin recipients in the Phase III study also provide further evidence of this (Opoku et al. 
2018). Adolescents (12 to 17 years of age) with pre-treatment microfilariae densities of between 
10.51 and 74.21 microfilariae per mg of skin were treated in the Phase III study (n = 77). Fifteen 
(15) of 24 (62.5%) ivermectin treated adolescents did not achieve zero skin microfilariae density 
at any time point (Month 1, Month 6, Month 12 and/or Month 18) compared with 1 of 53 (1.9%) 
moxidectin treated adolescents. Two-thirds of these subjects were enrolled in the Volta region 
of Ghana (see Section 3.4.3 for further detail). 
3.3 Moxidectin 
This section presents a brief summary of the known preclinical and clinical profile of 
moxidectin. A detailed description of the chemistry, pharmacology, efficacy and safety of 
moxidectin is provided in the current moxidectin Investigator’s Brochure. The current approved 
prescribing information for use of moxidectin tablets for onchocerciasis is available at 
Drugs@FDA (www.fda.gov/drugsatfda).  
Moxidectin is a macrocyclic lactone of the milbemycin class. It is derived (semi-synthetic) from 
the actinomycete Streptomyces cyanogriseus.  


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3.3.1 Nonclinical 
3.3.1.1 Pharmacology 
The mechanism by which moxidectin exhibits its effect against O. volvulus is not known. The 
primary pharmacology of moxidectin is proposed to be through binding to the glutamate-gated 
chloride channels. Moxidectin also binds to gamma-aminobutyric acid (GABA) receptors and/or 
adenosine triphosphate-binding cassette transporters. This leads to increased permeability, 
influx of chloride ions, hyperpolarization and muscle paralysis (Arena et al. 1995, Martin et al. 
2002, Yates et al. 2003). Additionally, there is a reduction in parasite motility (Tompkins et al. 
2010) and reduced excretion of immunomodulatory proteins of both male and female adult 
worms (Wolstenholme and Rogers 2005, Geary and Moreno 2012, Wolstenholme et al. 2016). 
Studies also suggest that while moxidectin is not effective in killing the adult worms, it does 
reduce adult worm fertility (Bourguinat et al. 2007, Stitt et al. 2011). 
Moxidectin exhibits anthelminthic activity across the nematode and arthropod phyla (Geary and 
Moreno 2012) and has demonstrated efficacy in a number of Onchocerca species, including 
O. ochengi in cattle (Trees et al. 2000), O. cervicalis in horses (Monahan et al. 1995, Mancebo 
et al. 1997), as well as Dirofilaria immitis in dogs (Nolan and Lok 2012). Moxidectin was not 
macrofilaricidal in the Onchocerca ochengi model in cattle (Trees et al. 2000).  
For further information, please refer to the Investigator’s Brochure. 
3.3.1.2 Nonclinical Safety 
3.3.1.2.1 
Safety Pharmacology 
The safety pharmacology of moxidectin has been studied using a panel of in vitro and in vivo 
pulmonary, neurofunctional and cardiac assessments. Moxidectin did not show significant 
binding activity to 64 different biological receptors in the NovaScreen assay. The inhibitory 
concentration for a 50% decrease (IC50) in the human ether-a-go-go-related gene current was 
calculated at > 10 micromolar (µM) (6.4 µg/milliliter (mL)) moxidectin.  
Moxidectin caused mild neurofunctional and respiratory effects in rats as well as a mild 
reduction in heart rate relative to baseline in dogs. Oral administration of 1.0 mg/kg moxidectin 
to beagle dogs resulted in a statistically significant decrease in heart rate, but no consistent 
changes in systolic, diastolic or mean arterial blood pressure. There were no effects on the ECG, 
including the corrected QT (QTc) interval.  


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For more information, please refer to the Investigator’s Brochure.  
3.3.1.2.2 
Toxicology 
The nonclinical toxicology profile of moxidectin is characterized by low acute toxicity, 
consisting mostly of transient central nervous system (CNS)-related clinical signs. Decreased 
body weight and/or body weight gain were also common findings, which were attributed to a 
change in consumption of food. In single and repeat dose toxicity studies with moxidectin, 
transient CNS signs were reported in mice, rats and dogs. There was no target organ toxicity in 
any of the studies based on evaluation by clinical and anatomic pathology. Moxidectin was not 
genotoxic and showed no carcinogenic potential in lifetime mouse and rat bioassays. 
Moxidectin resulted in increased incidence of malformations in rats at maternally toxic doses, 
but not in rabbits, and decreased pup survival during the lactation period in one and three 
generation pre- and post-natal rat studies.  
Macrocyclic lactones are known to interact with GABA-A receptors, expressed in nematodes 
and in the mammalian CNS. There was no histological evidence for direct neurotoxicity in 
nonclinical studies, but transient neurobehavioral effects were noted. Entrance into the brain is 
restricted by the P-glycoprotein (P-gp) efflux transporter, while toxicity is mediated through the 
brain GABA-A receptors. In P-gp-deficient mice, moxidectin was less toxic than ivermectin 
(lethal dose in 50% (LD50) was 0.46 and 2.3 micromoles (mol)/kg for ivermectin and 
moxidectin, respectively), had a lower brain-to-plasma concentration ratio and entered into the 
brain more slowly than ivermectin (Menez et al. 2012). Higher brain concentrations are required 
for moxidectin toxicity than ivermectin which causes a greater potentiation of GABA action. 
Differences in the accumulation of ivermectin and moxidectin in the brain and in the interaction 
of ivermectin and moxidectin with GABA-A receptors account for differences in neurotoxicity 
seen in nonclinical studies (Menez et al. 2012). 
For more information, please refer to the Investigator’s Brochure.  


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3.3.1.2.3 
Juvenile Nonclinical Safety 
The toxicity profile and toxicokinetics of moxidectin in juvenile dogs was evaluated in a pivotal 
single-dose oral (capsule) study. Moxidectin was administered to juvenile (11 weeks old) dogs 
at doses up to 3 mg/kg. There were no deaths and clinical observations related to the CNS (i.e. 
tremors, ataxia, abnormal posture, decreased motor activity, salivation, emesis, ptosis, and 
disorientation) were observed in all juvenile dogs in the highest dose group (3 mg/kg). The 
CNS-related clinical observations were not considered adverse because the findings were 
transient (occurring only within 24 hours after dosing and not during the remainder of the 12-
week observation period) and because the dogs 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 juvenile dogs was 
3 mg/kg. 
For more information, please refer to the Investigator’s Brochure.  
3.3.1.3 Absorption, Distribution, Metabolism and Excretion  
Moxidectin is a Biopharmaceutics Classification System Class 2 compound with high 
permeability and low solubility, which is not affected by pH.  
The pharmacokinetics of moxidectin in rats and dogs was characterized by oral absorption, low 
plasma clearance, and a high volume of distribution, leading to a long terminal elimination 
half-life (t½). The distribution of moxidectin is governed primarily by its high degree of 
lipophilicity; in rats, moxidectin was shown to be distributed to and reside predominantly in fat. 
Moxidectin is minimally metabolized in vivo. Moxidectin has also been shown to be a weak 
substrate of breast cancer resistance protein 1 (Perez et al. 2009). Moxidectin produced weak or 
no inhibition of seven major human cytochrome (CYP) P450 enzymes in vitro but did induce 
CYP3A4 messenger ribonucleic acid and enzyme activity in vitro. However, a subsequent 
clinical study showed that moxidectin was not a CYP3A4 inducer in vivo (Section 3.3.2.1). 
In rat studies, moxidectin is likely cleared by a combination of biliary excretion of unchanged 
drug and oxidative metabolism. For more information, please refer to the Investigator’s 
Brochure. 


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3.3.2 Clinical  
The moxidectin clinical program encompasses eight completed single oral dose trials spanning 
Phases I to III and involving a total of 1904 subjects.  
In six completed Phase I studies, 244 healthy volunteers received moxidectin at doses of 3 to 
36 mg and 16 healthy volunteers received placebo. The studies were: 
• A single-ascending dose, placebo-controlled, double-masked, safety, tolerability, and 
pharmacokinetic study of orally administered moxidectin in normal volunteers 
(3110A1-100-EU). 
• A study of the relative bioavailability of a tablet and a liquid formulation of 
moxidectin in healthy subjects (3110A1-101-EU). 
• An open-label, single-dose study to evaluate the excretion of moxidectin into the 
breast milk of lactating, non-breastfeeding women (3110A1-1002-EU). 
• An open-label, single-dose, 4-period, sequential study to determine the effect of 
moxidectin on CYP3A4 activity in healthy subjects using midazolam as a probe 
substrate (3110A1-1004-EU). 
• An open-label, randomized, single-dose, parallel-group study to determine the effect 
of a high-fat meal on the relative bioavailability and pharmacokinetics of a single 
dose of moxidectin administered orally to healthy subjects (3110A1-1005-EU). 
• 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 (MDGH-MOX-1008). 
In one Phase II and one Phase III study enrolling subjects with onchocerciasis, 1105 subjects 
received moxidectin at doses of 2 mg to 8 mg while 539 received ivermectin at the standard-of-
care dose of 150 μg/kg. The studies were:  
• A randomized, single-ascending-dose, ivermectin-controlled, double-blind, safety, 
tolerability, pharmacokinetic, and efficacy study of orally administered moxidectin 
in subjects with Onchocerca volvulus infection (3110A1-200-GH; Phase II) 
• A single dose, ivermectin-controlled, double blind, efficacy, safety, and tolerability 
study of orally administered moxidectin in subjects infected with 
Onchocerca volvulus (ONCBL60801; Phase III) 


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3.3.2.1 Clinical Pharmacology  
Moxidectin displays linear, dose-proportional pharmacokinetics. Following a single oral 
moxidectin dose (ranging from 3 mg to 36 mg, tablet or solution) administered to fasting 
healthy volunteers, the non-compartmentally-derived apparent moxidectin plasma 
clearance (CL/F) ranged from 2760 to 3506 mL/h in healthy volunteers and 3500 mL/h in 
patients and the mean t½ ranged from 485 to 1139 hours (approximately 20 to 47 days). 
Moxidectin was rapidly absorbed; the median Tmax in a fasted state was 3 to 4 hours post-dose. 
Moxidectin has a large apparent volume of distribution, and rapid decline of moxidectin 
concentrations occurred within 48 hours of dose administration in all studies, and, thereafter, 
plasma concentrations declined slowly in accordance with the long t½. Population 
pharmacokinetic analyses showed that the long t½ was governed by tissue distribution rate-
limited elimination. 
There were no clinically relevant effects of age, gender, race, weight, renal function or hepatic 
function on the pharmacokinetics of moxidectin from a population-pharmacokinetic model. 
Moxidectin absorption is resilient to the effects of food. Administration of moxidectin in a fed 
state modestly slows absorption and increases bioavailability, although not to a clinically 
relevant extent. Moxidectin does not induce or inhibit clinically relevant drug-drug interactions 
and it is unlikely to be a victim of drug-drug interactions via concomitant medications. 
Moxidectin is minimally metabolized and primarily excreted unchanged in the feces. Renal 
clearance of moxidectin and its metabolites is low. Moxidectin was observed in the breast milk 
of lactating women after single dose administration at a relative infant dose of less than 10% of 
the maternal dose. 
For more information, please refer to the Investigator’s Brochure.  


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3.3.2.2 Clinical Safety & Efficacy 
3.3.2.2.1 
Overview of Safety in Healthy Volunteers 
Safety data are available from six studies in healthy adult volunteers. Moxidectin was well 
tolerated when given as a single dose of between 3 and 36 mg to healthy volunteers. There was 
no treatment or dose related relationship in the incidence, nature and severity of AEs identified. 
There were no clinically relevant or treatment-related changes in laboratory parameters, 
physical examination findings, vital signs or ECGs/cardiac function. In placebo-controlled 
studies, moxidectin had a safety profile similar to placebo. No subject withdrew due to an AE 
and there were no SAEs or deaths. 
AE and laboratory findings reported for each of the completed Phase I studies are summarized 
in the Investigator’s Brochure. 
3.3.2.2.2 
Overview of Safety and Efficacy in Patients with Onchocerciasis 
The safety of moxidectin has been evaluated in patients with onchocerciasis. Signs and 
symptoms associated with microfilarial death, sometimes referred to as the “Mazzotti reaction” 
were commonly observed. These reactions are caused by an immunologically-mediated reaction 
to the death of microfilariae and manifest as pruritus, headache, pyrexia, rash, urticaria, 
hypotension (including symptomatic orthostatic hypotension and dizziness), tachycardia, edema, 
lymphadenopathy, arthralgia, myalgia, chills, paresthesia and asthenia. Ophthalmological 
manifestations include conjunctivitis, eye pain, eye pruritus, eyelid swelling, blurred vision, 
photophobia, changes in visual acuity, hyperemia, ocular discomfort and watery eyes. These 
adverse reactions generally occur and resolve in the first week post-treatment. 
In the two studies conducted in onchocerciasis patients (3110A1-200-GH and ONCBL60801), 
the profile of AEs reported for moxidectin was similar to the profile in ivermectin recipients. In 
these studies, the most commonly occurring events were pruritus, edema, headache, hypotension 
and compensatory tachycardia, rash and urticaria, myalgia, arthralgia, pyrexia and chills, 
lymphadenopathy, paresthesia and asthenia (see Table 2). These events were transient and self-
limiting, generally occurring and resolving within the first week of treatment. In general, there 
was a transient (first 48 hours) increase in the number of moxidectin subjects reporting efficacy-
associated AEs compared to ivermectin. There was not an increased need for medical or 
therapeutic intervention for management of efficacy-related events with moxidectin when 


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compared to ivermectin. Given that the spectrum of symptoms and severity were similar, the 
guidance to patients and physicians are otherwise unchanged compared to ivermectin for 
onchocerciasis patients. 
Table 2: Treatment-emergent Adverse Events Occurring in > 10% of Moxidectin-treated 
Patients with Onchocerciasis in ONCBL60801 (Phase III) 
Adverse Event 
Moxidectin 
N = 978 
n (%) 
Ivermectin 
N = 494 
n (%) 
Eosinophilia 
721 (74) 
390 (79) 
Pruritus 
640 (65) 
268 (54) 
Musculoskeletal pain a 
623 (64) 
257 (52) 
Headache 
566 (58) 
267 (54) 
Lymphocytopenia* 
470 (48) 
215 (44) 
Tachycardia b 
382 (39) 
148(30) 
Orthostatic tachycardia c 
333 (34) 
130 (26) 
Non-orthostatic tachycardia d 
179 (18) 
57 (12) 
Rash e 
358 (37) 
103 (21) 
Abdominal pain f 
305 (31) 
173 (35) 
Hypotension g 
289 (30) 
125 (25) 
Orthostatic hypotension h 
212 (22) 
81 (16) 
Pyrexia/Chills 
268 (27) 
88 (18) 
Leukocytosis 
240 (25) 
125 (25) 
Influenza like illness 
226 (23) 
102 (21) 
Neutropenia** 
197 (20) 
112 (23) 
Cough 
168 (17) 
88 (18) 
Lymph node pain 
129 (13) 
28 (6) 
Dizziness 
121 (12) 
44 (9) 
Diarrhea/Gastroenteritis/Enteritis 
144 (15) 
84 (17) 
Hyponatremia 
112 (12) 
65 (13) 
Peripheral swelling 
107 (11) 
30 (6) 
a Includes “myalgia”, “arthralgia”, “musculoskeletal pain”, “pain” and “back pain” 
b Includes “orthostatic heart rate increased”, “postural orthostatic tachycardia syndrome”, “heart rate increased” and 
“sinus tachycardia” 
c Includes “orthostatic heart rate increased” and “postural orthostatic tachycardia syndrome” 
d Includes “heart rate increased”, “tachycardia”, and “sinus tachycardia” 
e Includes “rash,” “papular rash” and “urticaria” 
f Includes “abdominal pain”, “abdominal pain upper” and “abdominal pain lower” 
g Includes “orthostatic hypotension”, “blood pressure orthostatic decreased”, “blood pressure decreased”, “mean 
arterial pressure decreased”, “hypotension” 
h Includes “orthostatic hypotension”, and “blood pressure orthostatic decreased” 
*Lymphocytopenia is defined as absolute lymphocyte count less than 1 x 109/L 
**Neutropenia is defined as absolute neutrophil count less than 1 x 109/L 
There was no pattern indicating a temporal association with treatment or with body system of 
SAEs occurring in either the 3110A1-200-GH or the ONCBL60801 studies. In both studies, 
there were no SAEs regarded by the investigator (or Sponsor) as being treatment related. 
Treatment-emergent SAEs (occurring during the first 180 days post-dose) are shown in Table 3. 


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Table 3: Number (%) of Subjects Reporting Treatment-Emergent Serious Adverse Events 
(ONCBL60801) 
Preferred Term 
Moxidectin 
N = 978  
n (%) 
Ivermectin 
N = 494  
n (%) 
No. subjects with ≥ 1 treatment emergent serious 
adverse event 
39 (4.0) 
18 (3.6)* 
No. of treatment emergent serious adverse events 
52 
25 
Malaria 
15 (1.5) 
9 (1.8) 
Gastroenteritis 
2 (0.2) 
0 
Respiratory tract infection 
0 
2 (0.4) 
Diarrhea 
1 (0.1) 
3 (0.6) 
Loss of consciousness 
2 (0.2) 
0 
Enteritis 
2 (0.2) 
0 
Gastritis 
2 (0.2) 
1 (0.2) 
Abdominal abscess 
0 
1 (0.2) 
Abscess limb 
1 (0.1) 
0 
Cellulitis 
1 (0.1) 
0 
Fungal skin infection 
1 (0.1) 
0 
Peritonitis 
1 (0.1) 
0 
Pneumonia 
1 (0.1) 
1 (0.2) 
Sepsis 
0 
1 (0.2) 
Shigella infection 
1 (0.1) 
0 
Abdominal pain 
1 (0.1) 
0 
Abdominal pain lower 
1 (0.1) 
0 
Abdominal pain upper 
0 
1 (0.2) 
Hematemesis 
1 (0.1) 
0 
Alcohol poisoning 
1 (0.1) 
0 
Clavicle fracture 
1 (0.1) 
0 
Contusion 
0 
1 (0.2) 
Head injury 
1 (0.1) 
0 
Limb injury 
1 (0.1) 
0 
Snake bite 
1 (0.1) 
0 
Splenic rupture 
1 (0.1) 
0 
Diabetic ketoacidotic hyperglycemic coma 
0 
1 (0.2) 
Hemiplegia 
1 (0.1) 
0 
Meningism 
0 
1 (0.2) 
Cardiac arrest 
1 (0.1) 
0 
Cardiac failure congestive 
1 (0.1) 
0 
Chills 
0 
1 (0.2) 
Influenza like illness 
0 
1 (0.2) 
Asthma 
1 (0.1) 
0 
Cough 
0 
1 (0.2) 
Macular hole 
1 (0.1) 
0 
Hepatitis chronic active 
1 (0.1) 
0 
Dehydration 
1 (0.1) 
0 
Rheumatic disorder 
1 (0.1) 
0 
Dysmenorrhea 
1 (0.1) 
0 
Skin ulcer 
1 (0.1) 
0 
* This includes a pre-treatment hospitalization for respiratory tract infection included as a result of missing date 
information. 


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The efficacy of moxidectin was demonstrated in two adequate and well-controlled trials 
comparing moxidectin and ivermectin as part of US FDA marketing approval activities. In both 
trials, moxidectin was superior to ivermectin in decreasing the number of O. volvulus 
microfilariae in the skin 12 months post-treatment. Both trials also demonstrated that more 
moxidectin-treated patients had no detectable microfilariae in skin samples 12 months post-
treatment. 
Further details can be found in the Investigator’s Brochure. 
3.4 Background Rationale  
3.4.1 Study Rationale (Study Goals and Objectives) 
Moxidectin was superior to ivermectin in suppressing skin and ocular microfilariae in the 
Phase III study, in more patients, to a greater extent and for longer. It is anticipated that the 
improved efficacy of moxidectin will be important in the control and elimination of 
onchocerciasis. Therefore, the purpose of this study is to determine an optimal pediatric dose of 
moxidectin for use in children with onchocerciasis aged 4 to 11 years to achieve exposure in the 
range observed in adults administered a dose of 8 mg. This will allow the use of moxidectin 
across the communities affected by this disease, including in mass drug administration programs 
for onchocerciasis control and elimination.  
3.4.2 Age Rationale 
This study will evaluate moxidectin in children aged 4 years and older. As infection rates in 
children under 4 years of age have been shown to be comparatively low in meso- and 
hyperendemic areas, the WHO and the African Program for Onchocerciasis Control previously 
recommended a lower age limit of 4 years for use of moxidectin in onchocerciasis 
control (World Health Organization 2008). 
This study also includes adolescents aged 12 to 17 years, noting that this age range was enrolled 
into the Phase III study. Although safety and efficacy were evaluated in this age group in the 
Phase III study, pharmacokinetic data were not collected. This study will permit the 
characterization of the pharmacokinetics of moxidectin in adolescents, as well as assess 
pharmacokinetics and safety in children (aged 4 to 11 years).  


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3.4.3 Design Rationale 
The study employs an adaptive approach using modelled and experimental data, allowing the 
use of pharmacokinetic modelling assumptions for dose selection. Non-compartmental 
pharmacokinetic and safety data analyses will occur in an ongoing manner during the study. 
Pharmacokinetic data will be used to confirm or adjust the population pharmacokinetics 
modelling and, ultimately, the dosage. This design should minimize the number of children 
required to determine a dose with similar exposures to an 8 mg dose in adolescents and adults, 
and the number of invasive procedures and inconvenience for each child. There is a 
considerable body of data available on the use of moxidectin in humans, including children aged 
12 to 17 years of age. Moxidectin was well tolerated at all doses studied. In healthy volunteers, 
the safety profile was similar to placebo and no treatment-related laboratory or clinical toxicities 
were identified. In onchocerciasis patients, the nature, incidence and severity of adverse events 
associated with moxidectin efficacy was similar to ivermectin, and there were no serious 
adverse events due to efficacy and no treatment-related serious adverse events in any 
patient (Section 3.3.2.2).  
The requirement for inclusion of a control group(s) was assessed in the context of available 
standard therapies, the adequacy of evidence to support the chosen design and desired outcomes, 
and ethical considerations regarding the protection of children in clinical investigations.  
Inclusion of a placebo control was regarded as inappropriate for this patient population as it is 
not required for the study to meet its objectives (identification of an optimal moxidectin dose for 
children 4 to 11 years of age) and would expose children receiving placebo to greater than 
minimal risk (due to the collection of multiple blood samples for pharmacokinetic analysis) 
without the possibility of a direct benefit. Similarly, the Sponsor’s decision not to include an 
active comparator was considered in the context of risks to benefit ratio for individual subjects. 
The Sponsor believes, and has supporting pharmacokinetic modeling data, that comparison of 
MDGH-MOX-1006 study data to existing modeling data from adults will be sufficient to 
distinguish between an optimal and suboptimal dose of moxidectin based on pharmacokinetic 
parameters. Not including an active comparator group also reduces the number of children 
required to participate in the study.  


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Microfilariae density assessment by skin snip, the gold standard diagnostic method for 
O. volvulus infection, has not been included in this study as the efficacy of moxidectin has 
already been demonstrated in completed Phase II and III studies (see Section 3.3.2.2) and is not 
an objective of the study. Additionally, this diagnostic method is invasive and can potentially 
scar skin at the sampling sites, which is not considered to be appropriate or ethical in the context 
of this study. In the absence of skin snip assessments to confirm infection with O. volvulus, the 
study will recruit children from an area designated as endemic for O. volvulus infection and 
undergoing ivermectin mass drug administration. This ensures the relevance of the clinical 
investigation to the intended study population. Specifically, subjects will be recruited from 
communities located in the Nkwanta district, northern Volta region, Ghana, an area assessed as 
endemic for onchocerciasis by the WHO (World Health Organization 2019). In recognition of 
the prevalence of onchocerciasis in this region, community-directed treatment with ivermectin 
commenced in October 2017 with ongoing 6-monthly rounds of treatment planned.  
O. volvulus 16 antigen immunoglobulin G4 (Ov16 IgG4) positivity determined using the Ov16 
IgG4 antibody rapid format card test was originally included as an eligibility criterion in order 
to provide a benefit to study participants, since it was assumed that a positive test would indicate 
that the participant had been exposed to O. volvulus. However, this criterion has now been 
eliminated for the following reasons: 
• Recently-published results of a WHO external advisory committee review of large-scale 
evaluation of different assays for detecting Ov16 IgG4 antibodies in different settings 
and countries has identified significant discrepancies between the results obtained with 
different assays and concerns about both false positive and false negative results (World 
Health Organization 2020).   
• The concerns about false positive and false negative results, together with the fact that 
Ov16 IgG4 antibody testing is designed to be a surveillance tool for onchocerciasis 
elimination programs in the late and post-control stages and not an individual diagnostic 
(Abbott 2020), indicate that it will not be possible to reliably identify individual children 
who have been exposed to O. volvulus using the Ov16 IgG4 antibody test. In addition, 
the Ov16 IgG4 antibody test is not registered in Ghana and is consequently an 
investigational diagnostic. 


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• While the study presents a minor increase over minimal risk to the participating children, 
it can be justified on the basis that it is not possible to gather the necessary data in adults 
and the study is being conducted in a region designated as endemic for O. volvulus, 
where children are at risk of O. volvulus infection. Consequently, the participants 
represent the population which will benefit from the identification of a paediatric dose 
that will allow children younger than 12 years to be included in moxidectin-based 
elimination strategies.  
Pharmacokinetic results are not anticipated to be affected by infection status. Potential AEs 
associated with effective treatment of onchocerciasis are expected to be manageable and 
transient based on the prior experience in the Phase II and Phase III study. Since the Phase III 
study was recruited from the villages from which the participants in the current study will be 
recruited, a number of members of these communities will be familiar with clinical studies and 
biological sample collection. 
Protocol MDGH-MOX-1006 is specifically designed to determine the optimal dose of 
moxidectin for onchocerciasis treatment in the 4- to 11-year-old age group. The inclusion of 
adolescents 12 to 17 years of age will provide additional pharmacokinetic data for inclusion in 
the population pharmacokinetic model used to predict drug exposures across all age groups and 
to support dose selection for children aged 4 to 11 years. Some study participants may have skin 
microfilariae and moxidectin treatment will be of benefit to these individuals. In recognition that 
the study involves a minor increase over minimal risk to children without known direct benefit 
to individual subjects (i.e. without confirmation of O. volvulus microfilarial burden pre-
treatment), the Sponsor points to (1) engagement with the investigator, (2)  confirmation that the 
study design is acceptable based on protocol review by local and regional independent experts 
on the DSMB, (3) protocol amendments based on local (UHAS), country (Ghana Health Service 
(GHS)) and independent (WHO) ethics committee review and (4) protocol amendment 
following Ghana Food and Drugs Administration review prior to study conduct. The study is 
also being conducted under United States Food and Drug Administration IND 126876 and in 
accordance with the requirements of the United States (US) Code of Federal Regulations, 
including Title 21 Sections 50.52, 50.53 and 50.55.   


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3.4.4 Dose Rationale 
The proposed dose is 8 mg (4 x 2 mg tablets) for adolescents (aged 12 to 17 years) and children 
aged 8 to 11 years. These doses have been chosen with consideration of exposure multiples of 
nonclinical studies in both adult and juvenile animals, and based on clinical pharmacokinetics 
and population pharmacokinetics modelling data.  
As determined in clinical studies, including a large Phase III study (Section 3.3.2.2.2), 
moxidectin has a substantial safety margin for both AUC and Cmax, supported by both 
nonclinical and clinical studies. In single ascending dose clinical studies, there was no evidence 
of clinically relevant safety findings after administration of moxidectin (oral liquid and tablet 
formulations) at dosages of up to 36 mg to healthy adult subjects (Section 3.3.2.2.1). 
Additionally, moxidectin 8 mg administered to 55 adolescents in the Phase III study was well 
tolerated. For children aged 8 to 11 years, population pharmacokinetics modelling has 
determined that the Cmax and AUC values resulting from an 8 mg dose will also be within 
existing exposure safety multiples and the dose of moxidectin will not exceed 8 mg for any 
subject. These data are further described below. 
3.4.4.1 Nonclinical Dose Rationale 
From nonclinical data, the exposure risk has been determined by examining data from species 
that are sensitive to the toxicological effects of moxidectin.  
Moxidectin in dogs has a lower NOAEL and longer half-life than in rodents, and the same 
NOAEL has been identified in adult and juvenile dogs. Compared to adult dogs, juvenile dogs 
dosed at 3 mg/kg, the highest dose tested and equivalent to 23 times a single oral 8 mg dose in 
adult humans (0.13 mg/kg in a 60 kg person) had higher Cmax but lower AUC values in both 
sexes. For juvenile dogs Cmax was elevated by 1.5-fold in males and 1.3-fold in females while 
for AUC values the ratios were 0.44 for males and 0.77 for females. The exposure in dogs at the 
3 mg/kg NOAEL (see Section 3.3.1.2.3) when compared with that in adult humans at an 8 mg 
dose provides an estimated safety margin of at least 7-fold for pediatric subjects.  
In a neurofunctional and pulmonary study in male rats, the NOAEL was 5 mg/kg, with 
corresponding Cmax of 1116 ng/mL, which was above the previously measured Cmax in adults 
and predicted Cmax to be reached in the pediatric study if all age groups received a dose of 8 mg 
(Table 4).   


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In two-year carcinogenicity studies in mice and rats (Section 3.3.1.2.2), there was no evidence 
of tumorigenicity in mice administered a mean dietary dose of 8.7 mg/kg/day moxidectin 
(approximately equivalent to 5 times the recommended human dose of 8 mg based on body 
surface area comparison) or rats administered a mean dietary dose of 6.1 mg/kg/day moxidectin 
(approximately equivalent to 7 times the recommended human dose based on body surface area 
comparison).  
Moxidectin administered orally to pregnant rats or pregnant rabbits during the period of 
organogenesis was not associated with significant embryo-fetal developmental effects at doses 
of approximately 15 times (rats) or 24 times (rabbit) the 8 mg dose based on body surface area.  
Daily parental oral administration of dietary moxidectin to rats for 70 days prior to mating, and 
through mating, gestation, and lactation in a pre- and post-natal three generation study was 
associated with decreased survival and body weights for first-generation offspring without 
maternal toxicity at moxidectin doses approximately 1.3-times the recommended human dose 
based on body surface area comparison (>1.1 mg/kg/day). However, daily dietary moxidectin 
did not produce maternal toxicity or adverse effects for first- and second-generation offspring at 
doses approximately equivalent to the recommended human dose based on body surface area 
comparison (0.82 mg/kg/day). Offspring were assessed for survival, body weights, and fertility; 
developmental milestones were not assessed in this study. 
3.4.4.2 Population Pharmacokinetic Modelling 
Concentration-time profiles were simulated from a previously developed population 
pharmacokinetic model of moxidectin. In brief, the model was built using pharmacokinetic data 
from healthy adult volunteers and adult patients infected with O. volvulus. The model comprises 
three compartments with an n-transit absorption process and first-order elimination. To allow 
the potential to extrapolate to other populations, the model incorporated allometry where 
consistent with the observed data (central volume of distribution [Vc/F]), inter-compartmental 
clearance between the central and second peripheral compartments [CLd2/F] and volume of 
distribution of the second peripheral compartment [Vp2/F]). The model includes effects of food 
and formulation on absorption and relative bioavailability. The model also stipulates that 
females have larger values of clearance from the second compartment (CLd2/F) and Vp2/F than 
males; subjects with larger values of body mass index have increased Vp2/F (stratified by 


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Phase I and Phase II). As the population pharmacokinetic model does not include covariates of 
age or body size to assess effects on the total clearance, it was not able to establish differences 
in AUC by dose in pediatrics. However, for a given dose and AUC, the Cmax did alter, due to 
covariate effects impacting the volume parameters (i.e. body weight). 
The outcomes of the simulation predicted that children have a similar exposure (AUC) to adults 
and that, for a given dose, smaller body size was associated with higher values of Cmax (Table 4). 
Specifically, the simulation model predicted that adolescents 12 to 17 years receiving 8 mg of 
moxidectin may achieve similar exposures (AUC) to adults receiving 8 mg, with a higher Cmax 
(median 82.5 nanograms (ng) /mL vs. 56.8 ng/mL in O. volvulus infected adults). For children 
aged 8 to 11 years (as well as children 4 to 7 years), exposures are also predicted to be similar to 
adults, while median Cmax is predicted to be 116 ng/mL (maximum 214 ng/mL). This is well 
within the safety margins of moxidectin in humans; in adults, moxidectin has been studied up to 
a median Cmax of 244 ng/mL and a maximum of 473 ng/mL. The full pharmacokinetic report has 
been provided for reference (see Appendix 16.2). 
Table 4: Summaries of Cmax and AUC inf for Children 4 to 11 years (8 mg), Adolescents 12 
to 17 years (8 mg) and  Adult O. volvulus-infected Individuals and Healthy Volunteers 
(8 mg, 16 mg, 36 mg) Emerging from the Population Pharmacokinetic Model Used to 
Determine the Starting Dose for Children 8 to 11 Years 
 
Age Cohort (Dose) 
Cmax (ng/mL) 
AUCinf (ng*h/mL) 
 
Mean 
SD 
Median 
IQR 
Mean 
10th 
Percentile 
90th 
Percentile 
4 to 7 years (8 mg) 
157 
35.8 
156 
47.2 
2478* 
1317* 
3858* 
8 to 11 years (8 mg) 
118 
25.2 
116 
33.8 
2475 
1316 
3854 
12 to17 years (8 mg) 
83.5 
17.2 
82.5 
23.9 
2471 
1314 
3849 
Adults (Oncho, 8 mg) 
57.6 
11.7 
56.8 
15.9 
2466 
1312 
3844 
Adults (HV; 8 mg) 
55.6 
12.0 
54.3 
16.4 
3471 
1899 
5210 
Adults (HV; 16 mg) 
111 
24.0 
109 
32.7 
6942 
3798 
10420 
Adults (HV; 36 mg) 
250 
54.1 
244 
73.6 
15620 
8546 
23445 
The predicted mean and 10th and 90th percentile AUCinf for children 4 to 7 years will be re-estimated after 
pharmacokinetic data for 8 to 11 years and adolescents 12 to 17 years are available to update the model as a basis 
for determining the first dose for children 4 to 7 years to be proposed to the DSMB (see Section 13.5.3). Adults = 
18+ years, Oncho = O. volvulus infected, HV = healthy volunteers, IQR = interquartile range, AUCinf = AUC from time 
0 extrapolated to infinity, SD = Standard Deviation.  
To date, the population pharmacokinetic model used for the simulations has not been verified 
with pharmacokinetic data from children or adolescents. See Section 13.5.3 for a summary of 
planned addition of pharmacokinetic and demographic data from Cohorts I to III to the 
population pharmacokinetic model.  


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3.4.4.3 Consideration of Dose Format (Ability of Children to Swallow Dose) 
Tablets are the most common dosage form used in onchocerciasis-endemic regions in both 
children and adults. The moxidectin tablet presentation (dimensions 8.0 mm x 4.5 mm x 
3.0 mm, total weight 100 mg) is smaller than or comparable to tablets which children in this 
region routinely swallow, including biltricide, albendazole, mebendazole, azithromycin, and 
ivermectin. However, it is acknowledged that this study may exclude otherwise eligible children 
due to their inability to swallow tablets (see Section 7.3.3 for guidance on evaluation of ability 
to swallow tablets). 
The Sponsor is currently exploring alternative moxidectin presentations, including chewable and 
liquid formats. 


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4 
OBJECTIVES AND ENDPOINTS  
4.1 Objectives  
The primary objective of this study is to identify an optimal dose of moxidectin for the 
treatment of children aged 4 to 11 years with onchocerciasis. 
A secondary objective is to evaluate the safety and pharmacokinetics of a single dose of 
moxidectin in children and adolescents aged 4 to 17 years.  
4.2 Endpoints 
Dose(s) for children aged 4 to 11 years will be selected based on non-compartmental exposure 
metrics including AUC assessed up to and including Day 28 and a population pharmacokinetic 
model.  
Pharmacokinetic parameters of moxidectin in children and adolescents aged 4 to 17 years, 
including Cmax, Tmax, and other pharmacokinetic parameters will be determined by non-
compartmental analysis or other methods, as appropriate.  
The safety endpoints include the incidence and severity of AEs, physical examination findings, 
changes in vital signs, and laboratory safety parameters at all time points in the study. 
 


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5 
STUDY DESIGN 
5.1 Study Design 
This is a prospective, age-stratified, adaptive, open-label, single-dose pharmacokinetic and 
safety study of moxidectin in children and adolescents aged 4 to 17 years with, or at risk of, 
onchocerciasis infection. 
5.2 Number of Subjects 
The expected recruitment is 27 subjects enrolled in 3 Cohorts (approximately 9 subjects per 
cohort), with subjects allocated to cohorts on the basis of their age at Screening. However, an 
additional 4 cohorts (i.e. up to a maximum of 36 additional subjects) may be enrolled if required 
to achieve pharmacokinetic parameters within the required range.  
5.3 Cohorts and Dosing Regimens (Methodology) 
Cohorts I and II will be recruited concurrently.  
The dose regimen is:  
Cohort I: (n = 9 subjects aged 12 to 17 years, inclusive): a single oral dose of moxidectin 8 mg.  
Cohort II: (n = 9 subjects aged 8 to 11 years, inclusive): a single oral dose of moxidectin 8 mg.  
A sentinel group of three subjects will be enrolled in Cohort II. If the investigator considers, 
based on their experience with onchocerciasis treatments, that safety up to and including Day 3 
in these subjects is acceptable, the additional 6 subjects will be enrolled. If safety concerns arise 
in the sentinel group, the DSMB will review the data and make a recommendation to continue 
dosing as planned, or to modify or stop dosing. 
Once all Cohort I and II subjects complete Day 28, a safety and non-compartmental 
pharmacokinetic data review will be performed by the DSMB (See Section 11). If 3 or more of 
the 9 subjects in Cohort II have moxidectin exposures above the target range, defined as AUCs 
to Day 28 greater than the predicted 90th percentile mean AUC (see Table 4), a reduced dose of 
moxidectin will be selected for dosing of additional subjects in the Cohort II age range. The new 
dose will be in decrements of 2 mg, reflecting the 2 mg moxidectin tablet format used in the 
study. If Cohort II pharmacokinetic analyses for 9 subjects (per dose and cohort) cannot be 
calculated due to the availability of results from too few samples, additional subjects may be 
enrolled at that dose. The process is outlined in Figure 1.  


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Figure 1: Enrolment and Dosing Decision Tree 
 
 
Upon successful completion of Cohort II and selection of a starting dose for Cohort III based on 
pharmacokinetic modelling with inclusion of Cohort I and II data and consideration of all 
predicted pharmacokinetic parameters, and DSMB recommendation (see Section 11), Cohort III 
will be enrolled.  
Cohort III (n = 9, subjects aged 4 to 7 years, inclusive) will receive a single oral dose of 
moxidectin at the recommended dose level.  
Initially, a sentinel group of 3 subjects will be enrolled. If safety up to and including Day 3 in 
these subjects is considered acceptable, based on the investigator’s experience with 
onchocerciasis treatments, the additional 6 subjects will be enrolled. If safety concerns arise in 
the sentinel group, the DSMB will review the data and make a recommendation to continue 
dosing as planned, or to modify or stop dosing. 
Once all Cohort III subjects complete Day 28, a safety and pharmacokinetic data review will be 
performed by the DSMB. If 3 or more of the 9 Cohort III subjects have moxidectin exposures to 


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Day 28 below or above the target range, defined as AUCs less than the 10th percentile or greater 
than the 90th percentile mean AUC predicted by the population pharmacokinetic model, a 
revised dose of moxidectin will be determined in increments or decrements of 2 mg (maximum 
dose 8 mg) and Cohort III will be repeated with at least 9 new subjects enrolled at the new dose. 
If 3 or more of the 9 subjects enrolled at the new dose have moxidectin exposures outside the 
target range, the moxidectin dose may be adjusted once more and Cohort III repeated for a 
second time with at least 9 further subjects. 
Subsequent to the enrolment of the initial group of 3 subjects in each of Cohort II and 
Cohort III, additional subjects will be enrolled in groups of at least 3. This is for operational and 
social reasons (to ensure subjects have other children to spend their time with while in the 
research clinic so they don’t feel lonely).  
5.4 Study Sites  
This will be a single center study. The study will be conducted at the School of Public Health, 
UHAS Research Centre, formerly the OCRC research facility, Volta Region, Ghana, which was 
the site for the Phase II and III studies of moxidectin. The Investigator was a Co-investigator on 
the Phase II study and the Principal Investigator (PI) on the Phase III study and thus has 
substantial experience with moxidectin. 
5.5 Estimated Duration of the Study 
The on-study period per subject is approximately 28 weeks in total: up to 30 days for Pre-
screening (including consent/assent) and Screening (including up to 7 days in the research 
center for Screening ) prior to Baseline (pre-treatment on Day 0) and 7 days stay in the research 
center and 23 weeks outpatient follow-up post-treatment. 
It is anticipated that the total duration of the study will be up to 15 months, including 6 months 
for recruitment in the event that more than one cohort per age group is required and for data 
analysis and reporting. 
5.6 Expansion in Children 4 to 11 years, Inclusive 
Once an appropriate dose (or doses if required) has been identified, it is intended that an 
expansion study in children 4 to 11 years of age, inclusive, will be conducted. A protocol 
amendment will be generated to allow enrolment of further subjects in an expansion cohort for 
this study in order to further evaluate safety and potentially add further pharmacokinetic data. In 


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addition, or alternatively, children in these age groups may be included in treatment protocols 
for community studies with intensified safety monitoring requirements such as daily AE 
assessment in the immediate post-dose period and with DSMB oversight. 


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6 
STUDY POPULATION 
6.1 Selection of Subjects 
Study recruitment will occur in villages in the Kpassa sub-district of the Nkwanta North district, 
including Wii, Azua and Jagri-Do (for ethically relevant considerations relating to the choice of 
these communities see Section 14.1.2).  
The nature of the study and the possible risks will be explained to all potential subjects and their 
parent(s)/guardian(s) (legally acceptable representative, LAR) and communities. Written 
informed consent will be obtained from each child’s parent(s)/guardian(s) and assent will be 
obtained from each child (as and if appropriate for age) prior to performing any study -related 
procedures. For children too young or immature to give assent, the investigator will search for 
indication of ‘deliberate objection’ as per commentary to the Council for International 
Organizations of Medical Sciences (CIOMS) Guideline 17 (Council for International 
Organizations of Medical Sciences (CIOMS) 2016) (this is subsequently considered to be 
implied in the use of the term ‘assent’). The consent/assent process is described in 
Section 14.1.2.  
After obtaining written informed consent/assent, children will, where possible, be assessed in 
the village setting against eligibility criteria not requiring medical or laboratory examinations, as 
described in Section 6.2 and Section 6.3. This is intended to minimize the number of potentially 
ineligible children who travel to the study site to determine eligibility. Those who continue to be 
eligible for the study will receive transportation to the research center together with a parent or 
guardian for the remaining Screening assessments.  
Eligibility will be determined at Screening unless specified below. Subjects who meet all 
inclusion and none of the exclusion criteria will be eligible for participation in the study.  
6.2 Inclusion Criteria 
The criteria for entry into the study are: 
1. Age 4 to 17 years, inclusive: 
Cohort I: 12 to 17 years;  
Cohort II: 8 to 11 years;  
Cohort III: 4 to 7 years.  


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2. Live in a region designated by the WHO as endemic for O. volvulus infection (World Health 
Organization 2019). Specifically, participants will be recruited from the Kpassa sub-district 
of the Nkwanta North district. The specific communities will include Wii, Jagri-Do, and 
Azua where mass drug administration with ivermectin for onchocerciasis commenced in 
October 2017; 
3. Willing and able to remain at the research center from Screening up to Day 7; 
4. Provision of parental or guardian written informed consent and child assent / lack of 
expression of ‘deliberate objection’ (as appropriate for age); 
5. Females of childbearing potential must commit to using a highly effective method of 
contraception as per local family planning guidelines from Baseline (pre-treatment on 
Day 0) until approximately 6 months (Week 24) after treatment with study drug; 
6.3 Exclusion Criteria 
The criteria for exclusion from the study are: 
1. History of serious medical or psychiatric condition which, in the opinion of the investigator, 
would put the subject at increased risk by participating in the study or jeopardize study 
outcomes; 
2. Known or suspected concurrent clinically significant renal, cardiac, pulmonary, vascular, 
metabolic (thyroid disorders, adrenal disease), immunological disorders or malignancy, 
congenital heart disease, chronic lung disease; 
3. Has received an investigational product within 28 days, or 5 half-lives, of Baseline, 
whichever is longer; 
4. Has received ivermectin or any other anti-helminthic treatments within 28 days of Baseline; 
5. Has received a vaccination within 7 days of Baseline; 
6. Known or suspected hypersensitivity to macrocyclic lactones or excipients used in the 
formulation of moxidectin; 
7. Poor venous access; 
8. Unable to swallow tablets (flat oval, 8.0 millimeters (mm) x 4.5 mm x 3.0 mm); 
9. Weight: 
• Cohort I (12 to 17 years): < 30 kg 
• Cohort II (8 to 11 years): < 18 kg 
• Cohort III (4 to 7 years): < 12 kg 


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10. Clinically relevant laboratory abnormalities at Screening, including: 
• Hemoglobin < 9.5 g/dL 
• Neutrophil (granulocyte) count < 1.5 x 109/L  
• Platelet count < 110 x 109/L  
• ALT > 1.5 times ULN 
• Total bilirubin > 1.5 times ULN 
11. Hepatitis B, Hepatitis C, or HIV positive; 
12. Known or suspected malaria or other ongoing viral, bacterial, or plasmodium infection at 
Screening and/or Baseline; 
13. Loa loa co-infection; 
14. Unwilling, unlikely or unable to comply with all protocol specified assessments; 
15. For females of child-bearing potential, pregnant or breastfeeding, or planning to become 
pregnant; 
16. Previous enrolment in this study; 
17. Is a sibling of another child already enrolled in this study. 
 
6.4 Other Study Eligibility Criteria Considerations 
In order to assess any potential impact on subject eligibility with regard to safety, the 
investigator must refer to the current Investigator’s Brochure and other documentation provided 
by the Sponsor for detailed information regarding warnings, precautions, contraindications, 
AEs, and other relevant data pertaining to the drug product being used in this study. The 
investigator should also consult with the Medical Monitor as necessary.  
6.4.1 Contraception 
Female subjects of child-bearing potential (post-commencement of menarche and physically 
able to bear children) must have a negative pregnancy test (with a sensitivity of at least 
50 International Units (IU)/mL) performed at Screening (serum) and at Day 28, Week 12 and 
Week 24 (urine) as indicated in Table 1. 
In addition, they must agree not to attempt to become pregnant and must commit to using a 
highly effective method of birth control (failure rate of less than 1% when used consistently and 
correctly) in accordance with local family planning guidelines, for approximately 6 months (to 
the Week 24 visit) following study drug administration.  


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Reliable methods of contraception include: 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal; 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable; 
• intrauterine device;  
• sexual abstinence. 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
intercourse during the entire period of the study. Compliance with the commitment to sexual 
abstinence will be evaluated at the Day 14, Day 28, Week 12 and Week 24 visits by asking 
subjects whether they have been abstinent. In addition, a pregnancy test will be carried out for 
all girls of child-bearing capacity as described above, regardless of the chosen method of 
contraception. 
Counselling and provision of contraceptives (if needed) will be carried out by the staff of the 
Family Planning Unit of the Hohoe Municipal Hospital.  
6.4.2 Rescreening 
Subjects with clinically relevant laboratory abnormalities that are exclusionary may be re-tested 
once, within the screening window, under the same subject identifier. Rescreening for other 
reasons is not permitted.  


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7 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
7.1 Study Schedule of Evaluations 
The schedule of assessments is presented in Table 1. 
7.2 Visit Windows 
Consent/assent may be obtained up to 30 days prior to the day of planned study drug 
administration (Day 0) and before any study-specific procedures are conducted. Screening (with 
the exception of initial assessment of eligibility criteria not requiring medical or laboratory 
examinations, as described in Section 6.1) must be conducted in the window of Day -7 to Day -
1. 
All visit dates are calculated from Day 0, the date of the Baseline (pre-dose) assessment and 
study drug administration. Hours are calculated from the time of administration of moxidectin.  
Assessments should be performed within the specified time window (Table 5): 
Table 5: Allowable Visit Windows 
Time point 
Window 
Hours 1 and 2 
± 10 minutes 
Hour 4 
± 30 minutes 
Hour 8 
± 1 hour 
Hours 24, 48 and 72 
± 2 hours 
Day 7 
± 1 day 
Day 14 
± 2 days 
Day 28 
± 4 days 
Week 12 
± 14 days 
Week 24 
± 28 days 
 
7.3 Study Procedures / Assessment Periods 
For further details on timing of clinical procedures, please refer to Table 1. 
Additional visits and/or assessments may be conducted as clinically indicated. These data will 
be captured in the CRF as unscheduled visits, as appropriate. 
Study procedures will be conducted in the presence and with the help of the parent/guardian 
who accompanies the subject to the research center, as per the wishes of the accompanying 
parent/guardian and child. 
7.3.1 Consent/Assent 
The process for obtaining informed consent and assent is described in Section 14.1.2.  


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7.3.2 Pre-Screening (Screening Conducted in the Community) 
Subjects for whom informed consent/assent has been obtained as described in Section 14.1.2 
will be evaluated for eligibility criteria not requiring medical or laboratory examinations, as 
described in Section 6.1. These evaluations will be conducted between Day 30 and Day -1 and 
may also be performed in the research center during Screening.  
7.3.3 Screening 
Subjects who pass pre-screening and their parent or guardian will be invited to attend the 
research center for Screening. Screening must be conducted between Day -7 and Day -1. 
As subjects will be recruited from villages not proximal to the study center, they and their 
parents/guardians will be provided with accommodation for the duration of their stay in a newly 
renovated dormitory-style ward on the campus of the Hohoe Municipal Hospital. The dormitory 
ward has four separate rooms and each group of parents/guardians with their children can 
choose how to occupy these. A registered nurse will be on duty at all times. The dormitories 
have comfortable beds with mattresses and sheets and there is also a recreational area with large 
screen television and an outdoor space. The subjects and their parents/guardians will be 
provided with three meals daily.  
Unless already completed at Pre-screening, the following assessments / study requirements will 
be performed and documented: 
• Medical history, including medication history and evaluation of ability to swallow 
tablets (see Section 7.4.1) 
• A complete physical examination including assessment of all appropriate body 
systems and evaluation of venous access to determine study eligibility (see 
Section 7.4.1) 
• Vital signs (blood pressure, pulse, temperature and respiratory rate) measurement 
after lying semi-supine for 5 minutes (see Section 7.4.1) 
• Body height and weight measurement (see Section 7.4.1) 
• Measurement of upper arm circumference as an indicator of lean body weight (see 
Section 7.4.1) 
• 12-lead safety ECG (see Section 7.4.2) 
• Collection of blood samples for testing: 


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o Pharmacokinetic analysis (plasma) (see Section 7.4.3.2) 
o Hematology and clinical chemistry (see Section 7.4.3.1) 
o Serum pregnancy test for females of childbearing potential (see Section 7.4.3.4) 
o HIV, hepatitis B surface antigen, hepatitis C virus (see Section 7.4.3.3) 
o Loa loa infection (if relevant; see Section 7.4.3.3) 
• AE assessment (see Section 10.2.1) 
• Concurrent medication assessment (see Section 9) 
All required test results must be available before eligibility can be confirmed.  
The ability of children to swallow tablets will be assessed by the investigator based on 
discussion with the child and their parent(s)/guardian(s) of the child’s previous experience with 
taking tablets of a similar size (see Section 3.4.4.3). Parent(s)/guardian(s) and the child will be 
shown a tablet of a similar size to moxidectin as an example. 
Eligible girls of child-bearing potential and their accompanying parent/guardian will have a 
discussion with a family planning nurse about the need for contraception and the different 
options available, and will be provided with a contraceptive as needed, as described in 
Section 6.4.1.  
If the subject is ineligible for the study, the investigator will discuss the reason for ineligibility 
with the subject and their parent(s)/guardian(s). If the subject is ineligible to participate in the 
study due to a clinically significant laboratory abnormality or medical condition, including a 
positive test for HIV, hepatitis B or hepatitis C, referral will be made to an appropriate GHS 
treatment facility for follow-up. Transport for the subject and their parent/guardian to return to 
their village will be arranged for the day following Screening. 
7.3.4 Day -1 
Subjects will be required to fast overnight (from after dinner, which will be served at 
approximately 19:00) prior to dosing (see Section 8.5.1). Water may be consumed ad libitum 
during that time.  
7.3.5 Day 0 (Baseline, Dosing and Post-Dose Assessment) 
7.3.5.1 Pre-dose  
The following will be performed and documented pre-dose: 


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• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• Final confirmation of eligibility. Only subjects continuing to meet all of the inclusion 
criteria and none of the exclusion criteria will be dosed with moxidectin 
7.3.5.2 Dosing  
Administration of moxidectin tablets to fasted subjects (see Section 8.5.1) and recording of time 
(Hour 0). If a subject vomits within 30 minutes of taking the dose of moxidectin, the subject will 
be assessed as described in Section 12.2. 
7.3.5.3 Post-Dose 
The subject must be assessed throughout the post-dosing period with specific assessments at 
Hours 1 (± 10 minutes), 2 (± 10 minutes), 4 (± 30 minutes) and 8 post-dose (± 1 hour). 
The following assessments/study requirements will be performed and documented post-dose: 
• Vital signs measurement at Hours 1 and 8, and, if clinically indicated, at Hours 2 and 
4 (see Section 7.4.1) 
• Targeted physical examination (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Collection of blood samples (plasma) at Hours 1, 2, 4 and 8 hours for moxidectin 
concentration determination (see Section 7.4.3.2) 
• Provision of a meal 2 hours post dose, after Hour 2 blood sample collection. 
• Continuous AE assessment (see Section 10.2.1) 
• Continuous concurrent medications assessment (see Section 9) 
Subjects will remain in the research center. 
7.3.6 Day 1 (24 hours) 
The following will be performed and documented at Hour 24 (± 2 hours): 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Collection of blood sample (plasma) for moxidectin concentration determination 
(see Section 7.4.3.2) 


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• AE assessment (see Section 10.2.1) 
• Concurrent medications assessment (see Section 9) 
Subjects will remain in the research center. 
7.3.7 Day 2 (48 hours) 
The following will be performed and documented at Hour 48 (± 2 hours): 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Adverse event assessment (see Section 10.2.1) 
• Concurrent medications assessment (see Section 9) 
Subjects will remain in the research center. 
7.3.8 Day 3 (72 hours) 
The following will be performed and documented at Hour 72 (± 2 hours): 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Collection of blood sample (plasma) for moxidectin concentration determination 
(see Section 7.4.3.2) 
• AE assessment (see Section 10.2.1) 
• Concurrent medications assessment (See Section 9) 
Subjects will remain in the research center. 
7.3.9  Day 7 
The following will be performed and documented at Day 7 (± 1 day): 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Collection of blood samples for hematology and clinical chemistry and moxidectin 
concentration determination (see Sections 7.4.3.1 and 7.4.3.2) 


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• AE assessment (see Section 10.2.1) 
• Concurrent medications assessment (see Section 9) 
Subjects will be discharged from the research center after these assessments. Subjects may 
remain if clinically indicated and any ongoing AEs should be managed as required.  
7.3.10 Day 14 Visit 
The following will be performed and documented at Day 14 (± 2 days): 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Collection of blood sample for moxidectin concentration determination (see 
Section 7.4.3.2) 
• AE assessment (see Section 10.2.1) 
• Concurrent medications assessment (see Section 9) 
7.3.11 Day 28 Visit 
The following will be performed and documented at Day 28 (± 4 days): 
• A targeted physical examination (see Section 7.4.1) 
• Body weight measurement (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Collection of blood samples for hematology and clinical chemistry and moxidectin 
concentration determination (see Sections 7.4.3.1 and 7.4.3.2) 
• Urine pregnancy test for females of child-bearing potential (see Section 7.4.3.4) 
• AE assessment (see Section 10.2.1) 
• Concurrent medications assessment (see Section 9) 
7.3.12 Week 12 Visit 
The following tests will be performed and documented at Week 12 (± 14 days): 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 


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• Collection of blood samples for hematology and clinical chemistry and moxidectin 
concentration determination (see Sections 7.4.3.1 and 7.4.3.2) 
• Urine pregnancy test for females of child-bearing potential (see Section 7.4.3.4) 
• AE assessment (see Section 10.2.1) 
• Concurrent medications assessment (see Section 9) 
7.3.13 Week 24, Exit Evaluation 
The following will be performed and documented at Week 24 (± 28 days) or upon early 
withdrawal if agreed by the subject: 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Weight measurement (see Section 7.4.1) 
• Collection of blood samples for clinically indicated hematology and/or clinical 
chemistry (see Section 7.4.3.1) 
• Urine pregnancy test for females of child-bearing potential (see Section 7.4.3.4) 
• AE assessment (see Section 10.2.1) 
• Concurrent medications assessment (see Section 9) 
These procedures should be conducted in the case of that a subject withdraws from the study 
prior to Week 24. This is the final study visit. 
7.3.14 Unscheduled Visits 
The following should be performed and documented at unscheduled visits as clinically 
indicated: 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• 12-lead ECG if clinically indicated (see Section 7.4.2) 
• Collection of blood samples for clinically indicated hematology and/or clinical 
chemistry (see Section 7.4.3.1) 
• Urine pregnancy test for females of child-bearing potential (see Section 7.4.3.4) 
• AE assessment (see Section 10.2.1) 


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• Concurrent medications assessment (see Section 9) 
7.4 Details of Scheduled Assessments 
7.4.1 Demographic Data, Medical History, Physical Examination, Vital Signs 
Demographic data will include sex, date of birth, height (in centimeters [cm]), upper arm 
circumference (in cm) and weight (in kg), as well as history of living in a Loa loa endemic area. 
The medical history will include any significant diagnosed medical conditions or surgical 
history and medication history. 
A complete physical examination (including head, eyes, ears, nose, throat, lungs, lymph nodes, 
heart, abdomen and skin) and body weight and height measurements will be conducted at 
Screening to determine study eligibility.  
A targeted physical examination based on prior findings and reported AEs will be performed on 
Day 0 pre-dose and at all subsequent visits. Targeted physical examinations may also be 
performed at Hours 1, 2, 4 and 8 on Day 0 and at unscheduled visits as clinically indicated.  
Body weight measurement will be repeated at the Day 28 and Week 24/Early Withdrawal visits 
and may be performed at unscheduled visits if clinically indicated. 
Vital signs, to be measured after the subject has been semi-supine for 5 minutes, are:  
• Body temperature (degrees Celsius; °C) 
• Respiratory rate (breaths per minute) 
• Pulse rate (beats per minute) 
• Blood pressure (millimeters of mercury [mmHg]) 
Vital signs will be assessed in association with other signs and symptoms detected upon 
physical examination for potential clinical significance and determination of study eligibility 
and AEs. Vital signs normal reference ranges as published in the American Heart Association 
Pediatric Advanced Life Support Guidelines 2015 and Canadian Paediatric Society Position 
Statement on Temperature Measurement in Paediatrics 2013 (Canadian Paediatric Society 2013, 
American Heart Association 2016) and as summarized in Appendix 16.3 may be used to assist a 
diagnosis. 


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7.4.2 Electrocardiograms 
Standard 12-lead ECGs will be recorded at Screening and at physician discretion during the 
study. The ECG recordings will be performed once the subject has been resting semi-supine for 
at least 10 minutes and will be measured in triplicate over approximately 3 minutes. The 
following parameters will be reported: QRS, QT, QTcB (Bazett's correction formula), QTcF 
(Fridericia's correction formula), RR and PR intervals. Repeat measurements will be performed 
if there are any identified clinical abnormalities observed or artifacts are present. All ECG 
recordings will be reviewed by the investigator or nominee and a clinical assessment 
documented in the research center notes [(normal, abnormal (not clinically significant) or 
abnormal (clinically significant)]. Any new clinically significant findings after Baseline will be 
reported as AEs.  
7.4.3 Blood and Urine Samples 
The following blood samples are to be collected:  
• A 0.5 mL sample of blood for hematology assessments and 1.5 mL for biochemistry 
assessments at each of Screening, Days 7 and 28, and Week 12 (total 8 mL across all 
visits) and at other visits if clinically indicated (see Section 7.4.3.1) 
• 1.5 mL for pharmacokinetic analysis at each of Screening, Hours 1, 2, 4, 8 and 24, 
Days 3, 7, 14, and 28 and Week 12 (total 16.5 mL across all visits) (see 
Section 7.4.3.2) 
• up to 5 mL for testing for HIV, hepatitis B surface antigen, and hepatitis C virus 
RNA and, if required, Loa loa testing (see Section 7.4.3.3) 
• up to 4 mL for serum pregnancy testing at Screening (see Section 7.4.3.4) 
Planned blood sample collection will be no more than 33.5 mL for females requiring pregnancy 
testing (≥ 12 years and ≥ 30 kg) and 29.5 mL for all other subjects. The maximum blood sample 
collection in any 4-week period for any subject is 30 mL (when pregnancy testing is required). 
For a child of 4 to 7 years weighing an allowable minimum 12 kg, the blood volume required in 
any 4 week period (26 mL) is less than the recommended maximum 3% of blood volume of 
28 mL and the maximum amount drawn within a single day (8.5 mL) is less than the 
recommended maximum 1% of blood volume of 9.6 mL (2001/20/EC 2008, Zisowsky et al. 
2010) 


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The first 24 hours after dosing requires a number of samples for pharmacokinetic analysis to be 
collected, in order to appropriately characterize moxidectin pharmacokinetics. The use of an 
intravascular catheter to facilitate venous access for sample collection during that time is 
recommended. In addition, an effective topical anesthetic for application to the skin prior to 
each application of a needle for blood sample collection is also strongly recommended. 
A single mid-stream urine sample will be collected from female participants of childbearing 
potential for pregnancy testing at Day 28, Week 12 and Week 24 / Early Withdrawal visits and, 
if clinically required, at unscheduled visits as (See Section 7.4.3.4). 
7.4.3.1 Safety Laboratory Tests 
Blood will be collected at scheduled time points and, if clinically indicated, at unscheduled 
visits, for safety laboratory testing. A maximum of 2 mL per visit will be collected at the 
scheduled time points at Screening, Days 7 and 28 and Week 12 (8 mL total; see Section 7.4.3 
for evaluation of blood volumes collected relative to guidance on blood collection in children). 
The handling and processing of hematology and clinical chemistry will be in accordance with 
the site’s usual processes. These tests will all be performed at the site’s local laboratory with 
equipment and test kits able to accurately analyze small sample volumes. Normal reference 
ranges for clinical chemistry and hematology for Ghanaian children (Dosoo et al. 2014) will be 
used in this study. These reference ranges are included in Appendix 16.4 to the protocol.  
Samples will be collected for the following tests at a minimum: 
Hematology: 
Hemoglobin, hematocrit, RBC count and RBC morphology, white blood cell 
and differential white blood cell count, platelet count. 
Chemistry: 
AST, ALT, GGT, amylase, creatine kinase, total protein, albumin, direct and 
total bilirubin, sodium, potassium, chloride, bicarbonate, phosphorus, BUN, 
creatinine. 
Other parameters may be tested if clinically indicated. 
7.4.3.2 Pharmacokinetic Samples 
Plasma will be prepared from 1.5 mL blood collected (with samples for safety testing as 
appropriate) at Screening and post-dose at Hours 1, 2, 4, 8, 24 and 72, Days 7, 14 and 28 and 
Week 12 (16.5 mL in total; see Section 7.4.3 for evaluation of blood volumes collected relative 


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to guidance on blood collection in children). Plasma will be divided into two aliquots of at least 
250 µL (unless insufficient sample available) and stored at -20°C. A single sample at each time 
point for each subject will be sent to Frontage Laboratories (Exton, Philadelphia, United States 
of America) for determination of moxidectin plasma concentration in a fully validated liquid 
chromatography (LC) with mass spectrometry (MS) LC/MS/MS method used in previous 
studies. The remaining samples will be stored as back-up during the study, should these be 
required. 
Details of the laboratory, and collection, processing, storage and shipping information for the 
samples will be described in the SRM.  
Any remaining samples after analysis and completion of the study will be destroyed. 
7.4.3.3 Testing for Other Infections 
Testing for the presence of infection with HIV, chronic hepatitis B and C will be conducted at 
Screening using commercially available rapid test kits as per the manufacturer’s instructions.  
Subjects who have resided in an area endemic for Loa loa will be tested for presence of 
infection. Instructions on sample collection and testing will be provided in the SRM.  
The volume of blood required for testing is detailed in Section 7.4.3. For information on 
referrals in case of positive tests, see Section 7.3.3. 
Testing for other infections (e.g. malaria) will be conducted as per investigator judgement in 
case of clinical suspicion. 
7.4.3.4 Pregnancy Test 
A serum pregnancy test will be performed at Screening for all females of child-bearing 
potential. Subjects with a positive result are not eligible for the study.  
At Day 28, Week 12 and Week 24 / Early Withdrawal (and at unscheduled visits as clinically 
indicated), a urine pregnancy test will be performed.  
Commercially available rapid test kits will be used as per the manufacturer’s instructions. 
7.4.3.5 Handling and Processing of Biological Specimens 
Blood and urine specimens collected during the trial may contain harmful pathogens. All 
personnel involved in collecting and handling biological specimens should follow appropriate 


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precautionary procedures for handling biohazardous materials as currently recommended by the 
national regulatory authority. The processing of all biological specimens will be in accordance 
with relevant institutional Standard Operating Procedures (SOPs).  
Further details of the handling of blood samples can be found in the SRM. 


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8 
INVESTIGATIONAL PRODUCT 
8.1 Randomization Process 
The study is not randomized. 
8.2 Blinding 
The study is open label. 
8.3 Treatment Allocation 
Treatment is allocated based on aged-based treatment cohorts.  
A Screening identification (ID) number will be allocated to each subject for whom 
parental/guardian informed consent and child assent (as appropriate for the age group, see 
Section 14.1.2) is provided. The Screening ID is a number prefixed with “S” starting with S001. 
It is allocated in sequence. If a subject fails Screening, the Screening ID number will not be 
reused.  
All subjects eligible for the study will also receive a Subject ID number. It is comprised of a 
cohort number (1, 2 or 3) and within each cohort, a sequential, ascending 3-digit ID number 
(beginning with 001, 002, 003). Together these will provide a unique subject identifier 
(e.g. 1001, 1002, 2001). Each subject will retain the same Subject ID for the duration of the 
study and the number will not be reused.  
8.4 Supply, Packaging and Labelling 
Moxidectin 2 mg tablets will be supplied by the Sponsor. Moxidectin will be supplied as oval-
shaped solid tablets for oral administration containing 2 mg of moxidectin, packaged in white 
high-density polyethylene bottles with polypropylene cap, desiccant sachet, rayon coil (filler) 
and induction sealed containing 500 tablets. Moxidectin 2 mg tablets will be shipped by the 
Sponsor prior to study start and in accordance with all applicable country and regulatory 
requirements.  
Bottle labelling will include at least the following: 
• Sponsor name and address 
• Moxidectin name, strength, and formulation 
• Batch number 
• Protocol number 


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• Storage temperature and conditions 
Details of the expiry or re-test date will be provided either on the label or in separate study 
documentation. A Certificate of Analysis will be provided and retained on file at site. 
8.5 Storage and Handling 
Moxidectin 2 mg tablets should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 20 to 25°C (68 to 77°F), with 
protection from light and moisture. Do not freeze. Temperature excursions are permitted to 
30°C (86°F) for up to 12 months. Unless otherwise labelled, the full contents of the container 
should be used within 7 days or unused contents discarded. To ensure the stability of the drug 
product and proper product identification, moxidectin 2 mg tablets should be administered 
directly from the container in which they are supplied. 
Only subjects enrolled in the study (i.e. those for whom eligibility has been confirmed on Day 0, 
see Section 13.3) may receive moxidectin 2 mg tablets. Prior to dispensing, moxidectin 2 mg 
tablets will be stored securely under the appropriate conditions at the clinical trial site in a 
secure area with access limited to authorized staff, and according to relevant laws. The PI or 
authorized designee will ensure these requirements are met.  
The PI is responsible for ensuring that moxidectin is dispensed in accordance with the protocol 
and only to subjects enrolled in the study. Authorized study personnel will dispense moxidectin 
according to the dose specified for the relevant cohort.  
8.5.1 Dosage and Administration of Moxidectin Tablets 
No subject will receive more than 8 mg of moxidectin (4 x 2 mg tablets).  
Each enrolled subject will receive a single oral dose of moxidectin, according to their age 
cohort: 
• Cohort I (12 to 17 years of age) will receive moxidectin 8 mg (4 x 2 mg tablets); 
• Cohort II (8 to 11 years of age) will receive moxidectin 8 mg or an adjusted (lower) 
dose based on data from the group treated with an 8 mg dose (see Section 5.3);  
• Cohort III (4 to 7 years of age) will receive a dose of moxidectin to be determined 
based on the population pharmacokinetic modelling, including data obtained from 
Cohorts I and II. 


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The appropriate number of tablets for an individual dose will be dispensed for each subject from 
the moxidectin supplied. 
The dose of moxidectin will be administered on Day 0 after fasting for not less than 6 hours. 
Subjects will be required to swallow moxidectin tablets with approximately 250 mL of water. A 
visual mouth check will be conducted post-dosing to ensure all tablets have been swallowed. 
Each subject must continue to fast for 2 hours post-dose. Water may be consumed ad libitum 
during that time. 
8.5.2 Dispensing and Accountability 
All moxidectin supplied is for use only in this clinical study and must not be used for any other 
purpose. 
The PI or designee is responsible for maintaining accurate records for all moxidectin received, 
stored, dispensed, and returned. The inventory and dispensing logs must be available for 
inspection by the study monitor. Moxidectin supplies, including any partially used or empty 
bottles, must be accounted for by the PI or designee and verified by the study monitor. 
At the end of the study, moxidectin may be returned to the Sponsor (or designee), or, if pre-
approved in writing by the Sponsor and Ghana Food and Drugs Authority, sent for safe 
destruction at an approved local facility. Records shall be maintained in the study site file. These 
records must show the identification and quantity of each unit disposed of, the method of 
destruction (taking into account the requirements of local law), and the person responsible for 
disposal of the test substance. A copy of such records shall be submitted to the Sponsor. 


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9 
CONCURRENT MEDICATIONS AND TREATMENTS 
Throughout the 24-week duration of the study, subjects may not receive treatment with 
ivermectin. 
Any concurrent medications administered, including vaccinations, vitamin supplements and 
herbal remedies or traditional medicines, must be recorded in source documents and the 
appropriate section of the CRF. 


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10 ADVERSE EVENTS AND TOXICITY MANAGEMENT 
10.1 Safety Parameters 
Safety assessments will include physical examinations, AEs, vital signs, and clinical laboratory 
tests. 
10.2 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. Pre-existing events which increase in frequency or severity or change 
in nature during or as a consequence of use of a drug in human clinical trials, will also be 
considered as AEs. AEs may also include complications that occur as a result of protocol-
mandated procedures (e.g. invasive procedures such as biopsies). 
Any AE with an onset date after investigational product administration up to the last day on 
study (including the follow-up, off study medication period of the study), should be recorded as 
an AE on the appropriate CRF page(s). 
An AE does not include: 
• medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is the AE 
• pre-existing diseases or conditions present or detected prior to start of investigational 
product administration, that do not worsen 
• situations where an untoward medical occurrence has not occurred (e.g. 
hospitalization for elective surgery, social and/or convenience admissions) 
• overdose of either investigational product or concomitant medication without any 
signs or symptoms unless the subject is hospitalized for observation. 
10.2.1 Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded in the source documents and the 
appropriate CRF page, including the date of onset and resolution, severity, relationship to 
investigational product, outcome and action taken with investigational product. 


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AEs should be recorded, and severity graded according to the Division of AIDS (DAIDS) Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1, July 2017. This is 
provided in Appendix 16.5 and is available at: https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
The relationship to investigational product therapy should be assessed using the definitions 
provided in Table 6. 
Table 6: Relationship to Investigational Product Assessment Terms 
Causality 
Comment 
Unrelated 
AE is clearly due to extraneous causes (e.g. underlying disease, environment, 
known effect of another drug) 
Unlikely 
The temporal association between the AE and study drug is such that study drug is 
not likely to have any reasonable association with the AE 
Possible 
The AE could have been produced by the subject’s clinical state or study drug 
Probable 
The AE follows a reasonable temporal sequence from the time of study drug 
administration, abates upon discontinuation of the study drug and cannot be 
reasonably explained by the known characteristics of the subject’s clinical state 
Definite 
The AE follows a reasonable temporal sequence from the time of study drug 
administration, abates upon discontinuation of the study drug and/or reappears 
when study drug is re-introduced 
These criteria in addition to good clinical judgment should be used as a guide for determining 
the causal assessment. If it is felt that the event is not related to Investigational Product, then an 
alternative explanation should be provided. 
10.2.2 Adverse Event Reporting Period 
All AEs, regardless of severity, causality or seriousness must be reported to the Sponsor, from 
commencement of Pre-screening until the end of the study or 28 days after the administration of 
study medication, whichever is later. However, any AE that the investigator believes is at least 
possibly related to study medication should be reported regardless of time elapsed from the 
dose.  
All AEs, including SAEs and deaths, will be reported to the reviewing Ethics Committees 
according to their specified timelines. 
10.3 Serious Adverse Events 
A SAE is defined as follows: 
Any AE that results in any of the following outcomes: 


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• death; 
• life-threatening situation; 
• inpatient hospitalization or prolongation of existing hospitalization; 
• persistent or significant disability/incapacity; or 
• congenital anomaly/birth defect in the offspring of a subject who received 
investigational product. 
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization, may be considered a SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events are: 
• intensive treatment in an emergency room or at home for allergic bronchospasm; 
• blood dyscrasias or convulsions that do not result in hospitalization; and/or 
• development of drug dependency or drug abuse. 
10.3.1 Clarification of (Serious) Adverse Events 
Death is an outcome of an AE, and not an AE in itself. In reports of death due to “Disease 
Progression”, where no other information is provided, the death will be assumed to have 
resulted from progression of the disease being treated with the investigational product. 
All deaths, regardless of cause, must be reported to the Sponsor for subjects on study and for 
deaths occurring within 30 days of investigational product dose or within 30 days of last study 
evaluation, whichever is longer. 
“Occurring at any dose” does not imply that the subject is receiving investigational product at 
the time of the event. 
“Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death, if it had occurred with 
greater severity. 
Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is a SAE. 


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“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not include 
presentation and care within an emergency department. 
The investigator should attempt to establish a diagnosis of the event based on signs, symptoms 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and/or SAE and not the individual signs/symptoms. 
10.3.2 Serious Adverse Event Reporting Requirements 
10.3.2.1 
All Serious Adverse Events 
The Sponsor has requirements for expedited reporting of SAE’s meeting specific requirements 
to worldwide regulatory authorities; therefore, all appropriate parties must be notified 
immediately regarding the occurrence of any SAE that occurs during the study. The procedures 
for reporting all SAEs, regardless of causal relationship, are as follows: 
• complete the “Serious Adverse Event Report” and 
o send to the Safety Desk within 24 hours of the investigator’s knowledge 
of the event by emailing to: 
 
o for fatal or life-threatening events, also provide copies of hospital case 
reports, autopsy reports, and other documents when requested and 
applicable 
The Safety Desk may request additional information from the investigator to ensure the timely 
completion of accurate safety reports. 
The investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications necessary for treatment of the SAE must be recorded in the subject’s CRF. 
10.3.2.2 
Investigator Reporting Requirements for SAEs 
Per Ghana Food and Drugs Authority guidelines, the investigator should report all SAEs to the 
Authority within 48 hours. Where required by local regulations, and in accordance with the 
local institutional policy, the investigator should also notify the EC of SAEs within the required 
timelines. 


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10.4 Follow Up of Serious and Non-Serious Adverse Events 
Follow-up of serious and non-serious AEs will continue through the last day on study or until 
the investigator determines that the subject’s condition is stable, whichever is longer. The 
Sponsor may request that certain AEs be followed until resolution. 
10.5 Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
or SAEs 
All laboratory values must be reviewed by the investigator as soon as practical after the data are 
available. 
Laboratory abnormalities that occur without related clinical symptoms and signs should not be 
recorded as an AE unless they represent a clinically significant event. Where possible, the 
overall diagnosis of the AE rather than the laboratory abnormality should be recorded in the 
CRF. This will avoid duplication of laboratory abnormalities in both the AE and laboratory 
reports. Abnormal laboratory results that are of clinical significance should be reviewed by the 
Medical Monitor. 
Any laboratory test result that meets the criteria for a SAE (refer to Section 10.3) should be 
recorded as an AE, the AE page of the CRF completed and a SAE form also completed in order 
to provide the Sponsor with additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken 
and resolution. 
10.6 Toxicity Management 
AEs and abnormal laboratory values, if appropriate, should be graded according to the DAIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events (see Section 10.2.1).  
Laboratory abnormalities should be assessed as “Clinically Significant” or “Not Clinically 
Significant”. 
For the purpose of monitoring toxicities, the baseline value is defined as the last value prior to 
the administration of the dose of moxidectin. All management (as described in Sections 10.3 
and 10.4) is based on changes from this value. 
10.7 Guidance for Dose Modification or Discontinuation of Treatment 
There will be no dose modification for individual subjects, since this is a single dose study.  


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Discontinuation of treatment is not applicable in a single dose study. 
10.8 Warnings and Precautions 
For information regarding precautions and AEs observed after treatment with moxidectin, 
whether related or unrelated to treatment, the investigator is referred to the Investigator’s 
Brochure for moxidectin. 
10.9 Risks for Women of Childbearing Potential or During Pregnancy 
The risks of treatment with moxidectin during pregnancy have not been evaluated in humans. 
For information on the risk assessed in animal studies, see Section 3.3.1.2.2 and the 
Investigator’s Brochure for moxidectin. Females of childbearing potential will be asked to agree 
to use a highly effective birth control regimen (see Section 6.4.1) while participating in the 
study and for approximately 6 months (Week 24) following dosing with the Investigational 
Product.  
10.10 Procedures to be Followed in the Event of Pregnancy 
The subject and their parent(s)/guardian(s) must be instructed to inform the investigator 
IMMEDIATELY if the subject or, if male, their partner, becomes pregnant during the study 
period. Contact information is provided on the study information sheet and the participant 
identification card each subject will receive. Subjects can also choose to ask the community 
coordinator (see Section 14.1.2.1) to contact the study team.  
The investigator should report all pregnancies to the Sponsor or designee within 48 hours of 
becoming aware of the pregnancy. 
In the event of pregnancy in a subject, the investigator will advise the subject to attend all ante-
natal visits and refer them to the appropriate GHS ante-natal service. Monitoring of the subject 
should continue until conclusion of the pregnancy (i.e. the investigator will ask the pregnant 
subject to contact the study team in case the GHS ante-natal service informs her of any 
abnormal finding). The outcome of the pregnancy should be reported to the Sponsor. Post-natal 
follow-up assessments of the health of the baby will be conducted by a pediatrician at least 
annually up to 2 years of age. In the event of a pregnancy in the partner of a subject, the 
investigator should seek informed consent from the partner to report the outcome of the 
pregnancy to the Sponsor and conduct follow-up assessments of the baby as described above for 
pregnant study subjects.  


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All abnormal GHS ante-natal service findings and results of follow-up assessments of babies 
will be reported to the Sponsor. 


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11 DATA AND SAFETY MONITORING BOARD (DSMB) 
A DSMB has been established with a charter that defines in detail its roles and responsibilities. 
The DSMB will review the safety and pharmacokinetic data following completion of enrolment 
and pharmacokinetic data analysis for both Cohorts I and II and recommend a starting dose for 
Cohort III. The DSMB will also meet as required during the study. The DSMB will also receive 
any reported SAEs throughout the study. 
The DSMB will recommend to the Sponsor whether the trial may continue as planned or if the 
trial should be modified or stopped. Any decision to modify or stop the study will be 
communicated to investigators and regulatory agencies by the Sponsor. ECs will be notified by 
the PI according to their requirements. 


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12 SUBJECT COMPLETION / WITHDRAWAL 
12.1 Subject Completion 
A subject will be deemed to have completed the study once all trial procedures have been 
conducted. Any AEs or SAEs still ongoing at the time of the Exit Evaluation will be followed in 
accordance with Section 10. 
12.2 Criteria for Premature Withdrawal from Treatment or the Study 
Participation in this study is voluntary. Please see Section 14.1.2 for further details on voluntary 
participation and informed consent and assent. 
Subjects (or their parent(s)/guardian(s)) also have the right to withdraw themselves (or their 
child/ward) from the study at any time for any reason. The PI must make every reasonable effort 
to understand the reason for the withdrawal and, if possible, retain the subject in the study if 
their concerns can be addressed. 
If a subject vomits in the 30 minutes after taking the dose of moxidectin, all Day 0 assessments 
should be completed, and the subject should be withdrawn from the study. Any AEs or SAEs 
still ongoing at the time of withdrawal will be followed in accordance with Section 10.  
The PI also has the right to withdraw subjects from the study for safety reasons (e.g. in the event 
of concurrent illness, AEs, or pregnancy), protocol non-compliance, or administrative or other 
reasons (see Section 12.6). 
An excessive rate of withdrawals from the study can render the study difficult to interpret. In 
particular, missing data could significantly impact on the interpretation of the results; therefore, 
unnecessary withdrawal of subjects from the study (e.g. based on misconceptions) should be 
avoided. 
The reasons for withdrawal of the subject must be recorded on the CRF (if given; if a reason is 
not given, this will be recorded). 
12.3 Withdrawal of Subjects from Moxidectin 
This is a single dose study, so treatment withdrawal is not relevant. 
If a subject is unable to take a full dose of Investigational Product (unable to swallow all 
required tablets) they should remain on study and be followed up according to protocol. 


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12.4 Withdrawal of Subjects from the Study 
Should a subject and their parent(s)/guardian(s) and/or the investigator decide on the withdrawal 
of a subject from the study, all efforts will be made to complete and report the observations as 
thoroughly as possible. 
The PI or delegate should contact the subject through a personal visit or through contact with a 
responsible relative to determine, if possible, the reason for withdrawal. A complete final 
evaluation should be made at the time of the subject withdrawal, with an explanation of the 
reason for the withdrawal. Where possible, subjects should be followed until any AEs are 
resolved or abnormal laboratory tests have returned to normal. 
12.5 Replacement of Withdrawn Subjects 
Any subjects who discontinue a clinical study of their own and/or their parent(s)/guardian(s) 
volition or are withdrawn by the PI are defined as “withdrawals”. Replacement subjects (up to a 
total study maximum of 63 participants treated) may be enrolled into the study at the request of 
the Sponsor to ensure adequate pharmacokinetic time points are obtained. 
12.6 Premature Termination of the Study 
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 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. 
• 
In the event that data obtained for Cohorts I or II does not enable determination of a 
starting dose for Cohort III, or Cohorts I to III data does not enable determination of 
an optimal dose. 
Conduct of the study at the investigational site may be terminated if the PI or site staff are found 
in significant violation of GCP, protocol, or contractual agreement, or are unable to ensure 
adequate performance of the study. 


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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. 


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13 DATA MANAGEMENT CONSIDERATIONS AND STATISTICAL ANALYSIS 
13.1 Hypothesis 
No formal hypothesis testing will be performed in this study. Analyses will be descriptive only. 
All planned analyses will be presented in a SAP. 
13.2 Sample Size Determination 
Cohorts of nine (9) subjects each is considered to be an adequate sample for full characterization 
of moxidectin pharmacokinetics and for dose selection based on achieving exposures within the 
acceptable range at the same dose. If one third of subjects or more is above or below the target 
AUC0-inf range, then a new dose will be chosen and a further 9 subjects will be targeted for 
recruitment. 
13.3 Enrolment and Randomization 
Subjects are considered enrolled after informed consent has been obtained and eligibility has 
been confirmed on the morning of Day 0. The study is not randomized. 
Subject disposition will be described according to the numbers of subjects screened (not 
enrolled), enrolled (not treated) and treated. Screen failure data will be included in the database 
only as necessary to determine the number of subjects screened but not enrolled and the 
reason(s) for ineligibility. 
13.4 Analysis Populations 
The pharmacokinetic analysis population will include all subjects who receive moxidectin and 
provide a minimum number of samples for the determination of plasma pharmacokinetic 
parameters.  
A subject will be included in the pharmacokinetic population if they have at least the following: 
1) Samples taken at Hours 4, 24 and 72; and 
2) One sample on either Day 14 or Day 28. 
Subjects in this population will be used for all pharmacokinetic summaries. Subjects in this 
population will be analyzed according to the dose received. 
Note that any deviation from the full sampling schedule (i.e., less samples) may compromise the 
accuracy of pharmacokinetic calculations, and thus may inhibit the ability to make dosing 
decisions for subsequent (e.g. younger) cohorts. As such, it is strongly recommended to adhere 


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to the full pharmacokinetic sampling schedule as best as possible, unless non-adherence is 
required to safeguard subject safety. 
The safety population will include all subjects who receive at least 2 mg 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 dose received (actual amount of investigational 
product swallowed). 
13.4.1 Demographic and Baseline Characteristics 
Demographic and baseline information including key medical conditions, will be summarized 
and tabulated by cohort. The purpose of these summaries is (1) to characterize the study 
population, and (2) to identify any baseline imbalances of clinical significance that may require 
consideration in the evaluation of safety and pharmacokinetics. 
13.4.2 Data Analysis Methods 
No formal hypothesis testing will be performed in this study. Analyses will be descriptive only. 
All planned analyses will be presented in a SAP that will be finalized prior to commencing the 
final data analysis.  
13.5 Statistical and Analytical Plan 
A detailed SAP in which all aspects of data analysis will be defined will be prepared prior to 
undertaking the final analysis and database lock. The SAP will be submitted to regulatory 
authorities prior to database lock, as required. 
13.5.1 Analysis of Demographics 
Demographic and other baseline characteristics will be described by age Cohort and dose and 
for the total population.  
13.5.2 Analysis of Pharmacokinetics 
Non-compartmental pharmacokinetic analyses will be conducted on emerging pharmacokinetic 
data from the study, to evaluate whether the dose taken will ensure subjects have AUC values 
anticipated to be within the range expected to be safe and efficacious based on Phase II and III 
studies in adults and adolescents.  


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Phoenix WinNonlin version 6.4, will be implemented for the calculation of pharmacokinetic 
parameters including AUC0-inf to ensure subjects fall within the pre-determined acceptable 
exposure range, and Cmax. 
Specific pharmacokinetic 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; 
• cumulative AUC from time 0 extrapolated to time t (where t = 24, 48, and 72 hours) 
(cumAUC0-t); 
• Cmax: maximum observed plasma concentration; 
• Tmax: time to maximum observed plasma concentration; 
• t½: terminal elimination half-life. 
Additional pharmacokinetic parameters, including CL, volume of distribution, and others may 
be determined as appropriate.  
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 two concentration values in the terminal portion of the curve and R-square greater 
than 0.95. Computed pharmacokinetic parameters for moxidectin in plasma will be summarized 
and listed for moxidectin, including mean, geometric mean, standard deviation, median, and 
range, as appropriate. 
13.5.3 Population Pharmacokinetics 
The pharmacokinetic and demographic data from Cohorts I and II (adolescents and older 
children) will be used to update the existing population pharmacokinetic model for moxidectin. 
Covariate effects for central volume, systemic clearance and peripheral compartments will be 
explored and the updated model will be used to forecast AUC0-inf and Cmax values by dose for 
Cohort III (children 4 to 7 years) to support dose selection.  
At the end of the clinical trial, the population pharmacokinetic model will be updated once more 
with all available adult and pediatric pharmacokinetic data to assist in providing robust dose 
recommendations across the age range of 4 to 11 years.  


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The population pharmacokinetic model updates will be conducted with the non-linear mixed 
effects modeling software NONMEM. For the first update, parameter estimates from the 
existing population pharmacokinetic model will be re-estimated using pharmacokinetic and 
demographic data from adults and Cohorts I and II. Standard diagnostic procedures will be 
employed to evaluate model fit. Any modifications to the existing structure of the model 
(e.g., parameterization of covariate effects) will be guided by these diagnostic procedures. The 
final model from this first update will be assessed using advanced procedures to ensure 
acceptable structural and simulation properties.  
For the second (last) model update, the modeling and evaluation procedures described above 
will be repeated using all available pharmacokinetic and demographic data (i.e., adults and 
Cohorts I, II and III). 
Full details of the population pharmacokinetic modeling and simulation procedures will be 
provided in a SAP. 
13.5.4 Analysis of Safety 
All subjects receiving any dose of moxidectin will be included in the safety analyses. 
AEs, concomitant medications and laboratory data will be listed and summarized by Cohort 
and/or by dose if more than one dose level is evaluated in an age group. 
AE data will be listed individually and incidence of AEs summarized by system organ class and 
preferred terms within a system organ class for each treatment group. When calculating the 
incidence of AEs, each AE, based on preferred terminology defined by Medical Dictionary for 
Regulatory Activities (Version 13.1, or later), will be counted only once for a given subject. A 
summary of the number and percent of subjects with the following treatment emergent AEs will 
be displayed: 
• All AEs 
• Drug-related AEs 
• Severe AEs 
• SAEs 
All the laboratory values will be classified by grade. Changes over time in laboratory parameters 
will be explored. Grade 3 and 4 laboratory abnormalities will also be summarized. 


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13.6 Pharmacokinetic Assessments for Dose Determinations 
Non-compartmental pharmacokinetic analyses will occur in an ongoing manner during the 
study. Based on these analyses, if 3 or more subjects enrolled in Cohort II or III have 
moxidectin exposures below or above the target range, defined as AUCs less than the 10th 
percentile or greater than the 90th percentile mean AUC predicted by the population 
pharmacokinetic model, then the dose will be modified and 9 new subjects will be enrolled into 
that age cohort at the new dose. The intention is to provide pharmacokinetic and safety data in 
each cohort for a minimum of 9 subjects at a dose that is considered optimal to provide 
therapeutic exposures. 
If the required pharmacokinetic parameters for 9 subjects (per dose and cohort) cannot be 
calculated due to the availability of results from too few samples, additional subjects may be 
enrolled at that dose. Pharmacokinetic data from 9 subjects at the dose(s) selected for each 
cohort will be obtained.  
The first dose level to be proposed to the DSMB for administration in children aged 4 to 7 years 
(Cohort III) (and subsequent dose levels, if applicable, see Section 5.3) will be selected 
following additional population pharmacokinetic modelling with allometric scaling including 
data obtained from Cohorts I and II. 


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14 GENERAL STUDY ADMINISTRATION 
14.1 Ethical Aspects (Ethical and Safety Considerations) 
14.1.1 Local Regulations/Declaration of Helsinki 
The PI will ensure that this study is conducted in full conformance with the protocol, the latest 
version of the Declaration of Helsinki (and its amendments) and with the requirements of 
national drug and data protection laws of Ghana. 
The Sponsor and the investigators will ensure strict adherence to the provisions of GCP and all 
applicable local and national regulations and those of applicable regulatory agencies, including 
the Ghana Food and Drugs Authority and the US FDA. The International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines 
will apply at a minimum. 
14.1.2 Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from 
parents/guardians and assent from potential subjects (or to look for expressions of ‘deliberate 
objection’ in younger children, as appropriate for their age and level of maturity) after adequate 
explanation of the aims, methods, objectives and potential hazards of the study prior to 
undertaking any study related procedures. The investigator should also explain that the potential 
subjects and their parent(s)/guardian(s) are completely free to refuse to enter the study or to 
withdraw from it at any time for any reason.  
The anticipated potential risks of participation and the safety profile of moxidectin in adults and 
children at least 12 years of age with onchocerciasis are described in Sections 3.3.2.2, 3.4.3 
and 10.9. 
Information about the study and the written informed consent and assent documents will be 
presented in the language(s) of the potential subject population. The investigator must utilize 
ethics committee approved consent and assent forms, in relevant local language(s), for 
informing the potential subjects and their parents/guardians and documenting written informed 
consent and assent. The ethics committees responsible for review and approval of these 
documents are described in Section 14.1.5.  
Both parents or guardians (unless one is deceased, unknown, incompetent, or not reasonably 
available, or when only one parent/guardian has legal responsibility for the care and custody of 


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the child (reason for sole parent/guardian consent must be documented)) of potentially eligible 
children will provide written (signature or thumbprint) and witnessed informed consent for their 
child/ward.  
Informed assent will be obtained from all children ≥ 12 years and will be considered for 
children from 7 years onward. Children who do not provide assent, including those aged 4 to 6 
years and those aged 7 to 11 years who may not be mature enough to give assent (as judged 
jointly by their parent(s)/guardian(s) and investigator) will be assessed for expressions of 
‘deliberate objection’ (i.e. expressions of disapproval or refusal), as per CIOMS guidelines 
(Council for International Organizations of Medical Sciences (CIOMS) 2016). Refusal to 
provide assent or an expression of deliberate objection by a child/adolescent must be respected 
even if the parents have given consent for their participation in the study. The investigator will 
consider the child ineligible and record this on the informed consent provided by the 
parent(s)/guardian(s). 
All children will be informed about the study in the presence of their parent(s)/guardian(s) and 
an independent witness. The independent witness will confirm that the child and the 
parent(s)/guardian(s) have understood the information provided and document this on the 
consent/assent form. 
14.1.2.1 
Informing Communities about the Study 
Information about the study will be shared with community leaders and members within the 
location(s) where recruitment for the study is planned to take place. The initial approach will be 
to explain the study, the informed consent and assent procedure, and the information document 
to the Municipal Assembly, which performs government business at the local level. Next the 
chiefs, elders, and/or opinion leaders will be informed and educated, followed by whole 
communities, if the elders do not object. During the community meeting, a ‘community 
coordinator’ will be selected. This will be a community member that the community thinks will 
best serve as a link between the subjects and the study team. Finally, the community will 
propose an impartial witness or witnesses for the informed consent/assent procedure.  
14.1.2.2 
Informing Potential Subjects and their Parents/Guardians 
Obtaining informed consent and assent for pediatric subjects in rural communities in areas 
endemic for onchocerciasis poses challenges to the investigator in dealing with two vulnerable 


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groups in order to enroll a single subject for the study. One group is the parents/guardians 
permitting their children/wards to participate, and the other group is the even more vulnerable 
potential subjects, who may or may not be able to give informed assent. 
The parents/guardians are considered vulnerable because the social, economic, and educational 
gap between the investigator and the rural population is such that they are likely to consider any 
proposal by a physician to be in their best interest and to accept it with little or no dissent. 
Moreover, many subjects may not have had access to modern clinical medicine and will be 
transported from their villages into the alien environment of the clinic to participate in 
assessment procedures that would normally be unduly invasive for them.  
In order to address these factors, recruitment will occur in villages from which participants in 
the Phase III study of moxidectin and another study conducted by the PI were recruited. Thus, 
potential subjects and their parents/guardians themselves, or people they can talk to, are likely to 
have first-hand experience in research study participation and procedures, the research center 
and moxidectin treatment, and will be able to better understand the information provided about 
the study during the informed consent process.  
Furthermore, the following informed consent procedure is planned: 
1. The process will take place in the community in order to remove any pressures 
imposed by its occurrence in the possibly unfamiliar research center environment.  
2. Initial information will be provided at a community meeting, which will allow 
meeting participants to benefit from the questions asked by other meeting 
participants. This will be followed by discussions with individual 
parent(s)/guardian(s) and their child/ward.  
3. Study information will be conveyed in the local language. The English version of the 
informed consent/assent information and forms will be translated and authenticated 
by a reputable individual or agency. Four different information and/or consent/assent 
documents are provided: 
i. an adolescent (12 to 17 years) and parent/guardian information sheet and 
assent and consent form written in language that is understandable to a child 
of 12 years of age (see Appendix 16.6);  


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ii. a separate parent/guardian information sheet and consent/assent form for 
parents of children aged 4 to 11 (see Appendix 16.7), also written in language 
understandable to children aged 12 years and including two consent/assent 
forms: 
1. one for parents/guardians and children <12 years who are providing 
assent (includes written parent/guardian consent and child assent); 
2. one for parents/guardians of children considered too immature to 
provide assent (includes written parent/guardian consent and 
documentation of assessment of expression of ‘deliberate objection’; 
consent will be obtained before discussion of the study with the 
child); 
iii. a simpler study information sheet for children aged 7 to 11 years considered 
mature enough to provide assent (see Appendix 16.8); and 
iv. an even simpler information sheet for children 4 to 6 years or older children 
considered too immature to provide assent (see Appendix 16.9). 
4. Every effort has been made to ensure that all aspects of the study and all elements 
regarded as essential for informed consent/assent are specified in the information 
documents. These are presented in chronological order and supplemented by images 
and schematic diagrams to facilitate comprehension. 
5. Understanding of the information provided about the study will be assessed using a 
short questionnaire consisting of a series of open and closed questions in the local 
language for parents/guardians, adolescents and children considered mature enough 
to give assent to answer. The questions to be asked are included at the end of the 
information documents, with space provided for recording responses and any 
questions asked by the child or parent(s)/guardian(s) (refer to Appendices 16.6, 16.7 
and 16.8). 
6. An impartial, literate local resident agreed to by the potential subject and their 
parent(s)/guardian(s) (impartial witness) must be present when study information is 
provided and discussed, and must countersign the consent/assent form to attest to the 
fact that the information has been given to and understood by the 
parent(s)/guardian(s) and child. 


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7. The informed consent/assent forms must be signed/thumbprinted in 2 originals, one 
of which must be given to the parent(s)/guardian(s) in front of the impartial literate 
witness on the same day that the informed consent/assent is given. 
8. At each subsequent study visit, the investigator should verbally confirm the 
continued consent/assent of the subject and that they are free to withdraw from the 
study at any time for any reason. 
14.1.2.3 
Informing Children Too Young/Immature to Give Assent. 
Information about the study, primarily based on pictures (Appendix 16.9) will be presented to 
children aged 4 to 6 years as well as older children considered not mature enough to provide 
assent in the joint judgement of the parent(s)/guardian(s) and the investigator.  
Early on in the presentation and discussion, a tablet similar in size and shape to moxidectin 
tablets will be shown and the child and their parent(s)/guardian(s) will be asked whether they 
think the child can swallow such tablets. If a child or their parent(s)/guardian(s) states that they 
cannot swallow a tablet of that size and shape, there will be no further discussion. Subsequently 
children will be told about the need to take blood and venous access will be assessed. If a child 
has poor venous access, there will be no further discussion. 
It is acknowledged that this constitutes evaluation of exclusion criteria 7 and 8 before the child 
has been presented with all information about the study and had the opportunity to express 
‘deliberate objection’ to all other elements of the study. This sequence was chosen since it does 
not include an invasive procedure or confidential health information and obtaining all other 
information about the study has no value for a child who will be excluded on the basis that they 
cannot swallow the tablets or have poor venous access.  
14.1.3 Compensation 
All study-related costs, including study medication, laboratory tests, contraceptives counselling 
and provision, and medical care will be provided free of charge. In addition, transportation will 
be provided to and from the study center, and accommodation and food will be provided for 
each (potential) subject and their accompanying parent/guardian while at the study center.  
The parent/guardian who accompanies the child to the study site will be compensated for loss of 
earnings according to the number of nights they are required to stay. The amount paid for each 
night’s stay will approximate to “by day” earnings of individuals in the village communities, 


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currently forty (40.00) Ghanaian Cedi per day. In addition, treatment-emergent adverse events 
occurring during the study will be treated in accordance with local treatment requirements and 
as clinically indicated without cost. 
14.1.4 Provision for Study Visits During School Time 
If the child is at the study center during school time, a teacher will be employed to provide 
educational activities and/or oversee homework during their stay to compensate for school time 
missed.   
14.1.5 Ethics Committees 
This protocol and any accompanying material provided to the potential subject and their 
parents/guardian (such as information sheets with descriptions of the study used to obtain 
informed consent/assent) will be submitted by the investigator to the Research Ethics 
Committee of the UHAS and the GHS Ethics Review Committee. Furthermore, the protocol 
will be submitted to the WHO Ethics Review Committee. Approval from all three ethics 
committees will be obtained before starting the study and must be documented in a letter to the 
investigator (or the WHO Responsible Officer submitting the protocol to the WHO Ethics 
Review Committee) specifying the protocol number and version and the date on which the 
committee met and the date it granted the approval.  
14.1.6 Conditions for Modifying the Protocol 
Protocol modifications to ongoing studies which could potentially adversely affect the safety of 
participating subjects or which alter the scope of the investigation, the scientific quality of the 
study, the experimental design, dosages, duration of therapy, assessment variables, the number 
of subjects treated or subject selection criteria, may be made only after consultation between an 
appropriate representative of the Sponsor and the PI. 
Protocol modifications (amendments) must be prepared by a representative of the Sponsor and 
may be reviewed and approved by the responsible Medical Monitor and (when applicable) the 
Statistician. 
All protocol modifications must be submitted to the ethics committees (UHAS, GHS and WHO, 
see Section 14.1.5) in accordance with local requirements and to regulatory bodies (Ghana Food 
and Drugs Authority and US FDA) as required. Approval must be granted before changes can 
be implemented. 


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In the event of an emergency, the investigator may institute any medical procedures deemed 
appropriate without a formal protocol amendment being granted. However, all such procedures 
must be promptly reported to the Sponsor, the Medical Monitor and the ethics committees. 
Administrative changes of the protocol are defined as minor corrections and/or clarifications 
that have no effect on the way the study is to be conducted, or on the safety of the subjects. Any 
administrative changes must be agreed upon by the Sponsor and the PI and must be documented 
in a memorandum. The PI (or WHO Responsible Officer) will then notify the ethics committees 
of such administrative changes. 
14.1.7 Conditions for Terminating the Study 
Both the Sponsor and the PI reserve the right to terminate the study at any time. Should this be 
necessary, the procedures will be arranged on an individual study basis after review and 
consultation by both parties. In terminating the study, the Sponsor and the PI will assure that 
adequate consideration is given to the protection of the subject’s interests. 
14.1.8 Blood Volumes Sampled Relative to Maximum Recommended Volumes 
Please refer to Section 7.4.3. 
14.1.9 Informing Study Subjects and Communities about the Study Results 
Once the final data from the study are available and a decision on further evaluation of 
moxidectin has been made, each community will be visited. The study subjects and their 
parents, as well as other interested community members, will be informed about the study 
results and any future activities to be undertaken to enable the use of moxidectin for control and 
elimination of onchocerciasis in endemic countries. Age appropriate information documents to 
be used for this purpose will be submitted for review and approval by the responsible ethics 
committees. 
14.1.10 Implementation of the Study in the context of the COVID-19 Pandemic 
All activities required for successful implementation of the study were reviewed, ranging from 
community mobilization and information (Section 14.1.2.1), informing potential participants 
and their parents/guardians about the study (Section 14.1.2.2) and obtaining parental informed 
consent and adolescent/child assent (Sections 7.3.1 and 14.1.2), through to screening in the 
village of residence, transport to and from the research center, treatment and follow up (Sections 
7.3.2 to 7.3.14).  


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The objective of this review was to determine whether changes in the standard methodology and 
approach could be identified that would minimize contact with research participants so that the 
study can be conducted during the pandemic in a way that minimizes risk of transmission of 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Further, it sought to determine 
whether the changes could potentially result in an overall positive benefit-risk ratio through 1) 
education of the population in the villages where participants will be recruited regarding 
coronavirus disease 2019 (COVID-19) and measures to minimize the risk of transmission, and 
2) contribution to screening for COVID-19 cases via referral of suspect cases to the Nkwanta 
North COVID-19 Rapid Response Team.   
Specifically, the review of the activities evaluated: 
• the extent to which processes can be conducted with physical distancing and the 
operational measures required to comply with national directives; 
• the extent to which those involved will have already undergone education on COVID-19 
and the precautions required to minimize SARS-CoV-2 transmission and, as a result, 
whether the study team will need to provide initial information on COVID-19,  or can 
build on previous information provided by the Ghana Ministries of Communication and 
Health via the radio and television; 
• how screening for suspected COVID-19 cases through temperature measurement and 
assessment of other symptoms, followed by referral of suspected cases to the Nkwanta 
North or Hohoe COVID-19 Rapid Response Team can be conducted at the beginning of 
all protocol-planned activities; and  
• additional measures that need to be taken to minimize the risk of SARS-CoV-2 
transmission during all activities where the physical distancing advised by the GHS 
(currently ≥6 feet) is not possible.   
Per the GHS Ethics Review Committee guidelines effective 7 May 2020, the measures that will 
be taken to adhere to current national directives on physical distancing and to protect the safety 
of participants, their communities and the study team are outlined below. As national, Nkwanta 
North COVID-19 Rapid Response Team or Hohoe COVID-19 Rapid Response Team directives 
evolve during the course of the pandemic (e.g. regarding the number of people allowed to 


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participate in meetings or the physical distance to be kept), these measures will be adapted 
accordingly.   
All measures to minimize risk of transmission of COVID-19 will be implemented in 
coordination and collaboration with the Nkwanta North COVID-19 Rapid Response Team or 
Hohoe COVID-19 Rapid Response Team, as applicable, based on where the protocol-planned 
activities take place.  
14.1.10.1 Informing Communities About the Study 
Measures to minimize the risk of transmission of SARS-CoV-2 will be implemented as follows. 
14.1.10.1.1 District Directors, Disease Control Officers and Local Health Center 
Staff 
• Those involved in meetings to discuss the study will have already undergone education 
on COVID-19, have procedures in place for screening for COVID-19 symptoms before 
entering the buildings where meetings are held and will be wearing masks. 
• Meetings will be arranged so that the government-advised maximum group size 
applicable at the time is not exceeded. 
• Offices/meeting rooms will be set up in compliance with government-advised physical 
distancing and procedures will be in place to refer anybody with COVID-19 symptoms 
to the Nkwanta North COVID-19 Rapid Response Team designated local health 
facility/COVID-19 team. 
• Documents distributed at the meetings will be left with meeting participants. 
14.1.10.1.2 Chiefs, Elders and Opinion Leaders  
• By the time meetings with chiefs, elders and opinion leaders are initiated, most 
participants are likely to have received information about COVID-19 provided by the 
government via radio or television. 
• Meetings will be arranged so that the government-advised maximum group size 
applicable at the time is not exceeded. 
• Meetings will be set up an open space, church or school, with the study team ensuring 
that seating meets the current government-advised maximum group size and physical 


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distancing requirements for individuals who do not live together. The study team will 
use megaphones to ensure they can be heard. 
• The study team will measure the temperature of all participants using non-contact 
thermometers and ask about other symptoms of COVID-19, as well as any COVID-19 
tests. Suspected COVID-19 cases will be excluded from the meeting and asked to self-
isolate to the extent possible. The study team will inform the COVID-19 Rapid 
Response Team, so that the suspected cases can receive the appropriate evaluation and 
follow-up. 
• The study team will provide cloth masks for all meeting participants and ensure 
availability of soap and water (or hand sanitizer) for hand washing/sanitizing. This will 
ensure that all meeting participants wash/sanitize their hands before entering and on 
leaving the meeting space, and wear masks throughout the meeting. 
• The study team will initiate the meeting with a demonstration of the proper use and 
cleaning of cloth masks and information on COVID-19 symptoms, how to minimize the 
risk of infection and the need to call the Nkwanta North COVID-19 Rapid Response 
Team if they or somebody they know experience symptoms. 
• Documents and cloth masks will be left with participants. 
14.1.10.1.3 Village Communities, Potential Participants and Their Parents  
In addition to the procedures described in Section 14.1.10.1.2 for screening for COVID-19 
symptoms, physical distancing, hand washing, wearing of masks, and provision of general 
information on COVID-19 and minimizing the risk of infection, the following measures will be 
implemented: 
• By the time meetings are initiated with village communities, many, but not all 
community meeting participants are likely to have heard the information about COVID-
19 provided by the government via radio or television. 
• Meetings will be arranged in an open space, church or school so that seating 
arrangements can meet the government-advised maximum group size and physical 
distancing requirements for individuals who do not live together that are applicable at 
the time. To achieve this, meetings may be arranged at the sub-village level, including 


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with family groups who are interacting on a daily basis, or even by arranging meetings 
for individual family groups. The village coordinator (Section 14.1.2.1), a literate 
witness (Section 14.1.2) and a translator will always be present, together with up to five 
study team members.  
14.1.10.2 Obtaining Informed Consent/Assent  
Meetings to accomplish the final steps in informing potential participants and their 
parents/guardians about the study and obtain informed consent/assent will include the 
child/adolescent and their parents/guardian, the village coordinator, the witness, the translator 
and the investigator. 
In addition to procedures described in Sections 14.1.10.1.2 and 14.1.10.1.3 for screening for 
COVID-19 symptoms, physical distancing, hand washing, wearing of masks, and provision of 
general information on COVID-19 and minimizing the risk of infection, the following measures 
will be implemented: 
• Suspected cases of COVID-19 identified by symptom screening will be excluded from 
meetings.  If the suspect case is a village coordinator, witness or translator, they will be 
replaced. If the suspect case is a child or parent/guardian, the child and parent/guardian 
will be asked whether they want to be contacted about study participation once they have 
tested negative or recovered from COVID-19, as applicable.  
14.1.10.3 Pre-screening in Villages 
In addition to procedures described in Sections 14.1.10.1 and 14.1.10.2 for screening for 
COVID-19 symptoms, physical distancing, hand washing, wearing of masks, and provision of 
general information on COVID-19 and minimizing the risk of infection, the following measures 
will be implemented: 
• Study team members will wear medical-grade masks and wash/sanitize hands between 
interactions with different participants involving physical contact.   
• Waiting areas for pre-screening participants will be set up to ensure government-
required physical distancing between different child/parent/guardian pairs. 
• While the COVID-19 pandemic is ongoing, as many protocol-planned screening 
activities as possible that do not require medical or laboratory examinations (see 


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Sections 6.1, 6.2 and 6.3) will be conducted in the villages to minimize the number of 
potential screen failures and their accompanying parent/guardian being transported to the 
UHAS research center for screening: 
14.1.10.4 Transport Between Villages and the UHAS Research Center 
In addition to procedures described in Sections 14.1.10.1, 14.1.10.2 and 14.1.10.3 for screening 
for COVID-19 symptoms, physical distancing, hand washing, wearing of masks, and provision 
of general information on COVID-19 and minimizing the risk of infection, the following 
measures will be implemented: 
• To the extent possible, children/adolescents and accompanying parents/guardians being 
transported together to the Center will be selected so they are in frequent contact with 
each other during their daily lives. 
• Only children/adolescents and their parents/guardians who pass COVID-19 screening 
will be allowed to travel to the Research Center.  
• The number of passengers per vehicle will be limited to 8 (including 1 driver and 1 
coordinator). 
• Before entering the vehicle, everybody with wash/sanitize their hands and put on face 
masks. 
• The standard cleaning of vehicles between trips will be expanded to include use of 
bleach or other SARS-CoV-2-suitable disinfectants. 
14.1.10.5 Accommodation in the UHAS Research Center  
• The standard welcome and introduction to the Research Center will be expanded to 
include a demonstration on the proper use and cleaning of cloth masks, and information 
on measures such as wearing of masks, regular hand-washing and physical distancing 
between people who do not normally live in the same house that will be adopted by both 
participants and the study team to minimize the risk of COVID-19 infection. 
• The number of child/adolescent and parent/guardian pairs per ward and eating at the 
same time will be reduced as shown in Figure 2. 


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• The normal cleaning routine (morning, evening) will be expanded to three times a day 
(morning, mid-day, evening) and toilets and washrooms will be cleaned using bleach or 
other SARS-CoV-2-effective disinfectants every 3 hours during the day. 
Figure 2: Capacity and Utilization of Participant and Parent/Guardian Wards and 
Recreational Areas During the COVID-19 Pandemic 
 
14.1.10.6 Protocol-Planned Examinations 
• Each morning, study participants and their accompanying parent/guardian will undergo 
temperature measurement and be questioned about other signs and symptoms of 
COVID-19. Individuals meeting suspected case criteria will be isolated and the Hohoe 
COVID-19 Rapid Response Team will be notified.  
• Staff will wear medical-grade masks during all examinations involving physical contact 
and wash hands between interaction with different study participants. 
• Children/adolescent and parents/guardians will wear cloth masks (provided and washed 
on a daily basis by the Research Center). 
• All equipment will be disinfected between examination of different study participants. 
• The normal cleaning routine (morning, evening) of all examination rooms will be 
expanded to three times a day (morning, mid-day, evening).  
• Laboratory samples will be taken by staff wearing medical-grade masks and gloves and 
will be handled according to standard biosafety precautions. 
14.2 Study Documentation, Case Report Forms and Record Keeping 
14.2.1 Investigator Files and Retention of Documents 
The PI is responsible for maintaining adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 


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should be classified into two separate categories: (1) Investigator Site File, and (2) subject 
clinical source documents. The PI must ensure members of the study team are aware of and 
adhere to these requirements, by implementation of adequate training and according to relevant 
site SOPs. 
The Investigator Site File will contain the protocol/amendments, completed CRFs and data 
clarification forms (or electronic (e)CRF data queries and audit trails), EC and 
governmental/regulatory authority approvals with correspondence, informed consent/assent 
forms, drug records, staff curriculum vitae and authorization forms and other appropriate 
documents and correspondence. Subject clinical source documents may include subject 
hospital/research center records, physician and nurse’s notes, appointment books, original 
laboratory reports, ECG tracings etc.  
All essential documents should be retained for at least 25 years after the end of the clinical trial. 
These documents should be retained for a longer period however if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. The Sponsor will inform the 
investigator/institution as to when these documents no longer need to be retained. The PI must 
notify the Sponsor prior to destroying any clinical study records. 
Should the PI wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the PI cannot guarantee this archiving requirement at the study site for any or all of the 
documents, special arrangements must be made between the PI and the Sponsor to store these in 
a sealed container(s) outside of the site so that they can be returned sealed to the PI in case of a 
regulatory audit. Where source documents are required for the continued care of the subject, 
appropriate copies should be made for storage off-site. 
14.2.2 Background Data 
The PI shall supply the Sponsor, on request, with any required background data from the study 
documentation or research center records. This is particularly important when CRFs are illegible 
or when errors in data transcription are suspected. In case of special problems and/or 
governmental queries or requests for audits and inspections, it is also necessary to have access 
to the complete study records, provided that subject confidentiality is protected. 


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14.2.3 Audits and Inspections 
The PI should understand and agree that source documents for this trial should be made 
available to appropriately qualified personnel from the Sponsor or its representative or to 
regulatory authority or health authority inspectors after appropriate notification. The verification 
of the CRF data will be by direct inspection of source documents. 
14.2.4 Case Report Forms 
CRFs (eCRFs) must be completed for each subject enrolled and signed by the PI. This also 
applies to records for those subjects who fail to complete the study. If a subject withdraws from 
the study, the reason must be noted on the CRF. 
Data collection and entry into the CRF will be completed by authorized study site personnel 
designated by the PI. Appropriate training will be completed with the PI and all authorized 
study site personnel prior to the study being initiated and any data being entered into the CRF 
for any study subjects. 
The CRF is essentially a data entry form and should not be considered to constitute an original, 
or source, document. 
All data must be entered in English.  
The CRFs should always reflect the latest observations on the subjects participating in the trial; 
therefore, the CRFs are to be completed as soon as possible after the subject’s visit. The PI must 
verify that all data entries in the CRFs are accurate and correct. If some assessments are not 
done, or if certain information is not available or not applicable or unknown, this should be 
indicated in the CRF.  
The CRFs, as well as the protocol, are confidential. The CRFs remain the property of the 
Sponsor at all times. 
14.3 Monitoring the Study 
Before the start of the trial, a representative of the Sponsor or designee will contact the 
investigational site to ensure facilities are adequate and discuss responsibilities with the site staff 
with regards to following the protocol and regulatory and ethical requirements. 
During the trial, the designated Study Monitor will regularly visit the site to monitor and 
confirm protocol, regulatory and ethical adherence, confirm data accuracy and provide 


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information and support as needed. It is understood that the responsible Study Monitor, as the 
Sponsor representative, will contact and visit the PI regularly and that he/she will be allowed, on 
request, to inspect the various records of the trial (CRFs and other pertinent data) provided that 
subject confidentiality is maintained in accordance with local requirements. 
In accordance with ICH GCP guidelines, the Study Monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the CRFs for 
consistency. 
The PI agrees to cooperate with the monitor to ensure that any problems detected in the course 
of these monitoring visits are resolved. The SRM will include Study Monitor and back up 
contact details in the event they have queries or require assistance. 
14.4 Confidentiality of Trial Documents and Subject Records 
The PI must assure the subjects’ anonymity will be maintained and that their identities are 
protected from unauthorized parties. Documents not for submission to the Sponsor (e.g. 
subject’s written consent/assent forms), should be maintained by the PI in strict confidence. 
On CRFs or other documents submitted to the Sponsor or designee, subjects should not be 
identified by their names, but by subject ID. The PI must keep a subject enrolment log showing 
identification codes and participant names. This log must be made available to the Study 
Monitor but not provided to the Sponsor. 
All information concerning the study treatment shall remain the sole property of the Sponsor. 
The PI agrees to use this information only in accomplishing the study and will not use it for any 
other purposes without written consent from the Sponsor. 
14.5 Publication of Data (Dissemination of Results) 
The Sponsor will list the study on a public database listing of clinical trials, for example, 
www.clinicaltrials.gov. 
In accord with standard editorial and ethical practice, the Sponsor will support initial publication 
of analyses and conclusions from the entirety of trial data only.  
The results of this study may be published or presented at scientific meetings. Per local 
regulatory guidelines, publication will only proceed 30 days after the Sponsor receives Ghana 
Food and Drug Authority's acknowledgement of receipt of the final study report. Sponsor-


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initiated publications and/or presentations will be agreed upon between the PI and Sponsor. PI-
initiated publications and/or presentations will be provided for review by the Sponsor at least 
30 days prior to submission to allow the Sponsor to provide comments based on information 
from other studies that may not yet be available to the PI. 
Any formal publication of the study in which input of the Sponsor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the PI and the appropriate 
Sponsor personnel. Authorship will be determined by mutual agreement in accordance with 
International Committee of Medical Journal Editors recommendations. Additional authors will 
be agreed prior to journal submission. 
14.6 Anticipated Subject Accrual and Duration of the Study 
The anticipated subject accrual to the study will be up to a maximum total of 63 subjects on 
study for 28 weeks, recruited over a 35-week period. Duration of study is expected to be 
approximately 15 months. The PI should continually compare the actual and expected accrual 
rates and make every effort to ensure that they are as closely matched as possible. If the PI 
anticipates major problems with recruitment, or delay in the expected completion date, he/she 
should discuss this with the Sponsor as early as possible. 


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Zisowsky, J., A. Krause and J. Dingemanse (2010). "Drug Development for Pediatric 
Populations: Regulatory Aspects." Pharmaceutics 2(3): 364-388. 
Zoure, H. G., M. Noma, A. H. Tekle, U. V. Amazigo, P. J. Diggle, E. Giorgi and J. H. Remme 
(2014). "The geographic distribution of onchocerciasis in the 20 participating countries of the 
African Programme for Onchocerciasis Control: (2) pre-control endemicity levels and estimated 
number infected." Parasit Vectors 7(1): 326. 
 


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16 APPENDICES 
16.1 World Health Organization Designation of Onchocerciasis Endemicity 
Figure 3: Onchocerciasis Endemicity (2017) and Status of Onchocerciasis Therapeutic 
Mass Drug Administration Coverage (2016) in Ghana 
 
 


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16.2 Population Pharmacokinetic Simulation of Moxidectin to Determine Initial 
Dosing Recommendations for Subjects in Study MDGH-MOX-1006 
(d3 Medicine Report, 9 Dec 2016, and Statistical Appendix, 26 Nov 2019) 
 
 
 
 
 


d3 Medicine, A Certara Company
Report (Conﬁdential)
Population Pharmacokinetics Simulation of Moxidectin to
Determine Initial Dosing Recommendations for Participants in
Study MDGH-MOX-1006
Sponsor
Medicines Development for Global
Health
Document Issued
09 Dec 2016
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1
List of Abbreviations
AUC
Area under the curve
BMI
Body mass index
CDTI
Community-directed treatment with ivermectin
CL/F
Clearance from the central compartment
CLd2/F
Inter-compartmental clearance between the central and second pe-
ripheral compartments
Cmax
Maximum concentration
PK
Pharmacokinetic
SAP
Statistical analysis plan
Vc/F
Volume of distribution of the central compartment
Vp2/F
Volume of distribution of the second peripheral compartment
WHO
World Health Organization
1
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Contents
1
List of Abbreviations
1
2
Introduction
4
3
Objectives
4
4
Methods
5
4.1
Model for Simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
4.2
Simulation Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
4.3
Evaluations of Simulations . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
5
Software
8
6
Changes to the planned analyses
8
7
Results
9
7.1
Demographic Proﬁles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
7.2
Simulations
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
8
Discussion
19
9
Conclusions
19
2
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List of Figures
1
Schematic of the population pharmacokinetic model of moxidectin . . . . . .
6
2
Relationship between height and weight assumed for the simulations . . . . .
9
3
Simulated pharmacokinetic proﬁles for adults and healthy volunteers
. . . .
10
4
Summaries of simulated exposure metrics for children 4-11 years (8 mg), ado-
lescents 12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16
mg, 36 mg)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
5
Summaries of simulated exposure metrics for children 4-11 years (2 mg), ado-
lescents 12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16
mg, 36 mg)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
6
Summaries of simulated exposure metrics for children 4-11 years (4 mg), ado-
lescents 12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16
mg, 36 mg)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
7
Summaries of simulated exposure metrics for children 4-11 years (6 mg), ado-
lescents 12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16
mg, 36 mg)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
3
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2
Introduction
Onchocerciasis is a skin and eye disease caused by the parasitic worm Onchocerca volvulus.
The disease is transmitted to humans through the bite of a black ﬂy (genus Simulium) [1].
Once matured in the human body, the adult female worm (macroﬁlaria) produces larval
worms (microﬁlariae) that distribute in the skin and eye [1]. Microﬁlariae can cause se-
rious skin conditions and visual impairment that may lead to irreversible blindness [2, 1].
Onchocerciasis is commonly known as “river blindness” since the black ﬂies that transmit
the disease live near fast-running rivers and streams in inter-tropical zones (mostly in sub-
Saharan Africa) [1]. The World Health Organization (WHO) has listed onchocerciasis as
a neglected tropical disease for which new treatments are sought [3]. Substantial eﬀort is
being made to control onchocerciasis due to its severe health and economic burden [1, 2].
The current control strategy for onchocerciasis is community-directed treatment with
ivermectin (CDTI). This strategy is currently implemented in mesoendemic and hyperen-
demic areas [2]. Although the microﬁlaricidal eﬀect of ivermectin typically results in a rapid
decrease in skin microﬁlarial load, the microﬁlariae may begin to reappear in the skin three
to six months after treatment [2]. Multiple doses of ivermectin have been reported to lead
to a reduction in microﬁlarial load [4, 5, 6, 7, 8, 9].
A possible alternative to ivermectin is moxidectin. Moxidectin is an anthelmintic drug
developed by Fort Dodge Animal Health [2]. It is used for prevention of canine heartworm
and treatment of internal and external parasites in sheep, horses and cattle [2]. Currently,
moxidectin is being developed in collaboration with the WHO as a treatment for onchocer-
ciasis in humans [2].
A population pharmacokinetic (PK) model of moxidectin has been developed using PK
data from healthy adult volunteers [10, 11] and adult patients infected with Onchocerca
volvulus [12, 13]. The model accounted for the eﬀects of food, formulation and body com-
position [13]. Importantly, the model was built with the intention of extrapolation to other
populations, including paediatrics [13]. As such, this model has the potential to aid de-
termination of dosing strategies for future studies of moxidectin in children, such as Study
MDGH-MOX-1006. Study MDGH-MOX-1006 is a Phase 1 study in children and adolescents
4-17 years old, where dosing regimens for children 4-11 years have not yet been established.
Adolescents 12-17 years participating in Study MDGH-MOX-1006 will receive a single oral
dose of 8 mg, which was shown in Study ONCBL60801 (Phase 3) to be eﬃcacious and
well-tolerated in this group.
3
Objectives
The objectives of this work were to:
4
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1. Predict (by population PK simulation) the range of exposures achieved with a single
8 mg oral dose of moxidectin in adolescents 12-17 years.
2. Use available data sources, including demographic data from the adolescents who par-
ticipated in Study ONCBL60801, to facilitate simulations to support initial dosing
recommendations of moxidectin for children 4-11 years who will participate in Study
MDGH-MOX-1006.
4
Methods
4.1
Model for Simulation
Concentration-time proﬁles were simulated from a previously developed population PK
model of moxidectin [13]. In brief, the model was built using PK data from healthy adult
volunteers [10, 11] and adult patients infected with Onchocerca volvulus [12]. The model
comprises three compartments with an n-transit absorption process and ﬁrst-order elimi-
nation (Figure 1). To allow the potential to extrapolate to other populations, the model
incorporated allometry [14] where consistent with the observed data (central volume of dis-
tribution [V c/F], inter-compartmental clearance between the central and second peripheral
compartments [CLd2/F] and volume of distribution of the second peripheral compartment
[Vp2/F] [13]). The model includes eﬀects of food and formulation on absorption and relative
bioavailability (Figure 1, Table 1). The model also stipulates that females have larger values
of CLd2/F and Vp2/F than males; subjects with larger values of body mass index (BMI)
have increased Vp2/F (stratiﬁed by Phase 1 and Phase 2; Figure 1, Table 1). See [13] for full
details of the population PK model.
5
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Gut
Central
Vc/F (L) †
Peripheral 1
Vp1/F (L)
Peripheral 2
Vp2/F (L) †**
CL/F (L/h)
CLd1/F (L/h)
CLd2/F (L/h) †
ktr*
Transit 1
Transit 2
Dose
*ktr = 3/MTT; food, formulation and Study 101 design effects 
(fractional changes) incorporated
† Allometry imposed
** Study 101 design effect (fractional change) incorporated
Other notes:
•
Food and formulation effects (fractional changes) incorporated 
into relative bioavailability
•
Study 101 effect (fractional change) incorporated into the 
residual standard deviation
Figure 1. Schematic of the population PK model of moxidectin. ktr = transit rate constant, CL/F
= apparent clearance, Vc/F = apparent volume of distribution of the central compartment, CLd1/F
= apparent inter-compartmental clearance between the central and ﬁrst peripheral compartments,
Vp1/F = apparent volume of distribution of the ﬁrst peripheral compartment, CLd2/F = apparent
inter-compartmental clearance between the central and second peripheral compartments, Vp2/F =
apparent volume of distribution of the second peripheral compartment.
Table 1. Parameter estimates from the ﬁnal population PK model of moxidectin
Parameter
Estimate
%RSE
BSV
%RSE
MTT (h)
1.65
5.1
0.187
13.3
CL/F (L/h)
3.63
5.6
0.162
11
Vc/F (L/70 kg)
129
4.4
0.0528
16.1
CLd1/F (L/h)
5.06
4.7
Vp1/F (L)
246
7
CLd2/F (L/h/70 kg)
2.97
7.3
0.128
14.9
Vp2/F (L/70 kg)
1080
5.8
0.188
11.3
Phase 1 eﬀect* on CL/F
0.694
20.1
Phase 1 eﬀect* on Vc/F
0.839
32.1
Phase 1 eﬀect* on CLd1/F
0.843
40.5
Phase 1 eﬀect* on Vp1/F
0.479
11.5
Phase 1 eﬀect* on CLd2/F
1.87
15.4
Phase 1 eﬀect* on Vp2/F
1.3
38.5
Food eﬀect* on MTT
2.12
12.1
Food eﬀect* on relative bioavailability
1.39
17.4
Formulation eﬀect* on MTT (ﬁxed)
0.292
0
Formulation eﬀect* on relative bioavailability
1.21
13.5
Sex eﬀect* on CLd2/F
1.52
26.4
Sex eﬀect* on Vp2/F
1.64
23.9
Phase 1 BMI eﬀect** on Vp2/F
1.56
23.6
Phase 2 BMI eﬀect** on Vp2/F
0.598
58
Study 3110A1-101-EU eﬀect* on MTT (ﬁxed)
0.477
0
Study 3110A1-101-EU eﬀect* on Vp2/F
1.19
45.9
Proportional error (SD; %)
22.6
1.1
Study 3110A1-101-EU eﬀect* on proportional error
0.855
13.9
%RSE=Percent relative standard error; BSV=Between-subject variance,
*Fractional change; **Exponent from power function; SD=Standard deviation
6
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4.2
Simulation Procedure
The simulation procedure resembled the proposed study design of Study MDGH-MOX-1006.
The following single oral doses of moxidectin under fasted conditions were evaluated: 2 mg,
4 mg, 6 mg and 8 mg. For each dose, the simulation procedure was as follows:
1. Two virtual age cohorts were generated: 4-7 years and 8-11 years.
For the 8 mg
dose, an additional adolescent cohort (12-17 years) was generated. The 4-7 years and
8-11 years cohorts each consisted of 9 virtual individuals (4 females, 5 males). The
adolescent cohort (8 mg only) consisted of 12 virtual individuals (6 female, 6 male; i.e.,
one male and one female for each age). Within each age cohort, individual weights,
heights and body mass index (BMI) were simulated based on observed demographic
proﬁles from Study ONCBL60801 (restricted to subjects from Ghana; ≥12 years) and
WHO growth charts (children 5-11 years, with consideration of children 12-17 years)
[15]. Demographic data from Study 3110A1-GH-200 [12] were also used to investigate
and establish demographic proﬁles.
2. Each individual’s (simulated) demographic data (i.e., sex, weight and BMI) were used
in conjunction with the population PK model (Section 4.1) to simulate a correspond-
ing moxidectin concentration-time proﬁle. To facilitate calculation of PK exposure
metrics (see step 3 below), an intensive PK sampling design (hourly up to 4 days post-
administration; every 4.5 days up to 12 months post-administration) was speciﬁed for
each individual.
3. For each individual, the area under the curve (AUC) and maximum concentration
(Cmax) was derived from their simulated PK proﬁle.
This process was repeated 1000 times. Therefore, for each dose, there were 9×1000 simu-
lated PK proﬁles (and corresponding PK exposure metrics) for the 4-7 years and 8-11 years
cohorts; 12×1000 proﬁles and exposure metrics for the adolescent cohort (8 mg only).
For purposes of comparison, an additional 1000 moxidectin PK proﬁles were simulated
for each of the following scenarios in adults:
• Typical adult male (weight=58.2 kg, BMI=20.7 kg/m2 [13]), single oral 8 mg dose,
fasted conditions.
• Typical adult female (weight=59.7 kg, BMI=23.9 kg/m2 [13]), single oral 8 mg dose,
fasted conditions.
• Typical healthy adult male (weight=74.6 kg, BMI=23 kg/m2 [16]), single oral 8 mg
dose, fasted conditions.
• Typical healthy adult male (weight=74.6 kg, BMI=23 kg/m2 [16]), single oral 16 mg
dose, fasted conditions.
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• Typical healty adult male (weight=74.6 kg, BMI=23 kg/m2 [16]), single oral 36 mg
dose, fasted conditions.
The AUC and Cmax were derived for each simulated proﬁle (thus resulting in 1000 AUCs
and Cmaxs for each adult cohort above).
4.3
Evaluations of Simulations
For each dose, the resulting simulated PK proﬁles and exposure metrics were summarised
graphically (stratiﬁed by age cohort for children and adolescents; all together for adults).
Speciﬁcally, the 10th, 50th and 90th percentiles of the simulated moxidectin concentrations
over time were derived and presented for adults (to exhibit/conﬁrm the simulation model);
distributions of the simulated PK exposure metrics for all age cohorts were displayed via
boxplots. Numerical summaries of the PK exposure metrics (again stratiﬁed by age cohort
for children and adolescents; all together for adults) were also presented. These graphical
and numerical summaries were compared across doses and age cohorts.
5
Software
The simulations were performed in R [17] using the mrgsolve package [18]. Summaries of
the simulations were conducted in R [17].
6
Changes to the planned analyses
There were three changes to the planned analyses as speciﬁed in the statistical analysis plan
(SAP) [19]:
• The PK sampling schedule for the simulations was originally speciﬁed as hourly up
to 4 days post-administration and daily up to 365 days post-administration [19]. The
schedule speciﬁed in Section 4.2 was employed to avoid unnecessary computational
expense.
• The simulations for healthy adults, which were not speciﬁed in the SAP [19], were
derived to provide additional means for comparison.
• The 10th, 50th and 90th percentiles of the simulated moxidectin concentrations over
time were computed and exhibited for adults only (originally planned for all age cohorts
[19]). This was done to restrict the graphical and numerical summaries to the most
relevant simulated metrics for decision making, which were Cmax and AUC.
8
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7
Results
7.1
Demographic Proﬁles
Figure 2 displays the relationship between height and weight (by sex) assumed for the sim-
ulations.
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●
10
20
30
40
50
100
120
140
160
Males
Predicted weight (kg)
Predicted height (cm)
4 years
5 years
5.5 years
6 years
7 years
8 years
9 years
9.5 years
10 years
11 years
12 years
13 years
14 years
15 years
16 years
17 years
s
rs
1
6
rs
1
14
1
ar
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13
1
●Predictions used for simulations
Study ONCBL60801
WHO (10th percentile)
●
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10
20
30
40
50
100
120
140
160
Females
Predicted weight (kg)
Predicted height (cm)
4 years
5 years
6 years
7 years
8 years
9 years
10 years
11 years
12 years
13 years
14 years
15 years
16 years
17 years
ars
ea
years
ars
1
●Predictions used for simulations
Study ONCBL60801
WHO (10th percentile)
Figure 2. Relationship between height and weight assumed for the simulations. The black open
circles represent the data used in the simulations, the gray open squares indicate the observed data
from Study ONCBL60801 and the gray open triangles represent data from WHO growth charts
(10th percentile).
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7.2
Simulations
Figure 3 displays the simulated PK proﬁles for adults (with observed PK data from Study
3110A1-GH-200 [12]) and healthy volunteers (with observed PK data from Study 3110A-
EU-1005 [11]). The simulations were consistent with the observed data.
1
10
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1000
10000
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50.0
Infected Patients (8 mg)
Time (h)
Concentration (ng/mL)
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Figure 3.
Simulated PK proﬁles for adults and healthy volunteers.
In both plots, the solid
red line indicates the median of the simulations and the dashed red lines represent the 10th and
90th percentiles of the simulations. The open black circles indicate observed PK data from Study
3110A1-GH-200 (8 mg only; left panel) and Study 3110A1-EU-1005 (8 mg, fasted; right panel).
Figure 4 displays the predicted Cmax and AUC for children 4-11 years (8 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (HV; 8 mg, 16 mg, 36 mg). Tables
2 and 3 report the corresponding numerical summaries. The 4-7 years, 8-11 years and 12-17
years cohorts had very similar exposure (AUCs) to adults; this was due to all groups receiving
the same dose and clearance from the central compartment (CL/F) not being inﬂuenced by
weight. Younger age (i.e., smaller body size) was associated with higher values of Cmax; this
was due to all groups receiving the same dose and allometric scaling of Vc/F. In particular,
the median predicted Cmax for adolescents was 80.9 ng/mL, which was approximately 47%
greater than in adults.
10
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
Page 114
 
03 Jul 2020


Population Pharmacokinetics Simulation MDGH-MOX-1006
Medicines Development for Global Health
Page 11 of 21
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Age Range (years); Dose
Cmax (ng/mL)
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18+(HV); 36 mg
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5000
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Age Range (years); Dose
AUC (ng/mL × h)
Figure 4. Summaries of simulated exposure metrics for children 4-11 years (8 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg). Within each plot,
the green solid line indicates the median for adults (8 mg) and the green dashed line indicates the
median for the adolescents (8 mg).
11
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
Page 115
 
03 Jul 2020


Population Pharmacokinetics Simulation MDGH-MOX-1006
Medicines Development for Global Health
Page 12 of 21
Table 2. Summaries of simulated Cmax (ng/mL) for children 4-11 years (8 mg), adolescents 12-17
years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg)
Age Cohort (Dose)
Mean
SD
Median
IQR
Min
Max
4-7 years (8 mg)
156
39.4
152
52
51.1
331
8-11 years (8 mg)
117
28.3
114
37.7
41.1
228
12-17 years (8 mg)
83.2
20.8
80.9
27.6
28.8
181
18+ (8 mg)
56.6
12.5
55.1
16.8
23
108
18+ (HV; 8 mg)
53.3
11.5
52.1
15.6
22.3
97.4
18+ (HV; 16 mg)
107
23.1
104
31.1
44.5
195
18+ (HV; 36 mg)
240
51.9
235
70
100
438
Table 3.
Summaries of simulated AUC (ng/mL*h) for children 4-11 years (8 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg)
Age Cohort (Dose)
Mean
SD
Median
IQR
Min
Max
4-7 years (8 mg)
2450
1020
2240
1310
633
8020
8-11 years (8 mg)
2450
1020
2240
1310
632
8020
12-17 years (8 mg)
2440
1020
2240
1310
632
8010
18+ (8 mg)
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1010
2230
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632
8010
18+ (HV; 8 mg)
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3200
1850
911
11400
18+ (HV; 16 mg)
6970
2860
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3700
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22800
18+ (HV; 36 mg)
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6430
14400
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4100
51200
12
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
Page 116
 
03 Jul 2020


Population Pharmacokinetics Simulation MDGH-MOX-1006
Medicines Development for Global Health
Page 13 of 21
Figure 5 displays the predicted Cmax and AUC for children 4-11 years (2 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (HV; 8 mg, 16 mg, 36 mg). Tables
4 and 5 report the corresponding numerical summaries. The AUCs were inﬂuenced only by
dose since weight did not impact CL/F. Hence, the 4-7 and 8-11 years cohorts exhibited
similar AUCs, which were approximately 25% of the simulated exposures for adults. For a
given dose, younger age groups exhibited higher values of Cmax; this was due to allometric
scaling of Vc/F.
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18+(HV); 36 mg
200
500
2000
5000
20000
Age Range (years); Dose
AUC (ng/mL × h)
Figure 5. Summaries of simulated exposure metrics for children 4-11 years (2 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg). Within each plot,
the green solid line indicates the median for adults (8 mg) and the green dashed line indicates the
median for the adolescents (8 mg).
13
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
Page 117
 
03 Jul 2020


Population Pharmacokinetics Simulation MDGH-MOX-1006
Medicines Development for Global Health
Page 14 of 21
Table 4. Summaries of simulated Cmax (ng/mL) for children 4-11 years (2 mg), adolescents 12-17
years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg)
Age Cohort (Dose)
Mean
SD
Median
IQR
Min
Max
4-7 years (2 mg)
38.9
9.84
38.1
13
12.8
82.7
8-11 years (2 mg)
29.2
7.07
28.5
9.42
10.3
56.9
12-17 years (8 mg)
83.2
20.8
80.9
27.6
28.8
181
18+ (8 mg)
56.6
12.5
55.1
16.8
23
108
18+ (HV; 8 mg)
53.3
11.5
52.1
15.6
22.3
97.4
18+ (HV; 16 mg)
107
23.1
104
31.1
44.5
195
18+ (HV; 36 mg)
240
51.9
235
70
100
438
Table 5.
Summaries of simulated AUC (ng/mL*h) for children 4-11 years (2 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg)
Age Cohort (Dose)
Mean
SD
Median
IQR
Min
Max
4-7 years (2 mg)
612
255
561
328
158
2010
8-11 years (2 mg)
611
255
560
327
158
2000
12-17 years (8 mg)
2440
1020
2240
1310
632
8010
18+ (8 mg)
2440
1010
2230
1300
632
8010
18+ (HV; 8 mg)
3490
1430
3200
1850
911
11400
18+ (HV; 16 mg)
6970
2860
6410
3700
1820
22800
18+ (HV; 36 mg)
15700
6430
14400
8320
4100
51200
14
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
Page 118
 
03 Jul 2020


Population Pharmacokinetics Simulation MDGH-MOX-1006
Medicines Development for Global Health
Page 15 of 21
Figure 6 displays the predicted Cmax and AUC for children 4-11 years (4 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (HV; 8 mg, 16 mg, 36 mg). Tables
6 and 7 report the corresponding numerical summaries. The AUCs were inﬂuenced only by
dose since weight did not impact CL/F. Hence, the 4-7 and 8-11 years cohorts exhibited
similar AUCs, which were approximately half of the simulated exposures for adults. For a
given dose, younger age groups exhibited higher values of Cmax; this was due to allometric
scaling of Vc/F.
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12−17; 8 mg
18+; 8 mg
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18+(HV); 36 mg
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8−11; 4 mg
12−17; 8 mg
18+; 8 mg
18+(HV); 8 mg
18+(HV); 16 mg
18+(HV); 36 mg
500
1000
5000
20000
50000
Age Range (years); Dose
AUC (ng/mL × h)
Figure 6. Summaries of simulated exposure metrics for children 4-11 years (4 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg). Within each plot,
the green solid line indicates the median for adults (8 mg) and the green dashed line indicates the
median for the adolescents (8 mg).
15
Sponsor: Medicines Development for Global Health
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Page 16 of 21
Table 6. Summaries of simulated Cmax (ng/mL) for children 4-11 years (4 mg), adolescents 12-17
years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg)
Age Cohort (Dose)
Mean
SD
Median
IQR
Min
Max
4-7 years (4 mg)
77.9
19.7
76.1
26
25.6
165
8-11 years (4 mg)
58.4
14.1
57
18.8
20.5
114
12-17 years (8 mg)
83.2
20.8
80.9
27.6
28.8
181
18+ (8 mg)
56.6
12.5
55.1
16.8
23
108
18+ (HV; 8 mg)
53.3
11.5
52.1
15.6
22.3
97.4
18+ (HV; 16 mg)
107
23.1
104
31.1
44.5
195
18+ (HV; 36 mg)
240
51.9
235
70
100
438
Table 7.
Summaries of simulated AUC (ng/mL*h) for children 4-11 years (4 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg)
Age Cohort (Dose)
Mean
SD
Median
IQR
Min
Max
4-7 years (4 mg)
1220
510
1120
655
316
4010
8-11 years (4 mg)
1220
509
1120
654
316
4010
12-17 years (8 mg)
2440
1020
2240
1310
632
8010
18+ (8 mg)
2440
1010
2230
1300
632
8010
18+ (HV; 8 mg)
3490
1430
3200
1850
911
11400
18+ (HV; 16 mg)
6970
2860
6410
3700
1820
22800
18+ (HV; 36 mg)
15700
6430
14400
8320
4100
51200
16
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Figure 7 displays the predicted Cmax and AUC for children 4-11 years (6 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (HV; 8 mg, 16 mg, 36 mg). Tables
8 and 9 report the corresponding numerical summaries. The AUCs were inﬂuenced only by
dose since weight did not impact CL/F. Hence, the 4-7 and 8-11 years cohorts exhibited
similar AUCs, which were approximately 75% of the simulated exposures for adults. For a
given dose, younger age groups exhibited higher values of Cmax; this was due to allometric
scaling of Vc/F.
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18+; 8 mg
18+(HV); 8 mg
18+(HV); 16 mg
18+(HV); 36 mg
500
1000
2000
5000
20000
50000
Age Range (years); Dose
AUC (ng/mL × h)
Figure 7. Summaries of simulated exposure metrics for children 4-11 years (6 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg). Within each plot,
the green solid line indicates the median for adults (8 mg) and the green dashed line indicates the
median for the adolescents (8 mg).
17
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
Page 121
 
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Medicines Development for Global Health
Page 18 of 21
Table 8. Summaries of simulated Cmax (ng/mL) for children 4-11 years (6 mg), adolescents 12-17
years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg)
Age Cohort (Dose)
Mean
SD
Median
IQR
Min
Max
4-7 years (6 mg)
117
29.5
114
39
38.4
248
8-11 years (6 mg)
87.5
21.2
85.5
28.3
30.8
171
12-17 years (8 mg)
83.2
20.8
80.9
27.6
28.8
181
18+ (8 mg)
56.6
12.5
55.1
16.8
23
108
18+ (HV; 8 mg)
53.3
11.5
52.1
15.6
22.3
97.4
18+ (HV; 16 mg)
107
23.1
104
31.1
44.5
195
18+ (HV; 36 mg)
240
51.9
235
70
100
438
Table 9.
Summaries of simulated AUC (ng/mL*h) for children 4-11 years (6 mg), adolescents
12-17 years (8 mg), adults (8 mg) and healthy volunteers (8 mg, 16 mg, 36 mg)
Age Cohort (Dose)
Mean
SD
Median
IQR
Min
Max
4-7 years (6 mg)
1840
764
1680
983
474
6020
8-11 years (6 mg)
1830
764
1680
981
474
6010
12-17 years (8 mg)
2440
1020
2240
1310
632
8010
18+ (8 mg)
2440
1010
2230
1300
632
8010
18+ (HV; 8 mg)
3490
1430
3200
1850
911
11400
18+ (HV; 16 mg)
6970
2860
6410
3700
1820
22800
18+ (HV; 36 mg)
15700
6430
14400
8320
4100
51200
18
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Medicines Development for Global Health
Page 19 of 21
8
Discussion
The simulation model predicted that adolescents 12-17 years receiving 8 mg of moxidectin
may achieve similar exposure (AUC) to adults receiving 8 mg, with a higher Cmax (≈81
ng/mL vs. ≈55 ng/mL in adults). The simulations also suggested that for a given dose,
smaller body size was associated with higher values of Cmax; this was due to allometric
scaling of Vc/F. AUC was conditional on dose but not body size; this was due to weight not
impacting CL/F.
The ﬁndings of the present simulation study reﬂect the features of the simulation model.
The model was built with the intention of extrapolating to other populations, including
paediatrics [13]. Hence, the model incorporated allometry [14] where consistent with the ob-
served data (Vc/F, CLd2/F and Vp2/F [13]). This led to younger (smaller) children achieving
a higher Cmax for a given dose. However, since allometry was not incorporated into CL/F
(due to no evidence of a relationship between weight and CL/F for infected patients or
healthy volunteers [13]), the predicted AUCs were not inﬂuenced by weight or body size
(only dose). The lack of a clear relationship between CL/F and weight was also observed in
a study of moxidectin in dogs; the results suggested that CL/F was similar between adults
and juveniles [2]. Since moxidectin may not be entirely consistent with allometric princi-
ples, the simulations presented in this report should be used in conjunction with clinical
experience and judgement in regards to determination of initial dosing recommendations for
children participating in Study MDGH-MOX-1006.
There are some caveats to this simulation study. To date, the population PK model used
for the simulations has not been veriﬁed with PK data from children or adolescents. Also,
this simulation study cannot make any formal (i.e., analytical) evaluations of safety (only
expected PK proﬁles and exposures).
9
Conclusions
The simulations suggested that for a given dose, moxidectin exposure may be similar across
age groups (including adults), however, Cmax may be higher in younger age groups. The
predicted (simulated) values of Cmax and AUC for all doses and ages considered in this
simulation study corresponded to doses that were well-tolerated in healthy volunteers (i.e.,
≤36 mg).
19
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Population Pharmacokinetics Simulation MDGH-MOX-1006
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Page 20 of 21
References
[1] World
Health
Organization.
Prevention
of
Blindness
and
Visual
Impairment;.
Available from:
http://www.who.int/blindness/partnerships/onchocerciasis_
disease_information/en/.
[2] Pﬁzer Inc and Aﬃliates. Investigator’s Brochure PF-05208746 (Moxidectin); 2011.
[3] World
Health
Organization.
Neglected
Tropical
Diseases.
[http://www.who.int/neglected diseases/diseases/summary/en/];.
[4] Duke B, Zea-Flores G, Munoz B. The embryogenesis of Onchocerca volvulus over the
ﬁrst year after a single dose of ivermectin. Trop Med Parasitol. 1991;42:175–180.
[5] Duke BO, et al MCP. Viability of adult Onchocerca volvulus after six 2-weekly doses
of ivermectin. Bull World Health Organization. 1991;69(2):163–168.
[6] Duke BO, et al GZF. Eﬀects of three-month doses of ivermectin on adult Onchocerca
volvulus. Am Journal of Trop Med Hygiene. 1992;46(2):189–194.
[7] Chavasse DC, et al RJP. The eﬀect of repeated doses of ivermectin on adult female
Onchocerca volvulus in Sierra Leone. Trop Med Parasitol. 1992;43(4):256–262.
[8] Plaisier AP, et al ESA. Irreversible eﬀects of ivermectin on adult parasites in onchocer-
ciasis patients in the Onchocerciasis Control Programme in West Africa. J Inf Dis.
1995;172(1):204–210.
[9] Klager SL, et al JAW. Viability and fertility of adult Onchocerca volvulus after 6 years
of treatment with ivermectin. Trop Med Int Health. 1996;1(5):581–589.
[10] Genetics Institute/Wyeth-Ayerst Research. A study of the relative bioavailability of
a tablet and a liquid formulation of moxidectin in healthy subjects. Wyeth Research
protocol number: 3110A1-101-EU; 2002.
[11] Wyeth Pharmaceuticals France. An open-label, randomized, single-dose, parallel-group
study to determine the eﬀect of a high-fat meal on the relative bioavailability and
pharmacokinetics of a single dose of moxidectin administered orally to healthy subjects.
Protocol number: 3110A1-1005-EU; 2008.
[12] Wyeth Research Division of Wyeth Pharmaceuticals Inc; Product Development and
Evaluation Unit, TDR, World Health Organization. A randomized, single-ascending-
dose, ivermectin-controlled, double-blind, safety, tolerability, pharmacokinetic, and ef-
ﬁcacy study of orally administered moxidectin in subjects with onchocerca volvulus
infection. Onchocerciasis Chemotherapy Research Centre protocol number: 33. Wyeth
Research protocol number: 3110A1-200-GH.; 2006.
20
Sponsor: Medicines Development for Global Health
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MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
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Page 21 of 21
[13] d3 Medicine. Population pharmacokinetic and pharmacodynamic analyses of mox-
idectin; 2016.
[14] Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharma-
cokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.
[15] World Health Organization. Growth reference 5-19 years;. Available from: http://
www.who.int/growthref/en/.
[16] Wyeth. Final report: an open-label, randomized, single-dose, parallel-group study to
determine the eﬀect of a high-fat meal on the relative bioavailability and pharmacoki-
netics of a single dose of moxidectin administered orally to healthy subjects. Protocol
number: 3110A1-1005-EU; 2010.
[17] R Core Team. R: A Language and Environment for Statistical Computing. Vienna,
Austria; 2015. Available from: https://www.R-project.org/.
[18] Baron KT, Hindmarsh AC, Petzold LR, Gillespie B, Margossian C, LLC MRG.
mrgsolve:
Simulation from ODE-Based Population PK/PD and Systems Pharma-
cology Models;.
R package version 0.7.5.
Available from: http://metrumrg.com/
opensourcetools.html.
[19] d3 Medicine, A Certara Company. Statistical Analysis Plan: Population pharmacoki-
netics simulation of moxidectin to determine initial dosing recommendations for partic-
ipants in Study MDGH-MOX-1006; 2016.
21
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
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(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
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Statistical Appendix 
 
MDGH-MOX-1006-SA 
Version 1.0 
 Page 1 of 8 
 
MDGH 
 Confidential      
November 2019  
 
 
STATISTICAL APPENDIX 
TITLE 
Supplementary Simulations of Moxidectin 
Pharmacokinetics in Pediatric Patients 
STUDY DRUG 
Moxidectin 
SPONSOR 
Medicines Development for Global Health 
PREPARED BY 
Kris Jamsen, Ph.D.  
Craig Rayner, Pharm.D, MBA  
Certara Inc. 
Sally Kinrade, Ph.D. 
Medicines Development for Global Health
DOCUMENT NUMBER 
MDGH-MOX-1006-SA 
DOCUMENT DATE 
26 November 2019 
CERTARA REFERENCE NO: 
MDGH-MOX-1006-SA-001 
 
CONFIDENTIAL 
This is a Medicines Development for Global Health document that contains confidential information. 
This material may be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from Medicines Development for Global Health. 
 
 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
Page 126
 
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Statistical Appendix 
 
MDGH-MOX-1006-SA 
Version 1.0 
 Page 2 of 8 
 
MDGH 
 Confidential      
November 2019  
TABLE OF CONTENTS 
STATISTICAL APPENDIX .............................................................................................................. 1 
TABLE OF CONTENTS ................................................................................................................... 2 
LIST OF TABLES .............................................................................................................................. 2 
1 
OBJECTIVES ......................................................................................................................... 3 
2 
METHODS .............................................................................................................................. 3 
3 
RESULTS ................................................................................................................................ 4 
4 
CONCLUSIONS ..................................................................................................................... 8 
5 
REFERENCES ....................................................................................................................... 8 
 
LIST OF TABLES 
Table 3-1 Summaries of simulated Cmax (ng/mL) assuming an 8 mg dose in the 4-7 and 8-11 year-
olds and the pre-defined doses in the other populations ............................................................... 4 
Table 3-2 Summaries of simulated AUC (ng.h/mL) assuming an 8 mg dose in the 4-7 and 8-11 year-
olds and the pre-defined doses in the other populations ............................................................... 4 
Table 3-3 Summaries of simulated Cmax (ng/mL) assuming a 2 mg dose in the 4-7 and 8-11 year-
olds and the pre-defined doses in the other populations ............................................................... 5 
Table 3-4 Summaries of simulated AUC (ng.h/mL) assuming a 2 mg dose in 4-7 and 8-11 year-olds 
and the pre-defined doses in the other populations ...................................................................... 5 
Table 3-5: Summaries of simulated Cmax (ng/mL) assuming a 4 mg dose in 4-7 year-olds and the 
pre-specified doses in the other populations ................................................................................. 6 
Table 3-6: Summaries of simulated AUC (ng.h/mL) assuming a 4 mg dose in 4-7 year-olds and the 
pre-specified doses in the other populations ................................................................................. 6 
Table 3-7: Summaries of simulated Cmax (ng/mL) assuming a 6 mg dose in 4-7 year-olds and the 
pre-specified doses in the other populations ................................................................................. 7 
Table 3-8: Summaries of simulated AUC (ng.h/mL) assuming a 6 mg dose in 4-7 and 8-11 year-olds 
and the pre-specified doses in the other populations .................................................................... 7 
 
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Statistical Appendix 
 
MDGH-MOX-1006-SA 
Version 1.0 
 Page 3 of 8 
 
MDGH 
 Confidential      
November 2019  
1 OBJECTIVES  
The objectives of this work were to: 
1) Update the results of the original moxidectin pharmacokinetics simulation study [1] by using 
the most recent, final population pharmacokinetic (PK) model of moxidectin [2]. 
2) Provide additional summaries of simulated moxidectin exposure measures to support the 
protocol for the pediatric study (Study MDGH-MOX-1006). 
2 METHODS 
The methods of the current simulation study were similar to those from the previous simulation 
study [1].  Key differences are: 
 The final population PK model of moxidectin, incorporating PK data from Study 1008, 
was used for the current simulations.  The previous simulation study used the final 
population PK model that was developed before data from Study 1008 were available.  
Details of the final model are described elsewhere [2]. 
 For each onchocerciasis patient age group (4-7 years, 8-11 years, 12-17 years and adults), 
moxidectin PK profiles were generated for 1000 virtual patients (500 male and 500 female), 
where corresponding individual exposure metrics (maximum concentration, or Cmax, and 
area under the concentration time curve, or AUC) were derived. Similarly to the previous 
work, patients 12-17 or 18+ years old received 8 mg (established doses for these groups); 
patients 4-7 or 8-11 years old received 2, 4, 6 or 8 mg. 
 For healthy subjects, moxidectin PK profiles were generated for 1000 virtual males, where 
corresponding individual Cmax and AUC were derived.  Similarly to the previous report, 
healthy subjects received 8, 16 or 36 mg. 
 For each (virtual) population and corresponding dose(s) described above, Cmax and AUC 
were summarized by the mean, standard deviation (SD), median, inter-quartile range (IQR), 
10th percentile, 90th percentile, minimum and maximum.   
Further details of the simulation methodology are described in the previous simulation report [1]. 
 
 
Sponsor: Medicines Development for Global Health
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Statistical Appendix 
 
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Version 1.0 
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 Confidential      
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3 RESULTS 
Table 3-1 and Table 3-2 display summaries of the simulated exposures, where the 4-7 and 8-11 
year-old patient groups received 8 mg and all other populations received their pre-defined doses.  
 
Table 3-1 Summaries of simulated Cmax (ng/mL) assuming an 8 mg dose in the 4-7 and 8-11 year-
olds and the pre-defined doses in the other populations 
  
 
Mean 
SD 
Median
IQR
10th perc.
90th perc. 
Min 
Max
4‐7 years (8 mg) 
 
157 
35.8 
156
47.2
112
203 
83.2 
308
8‐11 years (8 mg) 
 
118 
25.2 
116
33.8
86.3
151 
64.1 
214
12‐17 years (8 mg) 
 
83.5 
17.2 
82.5
23.9
62.4
106 
45.4 
141
18+ (8 mg) 
 
57.6 
11.7 
56.8
15.9
43.4
72.5 
31.2 
93.7
18+ HV (8 mg) 
 
55.6 
12 
54.3
16.4
41.2
71.7 
21.6 
105
18+ HV (16 mg) 
 
111 
24 
109
32.7
82.5
143 
43.3 
210
18+ HV (36 mg) 
 
250 
54.1 
244
73.6
186
323 
97.3 
473
 
 
Table 3-2 Summaries of simulated AUC (ng.h/mL) assuming an 8 mg dose in the 4-7 and 8-11 year-
olds and the pre-defined doses in the other populations 
  
Mean 
SD 
Median
IQR
10th perc.
90th perc. 
Min 
Max
4‐7 years (8 mg) 
2478 
1087 
2278
1383
1317
3858 
568.7 
8254
8‐11 years (8 mg) 
2475 
1086 
2275
1381
1316
3854 
568.4 
8255
12‐17 years (8 mg) 
2471 
1085 
2271
1380
1314
3849 
568.1 
8250
18+ (8 mg) 
2466 
1080 
2267
1373
1312
3844 
567.9 
8180
18+ HV (8 mg) 
3471 
1445 
3292
1725
1899
5210 
842.3 
12970
18+ HV (16 mg) 
6942 
2889 
6583
3450
3798
10420 
1685 
25940
18+ HV (36 mg) 
15620 
6501 
14810
7762
8546
23440 
3790 
58370
 
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Statistical Appendix 
 
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Version 1.0 
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 Confidential      
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Table 3-3 and Table 3-4 display summaries of the simulated exposures, where the 4-7 and 8-11 
year-old patient groups received 2 mg and all other populations received their pre-defined doses.  
 
Table 3-3 Summaries of simulated Cmax (ng/mL) assuming a 2 mg dose in the 4-7 and 8-11 year-
olds and the pre-defined doses in the other populations 
  
Mean 
SD  Median
IQR 
10th perc. 
90th perc. 
Min 
Max 
4‐7 years (2 mg) 
39.2 
8.94 
38.9
11.8 
28 
50.9 
20.8 
76.9 
8‐11 years (2 mg) 
29.4 
6.31 
29.1
8.45 
21.6 
37.7 
16 
53.5 
12‐17 years (8 mg) 
83.5 
17.2 
82.5
23.9 
62.4 
106 
45.4 
141 
18+ (8 mg) 
57.6 
11.7 
56.8
15.9 
43.4 
72.5 
31.2 
93.7 
18+ HV (8 mg) 
55.6 
12 
54.3
16.4 
41.2 
71.7 
21.6 
105 
18+ HV (16 mg) 
111 
24 
109
32.7 
82.5 
143 
43.3 
210 
18+ HV (36 mg) 
250 
54.1 
244
73.6 
186 
323 
97.3 
473 
  
 
Table 3-4 Summaries of simulated AUC (ng.h/mL) assuming a 2 mg dose in 4-7 and 8-11 year-olds 
and the pre-defined doses in the other populations 
  
Mean 
SD
Median
IQR
10th perc.
90th perc. 
Min
Max
4‐7 years (2 mg) 
619.5 
271.7
569.5
345.8
329.3
964.6 
142.2
2064
8‐11 years (2 mg) 
618.6 
271.5
568.6
345.4
328.9
963.4 
142.1
2064
12‐17 years (8 mg) 
2471 
1085
2271
1380
1314
3849 
568.1
8250
18+ (8 mg) 
2466 
1080
2267
1373
1312
3844 
567.9
8180
18+ HV (8 mg) 
3471 
1445
3292
1725
1899
5210 
842.3
12970
18+ HV (16 mg) 
6942 
2889
6583
3450
3798
10420 
1685
25940
18+ HV (36 mg) 
15620 
6501
14810
7762
8546
23440 
3790
58370
 
 
 
 
 
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Statistical Appendix 
 
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Version 1.0 
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 Confidential      
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Table 3-5 and Table 3-6 display summaries of the simulated exposures, where the 4-7 and 8-11 
year-old patient groups received 4 mg and all other populations received their pre-defined doses.  
 
Table 3-5: Summaries of simulated Cmax (ng/mL) assuming a 4 mg dose in 4-7 year-olds and the 
pre-specified doses in the other populations 
  
Mean 
SD 
Median
IQR
10th perc.
90th perc. 
Min
Max
4‐7 years (4 mg) 
78.3 
17.9 
77.8
23.6
56.1
102 
41.6
154
8‐11 years (4 mg) 
58.9 
12.6 
58.1
16.9
43.1
75.4 
32
107
12‐17 years (8 mg) 
83.5 
17.2 
82.5
23.9
62.4
106 
45.4
141
18+ (8 mg) 
57.6 
11.7 
56.8
15.9
43.4
72.5 
31.2
93.7
18+ HV (8 mg) 
55.6 
12 
54.3
16.4
41.2
71.7 
21.6
105
18+ HV (16 mg) 
111 
24 
109
32.7
82.5
143 
43.3
210
18+ HV (36 mg) 
250 
54.1 
244
73.6
186
323 
97.3
473
 
 
Table 3-6: Summaries of simulated AUC (ng.h/mL) assuming a 4 mg dose in 4-7 year-olds and the 
pre-specified doses in the other populations 
  
Mean 
SD
Median
IQR
10th perc.
90th perc. 
Min
Max 
4‐7 years (4 mg) 
1239 
543.5
1139
691.5
658.7
1929 
284.4
4127 
8‐11 years (4 mg) 
1237 
542.9
1137
690.7
657.9
1927 
284.2
4128 
12‐17 years (8 mg) 
2471 
1085
2271
1380
1314
3849 
568.1
8250 
18+ (8 mg) 
2466 
1080
2267
1373
1312
3844 
567.9
8180 
18+ HV (8 mg) 
3471 
1445
3292
1725
1899
5210 
842.3
12970 
18+ HV (16 mg) 
6942 
2889
6583
3450
3798
10420 
1685
25940 
18+ HV (36 mg) 
15620 
6501
14810
7762
8546
23440 
3790
58370 
 
 
 
 
 
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Statistical Appendix 
 
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Version 1.0 
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MDGH 
 Confidential      
November 2019  
Table 3-7 and Table 3-8 display summaries of the simulated exposures, where the 4-7 and 8-11 
year-old patient groups received 6 mg and all other populations received their pre-defined doses.  
 
Table 3-7: Summaries of simulated Cmax (ng/mL) assuming a 6 mg dose in 4-7 year-olds and the 
pre-specified doses in the other populations 
  
Mean 
SD
Median
IQR
10th perc.
90th perc. 
Min
Max
4‐7 years (6 mg) 
117 
26.8
117
35.4
84.1
153 
62.4
231
8‐11 years (6 mg) 
88.3 
18.9
87.2
25.3
64.7
113 
48.1
160
12‐17 years (8 mg) 
83.5 
17.2
82.5
23.9
62.4
106 
45.4
141
18+ (8 mg) 
57.6 
11.7
56.8
15.9
43.4
72.5 
31.2
93.7
18+ HV (8 mg) 
55.6 
12
54.3
16.4
41.2
71.7 
21.6
105
18+ HV (16 mg) 
111 
24
109
32.7
82.5
143 
43.3
210
18+ HV (36 mg) 
250 
54.1
244
73.6
186
323 
97.3
473
 
 
Table 3-8: Summaries of simulated AUC (ng.h/mL) assuming a 6 mg dose in 4-7 and 8-11 year-olds 
and the pre-specified doses in the other populations 
  
Mean 
SD
Median
IQR
10th perc.
90th perc. 
Min
Max
4‐7 years (6 mg) 
1858 
815.2
1709
1037
988
2894 
426.5
6191
8‐11 years (6 mg) 
1856 
814.4
1706
1036
986.8
2890 
426.3
6191
12‐17 years (8 mg) 
2471 
1085
2271
1380
1314
3849 
568.1
8250
18+ (8 mg) 
2466 
1080
2267
1373
1312
3844 
567.9
8180
18+ HV (8 mg) 
3471 
1445
3292
1725
1899
5210 
842.3
12970
18+ HV (16 mg) 
6942 
2889
6583
3450
3798
10420 
1685
25940
18+ HV (36 mg) 
15620 
6501
14810
7762
8546
23440 
3790
58370
 
 
 
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Statistical Appendix 
 
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 Confidential      
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4 CONCLUSIONS 
The results are consistent with the previous simulation study [1], suggesting that 8 mg may be an 
appropriate initial dose for the first pediatric cohort of Study MDGH-MOX-1006 (8-11 years). 
5 REFERENCES 
1) Certara Simulation Report. Population Pharmacokinteics Simulation of Moxidectin to 
Determine Initial Dosing Recommendations for Participants in Study MDGH-MOX-1006.  
December 2016. 
 
2) Certara Population Pharmacokinetic-Pharmacodynamic Analysis Report. Population 
Pharmacokinetic-Pharmacodynamic 
Analysis: 
Moxidectin. 
Reference 
# 
D3-
170606MDGH. July 2017. 
 
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(incorporating Amendments 1, 2, 3, 4 and 5) 
16.3 Vital Signs Reference Values for Children 
Pediatric vital signs reference ranges are provided in Table 7 (Canadian Paediatric Society 2013, 
American Heart Association 2016). 
Table 7: Vital Signs Reference Ranges for Children 
Parameter 
Normal Reference Range 
(low to high) 
Age 
3 to 5 years 
6 to 11 years 
12 to 15 years 
Heart rate (beats/minute) 
 
 
 
Awake rate 
80 to 120  
75 to 118  
60 to 100  
Sleeping rate 
65 to 100 
58 to 90 
50 to 90 
Respiratory rate (breaths/minute) 
20 to 28 
18 to 25 
12 to 20 
Systolic pressure (mmHg) 
89 to 112  
 
110 to 131  
6 to 9 years 
 
97 to 115 
 
10 to 11 years 
 
102 to 120  
 
Diastolic pressure (mmHg) 
46 to 72 
 
64 to 83 
6 to 9 years 
 
57 to 76 
 
10 to 11 years 
 
61 to 80 
 
Temperature, ear (oC) 
35.8 to 38 
35.8 to 38 
35.8 to 38 
°C = degrees Celsius, mmHg = millimeters of mercury 
 


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16.4 Laboratory Reference Values for Ghanaian Children 
Laboratory reference ranges for Ghanaian children are provided in Table 8 (Dosoo et al. 2014; 
bicarbonate reference range Royal College of Pathologists of Australasia 2012). 
Table 8: Laboratory Reference Ranges for Children 
Parameter 
Normal Reference Range 
(low to high) 
Age 
0.5 to < 5 years  
5 to 12 years 
> 12 to 18 years 
Enzymes 
 
 
 
Alanine aminotransferase (IU/L) 
7 to 55  
5 to 53 
8 to 55 
Aspartate aminotransferase (IU/L) 
23 to 72 
19 to 97 
14 to 62 
Amylase (IU/L) 
12 to 136 
33 to 133 
31 to 120 
Creatine kinase (IU/L) 
35 to 291 
59 to 515 
94 to 562 
Gamma-glutamyl transferase (IU/L) 
3 to 34 
7 to 31 
6 to 45 
Lactate dehydrogenase (IU/L) 
360 to 995 
277 to 823 
252 to 737 
Serum Proteins 
 
 
 
Total Proteins (g/dL) 
56.0 to 87.0 
54.0 to 87.9 
46.4 to 86.5 
Albumin (g/dL) 
35.9 to 50.0 
34.2 to 49.8 
35.4 to 49.3 
Metabolism 
 
 
 
Total Bilirubin (µmol/L) 
1.8 to 21.0 
1.7 to 18.9 
3.3 to 21.6 
Direct Bilirubin (µmol/L) 
0.4 to 3.6 
0.6 to 3.9 
0.9 to 4.0 
Cholesterol (µmol/L) 
1.7 to 5.0  
1.7 to 4.3 
1.8 to 4.6 
Glucose (µmol/L) 
3.2 to 6.8 
3.5 to 6.2 
3.6 to 6.7 
Iron (µmol/L) 
4.2 to 20.1 
3.88 to 19.00 
4.6 to 23.3 
Triglycerides (µmol/L) 
0.5 to 2.7 
0.5 to 1.91 
0.40 to 1.70 
Kidney Function 
 
 
 
Urea (mmol/L)) 
1.0 to 4.2  
1.0 to 4.5 
1.0 to 4.5 
Creatinine (µmol/L) 
17 to 52  
33 to 74 
39 to 79 
Uric acid (µmol/L) 
71 to 340 
72 to 274 
78 to 322 
Chloride (mmol/L) 
98 to 115 
99 to 114 
96 to 116 
Phosphorus (mmol/L) 
1.26 to 2.25 
1.03 to 1.84 
0.96 to 1.77 
Potassium (mmol/L) 
3.6 to 5.8 
3.6 to 5.6 
3.6 to 5.9 
Sodium (mmol/L) 
131 to 149 
135 to 151 
132 to 152 
Bicarbonate (mmol/L) 
17 to 30 
 
20 to 32 
2 years to < 10 years 
 
17 to 30 
 
10 years to 18 years 
 
20 to 32 
 
Hematology 
 
 
 
Hemoglobin (g/dL) 
8.0 to 12.7 
9.1 to 13.5 
9.5 to 14.4 
Hematocrit (%) 
24.4 to 38.8 
27.3 to 41.5 
29.4 to 44.9 
Red blood cell (x1012/L) 
3.22 to 5.55 
3.45 to 5.29 
3.53 to 5.57 
Mean corpuscular volume (fL) 
56 to 87 
68 to 89 
67 to 93 
Mean corpuscular hemoglobin (pg) 
16.9 to 29.7 
21.4 to 30.3 
21.2 to 32.0 
Mean corpuscular hemoglobin concentration (g/dL) 
30.0 to 36.9 
30.9 to 36.0 
30.5 to 36.6 
Red blood cell distribution width (%) 
12.5 to 21.6 
11.5 to 17.9 
11.6 to 16.1 
Platelet (x1012/L) 
110 to 637 
117 to 417 
113 to 363 
Platelet distribution width (%) 
8.8 to 25.4 
12.1 to 20.5 
12.4 to 22.6 
White blood cell, Total (x109/L) 
5.1 to 17.6 
4.1 to 11.9 
3.7 to 9.4 
Lymphocytes (%) 
34.9 to 75.6 
29.6 to 62.5 
26.6 to 58.9 
Lymphocytes (x109/L) 
2.3 to 11.9 
1.6 to 5.8 
1.4 to 4.0 
Monocytes (%) 
4.9 to 13.6 
5.0 to 13.3 
4.9 to 14.4 
Monocytes (x109/L) 
0.2 to 1.0 
0.2 to 1.1 
0.2 to 0.9 
Granulocytes (%) 
18.5 to 59.7 
28.3 to 62.4 
31.0 to 64.0 
Granulocytes (x109/L) 
1.5 to 8.5 
1.6 to 6.2 
1.6 to 5.2 
µmol/L = micromoles per liter, fL = femtoliter, g/dL = grams per deciliter, IU = international units, L = liter, mmol/L = millimoles per 
liter; pg = picogram 


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(incorporating Amendments 1, 2, 3, 4 and 5) 
16.5 Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 2.1, July 2017 
 
 
 
 
 


 
 
Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
Pediatric Adverse Events 
 
Corrected Version 2.1 
July 2017 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
US Department of Health and Human Services 
 
 
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Table of Contents 
Glossary and Acronyms ....................................................................................................................... 1 
Introduction ........................................................................................................................................... 3 
Instructions for Use .............................................................................................................................. 4 
Major Clinical Conditions .................................................................................................................... 7 
Cardiovascular ................................................................................................................................ 7 
Dermatologic .................................................................................................................................. 9 
Endocrine and Metabolic ............................................................................................................. 10 
Gastrointestinal ............................................................................................................................. 12 
Musculoskeletal ............................................................................................................................ 14 
Neurologic..................................................................................................................................... 15 
Pregnancy, Puerperium, and Perinatal ........................................................................................ 17 
Psychiatric ..................................................................................................................................... 18 
Respiratory .................................................................................................................................... 19 
Sensory .......................................................................................................................................... 20 
Systemic ........................................................................................................................................ 21 
Urinary .......................................................................................................................................... 23 
Site Reactions to Injections and Infusions ........................................................................................ 24 
Laboratory Values .............................................................................................................................. 25 
Chemistries ................................................................................................................................... 25 
Hematology ................................................................................................................................... 29 
Urinalysis ...................................................................................................................................... 31 
Appendix A.  Total Bilirubin Table for Term and Preterm Neonates ............................................. 32 
 
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 1 
Glossary and Acronyms 
AE 
Adverse event; Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or 
procedure. 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
AV 
Atrioventricular 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer or movement, 
continence, and feeding. 
 
Young Children 
Activities that are age and culturally appropriate, such as feeding one’s 
self with culturally appropriate eating implements. 
BMI z-score 
Body mass index z- score; A body reference norm. Specifically, the 
number of standard deviations a participant's BMI differs from the 
average BMI for their age, sex, and ethnicity. 
BMD t-score 
Bone mineral density t-score; The number of standard deviations above 
or below the mean bone mineral density of a healthy 30 year old adult 
of the same sex and ethnicity as the participant. 
BMD z-score 
Bone mineral density z-score; The number of standard deviations a 
participant's BMD differs from the average BMD for their age, sex, and 
ethnicity. 
BPAP 
Bilevel positive airway pressure; A mode used during noninvasive 
positive pressure ventilation. 
Chemical Pregnancy 
A pregnancy in which a positive pregnancy test is followed by a 
negative pregnancy test without evidence of a clinical pregnancy loss. 
CNS 
Central nervous system 
CPAP 
Continuous positive airway pressure 
DAERS 
DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited 
Adverse Events (EAEs) to DAIDS.  It facilitates timely EAE report 
submission and serves as a centralized location for accessing and 
processing EAE information for reporting purposes. 
Disability 
A substantial disruption of a person’s ability to conduct normal life 
functions. 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
Hospitalization 
Does not include the following hospital admissions: under 24 hours, 
unrelated to an adverse event (e.g., for labor and delivery, cosmetic 
surgery, social or administrative for temporary placement [for lack of a 
place to sleep]), protocol-specified, and for diagnosis or therapy of a 
condition that existed before the receipt of a study agent and which has 
not increased in severity or frequency.  
INR 
International normalized ratio  
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Glossary and Acronyms 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 2 
Intervention 
Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an adverse event.  
IV 
Intravenous 
IVIG 
Intravenous immune globulin 
LDL 
Low density lipoprotein 
LLN 
Lower limit of normal 
Life-threatening AE 
Any adverse event that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction when it 
occurred (i.e., it does not include a reaction that would have caused 
death if it had occurred in a more severe form). 
NA 
Not applicable 
Participant ID 
The identification number assigned to a study participant which is used 
to track study-related documentation, including any reported AEs. 
PR Interval 
The interval between the beginning of the P wave and the beginning of 
the QRS complex of an electrocardiogram that represents the time 
between the beginning of the contraction of the atria and the beginning 
of the contraction of the ventricles. 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc Interval 
The measure of time between the onset of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
rate. 
RBC 
Red blood cell 
SI 
Standard international unit 
ULN 
Upper limit of normal 
Usual Social & Functional Activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example: 
 
Adults 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby. 
 
Young Children 
Activities that are age and culturally appropriate, such as social 
interactions, play activities, or learning tasks. 
WBC 
White blood cell 
WHO 
World Health Organization  
WNL 
Within normal limits 
 
 
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 3 
Introduction 
The Division of AIDS (DAIDS) oversees more than 300 clinical trials domestically and 
internationally, which evaluate the safety and efficacy of therapeutic products, vaccines, and 
other preventive modalities.  Adverse event (AE) data collected during these clinical trials form 
the basis for subsequent safety and efficacy analyses of pharmaceutical products and medical 
devices.  Incorrect and inconsistent AE severity grading can lead to inaccurate data analyses and 
interpretation, which in turn can impact the safety and well-being of clinical trial participants and 
future patients using pharmaceutical products.  
 
Over the years, DAIDS scientific knowledge and experience have expanded, necessitating 
revisions of the DAIDS grading table which serves as a guide for assessing the severity of AEs 
(including clinical and laboratory abnormalities) in participants enrolled in DAIDS-sponsored 
and -supported clinical trials.  The Division of AIDS (DAIDS) Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) updates and replaces 
version 2.1 (March 2017).  
 
DAIDS is grateful to the DAIDS Grading Table Working Group, numerous government and 
non-government affiliated medical subject matter experts and reviewers who were instrumental 
in the revision of the DAIDS grading table. 
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 4 
Instructions for Use 
General Considerations 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.1 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs.  The term “severe” is not the same as the term “serious” in classifying 
AEs.  The severity of a specific event describes its intensity, and it is the intensity which is 
graded.  Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
 
Clinical sites are encouraged to report parameters in the DAIDS grading table as they are written 
to maintain data consistency across clinical trials.  However, since some parameters can be 
reported with more specificity, clinical sites are encouraged to report parameters that convey 
additional clinical information.  For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
 
The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with 
descriptions for each AE based on the following general guidelines:  
• Grade 1 indicates a mild event 
• Grade 2 indicates a moderate event 
• Grade 3 indicates a severe event 
• Grade 4 indicates a potentially life-threatening event 
• Grade 5 indicates death (Note: This grade is not specifically listed on each page of the 
grading table). 
 
Other points to consider include: 
• Use age and sex values as applicable. 
• Unless noted, laboratory values are for term neonates.  Preterm neonates should be assessed 
using local laboratory normal ranges. 
• Where applicable, Standard International (SI) units are included in italics. 
 
Selecting and Reporting a Primary AE Term 
When selecting a primary AE term to report, sites should select the term that best describes what 
occurred to the participant.  For example, a participant may present with itching, urticaria, 
flushing, angioedema of the face, and dyspnea.  If the underlying diagnosis is determined to be 
an acute allergic reaction, sites should report “Acute Allergic Reaction” as the primary AE term. 
 
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting System 
(DAERS) only if they meet expedited reporting criteria.  However, all primary AE terms should 
be reported using protocol-specific case report forms (CRFs).  Because the reported information 
is stored in different databases (i.e., safety and clinical), sites should report primary AE terms 
using the same terminology for data consistency.  
 
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Instructions for Use 
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Page 5 
When reporting using DAERS, other clinically significant events associated with a primary AE 
term that more fully describe the nature, severity, or complications of the primary AE term 
should be entered in the “Other Events” section.  However, the severity grade for these events 
must be lower than or equal to the severity grade of the primary AE term.  In the example above, 
dyspnea and angioedema of the face may be entered in the “Other Events” section, because they 
are more descriptive and provide additional information on the severity of the acute allergic 
reaction.  However, their severity grades must be lower than or equal to the severity grade of the 
primary AE term of “Acute Allergic Reaction”. 
 
Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs.  Therefore, sites should refer to their 
protocols and CRF requirements for further instructions.  
 
Grading Adult and Pediatric AEs 
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided.  If no distinction  
between adult and pediatric populations has been made, the listed parameter should be used for 
grading an AE in both populations. 
 
Reporting Pregnancy Outcomes 
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes 
and should be reported using the mother's participant ID.  If an infant is not enrolled in the same 
study as the mother, any identified birth defects should be reported using the mother's participant 
ID.  However, if an infant is enrolled in the same study as the mother or in another study, any 
identified birth defects should be reported using the infant's participant ID.  Sites should refer to 
the applicable network standards for reporting abnormal pregnancy outcomes on the CRFs. 
 
Determining Severity Grade for Parameters between Grades  
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE could be 
either grade 2 or grade 3), sites should select the higher of the two grades. 
 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements.  Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the clinical case report forms.  
 
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE.  
Sites should consult the Manual for Expedited Reporting of Adverse Events to DAIDS, Version 
2.0 and their protocol when making an assessment of the need to report an AE. 
 
Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory 
normal values fall within grading table laboratory ranges, the severity grading is based on the 
ranges in the grading table unless there is a protocol-specific grading criterion for the laboratory 
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Instructions for Use 
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Page 6 
value.  For example, “Magnesium, Low" has a grade 1 range of 1.2 to < 1.4 mEq/L, while a 
particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  If a study 
participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as 
grade 1. 
 
Appendix Usage 
Appendix A takes priority over the main grading table in all assessments of total bilirubin for 
term and preterm neonates. 
 
Using Addenda 1-3: Grading Tables Used in Microbicide Studies 
In protocols involving topical application of products to the female and male genital tracts or 
rectum, strong consideration should be given to using Addenda 1-3 (see below) as the primary 
grading tables for these areas.  Although these grading tables are used specifically in microbicide 
studies, they may be used in other protocols as adjuncts to the main grading table (i.e., the 
Division of AIDS (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0).  It should be clearly stated in a protocol which addendum is being used as the 
primary grading table (and thus takes precedence over the main grading table) and which 
addendum is being used in a complementary fashion.  
• Addendum 1 – Female Genital Grading Table for Use in Microbicide Studies- 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 2 – Male Genital Grading Table for Use in Microbicide Studies – 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 3 – Rectal Grading Table for Use in Microbicide Studies – 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table.  In addition, all deaths related to an AE are to be classified as 
grade 5.  
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Clinical adverse 
event NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
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 
 
 
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 7 
Major Clinical Conditions 
Cardiovascular 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arrhythmia   
(by ECG or physical 
examination) 
Specify type, if 
applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention 
indicated 
Non-life-threatening 
symptoms AND 
Non-urgent 
intervention indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg systolic 
OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 99th percentile  
+ 5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia  
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention 
indicated (e.g., 
oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
                                                          
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 
2011; DOI: 10.1542/peds.2009-2107C. 
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Cardiovascular 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 8 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion indicated 
Symptoms AND 
Transfusion of  ≤ 2 
units packed RBCs 
indicated  
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs  
> 10 cc/kg) indicated 
Prolonged PR Interval  
or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 to 
< 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block  
≤ 16 years of age 
1st degree AV block 
(PR interval  
> normal for age 
and rate) 
Type I 2nd degree 
AV block  
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular 
dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated  
Symptoms AND 
Intervention 
indicated  
Life-threatening 
embolic event (e.g., 
pulmonary embolism, 
thrombus)  
 
 
                                                          
2 As per Bazett’s formula. 
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Dermatologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Alopecia (scalp only)  
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 
(without skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities  
NA 
Rash 
Specify type, if 
applicable 
Localized rash  
Diffuse rash OR 
Target lesions  
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial 
ulcerations of 
mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving 
two or more distinct 
mucosal sites OR 
Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis  
 
                                                          
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 
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Endocrine and Metabolic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure)  
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional 
activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
                                                          
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
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Endocrine and Metabolic 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 11 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Lipohypertrophy5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes  
NA 
                                                          
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 
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Gastrointestinal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation)  
Constipation 
NA 
Persistent 
constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas  
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent 
episodes of 
unformed stools OR 
Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to  6 
stools over baseline 
per 24-hour period 
Increase of  ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting in 
severe dehydration, 
hypotensive shock) 
Dysphagia or  
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
with no intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
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Page 13 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema  
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding  
Nausea  
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral intake 
for 24 to 48 hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention 
indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or  
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 14 
Musculoskeletal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform 
basic self-care functions  
Myalgia (generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care functions 
Osteopenia6 
≥ 30 years of age 
BMD t-score  
-2.5 to -1 
NA 
NA 
NA 
   < 30 years of age 
BMD z-score  
-2 to -1 
NA 
NA 
NA 
Osteoporosis6 
≥ 30 years of age 
NA  
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
 
                                                          
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment 
of osteoporosis at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for 
Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of Sheffield.  
Sponsor: Medicines Development for Global Health
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MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 15 
Neurologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, or 
Attentional Disturbance 
below)  
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or  somnolence 
causing inability to 
perform usual social 
& functional 
activities 
Delirium OR  
Obtundation OR  
Coma 
Ataxia  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) 
Specify type, if applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform 
basic self-care functions 
OR Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
 
Specify type, if applicable 
Mild developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated  OR Headache 
with significant 
impairment of alertness 
or other neurologic 
function  
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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Neurologic 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 16 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional 
activities  
Disabling muscle 
weakness causing 
inability to perform 
basic self-care functions 
OR Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and painful 
neuropathy) 
Specify type, if applicable 
Minimal paresthesia 
causing no or 
minimal  
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or  paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures 
New Onset Seizure 
≥ 18 years of age 
NA 
NA  
1 to  3 seizures  
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal state 
Seizure lasting 5 to < 
20 minutes with  
< 24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality  
(e.g., severity or  
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
Syncope  
Near syncope 
without loss of 
consciousness (e.g., 
pre-syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 17 
Pregnancy, Puerperium, and Perinatal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Stillbirth (report using 
mother’s participant ID) 
Report only one 
NA 
NA 
Fetal death occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Birth (report 
using mother’s 
participant ID) 
Live birth at 34 to  
< 37 weeks  
gestational age 
Live birth at 28 to  
< 34 weeks 
gestational age 
Live birth at 24 to  
< 28 weeks 
gestational age 
Live birth at < 24 weeks 
gestational age 
Spontaneous Abortion 
or Miscarriage7 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy  
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
 
                                                          
7 Definition:  A pregnancy loss occurring at < 20 weeks gestational age. 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 18 
Psychiatric 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Insomnia  
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing no or 
minimal 
interference with 
usual social & 
functional activities  
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing more than 
minimal interference 
with usual social & 
functional activities 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early causing 
inability to perform 
usual social & 
functional activities 
requiring intervention 
or hospitalization 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial 
or complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 19 
Respiratory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second 
or peak flow 
reduced to  
≥ 70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to  
< 70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to  
< 50% OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation  
Dyspnea or Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal  
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 
90 to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 20 
Sensory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hearing Loss 
≥ 12 years of age 
 
NA 
 
Hearing aid or 
intervention not 
indicated 
 
Hearing aid or 
intervention indicated 
 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 4, 
6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at  ≤ 4 kHz 
> 20 dB hearing loss 
at > 4 kHz 
> 20 dB hearing loss 
at  ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, 
including hearing 
aids 
Audiologic indication 
for cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medical intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s)  
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional 
activities 
Disabling visual loss in 
affected eye(s) 
 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 21 
Systemic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Allergic 
Reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome8 
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion)  
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to  
< 102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain9 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Pain causing inability 
to perform usual 
social & functional 
activities  
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
                                                          
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).   
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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Systemic 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 22 
Serum Sickness10 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight11 
> 5 to 19 years of 
age 
WHO BMI z-score 
< -1 to -2 
WHO BMI z-score 
< -2 to -3 
WHO BMI z-score  
< -3 
WHO BMI z-score  
< -3 with life-threatening 
consequences 
2 to 5 years of age 
WHO Weight-for-
height z-score  
< -1 to -2 
WHO Weight-for-
height z-score  
< -2 to -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening consequences 
< 2 years of age 
WHO Weight-for-
length z-score  
< -1 to -2 
WHO Weight-for-
length z-score  
< -2 to -3 
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening consequences 
Unintentional 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR  
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
 
                                                          
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or 
dyspnea. 
11 WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs:  
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and  
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age. 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 23 
Urinary 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Urinary Tract 
Obstruction  
NA 
Signs or symptoms 
of urinary tract 
obstruction without  
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening 
consequences 
 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 24 
Site Reactions to Injections and Infusions 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Injection Site Pain or  
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb  
Pain or tenderness 
causing inability to 
perform usual social 
& functional 
activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization 
indicated 
Injection Site Erythema 
or Redness12 
Report only one 
> 15 years of age 
 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25  to 
< 100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤ 15 years of age 
≤ 2.5 cm in 
diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site Pruritus  
 
Itching localized to 
the injection site 
that is relieved 
spontaneously or in 
< 48 hours of 
treatment  
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment  
Generalized itching 
causing inability to 
perform usual social 
& functional 
activities  
NA 
                                                          
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area. 
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 25 
Laboratory Values*  
Chemistries 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0  
≥ 20  to < 30  
< 2.0  
< 20  
NA 
Alkaline Phosphatase,  
High 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences  
ALT or SGPT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) or 
Amylase (Total), High 
Report only one 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low  
(mEq/L; mmol/L) 
16.0 to <  LLN 
16.0 to <  LLN 
11.0  to < 16.0  
11.0  to < 16.0  
8.0  to < 11.0  
8.0  to < 11.0  
< 8.0  
< 8.0  
Bilirubin 
Direct Bilirubin13, 
High 
> 28 days of age 
 
 
NA 
 
NA 
 
> ULN with other 
signs and symptoms 
of hepatotoxicity. 
 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
 
1.1 to < 1.6 x ULN 
 
1.6 to < 2.6 x ULN 
 
2.6 to < 5.0 x ULN  
 
≥ 5.0 x ULN  
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
                                                          
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be reported to DAIDS in an 
expedited time frame unless it meets protocol-specific reporting requirements. 
 
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin. 
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Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 26 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6   to < 11.5 
2.65  to < 2.88 
11.5  to < 12.5  
2.88  to < 3.13 
12.5   to < 13.5  
3.13  to < 3.38 
≥  13.5  
≥  3.38 
< 7 days of age 
11.5  to < 12.4  
2.88  to < 3.10 
12.4  to < 12.9  
3.10  to < 3.23 
12.9  to < 13.5  
3.23  to < 3.38 
≥  13.5 
≥  3.38 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN  to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8  
≥ 7.2 
≥ 1.8  
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8  to < 8.4  
1.95  to < 2.10 
7.0   to < 7.8  
1.75  to < 1.95 
6.1  to < 7.0 
1.53  to < 1.75 
< 6.1  
< 1.53 
< 7 days of age 
6.5  to < 7.5 
1.63  to < 1.88 
6.0 to < 6.5 
1.50  to < 1.63 
5.50  to < 6.0 
1.38  to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
< LLN  to 4.0  
< LLN  to 1.0 
3.6 to < 4.0  
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9  
< 3.2 
< 0.8  
Cardiac Troponin I, 
High  
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
*Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase to 1.3 to 
< 1.5 x participant’s 
baseline 
> 1.8  to < 3.5  
x ULN OR Increase 
to 1.5 to < 2.0 x 
participant’s baseline 
≥ 3.5 x ULN OR 
Increase of  ≥ 2.0 x 
participant’s baseline 
Creatinine Clearance 14 
or eGFR, Low 
*Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2  
OR 
10 to < 30% decrease  
from participant’s 
baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 
OR 
 30 to < 50% 
decrease from 
participant’s baseline 
< 30 ml/min or 
ml/min/1.73 m2 
OR 
≥ 50% decrease from 
participant’s baseline or 
dialysis needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
 
 
110 to 125 
6.11 to < 6.95 
 
 
> 125 to 250 
6.95 to < 13.89 
 
 
 > 250 to 500  
13.89 to < 27.75 
 
 
≥  500  
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89  
> 160 to 250 
8.89 to < 13.89 
> 250  to 500 
13.89  to < 27.75  
≥  500 
≥ 27.75  
                                                          
14 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites should 
choose the method defined in their study and when not specified, use the method most relevant to the study population. 
  
*Reminder: Choose the method that selects for the higher grade. 
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Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 27 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glucose, Low  
(mg/dL; mmol/L) 
≥ 1 month of age 
55  to 64  
3.05  to <3.55  
40  to < 55 
2.22  to < 3.05  
30  to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
< 1 month of age 
50 to 54 
2.78  to < 3.00  
40 to < 50 
2.22 to < 2.78  
30 to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
Lactate, High 
ULN to  < 2.0 
x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences  
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences  
Lipase, High 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders  
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
 
200  to < 240 
5.18  to < 6.19  
 
240  to < 300  
6.19  to < 7.77  
 
≥  300 
≥  7.77  
 
NA 
< 18 years of age 
170  to < 200 
4.40  to < 5.15  
200 to < 300 
5.15  to < 7.77  
≥  300  
≥  7.77  
NA 
LDL, Fasting, High 
≥ 18 years of age 
 
130  to < 160  
3.37  to < 4.12  
 
160 to < 190  
4.12  to < 4.90  
 
≥ 190  
≥ 4.90  
 
NA 
> 2 to < 18 years of 
age 
110  to < 130  
2.85  to < 3.34  
130 to < 190  
3.34  to < 4.90  
≥ 190 
≥ 4.90  
NA 
Triglycerides, Fasting, 
High 
150 to 300  
1.71 to 3.42  
>300  to 500  
>3.42 to 5.7  
>500 to < 1,000  
>5.7 to 11.4  
> 1,000  
> 11.4 
Magnesium15, Low 
(mEq/L; mmol/L) 
1.2   to < 1.4  
0.60  to < 0.70  
0.9  to < 1.2  
0.45  to < 0.60  
0.6  to < 0.9  
0.30  to < 0.45  
< 0.6  
< 0.30  
Phosphate, Low  
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.65 to < LLN 
1.4 to < 2.0 
0.45 to < 0.65  
1.0 to < 1.4 
0.32 to < 0.45  
< 1.0 
< 0.32  
1 to 14 years of age 
3.0  to < 3.5 
0.97  to < 1.13  
2.5  to < 3.0 
0.81  to < 0.97  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
< 1 year of age 
3.5  to < 4.5 
1.13  to < 1.45  
2.5  to < 3.5 
0.81  to < 1.13  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
Potassium, High 
(mEq/L; mmol/L) 
5.6  to < 6.0 
5.6  to < 6.0  
6.0  to < 6.5 
6.0  to < 6.5  
6.5  to < 7.0 
6.5  to < 7.0  
≥ 7.0 
≥ 7.0  
Potassium, Low 
(mEq/L; mmol/L) 
3.0  to < 3.4 
3.0  to < 3.4  
2.5  to < 3.0 
2.5  to < 3.0 
2.0  to < 2.5 
2.0  to < 2.5  
< 2.0 
< 2.0  
                                                          
15 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 
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Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 28 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Sodium, High 
(mEq/L; mmol/L) 
146  to < 150 
146  to < 150  
150  to < 154 
150  to < 154  
154  to < 160 
154  to < 160  
≥ 160 
≥ 160  
Sodium, Low 
(mEq/L; mmol/L) 
130  to < 135 
130  to < 135  
125  to < 130 
125  to < 130 
121  to < 125 
121  to < 125  
≤ 120 
≤ 120  
Uric Acid, High 
(mg/dL; mmol/L) 
7.5  to < 10.0 
0.45  to < 0.59  
10.0  to < 12.0 
0.59  to < 0.71  
12.0  to < 15.0 
0.71  to < 0.89  
≥ 15.0 
≥ 0.89  
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 29 
Hematology 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Absolute CD4+ Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
300 to < 400 
300 to < 400 
 
 
 
200 to < 300 
200 to < 300 
 
 
 
100 to < 200 
100 to < 200 
 
 
 
< 100 
< 100 
Absolute Lymphocyte 
Count, Low  
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
600 to < 650 
0.600 x 109 to 
< 0.650 x 109 
 
 
 
500 to < 600 
0.500 x 109 to 
< 0.600 x 109 
 
 
 
350 to < 500 
0.350 x 109 to 
< 0.500 x 109 
 
 
 
< 350 
< 0.350 x 109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
 
800 to 1,000 
0.800 x 109 to 1.000 
x 109 
 
 
 
600 to 799 
0.600 x 109 to 0.799 
x 109 
 
 
 
400 to 599 
0.400 x 109 to 0.599 
x 109 
 
 
 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109 
750 to 999 
0.750 x 109 to 0.999 
x 109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109 
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109 
< 1,500 
< 1.500 x 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100 to < 200 
1.00 to < 2.00  
OR 
0.75 to < 1.00 
x LLN 
75 to < 100 
0.75  to < 1.00  
OR 
≥ 0.50 to < 0.75 
x LLN  
50 to < 75 
0.50  to < 0.75  
OR 
0.25 to < 0.50 
x LLN 
< 50 
< 0.50  
OR 
< 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin16, Low 
(g/dL; mmol/L) 17 
≥ 13 years of age  
(male only) 
 
 
10.0 to 10.9 
6.19 to 6.76 
 
 
 
9.0 to < 10.0 
5.57 to < 6.19 
 
 
7.0 to < 9.0 
4.34 to < 5.57 
 
 
< 7.0 
< 4.34 
≥ 13 years of age  
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
                                                          
16 Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been on hormone 
therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which they identify (i.e., a transgender 
female should be graded using the female sex at birth hemoglobin laboratory values). 
 
17 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results obtained by 
an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using appropriate conversion 
factor for the particular laboratory.  
 
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Hematology 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 30 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
57 days of age to < 13 
years of age  
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.5 x ULN 
1.5  to < 2.0 x ULN 
2.0  to < 3.0 x ULN 
≥  3.0 x ULN 
Methemoglobin  
(% hemoglobin) 
5.0  to < 10.0% 
10.0  to < 15.0% 
15.0  to < 20.0% 
≥  20.0% 
PTT, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.66  
x ULN 
1.66 to < 2.33  
x ULN 
2.33 to < 3.00  
x ULN 
≥  3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 125,000  
100.000 x 109  to 
< 125.000 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000  
25.000 x 109  to  
< 50.000 x 109 
< 25,000  
< 25.000 x 109 
PT, High  
(not on anticoagulation 
therapy 
1.1  to < 1.25  
x ULN 
1.25  to < 1.50  
x ULN 
1.50  to < 3.00  
x ULN 
≥  3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
 
 
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109 
 
 
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109 
 
 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109 
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109 
< 2,500 
< 2.500 x 109 
Sponsor: Medicines Development for Global Health
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MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 31 
Urinalysis 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to   
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be of 
menstrual origin) 
6  to < 10 RBCs per 
high power field 
≥ 10 RBCs per high 
power field 
Gross, with or 
without clots OR 
With RBC casts OR 
Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+  or higher 
NA 
 
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 32 
Appendix A.  
Total Bilirubin Table for Term and Preterm Neonates 
   PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Total Bilirubin18, High 
(mg/dL; µmol/L) 19 
 
Term Neonate20 
 < 24 hours of age 
 
4 to < 7  
68.4 to < 119.7  
7 to < 10  
119.7 to < 171  
10 to < 17  
171 to < 290.7  
≥ 17 
≥ 290.7  
24 to < 48 hours of 
age 
5 to < 8  
85.5 to < 136.8  
8 to < 12  
136.8 to < 205.2  
12 to < 19  
205.2 to < 324.9  
≥ 19  
≥ 324.9  
48 to < 72 hours of 
age 
8.5 to < 13  
145.35 to < 222.3  
13 to < 15  
222.3 to < 256.5  
15 to < 22  
256.5 to < 376.2  
≥ 22  
≥ 376.2  
72 hours to < 7 days 
of age 
11 to < 16  
188.1 to < 273.6  
16 to < 18  
273.6 to < 307.8  
18 to < 24  
307.8 to < 410.4 
≥ 24  
≥ 410.4  
7 to 28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
Preterm Neonate20  
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
32 to < 35 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
10 to < 14  
171 to < 239.4 
≥ 14  
≥ 239.4 
28 to < 32 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
6 to < 10  
102.6 to < 171  
≥ 10  
≥ 171  
< 28 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
 5 to < 8  
85.5 to < 136.8  
≥ 8  
≥ 136.8  
7 to  28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
 
 
                                                          
18 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first 
week of life followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this 
appendix corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 
4. 
19 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 
20 Definitions: Term is defined as ≥ 37 weeks gestational age; near-term, as ≥ 35 weeks gestational age; preterm, as < 35 weeks 
gestational age; and neonate, as 0 to 28 days of age. 
Sponsor: Medicines Development for Global Health
Protocol Number: MDGH-MOX-1006
MDGH-MOX-1006 Final v1.5 200703 
(incorporating Amendments 1, 2, 3, 4 and 5)
CONFIDENTIAL 
Page 170
 
03 Jul 2020


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16.6 Model Adolescent (12 to 17 years) and Parent/Guardian Information Sheet 
and Assent and Consent Form  
Title of Study: 
An open-label study of the pharmacokinetics and safety of a single dose 
of moxidectin per oral in participants aged 4 to 17 years with (or at high 
risk of) onchocerciasis to identify an optimal dose for treatment of 
children 4 to 11 years. 
Principal Investigator: 
Dr Nicholas Obuobisa Opoku 
Organization: 
University of Health and Allied Sciences (UHAS) 
Sponsor 
Medicines Development for Global Health 
Protocol Number(s): 
MDGH-MOX-1006 
UHAS-REC A.7 [6] 18-19 
GHS-ERC 015/06/19 
Protocol / Information 
Document Version/Date: 
Final v1.3 (incorporating Amendments 1, 2 and 3) / 27 Nov 2019 
General Information About the Study 
I am Dr................................................................., a doctor working at the University of Health 
and Allied Sciences in Hohoe. We are testing a new medicine called moxidectin in children 
aged 4 to 17 years. Moxidectin is a new treatment for onchocerciasis (river blindness), which 
you call “oncho”.  
Testing new medicines is called doing “research” or “a study” and means we want to learn 
something about the new medicine.  
Here, we explain to you and your parents or guardians what we already know about moxidectin, 
what will happen during the study and the risks and advantages of taking part in this study.  
This will help you decide whether you want to take part in this study or not and it will help your 
parents or guardians decide whether they will allow you to take part or not.  
If you do not want to take part or your parents or guardians don’t want you to take part, please 
don’t be afraid to tell us. Your care or the care of your parents or guardians at your local health 
care centers will not be affected by saying no to being in this study.  
Please ask questions about anything that you don’t understand or want to know more about. 
Before making a decision, you might also want to talk about it with others. 
What is oncho and what is being done to help people with oncho now? 
Oncho is caused by a worm that is passed from one person to another through the bites of the 
small black flies that you see at the riverside and in your community in the mornings and early 
evenings. Two types of these worms live in the human body. The young worms in the skin and 
eyes cause the disease, for example itching or a rash. The adult worms live for up to 14 years in 
swellings under the skin called nodules and produce millions of the young worms.  


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You and many of the adults and other children in your community may have oncho. Therefore, 
a medicine called ivermectin is now given to all people at least 5 years of age who are not 
pregnant or sick. 
Ivermectin kills most of the young worms so that people who have oncho and take ivermectin 
have less or even none of the disease. However, the adult worms quickly start to make new 
worms and so ivermectin is given to you every six months.   
What is the new medicine, moxidectin, and what does it do against the oncho 
worms? 
You may have already heard about moxidectin because about 10 years ago, 219 people from 
Wii, Azua, Jagri Akua and Bitaaba who had oncho and were at least 12 years of age took part in 
a study to test moxidectin. In that study, some people were given moxidectin and some people 
were given ivermectin. If you know anybody who took part in that study, they can tell you about 
their experience in the study. 
In the study, we found that moxidectin kills more young oncho worms in the skin than 
ivermectin and that moxidectin stops the adult worms from making new, young worms for a 
longer time than ivermectin. Here we are showing you pictures of the number of oncho worms 
in people before and after they took moxidectin or ivermectin. 
Number of Young Worms in the Skin Before and After Taking Moxidectin or Ivermectin 


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What do we know about unwanted effects of moxidectin? 
In that study we also found that people who took moxidectin and people who took ivermectin 
had similar unwanted effects, but some unwanted effects occurred in more people who took 
moxidectin than in people who took ivermectin. Many of these unwanted effects are caused by 
the body getting rid of the young oncho worms after they have been killed by moxidectin or 
ivermectin. On the next page we show you how many out of 100 people had unwanted effects 
after taking moxidectin or ivermectin. Please ask me if you don’t understand what these 
unwanted effects mean.   
Number of People with Unwanted Effects in 100 People Who Took Moxidectin or ivermectin 
Unwanted 
Effect 
Moxidectin 
Ivermectin 
Itching 
65 
 
54 
 
Muscle 
pain 
64 
 
52 
 
Headache 
58 
 
54 
 
Fast 
heartbeat  39 
 
30 
 
 
Rashes 
37 
 
21 
 
Stomach 
pain 
31 
 
35 
 
Feeling 
faint or 
dizzy 
when 
30 
 
25 
 


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Number of People with Unwanted Effects in 100 People Who Took Moxidectin or ivermectin 
Unwanted 
Effect 
Moxidectin 
Ivermectin 
standing 
up 
Fever 
/chills 
27 
 
18 
 
Common 
cold  
23 
 
21 
 
Cough 
17 
 
18 
 
Upset 
belly 
(Stomach 
flu) 
15 
 17 
 
Lymph 
node pain 
13 
 
6 
 
Dizziness  12 
 
9 
 
Swollen 
arm or 
leg 
11 
 
6 
 
Why are we doing a study of moxidectin in 4 to 17 year olds and asking you to 
take part? 
We have already given moxidectin to 1349 people with oncho. These included 53 adolescents 
aged 12 to 17 years with oncho who took 4 tablets of moxidectin (8 milligrams), the same 
number of tablets adults with oncho took. Thirty-one (31) of them lived in Wii, Azua, Jagri 
Akua or Bitaaba. From this study, we know that 4 tablets is the right number of tablets for 
people at least 12 years of age. 
Because moxidectin works better against the oncho worms than ivermectin, it would be good if 
moxidectin could also be given to children aged 4 to 11 years. Therefore, we want to find the 
right number of moxidectin tablets for children aged 4 to 11 years.   
How will we find out what number of moxidectin tablets is right for children aged 
4 to 11 years? 
When somebody takes moxidectin, it gets into their blood and from the blood, moxidectin can 
reach the young oncho worms in the body to kill them.  


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The right number of tablets for children aged 4 to 11 years is the number that leads to the same 
amount of moxidectin in their blood as in the blood of adults and adolescents 12 to 17 years of 
age who take 4 moxidectin tablets and does not cause severe unwanted effects.  
To find out the right number of tablets for children aged 4 to 11 years, we need to first give 
moxidectin tablets to adolescents aged 12 to 17 years, take a bit of blood and measure the 
amount of moxidectin in their blood and find out what unwanted effects they have.  
We think that we will have to give moxidectin to at least nine adolescents aged 12 to 17 years 
but not more than 18.  
What will happen in the study, where will it happen and how long will it take?  
First, we will do Screening. Screening means that we fill find out whether you have the oncho 
worm but are otherwise healthy and can take part in the study.  
The first step of Screening will happen in your community: 
• We will ask if you have a sister or brother who has already taken part in the study, because 
only one child from your family can take part. 
• If you are a young woman, we will ask whether you are breast-feeding a child because then 
you cannot take part in the study. 
• We will ask questions about health problems you have had in the past, medicines you have 
taken, look closely at your arms to see if it will be easy to take blood. 
This will take 1 to 2 days. 
If we find you cannot take part in the study, we will tell you and your parents or guardians why.  
If we find that you can go on to the second 
step of Screening, we will drive you and one 
of your parents or guardians by car to our 
study center in Hohoe.  
In Hohoe we have a special house for people 
taking part in our study and you will sleep 
there together with your parent or guardian 
and other children and their parents or 
guardians who take part in our study. We will 
give you free meals while you are in Hohoe.  


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In Hohoe:  
• We may ask you and your parent or guardian to tell us more about health problems you have 
had in the past and any medicines you have taken lately.  
• We will measure your height and weight. 
• We will examine how fast you breathe, how hard and fast your heart works and your body 
temperature (we call these measurements “vital signs”). 
• We will examine how well your heart works with a special 
machine called an electrocardiograph (an “ECG”). Here I am 
showing you the things we will put on your body for the 
ECG, like you see in this picture. This won’t hurt.  
• We will examine your body for signs of illness or pain. 
Some of this you can see in the pictures here. 
 
• Doctors can learn a lot about whether you are sick by testing 
your blood. We will take a bit of your blood (12.5 milliliters or 
a little bit more than 2 teaspoons) like you can see in this photo. 
Before we take the blood, we will put a cream on your arm so 
you won’t feel much pain.  
We will test the blood to find out how well some of the organs 
in your body work and for signs of HIV (AIDS infection) or the 
germs that cause liver disease (hepatitis B and C).  
If you have lived outside Ghana in an area where another worm 
called Loa loa occurs, we will test your blood to check whether 
you have the Loa loa worm. We will do this because people with lots of Loa loa worms can 


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have more unwanted effects when taking moxidectin and therefore they should not take part 
in our study. 
• If you are a girl who has started her monthly bleeding, we will also test your blood to see 
whether you are pregnant. If you are pregnant, you cannot take part in the study. 
All of this will take 1 to 2 days.  
We will explain everything we learn about your health. We will let you and your parent or 
guardian know whether you can take part in the study.  
What will happen after Screening if you cannot take part in the study? 
We will explain to you and your parent or guardian why you cannot take part in the study. If 
you need to be taken care of by a nurse or doctor, we will arrange for you to visit a clinic or 
hospital.  
On the day after Screening, we will drive you and your parent or guardian back to your 
community. 
What will happen after Screening if you can take part in the study? 
We will ask you to stay in Hohoe for 8 more days. 
Girls can take part in this study only if they are not pregnant and if they avoid becoming 
pregnant until around 6 months after they have swallowed moxidectin. We will tell you more 
about this a bit later.  
You will not be able to take ivermectin while you are on the study (for approximately 6 
months). 
On the day after Screening, we will:  
• Repeat some of the examinations we did during Screening before we give you moxidectin. 
• Ask you to swallow 4 moxidectin tablets 2 hours before you have breakfast. 
• Repeat again some of the examinations we did during Screening. 
• Take a bit of your blood (1.5 milliliters or 1/3 of a teaspoon) 4 times to measure the amount 
of moxidectin. We will use a special needle called a ‘cannula’ so that you only need to have 
one needle prick and we will use the special cream, so you won’t feel much pain.  
• Ask you several times to tell us if you are feeling unwell or have any pain. If you have pain 
or are feeling unwell, we will examine you to find out what we can do to make you feel 
better. If necessary, we will give you medicine.  
• We will also ask you and your parent or guardian to tell us immediately if you are not 
feeling well. Even during the night, there will always be a nurse to talk to. 
During the next 7 days, we will:  


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• Repeat some of the examinations we did during Screening. 
• Take a bit of your blood (1.5 milliliters or 1/3 of a teaspoon) on 2 days to measure the 
amount of moxidectin. 
• Take a bit more of your blood (3.5 milliliters total, 2/3 teaspoon) on the last day to measure 
the amount of moxidectin and test how well some of the organs in your body work. 
If you are feeling well, we will drive you and your parent or guardian back to your community 
on the 7th day after you have taken the moxidectin tablets. If not, we will ask you to stay longer 
until you feel well. 
2 weeks, 1 month, 3 months and around 6 months after you have swallowed the 
moxidectin tablets, we will:  
• Drive you and your parent or guardian to Hohoe again.  
• Each time we will ask you to tell us about any health problems and any medicines taken 
since we last saw you. 
• Each time we will repeat some of the examinations we did when you were last in Hohoe. 
• We will take a bit of your blood (1.5 milliliters or 1/3 of a teaspoon) on 2 visits to measure 
the amount of moxidectin in it. 
• We will take a bit more of your blood (3.5 milliliters or 2/3 teaspoon) on 1 visit to measure 
the amount of moxidectin in it and to find out how some of the organs in your body work. 
• Each time you and your parent or guardian will spend one night with us and we will give 
you free meals.  
What happens when you are in Hohoe during school time? 
There will be a teacher in our study center in Hohoe. The teacher will help you keep going with 
some of your schoolwork, to help make up for the school time you miss. 
What should you do if you are not feeling well when you are back in your 
community? 
You should let your parents or guardians know and contact us, either through the community 
coordinator or directly or you should go to the closest health clinic. The ‘community 
coordinator’ is the person chosen by the adults in your community to contact us whenever you 
want. We have written down the name for you.  
We will make sure that you are examined and receive medicine if you need it. If needed, we will 
drive you and your parent or guardian to the study center in Hohoe or a health clinic or hospital. 
Are there any potential advantages of taking part in this study? 
You may not have any advantages. 


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• You will have examinations of your health. These examinations are often used by doctors 
and nurses to find out whether people are sick. 
• If you have young oncho worms in your skin or eyes, moxidectin will cause most or all of 
them to die and prevent new young worms in your skin for up to about 1 year.  
• If you have health problems because of the young oncho worms in your skin or eyes, these 
will become better or even go away for up to about 1 year. 
Are there any possible risks of taking part in this study? 
Unwanted effects of taking moxidectin  
Almost all medicines cause unwanted effects.  
We have already told you about the unwanted effects we found in people with the oncho worm 
who took moxidectin or ivermectin. In most cases, these unwanted effects were mild, went away 
on their own and lasted less than a week. Please let me know if you would like us to look at the 
pictures again. 
You may have none, some or all of these unwanted effects. They may be mild, moderate or 
severe. They may occur soon after you have taken moxidectin or many hours or days later.  
Also, because moxidectin is a new medicine, there may be unwanted effects that we don’t know 
about yet and we don’t know whether they would be mild, moderate or severe or how long they 
may last. If we learn about new unwanted effects that may make you change your mind about 
taking part in this study, we will tell you and your parents or guardians immediately.  
Unwanted effects of taking blood  
Having blood taken may cause some pain, bruising, and a little bit of bleeding. Sometimes, it 
can also cause minor infection (where germs can get into the needle prick) or fainting. This has 
never happened in our studies because we get you to lie down and clean the skin to remove any 
germs before we take blood. If you have any unwanted effects, they can easily be treated.  
Why should girls who are pregnant or breast-feeding not take moxidectin and 
why should girls ensure that they don’t become pregnant during the study? 
As you may know, when ivermectin is distributed in your community, women who are pregnant 
should not take ivermectin until at least a week after their baby is born. 
We don’t know the effects of moxidectin on an unborn child or newborn baby that is breastfed 
by a mother who has taken moxidectin. Because of this, girls who are pregnant or breast-feeding 
cannot take part in this study and girls should not become pregnant during the study.  
If you already have monthly bleeding, we will test whether you are pregnant.  


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How can girls avoid becoming pregnant? 
You must agree to avoid becoming pregnant for around 6 months (until your last visit to 
Hohoe).  
A family planning nurse will discuss highly effective methods to avoid becoming pregnant with 
you and your parent or guardian. We call these methods “methods of contraception”. One 
method of contraception is not having sex. If you choose another method of contraception, we 
will provide it to you. 
What happens if a girl who takes part in the study becomes pregnant? 
If you become pregnant between taking moxidectin and around 6 months later, you should let us 
know immediately. We will advise you to attend all ante-natal care visits the Ghana Health 
Service offers. A doctor specializing in treating babies and children will examine the baby after 
birth and at least once a year until 2 years of age.  
What happens if a boy who takes part in the study makes someone pregnant? 
If you make someone pregnant between taking moxidectin and around 6 months later, you 
should also inform us immediately. We will ask you to let us visit your partner. We will advise 
her to attend all ante-natal care visits the Ghana Health Service offers and ask her to agree that a 
doctor specializing in treating babies and children will examine the baby after birth and at least 
once a year until 2 years of age.  
What happens to the blood samples? 
We will send the blood for measuring the amount of moxidectin to people in another country 
(the United States of America) to make the measurements. We will do the other tests in our 
country.  
We will not write your name on the blood samples, only a number. We call this number your 
‘participant number’. Only we know which number belongs to which adolescent or child who 
takes part in our study. 
We will only use your blood for measuring the amount of moxidectin and for the tests we have 
told you about. Once these measurements and tests are done, any blood left over will be 
destroyed.  
Who will know what we found out about your health during the study? 
We will keep the information we collect about your health in what we call “records”. We will 
keep these records private (confidential). This means that we will not share your name with 
anybody who does not belong to our study team without your permission, except when we must 
because it is the law.  


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We will keep all the records in a locked, secure area for at least 25 years and possibly longer. 
When we don’t need them anymore, they will be destroyed. 
The people who can see the records, including your name, are:  
• The doctors, nurses and laboratory staff working in our study team. 
• People coming to our study center in Hohoe to make sure that we do things right and follow 
the law. These are:  
o People from the Ghana Food and Drugs Authority and the United States Food and 
Drug Administration.  
o People from the ‘Sponsor’. The Sponsor is Medicines Development for Global 
Health, who make moxidectin tablets. They are giving us the money and the 
moxidectin tablets for the study and helping us write reports about what we learn. 
o People from the “Ethics Committees”. These are people that have been asked by the 
University of Health and Allied Sciences in Hohoe, the Ghana Health Service or the 
World Health Organization to make sure we do this study in the right way.  
The people who can see the study records but NOT your name or the names of your parents or 
guardians are: 
• People from the Sponsor and working with us and the Sponsor. The Sponsor will keep the 
study records without your name for at least 25 years. 
• People from the Ghana Food and Drugs Authority, the United States Food and Drug 
Administration, or the authorities in other countries or at the World Health Organization 
who look at study results to decide whether moxidectin can be used in Ghana and other 
countries. 
• Other people who want to learn about what happens when children 4 to 17 years of age take 
moxidectin.  
If you change your mind about taking part in the study and don’t want to take part anymore, we 
will stop collecting information. We and the Sponsor will still use the information that we 
collected before you told us you want to stop being in the study. However, if you have an 
unwanted effect that has not stopped, we will ask you to let us visit you to find out whether you 
need any treatment for this effect. Also, if you are pregnant, we will ask you if the doctor 
working with us who specializes in treating babies and children can come and examine the baby 
after birth and at least yearly for 2 years. If you are male and your partner becomes pregnant, we 
will ask you if we can contact your partner to ask her if we can examine the baby. You do not 
have to agree to this. 


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Will you or your parents have to pay anything to take part in the study? 
You or your parents or guardians will not pay anything. 
•
All examinations and medical care that are part of the study will not cost anything.
•
When you and your parent or guardian stay overnight in Hohoe, you will not pay anything.
We will give you free food and transportation by car to and from your home.
Will your parent/guardian be compensated for the time they spend with you at 
the study center? 
The parent or guardian who goes with you to Hohoe will be compensated, that means get money 
to make up for loss of earnings. The amount will be based on the number of nights spent in 
Hohoe. The amount for each night’s stay will be roughly the “by day” earnings of adults in your 
community, currently forty (40.00) Ghana Cedis per day. 
What happens if you have a permanent injury or health problem because you 
take part in this study? 
We do not think that anybody will have an injury from the study that will make them 
permanently sick or die. However, if this happens, the Sponsor’s insurance will pay you or your 
parents or guardians compensation.  
What happens after the study? 
After the study, you should take ivermectin when it is distributed in your community. 
We will tell you, your parents or guardians and your community about what we learnt. We will 
also tell you what we and the Sponsor plan to do so that the Ghana Health Service and the health 
services in other countries where people have oncho can decide whether they want to give out 
moxidectin in the way they are now giving out ivermectin.  
Who can you talk to if you want more information before you agree to take part in 
the study or during the study? 
If you want to talk to someone who is not in our study team about any worries about the study, 
your rights, an injury you may have suffered in the study, or any other questions, concerns or 
complaints about the study in the future, please contact: 
•
The Administrator of the Research Ethics Committee, Institute of Health Research,
University of Health and Allied Sciences by email at 
 or by telephone on
.
•
The Secretary to the Research Ethics Committee, Institute of Health Research,
University of Health and Allied Sciences, Mr. Fidelis Anumu, by telephone on +
. If you or your child have any questions, concerns or complaints about the
study in the future, you may also contact the Project Administrator later.


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•
The Administrative Secretary of the Ghana Health Service Ethics Review Committee,  
Ms Nana Abena Apatu, by telephone on 
 or by writing to The 
Administrative Secretary, Ghana Health Service Ethics Review Committee, Research and 
Development Division, Ghana Health Service, P. O. Box M190 Accra Ghana.
If you have any questions about the study or need medical help during the study, please contact 
the following members of the study team or your community coordinator:  
1. Dr. Nicholas O. Opoku (On-site Principal Investigator)
University of Health and Allied Sciences
School of Public Health Research Centre
Municipal Hospital Hohoe,
Telephone: 
 or 
 (mobile)
2. Dr. Felix Doe (Co-investigator)
Hohoe Municipal Health Directorate
Telephone: 
 or 
 (mobile)
3. Your Community Coordinator
Name:
Telephone: 
What if you or your parents/guardians do not want you to take part in the study 
or if you or your parents/guardians change your mind? 
It is your and your parents’ or guardians’ decision to take part in this study. 
You or your parents or guardians can tell us that you will stop taking part in the study at any 
time. You do not have to tell us why you want to stop.  
Not taking part in the study or changing your mind will not change the health care you and your 
family will receive from the Ghana Health Service.  
When you tell us that you will stop taking part in the study, we will ask you to let us do final 
examinations so that we know about your health and can tell you what you should look out for 
after leaving the study.  
We may decide that you cannot continue in the study. We will do this if you are not ready to 
come to Hohoe or if you do not want us to do the examinations or take blood, or if we find that 
it is better for your health. If this happens, we will explain the reasons to you and your parents 
or guardians. 


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What do you and your parents/guardians need to do if you want to take part in 
the study? 
You should discuss this with your parents and other people. 
You can only take part if both you and your parents or guardians agree that you can take part.  
After you have decided, please come and talk to us together with your parents or guardians and 
the person your community had chosen to be present when we provide you the information 
about the study. We will call this person “the witness”.  
We will ask you and your parents or guardians whether you have any questions. We will also 
ask you and your parents or guardians some questions to make sure you all know what will 
happen during the study. Then we will ask you and your parents or guardians to confirm that 
you want to take part in the study by putting your signature or thumbprint on a form. The 
witness will also sign the form.  
Help for your discussion with your parents/guardians, friends, family and others 
you want to talk this over with 
To help you in your discussions of the study with others, here is an overview of what will 
happen and where it will happen. 
You and your parents or guardians discuss whether 
you can take part in the study and you all agree. 
 
If you do not agree you don’t 
need to do anything. 
 
If you agree, you let us know. We will check whether we need to tell you more about the study. We 
will ask you and your parents or guardians to sign or thumbprint a form.  
 
Step 1 Screening in your community 
to ask questions about your health 
(1-2 days). 
 
If you cannot take part in Step 2 Screening, we 
will tell you why and tell you if you should see 
a nurse or doctor. 
 
If you can take part in Step 2 Screening, you and 
one of your parents/guardians will go to Hohoe. 


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You will stay in our 
special house with other 
children who will take 
part in the study and 
their parents or 
guardians. 
 
 
We will ask more 
questions, do 
examinations and take 
bits of blood to learn 
more about your health 
and find out whether 
you can take part in the 
study (1-2 days). 
 
 
 
 
 
If you can take part in the study and you still 
agree, you need to stay in Hohoe for 8 more days. 
If you cannot take part in the study, we will tell 
you why and take you home. If you have a 
health problem, we will arrange a visit to a clinic 
or hospital near your community. 
 
The next day, we will ask you to swallow the moxidectin tablets.  
On that day and the next 7 days we will take more bits of your blood and repeat some of the 
examinations we did during Screening.  
Then we will take you back to your community, unless you are not well, in which case you will stay 
until you are better.  


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2 weeks, 1 month, 
3 months and around 
6 months after you 
swallowed the 
moxidectin tablets, we 
will bring you and one 
parent or guardian back 
to Hohoe. 
Each time we will repeat some of the examinations we did when you were in Hohoe last time and on 
3 visits, we will take a bit of your blood.  
 
Assessment of Informed Assent – Questions for Adolescents 12 to 
17 Years 
Child Response 
Do you understand why you are being asked to participate in this study? 
☐ Yes        ☐ No 
Have you been able to ask questions and discuss the study? 
☐ Yes        ☐ No 
Questions: 
 
 
 
 
 
 
 
 
 
Do you understand that you can only take part if both you and your 
parents/guardians agree? 
☐ Yes        ☐ No 
Do you understand that during Screening we might find that you cannot take 
part in the study? 
☐ Yes        ☐ No 
Will we take blood during this study? 
☐ Yes        ☐ No 
How long will you be in the study? 
 
Do you understand you can tell us at any time that you want to stop being in 
the study, without having to tell us why? 
☐ Yes        ☐ No 
Is there any charge for being in the study? 
☐ Yes        ☐ No 
Do you understand that this is a study and that we do not know all unwanted 
effects of moxidectin? 
☐ Yes        ☐ No 
Do you know who to call if you have questions? 
☐ Yes        ☐ No 
Do you know that we will share what we learn about your health with many 
different people but only those coming to Hohoe to check we do things right 
can learn your name? 
☐ Yes        ☐ No 


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Assessment of Informed Assent – Questions for Adolescents 12 to 
17 Years 
Child Response 
Are you willing to come to Hohoe five times and have the examinations and 
blood taken that we told you about? 
☐ Yes        ☐ No 
For girls who already have monthly bleeding: Do you understand that you must 
avoid becoming pregnant for around 6 months and that we will give you what 
you need if you chose a method other than not having sex? 
☐ Yes        ☐ No 
 
Assessment of Informed Consent – Questions for Parents/ 
Guardians of Adolescents 12 to 17 Years 
Parent/Guardian 
Response 
Do you understand why your child/ward is being asked to participate in this 
study? 
☐ Yes        ☐ No 
Have you been able to ask questions and discuss the study? 
☐ Yes        ☐ No 
Questions: 
 
 
 
 
 
 
 
 
 
Do you understand that during Screening we might find that your child/ward 
cannot take part in the study? 
☐ Yes        ☐ No 
Do you understand that it is your decision to allow your child/ward to take part 
in this study and that your child/ward must also agree (that means your child is 
a “volunteer”)? 
☐ Yes        ☐ No 
Are you willing to allow your child/ward to have all the examinations? 
☐ Yes        ☐ No 
Will we take blood from your child/ward during this study? 
☐ Yes        ☐ No 
How long will your child/ward be in this study? 
 
Do you understand your child/ward can stop taking part in the study at any 
time, without having to tell us why? 
☐ Yes        ☐ No 
Is there any charge for being in the study? 
☐ Yes        ☐ No 
Do you understand that this is a study and that we do not know all unwanted 
effects of moxidectin? 
☐ Yes        ☐ No 
Do you know who to call if you or your child/ward has questions? 
☐ Yes        ☐ No 
Do you know that we will share what we learn about the health of your 
child/ward with many different people but only those coming to Hohoe to check 
we do things right can learn the child’s name? 
☐ Yes        ☐ No 


Sponsor: Medicines Development for Global Health 
Protocol Number: MDGH-MOX-1006 
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Assessment of Informed Consent – Questions for Parents/ 
Guardians of Adolescents 12 to 17 Years 
Parent/Guardian 
Response 
Are you willing to come to Hohoe five times and so that your child/ward can 
have the examinations and blood taken that we told you about? 
☐ Yes        ☐ No 
For parents/guardians of girls old enough to have a baby: Do you understand 
that your daughter/ward has to avoid becoming pregnant and that we will give 
her what she needs if you and she choose a method other than not having 
sex? 
☐ Yes        ☐ No 
 
 
 


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Agreement to Study Participation – Parents/Guardians and Adolescents 12 to 17 
Years 
CHILD PARTICIPATION AGREEMENT 
I have read or have had someone read all of the above, asked questions, received answers regarding 
participation in this study, and I agree that my child/ward should participate in this study as a volunteer. I 
will not have waived any of my rights by signing this parental consent form. Upon signing this form, I 
will receive a copy for my personal records. 
 
Signature/ 
Thumbprint 
of Parent/ 
Guardian/ 
LAR 
 
 
 
Name of Adolescent 
 
 
 
 
 
 
 
Name of Parent/Guardian/LAR  
 
 
Date 
 
 
 
 
 
 
Signature/ 
Thumbprint 
of Parent/ 
Guardian/ 
LAR  
 
 
 
Name of Parent/Guardian/LAR  
 
 
Date 
VOLUNTARY AGREEMENT (ADOLESCENTS 12 TO 17 YEARS) 
By signing or thumbprinting below, it means that you: 
• 
have understood what you will be doing for this study, 
• 
have had all your questions answered, 
• 
have talked to your parent(s)/legal guardian about this project, and 
• 
agree to take part in this research 
If you do not want to participate in this study, please do not sign or thumbprint this assent form. You and 
your parents/guardians will be given a copy of this form after you have signed/thumbprinted it. 
 
Signature/ 
Thumbprint 
of 
Adolescent 
 
  
Name of Adolescent  
 
 
Date 
IMPARTIAL WITNESS SIGNATURE 
I was present while the benefits, risks and procedures were read to the volunteer and their 
parents/guardians. All questions were answered, and the child and their parents/guardians have agreed 
the child will take part in the study.  
 
 
 
 
 
Name of Witness  
 
Signature of Witness  
 
Date 
SIGNATURE OF PERSON WHO OBTAINED CONSENT 
I certify that the reason the study is being done, what will happen in the study, and the potential 
advantages and possible risks associated with taking part in this research have been explained to the 
above-named adolescent and their parent(s)/guardian(s).  
 
 
 
  
Name of Person who Obtained Consent 
 
Signature of Person who Obtained Consent 
 
Date 


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16.7 Model Information Sheet and Consent Form for Parents/Guardians of 
Children 4 to 11 Years, Including Assent Form for Children 7 to 11 Years 
Title of Study: 
An open-label study of the pharmacokinetics and safety of a single dose 
of moxidectin per oral in participants aged 4 to 17 years with (or at high 
risk of) onchocerciasis to identify an optimal dose for treatment of 
children 4 to 11 years. 
Principal Investigator: 
Dr Nicholas Obuobisa Opoku 
Organization: 
University of Health and Allied Sciences (UHAS) 
Sponsor: 
Medicines Development for Global Health 
Protocol Number(s): 
MDGH-MOX-1006 
UHAS-REC A.7 [6] 18-19 
GHS-ERC 015/06/19 
Protocol / Information 
Document Version/Date: 
Final v1.3 (incorporating Amendments 1, 2 and 3) / 27 Nov 2019 
General Information About the Study 
I am Dr................................................................., a doctor working at the University of Health 
and Allied Sciences in Hohoe. We are testing a new medicine called moxidectin in children 4 to 
17 years of age. Moxidectin is a new treatment for onchocerciasis (River blindness), which you 
call “oncho”.  
Testing new medicines is called doing “research” or “a study” and means we want to learn 
something about the new medicine.  
Here, we explain to parents of children aged 4 to 11 years what we already know about 
moxidectin, what will happen during the study and the risks and advantages of taking part in this 
study. This will help you decide whether you will allow your child or ward to take part in the 
study or not.  
If you don’t want your child or ward to take part, please don’t be afraid to tell us. Your care or 
the care of your child or ward at your local health care centers will not be affected by saying no.  
Please ask questions about anything that you don’t understand or want to know more about. 
Before making a decision, you might also want to talk about it with others. 
What is oncho and what is being done to help people with oncho now? 
Oncho is caused by a worm that is passed from one person to another through the bites of the 
small black flies that you see at the riverside and in your community in the mornings and early 
evenings. Two types of these worms live in the human body. The young worms in the skin and 
eyes cause the disease, for example itching or a rash. The adult worms live for up to 14 years in 
swellings under the skin called nodules and produce millions of the young worms.  


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Many adults and children in your community may have oncho. Therefore, a medicine called 
ivermectin is now given to all people at least 5 years of age who are not pregnant or sick. 
Ivermectin kills most of the young worms so that people who have oncho and take ivermectin 
have less or even none of the disease. However, the adult worms quickly start to make new 
worms and so ivermectin is given to you every six months.   
What is the new medicine, moxidectin, and what does it do against the oncho 
worms? 
You may have already heard about moxidectin because about 10 years ago, 219 people from 
Wii, Azua, Jagri Akua and Bitaaba who had oncho and were at least 12 years of age took part in 
a study to test moxidectin. In that study, some people were given moxidectin and some people 
were given ivermectin. If you know anybody who took part in that study, they can tell you about 
their experience in the study. 
In the study, we found that moxidectin kills more young oncho worms in the skin than 
ivermectin and that moxidectin stops the adult worms from making new young worms for a 
longer time than ivermectin. We are showing you here pictures of the number of oncho worms 
in people before and after they took ivermectin or moxidectin. 
Number of Young Worms in the Skin Before and After Taking Moxidectin or Ivermectin 
What do we know about the unwanted effects of moxidectin? 


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In that study we also found that people who took moxidectin and people who took ivermectin 
had similar unwanted effects but some unwanted effects occurred in more people who took 
moxidectin than in people who took ivermectin. Many of these unwanted effects are caused by 
the body getting rid of the young oncho worms after they have been killed by moxidectin or 
ivermectin. On the next page we show you how many out of 100 people had unwanted effects 
after taking moxidectin or ivermectin. Please ask me if you don’t understand what these 
unwanted effects mean.   
Number of People with Unwanted Effects in 100 People Who Took Moxidectin or Ivermectin 
Unwanted 
Effect 
Moxidectin 
Ivermectin 
Itching 
65 
 
54 
 
Muscle 
pain 
64 
 
52 
 
Headache 
58 
 
54 
 
Fast 
heartbeat  39 
 
30 
 
 
 
Rashes 
37 
 
21 
 
Feeling 
faint or 
dizzy 
when 
standing 
up 
30 
 
25 
 


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Number of People with Unwanted Effects in 100 People Who Took Moxidectin or Ivermectin 
Unwanted 
Effect 
Moxidectin 
Ivermectin 
Stomach 
pain 
31 
 
35 
 
Fever 
/chills 
27 
 
18 
 
Common 
cold  
23 
 
21 
 
Cough 
17 
 
18 
 
Upset 
belly 
(Stomach 
flu) 
15 
 17 
 
Lymph 
node pain 
13 
 
6 
 
Dizziness  12 
 
9 
 
Swollen 
arm or 
leg 
11 
 
6 
 
Why are we doing a study of moxidectin in 4 to 17 year olds and asking your 
permission for your child/ward to take part? 
We have already given moxidectin to 1349 people with oncho. These included 53 adolescents 
aged 12 to 17 years with oncho who took 4 tablets of moxidectin (8 milligrams), the same 
number of tablets adults with oncho took. Thirty-one (31) of them lived in Wii, Azua, Jagri 
Akua or Bitaaba. From this study, we know that 4 tablets is the right number of tablets for 
people at least 12 years of age. 
Because moxidectin works better against the oncho worms than ivermectin, it would be good if 
moxidectin could also be given to children aged 4 to 11 years. Therefore, we want to find the 
right number of moxidectin tablets for children aged 4 to 11 years.   


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How will we find out what number of moxidectin tablets is right for children aged 
4 to 11 years? 
When somebody takes moxidectin, it gets into their blood and from the blood, moxidectin can 
reach the young oncho worms in the body to kill them.  
The right number of tablets for children aged 4 to 11 years is the number that leads to the same 
amount of moxidectin in their blood as in the blood of adults and adolescents aged 12 to 17 
years who take 4 moxidectin tablets. Of course, the children should also not have severe 
unwanted effects.  
To find out the right number of tablets for children aged 4 to11 years, we need to give them 
moxidectin tablets, take a bit of blood and then measure the amount of moxidectin in their blood 
and find out what unwanted effects they have.  
We will start by giving 4 moxidectin tablets to 9 adolescents aged 12-17 years and 9 children 
aged 8 and 11 years. We will measure the amount of moxidectin in their blood and examine 
them for unwanted effects. If the children aged 8 to 11 years have more moxidectin in their 
blood or more unwanted effects than we saw in adults or adolescents aged 12-17 years who took 
moxidectin, we will give a smaller number of moxidectin tablets to another group of 9 children 
8 to 11 years of age and measure the amount of moxidectin in their blood and examine them for 
unwanted effects. 
When we have learnt the right number of moxidectin tablets for children aged 8 to 11 years, we 
will ask 9 children aged 4 to 7 years children to take part in the study.  
We will give them moxidectin tablets and measure the amount of moxidectin in their blood and 
examine them for unwanted effects. If they have less moxidectin in their blood than we saw in 
adults or adolescents aged 12 to 17 year or children 8 to 11 years of age, we will give more 
moxidectin tablets to a second group of 9 children aged 4 to 7 years. If the first group have too 
much moxidectin or too many unwanted effects, we will give fewer moxidectin tablets to a 
second group of children aged 4 to 7 years. 
We think that we will have to give moxidectin to at least 9 children aged 8 to 11 and at least 9 
children aged 4 to 7 years, but maybe up to 52 children aged 4 to 11 years.  
What will happen in the study, where will it happen and how long will it take?  
First, we will do Screening. Screening means that we fill find out whether your child or ward 
has the oncho worm but is otherwise healthy and can take part in the study.  
The first step of Screening will happen in your community:  
• We will ask if a sister or brother has already taken part in the study, because only one child 
or ward from your family can take part. 


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• We will ask questions about health problems in the past, medicines taken, look closely at the 
child’s arm to see if it will be easy to take blood, and show an item that is the same size as 
the moxidectin tablets and ask the child and you if they could swallow a tablet of that size. 
This will take 1 to 2 days. 
If we find your child can not take part in the study, we will tell you and the child why.  
If we find that your child can go on to the second step of 
Screening, we will drive the child and one of you by car 
to our study center in Hohoe. 
In Hohoe we have a special house for people taking part 
in our study and you will sleep there together with the 
child and other children and their parents or guardians 
who take part in our study. We will give you free meals 
while you are in Hohoe. 
 
In Hohoe:  
• We may ask you and the child to tell us more about the child’s health problems in the past 
and any medicines they have taken lately.  
• We will measure the child’s height and weight. 
• We will examine how fast the child breathes, how hard and fast the heart works and the 
body temperature (we call these measurements “vital signs”). 
• We will examine how well the heart works with a 
special machine called an electrocardiograph (an 
“ECG”). Here I am showing you the things we will put 
on your body for the ECG, like you see in this picture. 
This won’t hurt. 
• We will examine the child’s body for signs of illness or 
pain. Some of this you can see in the pictures here. 


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• Doctors can learn a lot about whether somebody is sick by testing 
the blood. We will take a bit of blood (no more than 
8.5 milliliters or about 2 teaspoons) like you can see in this photo. 
Before we take the blood, we will put a cream on the child’s arm 
so they won’t feel much pain. 
We will test the blood to find out how well some of the organs in 
the child’s body work and for signs of HIV (AIDS infection) or 
the germs that cause liver disease (hepatitis B and C).  
If the child has lived outside Ghana in an area where another 
worm called Loa loa occurs, we will test the blood to check whether the child has the Loa 
loa worm. We will do this because people with lots of Loa loa worms can have more 
unwanted effects when taking moxidectin and therefore they should not take part in our 
study. 
All of this will take 1 to 2 days.  
We will explain everything we learn about the child’s health. We will let you and the child 
know whether the child can take part in the study.  
What will happen after Screening if your child/ward cannot take part in the 
study? 
We will explain to you and the child why they cannot take part in the study. If the child needs to 
be taken care of by a nurse or doctor, we will arrange for the child to visit a clinic or hospital.  
On the day after Screening, we will drive you and the child back to your community. 
What will happen after Screening if your child/ward can take part in the study? 
We will ask you and the child to stay in Hohoe for 13 more days. 
In each group of 9 children we will first give moxidectin to only 3 children.  Once we know 
what unwanted effects these 3 children have during the first 3 days after they have swallowed 
the moxidectin tablets, we will give moxidectin tablets to the other children in that group. 
Your child will not be able to take ivermectin while they are on the study (for approximately 
6 months). 


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On the day after Screening (for the first 3 children) or 5 days later, we will: 
•
Repeat some of the examinations we did during Screening before we give moxidectin to the
child.
•
Ask the child to swallow moxidectin tablets 2 hours before the child has breakfast.
•
Repeat again some of the examinations we did during Screening.
•
Take a bit of their blood (1.5 milliliters or 1/3 of a teaspoon) 4 times to measure the amount
of moxidectin. We will use a special needle called a ‘cannula’ so the child only needs to
have one needle prick and we will use the special cream, so they won’t feel much pain.
•
Ask you and the child several times to tell us if the child is feeling unwell or has any pain. If
the child has pain or is feeling unwell, we will examine them to find out what we can do to
make them feel better. If necessary, we will give the child medicine.
•
We will also ask you and the child to tell us immediately if the child is not feeling well.
Even during the night, there will always be a nurse to talk to.
During the next 7 days, we will: 
•
Repeat some of the examinations we did during Screening.
•
Take a bit of blood (1.5 milliliters or 1/3 of a teaspoon) on 2 days to measure the amount of
moxidectin.
•
Take a bit more blood (3.5 milliliters total or 2/3 teaspoon) on the last day to measure the
amount of moxidectin and test how well some of the organs in the child’s body work.
If the child is feeling well, we will drive you both back to your community on the 7th day after 
the child has taken the moxidectin tablets. If not, we will ask you and the child to stay longer 
until the child feels well. 
2 weeks, 1 month, 3 months and around 6 months after the child has swallowed the 
moxidectin tablets, we will:  
•
Drive the child and one parent or guardian to Hohoe again.
•
Each time we will ask you and the child to tell us about any health problems the child has
had and any medicine they have taken since we last saw the child.
•
Each time we will repeat some of the examinations we did the last time your child or ward
was in Hohoe.
•
We will take a bit of the child’s blood (1.5 milliliters or 1/3 of a teaspoon) on 2 visits to
measure the amount of moxidectin.
•
We will take a bit more of your child’s or ward’s blood (3.5 milliliters or 2/3 teaspoon) on 1
visit to measure the amount of moxidectin in it and to find out how some of the organs in the
child’s body work.


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•
Each time, the accompanying parent or guardian and the child will spend one night with us
and we will give you free meals.
What happens when your child/ward is in Hohoe during school time? 
There will be a teacher in our study center in Hohoe. The teacher will help the children keep 
going with schoolwork, to help make up for the school time they miss. 
What should you do if your child/ward is not feeling well when you are back in 
your community? 
You should contact us, either through the community coordinator or directly, or you should take 
the child to the closest health clinic. The “community coordinator” is the person chosen by your 
community to contact us whenever you want. We have written down the name for you.  
We will make sure that the child is examined and receives medicine if they need it. If needed, 
we will drive the child or ward and one parent or guardian to the study center in Hohoe or a 
health clinic or hospital. 
Are there any potential advantages of taking part in this study? 
The child may not have any advantages. 
•
The child will have examinations of their health. These examinations are often used by
doctors and nurses to find out whether people are sick.
•
If the child has the young oncho worms in their skin, moxidectin will cause most or all of
the young worms to die and prevent new young worms in the skin for up to about one year.
•
If child has health problems because of the young oncho worms in the skin or eyes, these
will become better or even go away for up to about 1 year.
Are there any possible risks of taking part in this study? 
Unwanted effects of taking moxidectin  
Almost all medicines cause unwanted effects. 
We have already told you about the unwanted effects we found in people with the oncho worm 
who took moxidectin or ivermectin. In most cases, these unwanted effects were mild, went away 
on their own and lasted less than a week. Please let me know if you would like us to look at the 
pictures again. 
Your child may have none, some or all of these unwanted effects. They may be mild, moderate 
or severe. They may occur soon after the child has taken moxidectin or many hours or days 
later.  
Also, because moxidectin is a new medicine, there may be unwanted effects that we don’t know 
about yet and we don’t know whether they would be mild, moderate or severe or how long they 


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may last.  If we learn about new unwanted effects that may make you change your mind about 
your child or ward taking part in this study, we will tell you and the child immediately.   
Unwanted effects of taking blood 
Having blood taken may cause some pain, bruising, and a little bit of bleeding. Sometimes, it 
can also cause minor infection (where germs can get into the needle prick) or fainting. This has 
never happened in our studies because we get the children to lie down and clean the skin to 
remove any germs before we take blood. If your child or ward has any unwanted effects, they 
can easily be treated.  
What happens to the blood we take? 
We will send the blood for measuring the amount of moxidectin to people in another country 
(the United States of America) to make the measurements. We will do the other tests in our 
country.  
We will not write the child’s name on the blood samples only a number. We call this number the 
child’s ‘participant number’. Only we know which number belongs to which child who takes 
part in our study. 
We will only use the blood for measuring the amount of moxidectin and for the tests we have 
told you about. Once these measurements and tests are done, any blood left over will be 
destroyed.  
Who will know what we found out about the child’s health during the study? 
We will keep the information we collect about your child’s or ward’s health in what we call 
“records”. We will keep these records private (confidential). This means that we will not share 
the child’s name with anybody who does not belong to our study team without your permission, 
except when we must because it is the law.  
We will keep all the records in a locked, secure area for at least 25 years and possibly longer. 
When we don’t need them anymore, they will be destroyed. 
The people who can see the records, including the child’s name, are: 
•
The doctors, nurses and laboratory staff working in our study team.
•
People coming to our study center in Hohoe to make sure that we do things right and follow
the law. These are
o
People from the Ghana Food and Drugs Authority, and the United States Food and
Drug Administration
o
People from the ‘Sponsor’. The Sponsor is Medicines Development for Global
Health, who make moxidectin tablets. They are giving us the money and the
moxidectin tablets for the study and helping us write reports about what we learn.


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o People from the “Ethics Committees”. These are people that have been asked by 
University of Health and Allied Sciences in Hohoe, the Ghana Health Service or the 
World Health Organization to make sure we do this study in the right way.  
The people who can see the records but NOT the child’s name or the names of the child’s 
parents or guardians are: 
• People from the Sponsor and working with us and the Sponsor. The Sponsor will keep the 
records without the child’s name for at least 25 years. 
• People from the Ghana Food and Drugs Authority, the United States Food and Drug 
Administration, or the authorities in other countries or at the World Health Organization 
who look at study results to decide whether moxidectin can be used in Ghana and other 
countries. 
• Other people who want to learn about what happens when children 4 to 17 years of age take 
moxidectin.  
If you change your mind about allowing your child or ward to take part in the study or the child 
doesn’t want to take part anymore, we will stop collecting information. We and the Sponsor will 
still use the information that we collected before you told us you wanted your child or ward to 
stop taking part in the study (or your child or ward told us they want to stop taking part in the 
study). However, if your child/ward has an unwanted effect that has not stopped, we will ask 
you to let us visit you and your child/ward to find out whether they need any treatment for this 
effect. You and your child/ward do not have to agree to this. 
Will you have to pay anything to take part in this study? 
You will not pay anything.  
• All examinations and medical care that are part of the study will not cost anything. 
• When you and the child stay overnight in Hohoe, you will not pay anything. We will give 
you free food and transportation by car to and from your home.  
Will the parent/guardian coming to Hohoe with the child be compensated for the 
time spent in Hohoe? 
The parent or guardian who goes with the child to Hohoe will be compensated, that means get 
money to make up for loss of earnings. The amount will be based on the number of nights spent 
in Hohoe for the study. The amount for each night’s stay will be roughly the “by day” earnings 
of adults in your community, currently forty (40.00) Ghana Cedis per day. 


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Protocol Number: MDGH-MOX-1006 
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What happens if the child has a permanent injury or health problem because of 
taking part in this study? 
We do not think that anybody will have an injury from the study that will make them 
permanently sick or die.  However, should this happen, the Sponsor’s insurance will pay you or 
the child compensation.   
What Happens After the Study? 
After the study, the child should take ivermectin when it is distributed in your community. 
We will tell you, the child and your community about what we learnt. This will happen after the 
last children finish the study. We will also tell you what we and the Sponsor plan to do so that 
the Ghana Health Service and the health services in other countries where people have oncho 
can decide whether they want to give out moxidectin in the way they are now giving out 
ivermectin.  
Who can you talk to if you want more information before you agree to let your 
child/ward take part in the study or during the study? 
If you want to talk to someone who is not in our study team about any worries about the study, 
your rights, an injury the child may have suffered in the study, or any other questions, concerns 
or complaints about the study in the future, please contact: 
•
The Administrator of the Research Ethics Committee, Institute of Health Research, 
University of Health and Allied Sciences by email at 
 or by telephone on
.
•
The Secretary to the Research Ethics Committee, Institute of Health Research, 
University of Health and Allied Sciences, Mr. Fidelis Anumu, by telephone on +
.  If you or your child have any questions, concerns or complaints about the 
study in the future, you may also contact the Project Administrator later.
•
The Administrative Secretary of the Ghana Health Service Ethics Review Committee,  
Ms Nana Abena Apatu,  by telephone on 
 or by writing to The 
Administrative Secretary, Ghana Health Service Ethics Review Committee, Research and 
Development Division, Ghana Health Service, P. O. Box M190 Accra Ghana.
If you have any questions about the study or need medical help during the study, please contact 
the following members of the study team or your community coordinator:  
1. Dr. Nicholas O. Opoku (On-site Principal Investigator)
University of Health and Allied Sciences
School of Public Health Research Centre
Municipal Hospital Hohoe,
Telephone: 
 or 
 (mobile)


Sponsor: Medicines Development for Global Health 
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2. Dr. Felix Doe (Co-investigator) 
Hohoe Municipal Health Directorate  
Telephone: 
 or 
 (mobile) 
3. Your Community Coordinator 
Name: 
 
Telephone: 
 
What if you do not want the child to take part in the study or the child does not 
want to take part in the study, or if you change your mind about taking part in the 
study? 
It is your and your child’s or ward’s decision to take part in this study.  
You or the child can tell us that the child will stop taking part in the study at any time. You do 
not have to tell us why you want to stop.  
Not taking part in the study or changing your mind will not change the health care you and your 
family will receive from the Ghana Health Service.  
When you tell us that you want the child to stop taking part in the study, or the child wants to 
stop, we will ask you to let us do final examinations so that we know about the child’s health 
and can tell you what you should look out for after the child leaves the study.  
If new information becomes available, we will tell you and your child or ward about it and 
discuss with you whether you and your child or ward want to continue in the study.  
We may decide that the child cannot continue in the study. We will do this if we see that the 
child is not ready to come to Hohoe or if you or the child do not want us to do the examinations 
or take the blood samples we told you about, or if we find that it is better for the child’s health. 
If this happens, we will explain the reasons to you and the child. 
What do you need to do to let us know that you allow your child/ward to take part 
in the study and your child or ward also wants to take part? 
You should discuss this with your child or ward and other people in your community. 
For children 8 to 11 years of age, we have a special document describing the study which we 
will discuss with them while you and a witness your community has chosen are present. If you 
and the child agree, we will ask you some questions about the study so we can find out what we 
need to explain better.  Then we will ask you, the witness and your child or ward to sign or 
thumbprint a form. 


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If your child or ward is 4 to 7 years of age, we will discuss the study with them using a simpler 
description of what will happen in the study. We will also do this if the child is older but you 
and we think they are not mature enough to understand the information in the document for the 
children aged 7 to 11 years. You and a witness your community has chosen will be present. We 
will look for signs that the child does not want to take part in the study. Because you know the 
child better than us, we will also ask you if you think the child is showing signs that they do not 
want to take part in the study. If your child or ward does not show such signs, we will ask you 
some questions about the study so we can find out what we need to explain better. Then we will 
ask you and the witness to sign or thumbprint a form.  
Help for your discussion with your child/ward, friends, family and others you 
want to talk this over with 
To help you in your discussions of the study with others, here is an overview of what will 
happen and where it will happen. 
You and your child discuss whether the child wants to 
take part in the study and you all agree  
 
If you do not agree you 
don’t need to do anything 
 
 
If you agree, you let us know. We will check whether we need to tell you more about the study. We 
will ask you and your child (if they are old enough) to sign or thumbprint a form.  
 
 
Step 1 Screening in 
your community to 
ask questions about 
the health of your 
child (1-2 days) 
 
If your child cannot take part in Step 2 
Screening, we will tell you why and tell you if 
your child should see a nurse or doctor 
 
 
If your child can take part in Step 2 
Screening, your child and one of their 
parents/guardians will go to Hohoe 


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You will stay in our 
special house with 
other children who 
take part in the study 
and their parents or 
guardians 
 
We will ask more 
questions, do 
examinations and 
take bits of blood to 
learn more about 
your child’s health 
and find out whether 
your child can take 
part in the study (1-2 
days) 
 
 
 
 
 
If your child can take part in the study and you 
still agree, you need to stay in Hohoe for 13 
more days. 
If your child cannot take part in the study, we will tell 
you why and take you home. If your child has a 
health problem, we will arrange a visit to a clinic or 
hospital near your community. 
The next day or 5 days later, we will ask your child to swallow the moxidectin tablets.  
On that day and the next 7 days we will take more bits of blood and repeat some of the examinations 
we did during Screening. 
Then we will take you back to your community, unless your child is not well and you stay until your 
child is well.  


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2 weeks, 1 month, 
3 months and around 
6 months after your 
child swallowed the 
moxidectin tablets 
we will bring your 
child and one parent 
or guardian back to 
Hohoe. 
Each time we will repeat some of the examinations we did when your child was in Hohoe last time 
and on 3 visits we will take a bit of your child’s blood.  
 
Assessment of Informed Consent – Questions for Parents/ 
Guardians of Children 4 to 11 Years 
Parent/Guardian 
Response 
Do you understand why your child/ward is being asked to participate in this 
study? 
☐ Yes        ☐ No 
Have you been able to ask questions and discuss the study? 
☐ Yes        ☐ No 
Questions: 
 
 
 
 
 
 
 
 
 
Do you understand that during Screening we might find that your child/ward 
cannot take part in the study? 
☐ Yes        ☐ No 
Do you understand that it is your decision to allow your child/ward to take part 
in this study and that your child/ward must also agree (7 to 11 years) or not 
show that they don’t want to take part (4 to 6 years) (that means your child is a 
“volunteer”)? 
☐ Yes        ☐ No 
Are you willing to allow your child/ward to have all the examinations? 
☐ Yes        ☐ No 
Will we take blood from your child/ward during this study? 
☐ Yes        ☐ No 
How long will your child/ward be in this study? 
 
Do you understand your child/ward can stop taking part in the study at any 
time, without having to tell us why? 
☐ Yes        ☐ No 
Is there any charge for being in the study? 
☐ Yes        ☐ No 
Do you understand that this is a study and that we do not know all unwanted 
effects of moxidectin? 
☐ Yes        ☐ No 
Do you know who to call if you or your child/ward has questions? 
☐ Yes        ☐ No 


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Assessment of Informed Consent – Questions for Parents/ 
Guardians of Children 4 to 11 Years 
Parent/Guardian 
Response 
Do you know that we will share what we learn about the health of your 
child/ward with many different people but only those coming to Hohoe to check 
we do things right can learn the child’s name? 
☐ Yes        ☐ No 
Are you willing to come to Hohoe five times and so that your child/ward can 
have the examinations and blood taken that we told you about? 
☐ Yes        ☐ No 
 
 
 
 


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Agreement to Study Participation – Parents/Guardians and Children 7 to 11 Years 
Mature Enough to Provide Assent (Check if Not Applicable  ☐) 
CHILD PARTICIPATION AGREEMENT 
I have read or have had someone read all of the above, asked questions, received answers regarding 
participation in this study, and I agree that my child/ward should participate in this study as a volunteer. I 
will not have waived any of my rights by signing this parental consent form. Upon signing this form, I 
will receive a copy for my personal records. 
 
Signature/ 
Thumbprint 
of Parent/ 
Guardian/ 
LAR 
 
  
Name of Child 
 
 
 
 
 
  
Name of Parent/Guardian/LAR  
 
 
Date 
 
 
 
 
 
 
Signature/ 
Thumbprint 
of Parent/ 
Guardian/ 
LAR  
 
  
Name of Parent/Guardian/LAR  
 
 
Date 
VOLUNTARY AGREEMENT (CHILDREN 7 to 11 YEARS PROVIDING ASSENT) 
By signing or thumbprinting below, it means that you: 
• 
have understood what you will be doing for this study, 
• 
have had all your questions answered, 
• 
have talked to your parent(s)/legal guardian about this project, and 
• 
agree to take part in this research 
If you do not want to participate in this study, please do not sign or thumbprint this assent form. You and 
your parents/guardians will be given a copy of this form after you have signed/thumbprinted it. 
 
Signature/ 
Thumbprint 
of 
Adolescent 
 
 
 
Name of Adolescent  
 
 
Date 
IMPARTIAL WITNESS SIGNATURE 
I was present while the benefits, risks and procedures were read to the volunteer and their 
parents/guardians. All questions were answered, and the child and their parents/guardians have agreed 
the child will take part in the study.  
 
 
 
 
 
Name of Witness  
 
Signature of Witness  
 
Date 
SIGNATURE OF PERSON WHO OBTAINED CONSENT 
I certify that the reason the study is being done, what will happen in the study, and the potential 
advantages and possible risks associated with taking part in this research have been explained to the 
above-named child and their parent(s)/guardian(s).  
 
 
 
  
Name of Person who Obtained Consent 
 
Signature of Person who Obtained Consent 
 
Date 


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Protocol Number: MDGH-MOX-1006 
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Agreement to Study Participation – Parents/Guardians and Children 4 to 6 Years 
or Too Immature for Assent (Check if Not Applicable  ☐) 
CHILD PARTICIPATION AGREEMENT 
I have read or have had someone read all of the above, asked questions, received answers regarding 
participation in this study, and I agree that my child/ward should participate in this study as a volunteer. I 
will not have waived any of my rights by signing this parental consent form. Upon signing this form, I 
will receive a copy for my personal records. 
 
Signature/ 
Thumbprint 
of Parent/ 
Guardian/ 
LAR 
 
  
Name of Child 
 
 
 
 
 
  
Name of Parent/Guardian/LAR  
 
 
Date 
 
 
 
 
 
 
Signature/ 
Thumbprint 
of Parent/ 
Guardian/ 
LAR  
 
  
Name of Parent/Guardian/LAR  
 
 
Date 
ASSESSMENT OF ‘DELIBERATE OBJECTION’ 
In the judgement of the parents/guardians and person who obtained their consent, did 
the child express ‘deliberate objection’? If yes, child cannot take part in study. 
☐  Yes 
☐  No 
 
 
 
 
Signature/ 
Thumbprint 
of Parent/ 
Guardian/ 
LAR  
 
 
 
Name of Parent/Guardian/LAR 
 
 
Date 
 
Signature/ 
Thumbprint 
of Parent/ 
Guardian/ 
LAR 
 
 
 
Name of Parent/Guardian/LAR  
 
 
Date 
IMPARTIAL WITNESS SIGNATURE 
I was present while the benefits, risks and procedures were read to the volunteer and their 
parents/guardians. All questions were answered, and the child and their parents/guardians have agreed 
the child will take part in the study.  
 
 
 
 
 
Name of Witness  
 
Signature of Witness  
 
Date 
SIGNATURE OF PERSON WHO OBTAINED CONSENT 
I certify that the reason the study is being done, what will happen in the study, and the potential 
advantages and possible risks associated with taking part in this research have been explained to the 
above-named child and their parent(s)/guardian(s).  
 
 
 
 
 
Name of Person who Obtained Consent 
 
Signature of Person who Obtained Consent 
 
Date 
 


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16.8 Model Information Sheet for Children 7 to 11 Years 
Title of Study: 
An open-label study of the pharmacokinetics and safety of a single dose 
of moxidectin per oral in participants aged 4 to 17 years with (or at high 
risk of) onchocerciasis to identify an optimal dose for treatment of 
children 4 to 11 years. 
Principal Investigator: 
Dr Nicholas Obuobisa Opoku 
Organization: 
University of Health and Allied Sciences (UHAS) 
Sponsor: 
Medicines Development for Global Health 
Protocol Number(s): 
MDGH-MOX-1006 
UHAS-REC A.7 [6] 18-19 
GHS-ERC 015/06/19 
Protocol / Information 
Document Version/Date: 
Final v1.3 (incorporating Amendments 1, 2 and 3) / 27 Nov 2019 
Introduction 
My name is ……………………………………………...…. and I am a doctor working at the 
University of Health and Allied Sciences in Hohoe. I am testing a new medicine called 
moxidectin in children 4 to 17 years of age. Moxidectin is a new medicine for an illness that you 
call “oncho”.  
Because of your age, I want to ask you whether you want to take part in this testing. Testing of a 
new medicine is called doing “research” or a “study” and means that we want to learn more 
about the new medicine. 
Do you have to take part in the study?  
Don’t worry, you and your parents or guardian will decide together whether or not you take part 
in this study. If you don’t want to take part, you don’t have to, even if your parents or guardian 
say that you can. You don’t have to tell us why you don’t want to take part. If you first decide to 
take part but then change your mind, you just have to tell us. You don’t have to tell us why you 
changed your mind. Nobody will get angry with you.  
I will tell you and your parents or guardian now why we want to do this study and what will 
happen in the study. If I say anything that you don’t understand or you have a question, please 
interrupt me and ask me. You can ask me questions again and again until I have explained in a 
way that you understand. 
Afterwards, you and your parents or guardian and friends can talk about it. Then you and your 
parents or guardian can let me know whether you want to take part in the study or not. 


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What is oncho and what is being done now to help people with oncho? 
Oncho is caused by a worm that is passed from one person to another through the bites of the 
small black flies that you see at the riverside and in your community in the mornings and early 
evenings. The very small young oncho worms in the skin and eyes can make people feel itchy, 
give them a rash or make them sick in other ways. 
These photos show the skin 
of people who have a rash 
because of oncho worms.  
Many adults and children in 
your community may have 
oncho. Therefore, a 
medicine called ivermectin 
is given two times a year to 
all people in your 
community who are at least 5 years of age. Ivermectin kills most of the young oncho worms.  
What does moxidectin do? 
We have already tested moxidectin in adults and children who were at least 12 years of age.  
Many of these adults and children were living in your community or in communities nearby.  If 
you or your parents know some of these people, you can ask them about it.   
We found out that when people at least 12 years of age take 4 tablets of moxidectin, the young 
oncho worms in the skin and eyes go away better and for longer than when people take 
ivermectin.   
All medicines have what we call ‘unwanted effects’. For example, some people who take 
ivermectin may feel more itchy in the first few days after they have taken ivermectin than before 
they took ivermectin.  But afterwards, their itching or itchy rash goes away. We found that when 
people at least 12 years of age took 4 tablets of moxidectin, some had unwanted effects just like 
some people have after taking ivermectin.  
Why do we want to test moxidectin in children your age? 
We want to do this testing to find out the right number of moxidectin tablets for children your 
age. 
How will we find out the right number of moxidectin tablets for children your 
age? 
When somebody takes moxidectin, the moxidectin gets into their blood and from the blood, it 
kills the young oncho worms in the body. To find the right number of moxidectin tablets for 


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children your age, we need to find out how much moxidectin is in their blood after they swallow 
moxidectin tablets.   
Also, by testing your blood, doctors can tell whether you are sick or getting sick. 
To find out how much moxidectin is in your blood and whether you 
are sick or getting sick, we need to take blood from your arm with a 
needle. Before we put the needle in your arm, we will put a cream 
on your arm so that it goes numb and you won’t feel much pain. 
Here I am showing you the needle and tube I will use and a picture 
of how I will use them.  
[Note: The Investigator will show the syringe and needle] 
To find out whether you have any unwanted effects after taking 
moxidectin, we will also need to do checks before and after you 
take moxidectin.  None of these checks will hurt. Here are some 
pictures of these checks.  
 
 
Where and when will 
this happen? 
If you and your parents or guardian agree that you can 
take part, we will first need to learn about your health. 
Here in your community, we will ask your parents or 
guardians about your health. If we learn something about your 
health that makes us think it is better for you not to take part, we 
will tell you that you cannot take part in the study.  
If you are healthy and if you still want to take part, we will take 
you by car with one of your parents or guardians our place in 
Hohoe.  
Your parent and you will sleep in a special house together with the other children and parents 
that have come. Here are some pictures.  


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We will take care of your food.  
We will do examinations to learn about your health. Your parent or guardian will be with you. 
We will: 
• Weigh you and measure how tall you are.  
• Examine your body.  
• Measure how hard and fast your heart works and examine how your heart works with a 
special machine called an “ECG” machine. 
• Measure how fast you breathe. 
• Find out whether you have a fever.  
• Take bits of your blood from your arm with a needle, after we have put a special cream on 
your arm so you don’t feel the needle prick much.   
If we find you have a health problem, you cannot take part in the study and we will drive you 
and your parent or guardian back home. We will tell you and your parent or guardian about the 
health problem so you can see a doctor or nurse close to your community if you need to do this 
to get better. 
If you can take part in the study, you and your parent will need to stay in Hohoe for between 8 
and 13 more days.  
We will ask you to swallow up to 4 moxidectin tablets with water.  
During the next days, we will take bits of your blood 7 times and we will do the health checks 
we did before you swallowed the moxidectin tablets. Every day, we will ask you how you are 
feeling. You and your parent or guardian should also tell us if you don’t feel well. We will 
always be there to talk to you whenever you want to, even at night.  
After these 7 days, we will drive you and your parent or guardian home. 
There will be 4 more trips from your community to Hohoe for you and your parent or guardian 
around 2 weeks, 1 month, 3 months and 6 months after you took the moxidectin tablets. Each 
time, we will do the examinations again and 3 times we will also take bits of your blood. You 
will stay at least one night each time before we take you home again. 


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Will you miss school? 
You may miss school while you are in Hohoe. We have made sure that there will be a teacher to 
help you keep going with your schoolwork while you stay in Hohoe. 
Will taking blood and swallowing moxidectin make you sick?  
We don’t think you will get sick during this study. You won’t feel much pain when we take bits 
of your blood, but you might have some pain or get a bruise afterwards.  
You might have unwanted effects, that means feel a bit unwell for a few days after you swallow 
the moxidectin tablets but if this happens, we are there to look after you. 
Who will we tell that you took part in the study and what we found out about your 
health? 
We will keep your name and everything we find out about your health private. This means that I 
will make sure that only the people working with me in Hohoe and people coming to Hohoe to 
check that we are doing the study the right way can know your name.  
We will tell the people who make the moxidectin tablets what we found out about your health, 
but we will not tell them your name. We will do this so that they can help us find the right 
number of moxidectin tablets for children your age and then tell the people in our country, and 
people in other countries who want to learn about moxidectin, what we found in our study. 
None of these people will know you name.  
What can you do if you want to know more before you and your 
parents/guardians decide whether you can take part in this study? 
You can ask me more questions now. In case you want to talk to me or other people who know 
about this study later, your parents know how to talk to me and others. 
How should you tell us that you and your parents/guardians have decided that 
you can take part in this study? 
I will come back to ask you what you and your parents have decided.  
If you don’t want to take part in the study, you do not need to do anything.  
If you have decided that you want to take part in this study and your parents agree, I will ask 
you to sign or thumbprint a form. Your parent or guardian and another person chosen by your 
community will be with you.  Before you do this, I will ask you some questions to see whether I 
need to explain more to you.  


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Assessment of Informed Assent – Questions for Children 7-11 
Years 
Child Response 
Do you understand why you are being asked to participate in this study? 
☐ Yes        ☐ No 
Have you been able to ask questions and discuss the study? 
☐ Yes        ☐ No 
Questions: 
 
 
 
 
 
 
 
 
 
Do you understand that during Screening we might find that you cannot take 
part in the study? 
☐ Yes        ☐ No 
Do you understand that you can only take part if both you and your 
parents/guardians agree? 
☐ Yes        ☐ No 
Will we take blood during this study? 
☐ Yes        ☐ No 
How long will you be in the study? 
 
Do you understand you can tell us at any time that you want to stop being in 
the study, without having to tell us why? 
☐ Yes        ☐ No 
Is there any charge for being in the study? 
☐ Yes        ☐ No 
Do you understand that this is a study and that we do not know all unwanted 
effects of moxidectin? 
☐ Yes        ☐ No 
Do you know that we will share what we learn about your health with many 
different people but only those coming to Hohoe to check we do things right 
can learn your name? 
☐ Yes        ☐ No 
Are you willing to come to Hohoe five times and have the examinations and 
blood taken that we told you about? 
☐ Yes        ☐ No 
 
 


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16.9 Model Information Sheet for Children 4 to 6 Years and Older Children 
Considered Not Mature Enough to Provide Assent 
Title of Study: 
An open-label study of the pharmacokinetics and safety of a single dose 
of moxidectin per oral in participants aged 4 to 17 years with (or at high 
risk of) onchocerciasis to identify an optimal dose for treatment of 
children 4 to 11 years. 
Principal Investigator: 
Dr Nicholas Obuobisa Opoku 
Organization: 
University of Health and Allied Sciences (UHAS) 
Sponsor: 
Medicines Development for Global Health 
Protocol Number(s): 
MDGH-MOX-1006 
UHAS-REC A.7 [6] 18-19 
GHS-ERC 015/06/19 
Protocol / Information 
Document Version/Date: 
Final v1.3 (incorporating Amendments 1, 2 and 3) / 27 Nov 2019 
Introduction 
My name is ……………………………………………………….. and I am a doctor in Hohoe. I 
want to find out how many tablets of a new medicine for the illness that you call “oncho” 
children should take.  
What is oncho? 
Oncho is an illness caused 
by worms so small that you 
cannot see them with your 
eyes. The oncho worms can 
make people itchy, have a 
rash or make them feel sick. 
These photos show the skin 
of people who have a rash 
because of oncho worms.  
To help people who have the oncho worm, a medicine called ivermectin is given to all children 
who are 5 years and older and all adults. Have you ever swallowed ivermectin?  
What is the new medicine? 
The new medicine is called moxidectin (we will call it “moxi” for short). When we gave moxi 
to children older than you and to adults, we found that it fights the oncho worms better than 
ivermectin.   


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I want to find out how many moxi tablets children the same age as you should take. To do this, I 
am asking you and other children your age to come with one of your parents to Hohoe. 
How big are the tablets? 
I am showing you here how big a moxi tablet is. The size is about the same as the size of 
ivermectin tablets. Do you think you can swallow a tablet like this?  
[Note – The investigator will show a tablet of similar shape and size to moxidectin tablets. 
If the child or their parents/guardians do not think the child can swallow the tablet, the 
information session ends here with a thank you to the child and parents] 
When people swallow moxi tablets, moxi gets into their blood and from the blood, moxi kills 
the oncho worms in the body. Do you know what blood is?  
[Note – If not, the investigator will explain what blood is]. 
To know how many tablets children your age should take, I need to find out how much moxi is 
in your blood. I will get bits of your blood by putting a needle in your arm.  
Please let me examine your arms to see whether it will be easy to take a bit of your blood. This 
won’t hurt. 
[Note – If the examination of the arms shows poor venous access, the information session 
ends here with a thank you to the child and parents] 
I will put a special cream on your arm so that you don’t feel much 
pain. I am showing you here the needle and the tube I will use to 
get bits of your blood and a picture of how I will use them. 
[Note: The Investigator will show the syringe and needle] 
Do you have to come to Hohoe? 
Don’t worry, you and your parents or guardians will together 
decide whether you do this. Nobody will get angry with you if you 
don’t want to do this.  
I will now tell you what will happen in Hohoe. 
If I say anything that you don’t understand or you have a question, please interrupt me and ask 
me. I will explain and if you don’t understand what I say, ask me again and again until I have 
explained in a way that is right for you. 
Afterwards, you and your parents or guardians can talk about it.  


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What if you first think you want to come to Hohoe but later you change your 
mind? 
Don’t worry, you just have to tell me or your parents or guardians. Nobody will get angry with 
you.  
What will happen if you want to come to Hohoe? 
We will ask your parents to tell us about your health. 
If your parents tell us that you have health problems, you will not go to Hohoe since it will be 
better for you not to do that. 
What will happen if you can go to Hohoe? 
If you do not have health problems, you and one of your parents 
will ride in a car together with other children and one of their 
parents to Hohoe.  
In Hohoe, you will all stay in our place. You and your parent will 
sleep in the same room together with the other children and parents who have come. We will 
give you food.  
 
Before we give you tablets to swallow, we will do some checks to find out more about your 
health. Here are pictures of some of the checks and here are the things that I will put on your 
body, like in the picture. None of these checks will hurt.  
 
If the checks find you are not healthy, it will be better for you not to swallow the tablets and we 
will drive you and your parent back to your community in the car. 
If you are healthy, we will ask you to swallow the tablets with a lot of water.  


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After you have swallowed the tablets, you and your parent will stay with us in Hohoe for 7 more 
days. We will do checks and take bits of your blood like we did before you swallowed the 
tablets.   
Afterwards we will bring you and your parent and the other children and their parents back to 
your community by car. 
We will ask you and your parent to come back to us at Hohoe four more times so we can do 
more checks and take bits of your blood like we did before you swallowed the tablets.  
Will you miss school? 
You may miss school while you are in Hohoe.  Therefore, we have made sure that there will be 
a teacher to help you keep going with your schoolwork while you are in Hohoe.  
Will the checks and taking bits of your blood and swallowing the tablets make 
you sick? 
We don’t think you will get sick. You won’t feel much pain when we take bits of your blood, 
but you might have some pain afterwards. You might feel a bit unwell for a few days after you 
swallow the tablets but if this happens, we are there to look after you. 
 


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16.10 Summary of Protocol Amendments 
16.10.1 
Rationale for Protocol Amendment No. 1 
This is a single center study to be conducted at the Department of Public Health, University of Health and Allied Sciences (UHAS) Research 
Centre, Hohoe Municipal Hospital, Volta Region, Ghana. The UHAS Research Ethics Committee in its feedback on review of the study (dated 
8 Mar 2019) requested site specific changes and clarifications to the protocol which have resulted in the requirement for this amendment. 
The following sections of the protocol have been amended and details are provided in Table 9 and Table 10. 
Table 9: Details of Administrative Protocol Amendments (Amendment 1) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Throughout document 
Not applicable 
Correction of minor typographical errors, 
including addressing removal of the full term 
and either the acronym remains or, where 
necessary, the acronym is added to replace 
the term upon second or subsequent use in 
the document (Section headings and tables 
are the exception). Headings changed to title 
case.  
Correction of grammar, spelling errors or 
abbreviation use to improve readability and 
consistency within the document  
 
Single line spacing  
1.5 line spacing 
Consistency with Ghana Health Service 
ethics committee format 
Cover page and footers 
Version 1.0 
25 January 2019 
Version 1.1 (incorporating Amendment 1)  
01 April 2019 
Version number updated to indicate protocol 
amendment 
Footers 
Page X of 66 
Page X 
Revised for publication to US FDA 
Investigational New Drug application 
Footers  
Page numbering restarted at Table of 
Contents 
Pages numbered consecutively through 
document 
Revised for publication to US FDA 
Investigational New Drug application 
Page 15 
Not applicable 
List of Figures 
List of Tables 
Added for consistency with Ghana Health 
Service ethics committee format 
Section and sub-section 
headings 
Not applicable 
Some Section and subsection headings 
expanded 
Addition of information to link original 
protocol headings with UHAS Research 
Ethics Committee defined protocol headings 
to assist locating information within protocol 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Abbreviations 
Not applicable 
LAR – legally authorized representative 
Addition of a term used in the model consent 
form appended to the protocol as per UHAS 
Research Ethics Committee request 
Abbreviations 
IP – Investigational Product 
Not applicable 
Removal of abbreviation to ensure clarity in 
document 
Abbreviations and 
Section 3.3.1.2.3 
No Observed Adverse Event Level (NOAEL) 
No Observed Adverse Effect Level (NOAEL) 
Correction of term 
Synopsis – Inclusion criteria 
Live in a region designated by the World 
Health Organization (WHO) as endemic for 
O. volvulus infection.   
Live in a region designated by the World 
Health Organization (WHO) as endemic for 
O. volvulus infection (World Health 
Organization, 2017). 
Addition of the reference for WHO 
designation of endemicity  
Appendix 16.5 
Not applicable 
Inclusion of Amendment 1 
Provision of changes from version 1.0.  
 
Table 10: Details of Non-Administrative Protocol Amendments (Amendment 1) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Title: Pages 1, 2 and 4 
An open-label study of the pharmacokinetics 
and safety of a single dose of moxidectin per 
oral in subjects aged 4 to 17 years with (or at 
risk of) onchocerciasis 
An open-label study of the pharmacokinetics 
and safety of a single dose of moxidectin per 
oral in subjects aged 4 to 17 years with (or at 
risk of) onchocerciasis to identify an optimal 
dose for treatment of children 4 to 11 years 
As requested by the research ethics 
committee, the objective of the study was 
added to the title 
Synopsis: Background  
Section 3.4.3 paragraph 5 
….or has ever been exposed to O. volvulus 
infection. 
…or has ever been exposed to O. volvulus 
infection, and to exclude those with no 
evidence of prior systemic exposure to that 
infection. This is to balance risks in study 
participation with potential individual benefit 
from treatment. Pharmacokinetic results are 
not anticipated to be affected by infection 
status. Potential adverse events (AEs) 
associated with effective treatment of 
onchocerciasis are expected to be 
manageable and transient. 
To provide further explanation regarding the 
rationale for inclusion of participants with 
current or risk of infection (based on 
evidence of prior systemic exposure to the 
infection) 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Synopsis: Number of centers,  
One 
One – School of Public Health, University of 
Health and Allied Sciences (UHAS) 
Research Centre, formerly the 
Onchocerciasis Chemotherapy Research 
Centre (OCRC) research facility, Volta 
Region, Ghana 
UHAS Research Ethics Committee 
requested addition of site details 
Inclusion criteria  
(page 5 and Section 6.2) 
Live in a region designated by the World 
Health Organization (WHO) as endemic for 
O. volvulus infection 
Live in a region designated by the World 
Health Organization (WHO) as endemic for 
O. volvulus infection (World Health 
Organization 2017). Specifically, participants 
will be recruited from the Kpassa subdistrict 
of the Nkwanta North district. The specific 
communities will include Wii, Jagri-Do and 
Azua, where mass drug administration with 
ivermectin for onchocerciasis commenced in 
October 2017. 
UHAS Research Ethics Committee 
requested inclusion of specific information 
about the region from which participants will 
be drawn 
Exclusion criteria  
(page 6 and Section 6.3) 
Not applicable 
17. Is a sibling of another child already 
enrolled in this study 
Addition of an exclusion criterion to ensure 
no more than one child from a family is 
enrolled in the study as per UHAS Research 
Ethics Committee request 
Section 5.4 Study Sites 
This will be a single center study. 
This will be a single center study. The study 
will be conducted at the School of Public 
Health, University of Health and Allied 
Sciences (UHAS) Research Centre, formerly 
the Onchocerciasis Chemotherapy Research 
Centre (OCRC) research facility, Volta 
Region, Ghana 
Additional details at the request of the 
Research Ethics Committee 
Section 5.5, paragraph 2 
It is anticipated that the total duration of the 
study will be up to 12 months, including 
6 months for recruitment in the event that 
more than one cohort per age is required   
It is anticipated that the total duration of the 
study will be up to 15 months, including 
6 months for recruitment in the event that 
more than one cohort per age is required and 
for data analysis and reporting. 
For consistency with Section 14.6 and 
clarification of what study ‘duration’ includes 
Section 12.2 
Criteria for Premature 
Withdrawal from Treatment or 
the Study 
Subjects have the right to withdraw from the 
study at any time for any reason. 
Participation in this study is voluntary. Please 
see Section 14.1.2 for further details on 
voluntary participation and informed consent. 
Subjects also have the right to withdraw from 
the study at any time for any reason. 
UHAS Research Ethics Committee 
requested inclusion of information about 
voluntary participation as well as voluntary 
withdrawal in this section 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 14.1.1  
Local regulations / 
Declaration of Helsinki, 2nd 
paragraph 
…and those of applicable regulatory 
agencies.  
…and those of applicable regulatory 
agencies, including the Ghana Food and 
Drugs Authority and the US FDA. 
Specificity added at the request of the 
Research Ethics Committee 
Section 14.1.2 Informed 
Consent, 1st paragraph 
Information about the study and the written 
informed consent document must be 
presented in the language(s) of the potential 
subject population. 
Information about the study and the written 
informed consent document should be 
presented in the language(s) of the potential 
subject population. 
Removal of the word “must” as per UHAS 
Research Ethics Committee feedback 
1st paragraph 
Not applicable 
The IECs responsible for review and 
approval of these documents include the 
Research Ethics Committee of the University 
of Health and Allied Sciences and the Ghana 
Health Service (GHS) Ethics Review 
Committee. 
Addition of specific details of the three 
reviewing IECs Specificity added at the 
request of the  
2nd paragraph 
If the reviewing IRB or IEC(s) do not 
otherwise mandate, informed assent must be 
obtained from all children ≥ 12 years… 
If the reviewing IRB or IEC(s) do not 
otherwise mandate, informed assent should 
be obtained from all children ≥ 12 years… 
Removal of the word “must” as per UHAS 
Research Ethics Committee feedback 
3rd paragraph 
The Investigator must also explain that the 
subject is completely free to refuse to enter 
the study or to withdraw from it at any time 
for any reason. 
The investigator should also explain that the 
subject is completely free to refuse to enter 
the study or to withdraw from it at any time 
for any reason. 
Removal of the word “must” as per UHAS 
Research Ethics Committee feedback 
Section 14.1.5 
Institutional Review Boards or 
Ethics Committees, 1st 
paragraph 
… will be submitted, by the Investigator, to at 
least one IRB or IEC. 
…will be submitted, by the investigator, to 
the Research Ethics Committee of the 
University of Health and Allied Sciences, the 
Ghana Health Service (GHS) Ethics Review 
Committee and the WHO Ethics Review 
Committee. 
Addition of specific IECs to which the 
protocol and other materials will be submitted 
(as requested by UHAS Research Ethics 
Committee) 
Section 14.1.6 
Conditions for Modifying the 
Protocol, 3rd paragraph 
All protocol modifications must be submitted 
to the IRB or IECs in accordance with local 
requirements and to regulatory bodies as 
required. 
All protocol modifications must be submitted 
to the IECs (UHAS, GHS and WHO) in 
accordance with local requirements and to 
regulatory bodies (Ghana Food and Drugs 
Authority and US FDA) as required.  
Addition of named IEC and regulatory 
bodies. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Model Parent Information Sheet and Consent Form 
General Information,  
Paragraph 2, Sentence 6 
Their care will not be affected by saying no to 
this study. 
Their care will not be affected by saying no to 
participation in this study. 
Additional wording for clarification 
General Information, 
Paragraph 4, dot point 4 
Consent to the use of your child’s personal 
and health information as described 
Consent to the use of their personal and 
health information as described 
Clarification 
What is River Blindness 
(Oncho)? Paragraph 1, 
Sentence 2  
Two types of worm live in the human body. 
Two types of these worms live in the human 
body. 
Correction to clarify meaning 
How Do I Know if My Child 
Can Take Part? Paragraph 2 
Not applicable 
Not more than one child from your family 
may be enrolled in this study. 
Additional sentence regarding limitation on 
enrolment per family 
Confidentiality, Paragraph 4, 
sentence 3 
This is roughly the “by day” amount paid to 
laborers in your community which is currently 
forty (40.00) Ghana Cedis per day. 
 
The amount paid for each night’s stay will be 
roughly the “by day” earnings of individuals in 
your community, currently forty (40.00) 
Ghana Cedis per day. 
 
UHAS Research Ethics Committee 
requested clarification of the compensation 
to be paid to parents / carers of children in 
the study. 
Consent form 
Not applicable 
 
Addition of signature and date panel for child 
12 years and over 
UHAS Research Ethics Committee 
requested children 12-17 years also sign the 
consent form  
Model Child Information and Assent Form 
Possible Risks and 
Discomforts, sentence 2 
If you have oncho, you might feel a bit unwell 
for a few days after you take the medicine. 
You might feel a bit unwell for a few days 
after you take the medicine. 
Removal of conditional phrase, as per UHAS 
Research Ethics Committee request 


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16.10.2 
Rationale for Protocol Amendment No. 2 
The GHS Research Ethics Committee in its feedback on review of the study (dated 18 Jul 2019) requested clarifications to the protocol which have 
resulted in the requirement for this amendment. 
Details of sections of the protocol amended are provided in Table 11 and Table 12.    
Table 11: Details of Administrative Protocol Amendments (Amendment 2) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Throughout document 
Not applicable 
Correction of minor grammatical and 
typographical errors. Definition of 
abbreviations on first use and, where 
necessary, replacement of the term with the 
acronym upon second or subsequent use in 
the document (section headings and tables 
are the exception). Headings changed to title 
case.  
To improve readability and consistency 
within the document.  
Cover page and footers 
Version 1.1 (incorporating Amendment 1)  
01 April 2019 
Version 1.2 (incorporating Amendments 1 
and 2)  
13 Aug 2019 
Version number and date updated to 
indicate protocol amendment. 
Abbreviations  
Not applicable 
Addition to the abbreviations table of 
definitions for abbreviated terms used within 
the document and removal of any 
abbreviated terms not used.  
To ensure clarity of meaning of abbreviated 
terms and that all and only those terms used 
in the document have been included. 
Section 3.1 Onchocerciasis 
….the WHO and US Food and Drug 
Administration (FDA) as one of the 
neglected tropical diseases for which new 
treatments are sought (The Henry J. Kaiser 
Family Foundation, 2015). 
… the WHO (African Programme for 
Onchocerciasis Control, 2015) and US FDA 
(The Henry J. Kaiser Family Foundation 
2015) as one of the neglected tropical 
diseases for which new treatments are 
sought. 
Addition of missing reference. 
Section 3.4.3 Design Rationale 
Paragraph 3 
…(identification of an optimal moxidectin 
dose for children 4 to 12 years of age)… 
…(identification of an optimal moxidectin 
dose for children 4 to 11 years of age)… 
Correction of typographical error to ensure 
consistency of specified age range. 
Section 3.4.3 Design Rationale 
Paragraph 4 
(World Health Organization).  
(World Health Organization, 2017). 
Addition of missing reference. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 5.3 Cohorts and 
Dosing Regimens 
(Methodology) 
Not applicable 
Not applicable 
Relocation of Figure 1 to follow in-text 
reference to the figure to improve readability. 
Appendix 16.5 Model Parent 
Information and Consent Form 
Section on Contraception 
Not applicable 
Not applicable  
Relocation of text next to the section on 
Pregnancy to keep associated topics 
together to assist understanding 
Appendix 16.7.1 Rationale for 
Protocol Amendment No. 1 
Nil 
New text 
Not applicable 
Not applicable 
To improve clarity of amendment details 
table. 
 
Not applicable 
Table headings changed to captions and 
hyperlinked cross-references added in text. 
To improve consistency and ease navigation 
within the document. 
 
Page X 
Not applicable 
Page references removed for consistency 
with Table 12. 
Section 15 References 
Not applicable 
Addition to reference list of missing and new 
references  
Revised to ensure completeness, following 
updates and additions to the text. 
  
Table 12: Details of Non-Administrative Protocol Amendments (Amendment 2) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 3.4.3 Design Rationale 
Paragraph 1 
There is a large amount of data available in 
adults and children aged 12 to 17 years of 
age. Adverse effects associated with 
moxidectin use were non-serious and 
manageable (Section 3.3.2.2). 
There is a considerable body of data 
available on the use of moxidectin in 
humans, including children aged 12 to 17 
years of age. Moxidectin was well tolerated 
at all doses studied. In healthy volunteers, 
the safety profile was similar to placebo and 
no treatment-related laboratory or clinical 
toxicities were identified. In onchocerciasis 
patients, the nature, incidence and severity 
of adverse events associated with 
moxidectin efficacy was similar to ivermectin, 
and there were no serious adverse events 
due to efficacy and no treatment-related 
serious adverse events in any patient. 
Text amended for clarity. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 6.4.1 Contraception 
Paragraph 2 
…a reliable method of birth control… 
…a reliable method of birth control (failure 
rate of less than 1% when used consistently 
and correctly) in accordance with… 
Definition of reliable method of birth control 
added for clarity. 
Section 6.4.1 Contraception 
Paragraph 3 
Not applicable 
If no local guidelines exist, WHO guidelines 
will be used.   
Reliable methods of contraception include: 
• 
combined (estrogen and progestogen 
containing) hormonal contraception 
associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• 
progestogen-only hormonal 
contraception associated with inhibition 
of ovulation: 
o oral 
o injectable 
o implantable 
• 
intrauterine device 
• 
sexual abstinence 
Sexual abstinence is considered a highly 
effective method only if defined as refraining 
from heterosexual intercourse during the 
entire period of the study. The reliability of 
sexual abstinence needs to be evaluated for 
each subject on an ongoing basis. 
Counselling and administration of 
contraceptives will be carried out by the staff 
of the Family Planning Unit of the Hohoe 
Municipal Hospital. 
Addition of information regarding reliable 
contraceptive methods and delivery of family 
planning services, including the family 
planning guidelines to be followed. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 7.3.3 Screening 
Paragraph 2 
Subjects and their carers will be provided 
with housing at the clinical trial site from 
Screening for confirmation of eligibility 
through to Day 7. 
As participants will be recruited from villages 
not proximal to the study center, they and 
their parents/guardians will be provided with 
accommodation for the duration of their stay 
in a newly renovated dormitory-style ward on 
the campus of the Hohoe Municipal Hospital. 
The dormitory will have separate rooms for 
males and females, with registered nurses 
on duty at all times. It will have comfortable 
beds with mattresses and sheets, a 
recreational area with large screen 
television, and an outdoor space. The 
participants and parents/guardians will be 
provided with three meals daily. 
Addition of information on the facilities to be 
provided for participants and their 
parents/guardians during their stay at the 
study clinic. 
Paragraph 5 
Not applicable 
If the subject is ineligible for the study, the 
investigator will discuss the reason for 
ineligibility with the subject and their 
parent(s)/guardian(s). If the subject is 
ineligible to participate in the study due to a 
clinically significant laboratory abnormality or 
medical condition, a referral to an 
appropriate Ghana Health Service (GHS) 
treatment facility for follow-up will be made. 
Transport for the subject and their 
parent(s)/guardian(s) to return to their village 
will be arranged for the day following 
Screening. 
Addition of procedures to be followed in the 
event a subject is found to be ineligible for 
the study. 
Section 7.3.5.2 Dosing 
Paragraph 1 
Not applicable 
If a subject vomits after taking the dose of 
moxidectin, the subject will be assessed as 
described in Section 12.4. 
Addition of instruction referencing where to 
find information on what to do in the event a 
child vomits soon after taking a dose of study 
medication. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 7.4.1 Demographic 
Data, Medical History, 
Physical Examination, Vital 
Signs 
Paragraph 5 
Not applicable 
Vital signs will be assessed in association 
with other signs and symptoms detected 
upon physical examination for potential 
clinical significance and determination of 
study eligibility and AEs. Vital signs normal 
reference ranges as published in the 
American Heart Association Pediatric 
Advanced Life Support Guidelines 2015 and 
Canadian Paediatric Society Position 
Statement on Temperature Measurement in 
Paediatrics 2013 and as summarized in 
Appendix 16.3 may be used to assist a 
diagnosis. 
Addition of information regarding 
assessment of vital signs, including provision 
of normal reference ranges.  
Section 7.4.3.2 Safety 
Laboratory Tests 
Paragraph 2 
Not applicable 
Normal reference ranges for clinical 
chemistry and hematology for Ghanaian 
children (Dosoo, et al. 2014) will be used in 
this study. These reference ranges are 
included in Appendix 16.4 to the protocol 
and will be available in the SRM. 
Addition of information regarding laboratory 
normal reference ranges to be used for the 
study. 
Section 7.4.3.3 
Pharmacokinetic Samples 
Paragraph 1 
… will be sent to the accredited laboratory… 
… will be sent to Frontage Laboratories 
(Exton, Philadelphia, United States of 
America) …in a fully validated liquid 
chromatography (LC) with mass 
spectrometry (MS) LC/MS/MS method used 
in previous studies. 
Addition of details of the bioanalytical 
laboratory and method of analysis of 
moxidectin in plasma samples. 
Section 8.5.1 Dosage and 
Administration of Moxidectin 
Tablets 
Paragraph 2 
Each randomized subject… 
Each enrolled subject…. 
Correction of an inconsistency in the text – 
study participants will not be randomized. 
Section 8.5.2 Dispensing and 
Accountability 
Paragraph 3 
…or, if approved in writing by the Sponsor, 
destroyed by the site in a manner pre-
approved by the Sponsor in writing as 
arranged by the PI or their designee, 
provided such disposition can be performed 
safely. 
….or, if pre-approved in writing by the 
Sponsor and Ghana Food and Drugs 
Authority, sent for safe destruction at an 
approved local facility. 
Clarification of requirement for pre-approval 
by both the Sponsor and Ghana Food and 
Drugs Authority if study drug is sent for 
destruction at a local facility. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 10.2.2Adverse Event 
Reporting Period 
Paragraphs 1 & 2 
…must be reported… 
…must be reported to the Sponsor,,… 
Clarification of AE reporting requirements. 
 
Not applicable 
All AEs, including SAEs and deaths, will be 
reported to the reviewing IECs/IRBs 
according to their specified timelines. 
 
Section 10.9 Risks for Women 
of Childbearing Potential or 
During Pregnancy  
…as per local family planning guidelines. 
(see Section 6.4.1). 
For clarity, information that is covered in 
another section of the protocol removed and 
replaced with a cross-reference to the 
relevant section. 
Section 10.10 Procedures to 
be Followed in the Event of 
Pregnancy 
Paragraph 2 
Not applicable 
…. and a pediatrician will conduct follow-up 
assessments of the health of the baby up to 
2 years of age. 
Inclusion of a 2-year follow-up period for a 
baby conceived during the 6 months of the 
study, as requested by the GHS Ethics 
Research Committee. 
Section 12.4 Withdrawal of 
Subjects from the Study 
Paragraph 3 
Not applicable 
If a subject vomits up to 30 minutes after 
taking the dose of moxidectin, all Day 0 
assessments should be completed and then 
the subject should be withdrawn from the 
study. Any AEs or SAEs still ongoing at the 
time of withdrawal will be followed in 
accordance with Section 10. 
Addition of information regarding 
management of participants who may vomit 
immediately after administration of 
moxidectin.  
Section 14.1.2 Informed 
Consent 
Paragraph 4 
Not applicable 
The anticipated potential risks of 
participation and the safety profile of 
moxidectin in adults and children at least 12 
years of age with onchocerciasis are 
described in Sections 3.3.2.2, 3.4.3 and 
10.9. 
Inclusion of cross reference to additional 
safety information on moxidectin. 
Section 14.1.2.1 Informing 
Communities about the Study 
Paragraph 4 
3.  ….and are presented in chronological 
order to facilitate comprehension;  
3. These are presented in chronological 
order, and will be supplemented by a 
schematic diagram to facilitate 
comprehension and simplify the process 
for the parents/guardians and subjects; 
Clarification and addition of information 
regarding obtaining informed consent from 
parents/guardians and subjects, including 
how study procedures will be explained and 
understanding confirmed. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
 
Not applicable 
4. Understanding of the study procedures 
will be assessed using a short test 
consisting of a series of open and closed 
questions in the local language for 
parents/guardians and subjects to 
answer. The questions to be asked are 
included at the end of the Parent 
Information Sheet and Consent Form, 
with space provided for recording 
responses (refer to Appendix 16.5); 
 
 
Not applicable 
7. At each subsequent study visit, the 
investigator will should verbally confirm 
the continued consent / assent of the 
subject and that they are free to withdraw 
from the study at any time for any reason. 
 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 14.1.3, Compensation  
Not applicable 
All study-related costs, including study 
medication, laboratory tests, and medical 
care will be provided free of charge. In 
addition, transportation will be provided to 
and from the study center, and 
accommodation and food will be provided for 
participants and their family/carers while at 
the study center. If the child is at the study 
center during school time, a teacher will be 
employed to provide educational activities 
and/or oversee homework during their stay 
to compensate for school time missed.   
Family/carers who accompany children to 
the study site to participate will be 
compensated for loss of earnings according 
to the number of nights they are required to 
stay. The amount paid for each night’s stay 
will approximate to “by day” earnings of 
individuals in the village communities, 
currently forty (40.00) Ghanaian Cedi per 
day. In addition, treatment-emergent adverse 
events occurring during the study will be 
treated in accordance with local treatment 
requirements and as clinically indicated 
without cost. 
Addition of a Section describing 
compensation for study subjects and their 
family/carers 
Section 14.1.5 Institutional 
Review Boards or Ethics 
Committees 
Paragraph 1  
Approval from the committee…. 
Approval from all three ethics committees     
Clarification that approval will be sought from 
three Research Ethics Committees and 
removal of text which is duplicated in the 
following section 
Paragraph 2 
Any modifications made to the protocol after 
receipt of IRB or IEC approval must also be 
submitted to the Investigator to the 
committee in accordance with institutional 
procedures and regulatory requirements. 
Not applicable (text deleted) 
 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 14.2.1 Investigator 
Files and Retention of 
Documents 
Paragraph 3 
…until at least 2 years after the last approval 
of a marketing application in an ICH region 
and until there are no pending or 
contemplated marketing applications in an 
ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical 
development of the investigational product. 
… for at least 25 years after the end of the 
clinical trial. 
Revision of requirement for essential 
document retention, per Ghana Food and 
Drug Authority requirements. 
Appendix 16.3 Vital Signs 
Reference Values for Children 
Not applicable 
Addition of new appendix, Vital Signs 
Reference Values for Children 
Inclusion of reference values for use for 
interpretation of vital signs.  
Appendix 16.4 Laboratory 
Reference Values for 
Ghanaian Children 
Not applicable 
Addition of new appendix, Laboratory 
Reference Values for Ghanaian Children 
Inclusion of reference values for use by the 
local safety laboratory.  
Model Patient Information Sheet and Consent Form 
Throughout document 
Not applicable 
Not applicable 
Simplification of words and phrases to assist 
in understanding of what will happen in the 
study 
General Information About the 
Research 
Last paragraph  
Not applicable 
You will also be given information cards that 
will tell you when and where your child will 
be given treatment and have tests done. 
Additional description of information cards 
explaining study visits and tests to be 
provided to parents. 
Screening 
Paragraph 1 
Not applicable 
… (see information on contraception and 
pregnancy below) … 
 
Additional text regarding location of 
information on contraception. 
Paragraph 2 
You and your child will be transported back 
to your village.  
If treatment is needed, the study doctor will 
arrange for your child to visit a Ghana Health 
Service treatment facility for follow-up. You 
and your child will be transported back to 
your village the next day after screening. 
Addition of information regarding provision of 
follow-up treatment, if needed, and timing of 
return to the village in the event a child is 
determined to be ineligible for the study.  
Days 1, 2, 3, and 7 
Not applicable. 
In addition, if at any time your child is not 
feeling well or has a problem, you should tell 
the study doctor or nurse immediately. 
Inclusion of advice to parents to tell study 
team members if a child is not feeling well.  


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Section 
Original Text 
Revised to Read 
Rationale for Change 
 
Not applicable 
The study team will try to time this long clinic 
stay during school holidays, but if it happens 
during school time, a teacher will be 
employed to provide educational activities for 
your child during their stay. 
Inclusion of a description for parents about 
the steps taken to limit the effects of their 
child missing classes. 
Side effects associated with 
moxidectin treatment 
Catarrh 
Catarrh (mucus in the nose and throat) 
Addition of an explanation of the medical 
term. 
Pregnancy 
Paragraph 1 
A test will also be done 3 more times during 
the study (on Day 28, Week 12 and at 
Week 24)....the study doctor will follow the 
pregnancy until the birth of the baby to check 
if it is healthy. 
She must use reliable contraception while 
she is on the study (see the section on 
contraception below). A pregnancy test will 
also be done 3 more times during the study 
(on Day 28, Week 12 and at 
Week 24)……The health of the baby will be 
checked at birth and until it is 2 years old. 
These checks will be carried out by a doctor 
who specializes in treating babies and 
children. 
Expansion of the section on pregnancy to 
include reference to contraception and 
describe the follow up procedures for a child 
until 2 years in the event of a pregnancy 
occurring during the study. 
Paragraph 2 
Not applicable 
If your child is male and fathers a child while 
participating in the research study, the study 
doctor should also be informed and they will 
ask for consent to follow up the baby. 
Expansion to the section on pregnancy to 
request notification to the study team should 
a male participant father a child. 
Contraception 
If your daughter is able to become pregnant 
she will be asked to commit to using reliable 
contraception from Screening and for 
6 months after taking the study medication. 
You and your daughter should discuss 
methods of reliable contraception with the 
study doctor. If she does become pregnant 
whilst participating in the research study, the 
study doctor should be informed 
immediately.  
If your daughter is able to become pregnant 
she will be asked to commit to using reliable 
contraception (which may be that she does 
not have sex at all) from Screening and for 
6 months after taking the study medication. 
The study family planning nurse will discuss 
methods of reliable contraception with you 
and your daughter and, if you agree, will give 
contraceptives to your daughter. If your 
daughter does become pregnant while she is 
in the research study, the study doctor 
should be informed immediately. 
For clarity, text moved to follow section on 
pregnancy and information added regarding 
abstinence as a reliable method of 
contraception. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
If your son fathers a child while participating 
in the research study, the study doctor 
should be informed. Consent to follow-up on 
the health of the baby at birth will be 
requested. 
Not applicable (text deleted) 
For clarity, text moved to section on 
pregnancy.  
Medicines 
Any other medicine or treatments they are 
prescribed or take, including vaccines, 
vitamins, herbal supplements or traditional 
remedies must be reported to the study team 
for inclusion in their study records 
Any other medicine or treatments they are 
given, including vaccines, contraceptives, 
vitamins, herbal supplements or traditional 
remedies must be reported to the study team 
so that they can be recorded in their study 
records. 
Simplification of text for clarity. 
Privacy (Confidentiality) 
Paragraph 4 
Not applicable 
If reports are written or talks given about this 
research, they will only discuss group 
results. They will not use your child’s name 
or any other personal information that could 
identify them. 
Additional text included to explain how the 
subject’s confidentiality will be protected. 
Costs and Compensation 
Paragraph 1 
There is no cost to you for your child to take 
part in this research study.  
You will not pay any money for your child to 
take part in this research study… 
…In addition, if your child is at the study 
center during school time, there will be a 
teacher at the center who will help your child 
going with some of their school work during 
their stay, to help make up for the school 
time they miss. 
Clarification and addition of text explaining 
compensation for missed work and school 
hours as a result of participation in the study. 
Contacts for Additional 
Information  
The Chairman Ghana Health Service Ethics 
Review Committee phone line at (+233 302 
681 109) or write to The Chairman …. 
The Administrative Secretary of the Ghana 
Health Service Ethics Review Committee by 
telephone +233 302 681 109 or write to The 
Administrative Secretary…. 
Amendment of contact details for GHS ERC 
Chair to GHS Administrator details. 
Assessment of Informed 
Consent Questions  
Not applicable 
Reformatting of table to facilitate recording 
both Yes/No answers and free text. 
Addition of one question: ‘Do you understand 
that this is a research study and not 
treatment?’ 
Proposed additional question at Principal 
Investigator’s request and amended 
formatting to facilitate collection of response 
information. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Model Child Information and Assent Form 
What Will Happen at the Study 
Visits? 
Paragraph 1 
General Information 
… If you have, you will go by car with a 
parent or other adult from your village to the 
study clinic in Hohoe to stay for between 9 
and 14 days.  
What Will Happen at the Study Visits? 
…. If you have had the worms, and you still 
agree, you will go by car with a parent or 
other adult from your village to the study 
clinic in Hohoe.  You will have to stay there 
for between 9 and 14 days. … This will 
include taking blood from your arm with a 
needle to test that you are well.  We can use 
a special cream to numb your skin so you 
won’t feel the needle prick. You will be 
weighed and measured and special 
equipment will be used to check how fast 
your heart is beating and if it is healthy, to 
measure your blood pressure and breathing 
are normal and that you don’t have a fever. 
Section heading revised and more specific 
description of study procedures in simple 
language added to assist understanding by 
children during the assent process. 
Paragraph 2 
You will be asked to swallow a dose of the 
medicine (up to 4 moxidectin tablets) with 
water. You will have some blood taken to 
measure how much medicine is in your body 
After you have had dinner that night, you will 
not be able to eat any more food until after 
you have taken the study medicine. The next 
day, before you eat any breakfast, you will 
be asked to swallow up to 4 moxidectin 
tablets with water. You will have some more 
blood taken from your arm using a special 
needle that can stay in your arm for the 
whole day so that 4 more blood samples can 
be taken without needing another needle 
prick. This blood will be used to measure 
how much study medicine is in your body 
since taking the tablets.  Two hours after you 
took the medicine, you will be given 
breakfast.  
 
Paragraph 3 
Not applicable 
You should also tell the doctors and nurses if 
you don’t feel well or have had any 
problems. The day after you took the 
medicine and on day 3 and day 7 before you 
go home, you will also be asked to give 
samples of blood. 
 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
What Will Happen at the Study 
Visits? 
Paragraph 4 
Not applicable 
… and, except for the last visit, to take a 
sample of blood.  These visits will happen at 
around week 2, 4, 12 and 24 after you took 
the dose of medicine. 
Addition of text describing which of the 4 
visits to the clinic after the initial stay will 
involve taking a sample of blood. 
Possible Risks and 
Discomforts 
Paragraph 2 
Not applicable 
You may also miss some school while you 
are at the clinic. However, there will be a 
teacher to help you keep going with your 
schoolwork while you stay at the clinic. 
Addition of text on what will happen to make 
up for school time lost when participating in 
the study. 
 


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16.10.3 
Rationale for Protocol Amendment No. 3 
The World Health Organization Responsible Officer, in her feedback on review of Version 1.2, requested:  
1) clarifications to the protocol text, as well as minor modifications (updates relating to the implementation of ivermectin mass treatment 
programs in the recruitment area, references, grammar and customization of standard phrasing/terms to this study); and 
2) simplification, addition of pictures, provision of context (ivermectin mass drug administration in the communities from which participants 
will be recruited, previous conduct of a moxidectin study with participants aged ≥12 years from these communities whom 
parents/guardians can contact about their experience) and improved targeting of the Model Information documents for different audiences 
(adolescents aged 12-17 years and their parents, parents of children aged 4 to 11 years, children aged 7 to 11 years and children aged 4 to 6 
years or older children not considered mature enough to provide assent). 
In response to these requests, the protocol has been amended. This amendment also afforded the opportunity to make administrative changes to 
improve document consistency and readability (e.g. corrections to formatting, grammar and use of abbreviations, and elimination of duplicated 
information and information not relevant for this study) and to update the information on the population pharmacokinetic modelling. 
Details of sections of the protocol amended are provided in Table 13 and Table 14.    
Table 13: Details of Administrative Protocol Amendments (Amendment 3) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Throughout 
Not applicable 
Not applicable 
Correction of grammatical and/or 
typographical errors. 
Definition of abbreviations on first use 
and replacement of the term with the 
acronym upon subsequent use in the 
document. 
Addition of cross references to facilitate 
document navigation. 
Removal of terms not used by 
applicable Ethics Committees (e.g. 
IRB, IEC). 
Adjustment of standard terminology to 
this study (e.g. reference to final or last 
dose) 
Addition, deletion or correction of 
literature references. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Throughout 
‘Clinic’ or ‘study clinic’ or ‘in-clinic’/’inpatient’ 
Research center or center or in-center 
Clearly differentiate between Ghana 
Health Service clinics and the research 
center. 
6 months 
Approximately 6 months (Week 24) 
Clarify that last follow up visit at 
Week 24 is only approximately 
6 months after study drug. 
Informed consent 
Informed consent and assent  
Consent forms 
[or similar wording] 
Informed consent and assent  
Informed consent and child assent / lack of ‘deliberate 
objection’  
Consent/assent 
[or similar wording] 
Clarify that informed consent by the 
parents/guardians and assent by the 
child is required for child participation 
in the study. 
Clarify that children too young or 
immature to provide assent will be 
informed about the study for evaluation 
of expression of ‘deliberate objection’ 
as per commentary to CIOMS 
Guideline 17. 
Note that for reasons of readability, 
‘assent’ is used to refer to both 
obtaining assent and evaluation for 
expression of ‘deliberate objection’. 
Cover page, Study 
Acknowledgement and 
footers 
Version 1.2 (incorporating Amendments 1 and 
2) 13 Aug 2019 
Version 2 (incorporating Amendments 1, 2 and 3) 27 
Nov 2019 
Version number and date updated to 
indicate protocol amendment. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Cover page 
Confidentiality 
Statement 
The information contained in this document, 
particularly unpublished data, is the property 
of, or under the control of Medicines 
Development for Global Health and is provided 
to you in confidence as an Investigator, 
potential Investigator, or consultant, for review 
by you, your staff, and an applicable 
Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). The 
information is only to be used by you in 
connection with authorized clinical studies of 
the investigational product described in the 
protocol. You will not disclose any of the 
information to others without written 
authorization from Medicines Development for 
Global Health, except to the extent necessary 
to obtain informed consent from those persons 
to whom the drug may be administered. 
Until publication of this protocol following approval by 
applicable Regulatory Authorities and Ethics 
Committees, any unpublished information contained in 
this document is the property of, or under the control of 
Medicines Development for Global Health and is 
provided to you in confidence as an Investigator, 
potential Investigator, or consultant, for review by you, 
your staff, and any applicable Regulatory Authority or 
Ethics Committee. The information is only to be used 
by you in connection with authorized clinical studies of 
the investigational product described in the protocol. 
Prior to publication, you will not disclose any of the 
information to others without written authorization from 
Medicines Development for Global Health, except to 
the extent necessary to obtain informed consent from 
those persons to whom the drug may be administered. 
Adjusted for the fact that Medicines 
Development for Global Health is a 
not-for-profit organization and that the 
protocol will be published following all 
required ethics committee and 
regulatory approvals. 
Synopsis, Inclusion 
Criteria 
Section 6.2, Inclusion 
Criteria 
4. Provision of parental or guardian written 
informed consent and assent as 
appropriate 
5. Females of childbearing potential must 
commit to using a reliable method of 
contraception as per local family planning 
guidelines from Screening until 6 months 
after treatment with study drug; 
4. Provision of parental or guardian written informed 
consent and child assent / lack of expression of 
‘deliberate objection’ (as appropriate for age) 
5. Females of childbearing potential must commit to 
using a highly effective method of contraception as 
per local family planning guidelines from Baseline 
(pre-treatment on Day 0) until approximately 
6 months (Week 24) after treatment with study 
drug; 
Clarification of text relating to age 
appropriate assent, including in 
children too young to give assent. 
Clarification of timing of required 
contraceptive coverage. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Synopsis, Exclusion 
Criteria 
Section 6.3 Exclusion 
Criteria 
Synopsis:  
3. Has received an investigational product 
within 28 days or 5 half-lives of Screening, 
whichever is longer; 
4. Has received ivermectin or any other anti-
helminthic treatments within 28 days of 
Screening; 
5. Has received a vaccination within 7 days of 
Screening; 
8. Unable to swallow tablets; 
Section 6.2: 
4. Has received ivermectin or any other anti-
helminthic treatments within 28 days of 
Screening; 
5. Has received a vaccination within 7 days of 
Screening; 
8. Unable to swallow tablets; 
Both:  
3. Has received an investigational product within 
28 days or 5 half-lives of Baseline, whichever is 
longer; 
4. Has received ivermectin or any other anti-
helminthic treatments within 28 days of Baseline; 
5. Has received a vaccination within 7 days of 
Baseline; 
8. Unable to swallow tablets (flat oval, 8.0 millimeters 
(mm) x 4.5 mm x 3.0 mm); 
Clarification of reference time point. 
Addition of tablet size to avoid 
misconception of the extent to which 
this exclusion criterion will impact study 
eligibility of small children. 
Synopsis, Design 
Details and Dose 
Regimens 
Cohort II: (8 to 11 years, n = 9) will receive 
moxidectin 8 mg (4 x 2 mg tablets) with 
adjustment as required based on 
pharmacokinetic outcomes 
For Cohorts II and III, if at least 3 of the 
subjects have moxidectin exposures below or 
above the target range, a revised dose will be 
determined in increments/decrements of 2 mg 
(maximum dose 8 mg) and the Cohort will be 
repeated with at least 9 new subjects enrolled 
at the new dose. 
Cohort II: (8 to 11 years, n = 9) will receive moxidectin 
8 mg (4 x 2 mg tablets). 
If for Cohorts II and III, the starting dose results in at 
least 3 of the subjects having moxidectin exposures 
above the target range, a revised dose will be 
determined in decrements of 2 mg and the Cohort will 
be repeated with at least 9 new subjects enrolled at the 
new dose. If for Cohort III, the starting dose results in 
at least 3 subjects having moxidectin exposures below 
the target range, a revised dose will be determined in 
increments of 2 mg to a maximum dose of 8 mg. 
Clarification that this adjustment will 
apply to the first dose level. 
Clarification that for Cohort II there will 
be no dose increment, while for Cohort 
III there may be either a dose 
increment or decrement. 
Synopsis, Study 
Procedures 
Consent to participate will be conducted in the 
village setting and may be obtained up to 
30 days prior to Screening. After obtaining 
written informed consent from the 
parent(s)/guardian(s) and assent from the child 
as appropriate (see Section 14.1.2 for details) 
the child will be tested for OV16 IgG4 antibody. 
Children with a positive test result and their 
parent, guardian or another trusted adult from 
the village assigned by the parent or guardian 
will be invited to attend the clinic for further 
Screening. 
Consent and assent (lack of expression of ‘deliberate 
objection’, as appropriate for age) will be obtained in 
the village setting and may be obtained up to 30 days 
prior to Baseline. After obtaining written informed 
consent from the parent(s)/guardian(s) and assent (or 
determining lack of expression of ‘deliberate objection’) 
from the child (see Section 14.1.2 for details) the child 
will be tested for OV16 IgG4 antibody. Children with a 
positive test result and meeting other eligibility criteria 
evaluated in the village, together with one parent or 
guardian, will be invited to attend the research center in 
Hohoe for further Screening. 
Clarification that assent will be sought 
from or a determination of lack of 
expression of ‘deliberate objection’ 
made for all children. 
Clarification that eligibility criteria other 
than OV16 IgG4 antibody can be 
evaluated in the village. 
Clarification that one parent or 
guardian will accompany all children to 
the research center in Hohoe. 


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Synopsis, 
Contraindications to 
Further Dosing  
As all subjects will receive a single dose only, 
there are no contraindications to further dosing 
of individuals who receive treatment. 
Recruitment of additional subjects in the study 
will be guided by the DSMB. 
Not applicable on an individual subject basis as all 
subjects will receive a single dose only. 
Dosing of additional subjects in the study will be guided 
by the DSMB. 
Clarification of text. 
Synopsis, Data and 
Safety Monitoring 
Board 
A DSMB of independent experts will be 
established prior to recruitment start, with a 
charter that defines in detail its roles and 
responsibilities. 
The DSMB will review the safety and 
pharmacokinetic data following completion of 
enrolment and pharmacokinetic data analysis 
for both Cohorts I and II.  
A DSMB of independent experts has been established, 
with a charter that defines in detail its roles and 
responsibilities. 
The DSMB will review the safety and pharmacokinetic 
data following completion of enrolment and 
pharmacokinetic data analysis for both Cohorts I and II 
and advise the sponsor on the dose with which Cohort 
III will be initiated. 
Resolution of discrepancy between 
synopsis and body of protocol. 
Synopsis, Special 
Protocol Requirements 
or Issues: 
The study will be conducted in an area(s) 
endemic for O. volvulus and currently 
participating in or planned for implementation 
of ivermectin treatment. 
The study will be conducted in communities 
familiar with clinical research. This will facilitate 
understanding of the process and enable 
parents, as well as children, to provide 
appropriate informed consent for study 
participation. Villages in the Volta region of 
Ghana already involved in onchocerciasis 
research have been identified as suitable 
locations from which to enroll subjects 
The study will be conducted in an area(s) endemic for 
O. volvulus and currently participating in 
implementation of ivermectin treatment 
The study will recruit subjects in communities in the 
Volta Region of Ghana familiar with clinical research 
and the research center in Hohoe where the in-center 
period of the study will be conducted, since participants 
in the Phase III study of moxidectin were recruited from 
these communities. This will facilitate understanding of 
the study and enable parents/guardians, as well as 
children, to provide appropriate informed consent and 
assent for study participation. 
Update to current status of ivermectin 
treatment implementation in the study 
area. 
Clarification of reasons for community 
familiarity with clinical research. 
Table 1, Table of 
Assessments 
Not applicable 
Addition of Baseline definition to Day 0 pre-dose 
heading and footnote. Addition of inclusion/exclusion 
criteria to Pre-screening assessments. Addition of 
footnotes to clarify that pregnancy testing is not 
required at unscheduled visits unless clinically 
indicated. Removal of redundant footnote regarding 
collection of pre-dose pharmacokinetic blood sample 
(table only specifies sample collection at Screening). 
Clarification of requirements for and 
timing of study assessments. 
Abbreviations  
Not applicable 
Addition of definitions for abbreviated terms used within 
the document and correction of one term.  
To ensure clarity of meaning of 
abbreviated terms. 


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Section 3.1 
Onchocerciasis 
Onchocerciasis is endemic in sub-Saharan 
Africa. Recent surveys indicate that the 
number of infected people in the African region 
is approximately 16 million (Zoure et al., 2014) 
and more than 200 million people are still 
considered to be at risk of infection (World 
Health Organization, 2018). 
Onchocerciasis is endemic in sub-Saharan Africa 
(Zoure et al., 2014), More than 200 million people are 
considered to be at risk of infection (World Health 
Organization, 2018). 
Correction of text attributable to the 
cited references. Data in Zoure et al. 
2014 do not cover all of Africa and with 
onchocerciasis elimination now 
targeted, the number infected is not a 
critical measure of medical need. 
 
Onchocerciasis Control Program (a 
WHO/United Nations collaboration that ran 
from 1974 to 2002) 
Onchocerciasis Control Program (a WHO-managed 
international collaboration that ran from 1974 to 2002) 
Correction of information on 
Onchocerciasis Control Program. 
 
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. 
The larvae develop into mature adult worms 
(macrofilariae) and become encapsulated in nodules, 
from which they release millions of microfilariae that 
migrate through the skin and eyes, a critical step in the 
cycle of reinfection and disease perpetuation. 
Clarification that nodules are not only 
palpable skin nodules but can be deep 
in the body 
Section 3.2 Current 
Treatment and Unmet 
Need 
In international programs, the most commonly 
used retreatment interval is 12 months.  
In Africa, the most commonly used retreatment interval 
is during mass drug administration is 12 months.  
Clarification that information provided 
applies to Africa. 
 
The aim of these international, community-
directed ivermectin treatment programs is to 
achieve control in affected communities and, 
ultimately, to work towards elimination of 
onchocerciasis in areas currently assessed as 
meso- or hyper-endemic for O. volvulus 
infection (Uniting to Combat Neglected Tropical 
Diseases, 2012) 
The aim of these community-directed ivermectin 
treatment programs is to achieve control of the disease 
as a public health problem in affected communities 
(Uniting to Combat Neglected Tropical Diseases 2012). 
Ultimately, the WHO and onchocerciasis endemic 
countries are working towards elimination of 
onchocerciasis where feasible 
Correction of text attributable to the 
cited reference. 
 
15 of 24 (62.5%) ivermectin treated subjects 
did not achieve zero skin microfilariae density 
at any time point (Month 1, Month 6, Month 12 
and/or Month 18) compared with 1 of 53 (1.9%) 
moxidectin treated subjects. 
Fifteen (15) of 24 (62.5%) ivermectin treated 
adolescents did not achieve zero skin microfilariae 
density at any time point (Month 1, Month 6, Month 12 
and/or Month 18) compared with 1 of 53 (1.9%) 
moxidectin treated adolescents. 
Clarification that numbers refer to 
adolescents.  
Section 3.3.1.2.3 
Juvenile Nonclinical 
Safety 
There were no unscheduled deaths and clinical 
observations 
There were no deaths and clinical observations 
Clarification of text. 


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Section 3.4.1 Study 
Rationale (Study Goals 
and Objectives) 
Therefore, the purpose of this study is to 
determine an optimal pediatric dose of 
moxidectin for use in children with 
onchocerciasis aged 4 to 11 years. This will 
allow the use of moxidectin across the 
community affected by this disease. 
Therefore, the purpose of this study is to determine an 
optimal pediatric dose of moxidectin for use in children 
with onchocerciasis aged 4 to 11 years to achieve 
exposure in the range observed in adults administered 
a dose of 8 mg. This will allow the use of moxidectin 
across the communities affected by this disease, 
including in mass drug administration programs for 
onchocerciasis control and elimination.  
Clarification of study goals. 
Section 3.4.3 Design 
Rationale 
In the absence of skin snip assessments to 
confirm infection with O. volvulus, the study will 
recruit children from an area designated as 
endemic for O. volvulus infection and targeted 
for ivermectin treatment implementation. 
In the absence of skin snip assessments to confirm 
infection with O. volvulus, the study will recruit children 
from an area designated as endemic for O. volvulus 
infection and undergoing ivermectin mass drug 
administration. 
Update to current status of ivermectin 
mass drug administration. 
 
Specifically, subjects will be recruited from 
communities located in the Nkwanta district, 
northern Volta region, Ghana, an area 
assessed in 2017 as endemic for 
onchocerciasis by the Expanded Special 
Project for Elimination of Neglected Tropical 
Diseases and the WHO (World Health 
Organization 2017). In recognition of the risk of 
onchocerciasis in this region, community-
directed treatment with ivermectin commenced 
in October 2017 with ongoing 6-monthly 
rounds of treatment planned. 
Specifically, subjects will be recruited from 
communities located in the Nkwanta district, northern 
Volta region, Ghana, an area assessed as endemic for 
onchocerciasis by WHO (World Health Organization 
2019). In recognition of the prevalence of 
onchocerciasis in this region, community-directed 
treatment with ivermectin commenced in October 2017 
with ongoing 6-monthly rounds of treatment planned. 
Correction of timing of endemicity 
assessment and date of reference.  
Elimination of reference to the 
Expanded Special Project for 
Elimination of Neglected Tropical 
Diseases since endemicity assessment 
pre-dates the creation of that project.  
Clarification that infection prevalence 
drives implementation of ivermectin 
community directed treatment. 
 
Potential AEs associated with effective 
treatment of onchocerciasis are expected to be 
manageable and transient 
Potential AEs associated with effective treatment of 
onchocerciasis are expected to be manageable and 
transient based on the prior experience in the Phase II 
and Phase III study. 
Clarification of basis for expectation 
that AEs will be manageable and 
transient. 
 
This assessment, and associated sample 
collection activities through the study, 
represent medical experiences commensurate 
with community experience in areas where 
onchocerciasis clinical investigations and/or 
surveillance programs have been 
implemented. 
Since the Phase III study was recruited from the 
villages from which the participants for this study will be 
recruited, a number of members of these communities 
will be familiar with clinical studies and biological 
sample collection.   
Clarification of source of familiarity with 
clinical investigations and sample 
collections 


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Protocol Number: MDGH-MOX-1006 
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Section 3.4.3 Design 
Rationale 
Protocol MDGH-MOX-1006 is specifically 
designed to yield vital knowledge about 
onchocerciasis treatment in the 4- to 17-year-
old age group, and the participating 
communities more generally. It is likely that at 
least some study participants will be actively 
infected with O. volvulus and, as such, 
moxidectin treatment would potentially be of 
benefit in these patients.  
Protocol MDGH-MOX-1006 is specifically designed to 
determine the appropriate dose of moxidectin for 
onchocerciasis treatment in the 4- to 11-year-old age 
group. The inclusion of adolescents 12 to 17 years will 
provide additional pharmacokinetic data for inclusion in 
the population pharmacokinetic model used to predict 
drug exposures across all age groups and to support 
dose selection for children aged 4 to 11 years. All 
enrolled children will have confirmed exposure to O. 
volvulus. Some study participants may have skin 
microfilariae and moxidectin treatment will be of benefit 
to these individuals.  
Clarification of design rationale. 
 
However, in recognition of the study involving a 
minor increase over minimal risk to children 
without known direct benefit to individual 
subjects (i.e. without confirmation of 
O. volvulus microfilarial burden pre-treatment), 
the Sponsor has engaged with investigators 
and communities and plans to consult with 
local, regional and independent (WHO) ethics 
committees prior to study conduct, and with 
consideration to the conduct of the study under 
IND 126876 and the requirements of the 
United States (US) Code of Federal 
Regulations, including Title 21 Sections 50.52, 
50.53 and 50.55.   
In recognition that the study involves a minor increase 
over minimal risk to children without known direct 
benefit to individual subjects (i.e. without confirmation 
of O. volvulus microfilarial burden pre-treatment), the 
Sponsor points to (1) engagement with the investigator, 
(2) confirmation that the study design is acceptable 
based on protocol review by local and regional 
independent experts on the DSMB, (3) protocol 
amendments based on the local (UHAS), country 
(Ghana Health Service (GHS)) and independent 
(WHO) ethics committee review and (4) protocol 
amendment following Ghana Food and Drugs 
Administration review prior to study conduct. The study 
is also being conducted under United States Food and 
Drug Administration IND 126876 and in accordance 
with the requirements of the United States (US) Code 
of Federal Regulations, including Title 21 
Sections 50.52, 50.53 and 50.55.     
Addition of information regarding 
protocol review by DSMB members 
and the Ghana Food and Drugs 
Administration.  


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Section 3.4.4.1 
Nonclinical Dose 
Rationale 
In a neurofunctional and pulmonary study in 
male rats, the NOAEL was 5 mg/kg, with 
corresponding Cmax of 1116 ng/mL, which was 
above the previously measured Cmax in adults 
and predicted Cmax to be reached in the 
pediatric study. 
Additionally, daily parental oral administration 
of dietary moxidectin to rats prior to mating, 
and through mating, gestation, and lactation 
was associated with decreased survival and 
body weights for first-generation offspring 
without maternal toxicity at moxidectin doses 
less than 2 times the recommended human 
dose based on body surface area comparison. 
However, daily dietary moxidectin did not 
produce maternal toxicity or adverse effects for 
first- and second-generation offspring at doses 
approximately equivalent to the recommended 
human dose based on body surface area 
comparison. 
In a neurofunctional and pulmonary study in male rats, 
the NOAEL was 5 mg/kg, with corresponding Cmax of 
1116 ng/mL, which was above the previously 
measured Cmax in adults and predicted Cmax to be 
reached in the pediatric study if all age groups received 
a dose of 8 mg (Table 4). 
Daily parental oral administration of dietary moxidectin 
to rats for 70 days prior to mating, and through mating, 
gestation, and lactation was associated with decreased 
survival and body weights for first-generation offspring 
without maternal toxicity at moxidectin doses less than 
approximately 1.3 times the recommended human 
dose  based on body surface area comparison 
(>1.1 mg/kg/day). However, daily dietary moxidectin 
did not produce maternal toxicity or adverse effects for 
first- and second-generation offspring at doses 
approximately equivalent to the recommended human 
dose based on body surface area comparison 
(0.82 mg/kg/day). 
Clarification of text, including doses 
administered in maternal dosing 
studies. 
 
Specifically, the simulation model predicted 
that adolescents 12 to 17 years receiving 8 mg 
of moxidectin may achieve similar exposures 
(AUC) to adults receiving 8 mg, with a higher 
Cmax (median 81 nanograms (ng) /mL vs. 
55 ng/mL in adults). For children aged 8 to 
11 years, exposures are also predicted to be 
similar to adults, while median Cmax is predicted 
to be 114 ng/mL (maximum 228 ng/mL). This is 
well within the safety margins of moxidectin in 
humans; in adults, moxidectin has been 
studied up to a median Cmax of 235 ng/mL and 
a maximum of 438 ng/mL. The full 
pharmacokinetic report has been provided for 
reference (see Appendix 16.2). 
Specifically, the simulation model predicted that 
adolescents 12 to 17 years receiving 8 mg of 
moxidectin may achieve similar exposures (AUC) to 
adults receiving 8 mg, with a higher Cmax (median 
83.5 nanograms (ng) /mL vs. 56.6 ng/mL in adults). For 
children aged 8 to 11 years (as well as children 4 to 7 
years), exposures are also predicted to be similar to 
adults, while median Cmax is predicted to be 116 ng/mL 
(maximum 214 ng/mL). This is well within the safety 
margins of moxidectin in humans; in adults, moxidectin 
has been studied up to a median Cmax of 244 ng/mL 
and a maximum of 473 ng/mL. The full 
pharmacokinetic report has been provided for 
reference (see Appendix 16.2). 
Update of text to reflect modelling, 
including data from an additional PK 
study in adults. 


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Table 4 
Title: Summaries of Simulated Cmax (ng/mL) 
and AUC inf (ng*h/mL) for Children 4-11 years 
(8 mg), Adolescents 12 to 17 years (8 mg), 
Adults (8 mg) and Results for Healthy 
Volunteers (8 mg, 16 mg, 36 mg) in Clinical 
Studies 
 
Footnote: * The predicted 10th and 90th 
percentile AUCinf for children 4 to 7 years will 
be calculated in the model after 
pharmacokinetic data for children 8 to 11 years 
and adolescents 12 to 17 years are updated in 
the model (see Section 13.5.3). Italicized 
values represent simulations. HV = healthy 
volunteers, IQR = interquartile range, 
AUCinf = AUC from time 0 extrapolated to 
infinity, SD = Standard Deviation.  
Title: Summaries of Cmax and AUC inf for Children 4 to 
11 years (8 mg), Adolescents 12 to 17 years (8 mg), 
and Adult O. volvulus-infected Individuals and Healthy 
Volunteers (8 mg, 16 mg, 36 mg) Emerging from the 
Population Pharmacokinetic Model Used to Determine 
the Starting Dose for Children 8 to 11 years 
  
Footnote: * The mean predicted and 10th and 90th 
percentile AUCinf for children 4 to 7 years will be re-
estimated after pharmacokinetic data for children 8 to 
11 years and adolescents 12 to 17 years are available 
to update the model as a basis for determining the first 
dose for children 4 to 7 years to be proposed to the 
DSMB (see Section 13.5.3). Adults = 18+ years, Oncho 
= O. volvulus infected, HV = healthy volunteers, 
IQR = interquartile range, AUCinf = AUC from time 0 
extrapolated to infinity, SD = Standard Deviation 
Modification of title of data table to aid 
interpretation. 
Update of data to take into 
consideration recent update of the 
model to include data from an 
additional PK study. 
Inclusion of 10th and 90th percentiles for 
all age/dose groups to facilitate 
comparison of exposure estimates for 
children 8 to 11 years of age receiving 
an 8 mg dose (first dose level planned) 
with exposure estimates based on 
measured PK data in adults.   
Adjustment of footnote to the updated 
table. 
Section 5.3 Cohorts 
and Dosing Regimens 
(Methodology) 
A sentinel group of three subjects will be 
enrolled in Cohort II. If safety up to and 
including Day 3 in these subjects is acceptable, 
the additional 6 subjects will be enrolled.  
A sentinel group of three subjects will be enrolled in 
Cohort II. If the investigator considers, based on their 
experience with onchocerciasis treatments, that safety 
up to and including Day 3 in these subjects is 
acceptable, the additional 6 subjects will be enrolled. If 
safety concerns arise in the sentinel group, the DSMB 
will review the data and make a recommendation to 
continue dosing as planned, or to modify or stop 
dosing. 
Clarification of process for assessment 
of safety in the sentinel group in Cohort 
II. 
Clarification of requirements for Cohort 
III dose level selection and initiation. 
 
If 3 or more of the 9 subjects in Cohort II have 
moxidectin exposures above the target range, 
defined as AUCs to Day 28 greater than the 
predicted 90th percentile mean AUC (see 
Table 4), a reduced dose of moxidectin will be 
selected for additional dosing of Cohort II 
subjects. The new dose will be in increments or 
decrements of 2 mg, reflecting the 2 mg 
moxidectin tablet format used in the study 
If 3 or more of the 9 subjects in Cohort II have 
moxidectin exposures above the target range, defined 
as AUCs to Day 28 greater than the predicted 90th 
percentile mean AUC (see Table 4), a reduced dose of 
moxidectin will be selected for dosing of additional 
subjects in the Cohort II age range. The new dose will 
be in decrements of 2 mg, reflecting the 2 mg 
moxidectin tablet format used in the study. 
Clarification that additional subjects in 
the Cohort II age range may be dosed 
and that dosing will be adjusted in 
decrements of 2 mg from the starting 
dose of 8 mg. 


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Protocol Number: MDGH-MOX-1006 
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Section 5.3 Cohorts 
and Dosing Regimens 
(Methodology) 
Upon successful completion of Cohort II and 
selection of a dose based on pharmacokinetic 
modelling with inclusion of Cohort I and II data, 
and consideration of all predicted 
pharmacokinetic parameters, Cohort III will be 
enrolled. 
For Cohort III (n = 9, subjects aged 4 to 
7 years, inclusive), a single oral dose of 
moxidectin will be at a dose to be determined 
by the population pharmacokinetics model but 
not exceeding 8 mg. 
Upon successful completion of Cohort II and selection 
of a starting dose for Cohort III based on 
pharmacokinetic modelling with inclusion of Cohort I 
and II data and consideration of all predicted 
pharmacokinetic parameters, and DSMB 
recommendation (see Section 11), Cohort III will be 
enrolled.  
Cohort III (n = 9, subjects aged 4 to 7 years, inclusive) 
will receive a single oral dose of moxidectin at the 
recommended dose level. 
Clarification that the DSMB will be 
involved in selection of the starting 
dose for Cohort III. 
 
Initially, a sentinel group of 3 subjects will be 
enrolled. If safety up to and including Day 3 in 
these subjects is acceptable, the additional 6 
subjects will be enrolled.  
Initially, a sentinel group of 3 subjects will be enrolled. 
If safety up to and including Day 3 in these subjects is 
considered acceptable, based on the investigator’s 
experience with onchocerciasis treatments, the 
additional 6 subjects will be enrolled. If safety concerns 
arise in the sentinel group, the DSMB will review the 
data and make a recommendation to continue dosing 
as planned, or to modify or stop dosing. 
Clarification of criteria for assessing 
safety in the sentinal group 
 
Once all Cohort III subjects complete Day 28, a 
safety and pharmacokinetic data review will be 
performed by the DSMB. If 3 or more of the 9 
Cohort III subjects have moxidectin exposures 
to Day 28 below or above the target range, 
defined as AUCs less than the 10th percentile 
or greater than the 90th percentile mean AUC 
predicted by the population pharmacokinetic 
model, a revised dose of moxidectin will be 
determined in increments of 2 mg (maximum 
dose 8 mg) and Cohort III will be repeated with 
at least 9 new subjects enrolled at the new 
dose.  
Once all Cohort III subjects complete Day 28, a safety 
and pharmacokinetic data review will be performed by 
the DSMB. If 3 or more of the 9 Cohort III subjects 
have moxidectin exposures to Day 28 below or above 
the target range, defined as AUCs less than the 10th 
percentile or greater than the 90th percentile mean 
AUC predicted by the population pharmacokinetic 
model, a revised dose of moxidectin will be determined 
in increments or decrements of 2 mg (maximum dose 
8 mg) and Cohort III will be repeated with at least 9 
new subjects enrolled at the new dose. 
Clarification that if a second group of 
children in the Cohort III age range is 
enrolled, the dose may be an 
increment or a decrement. 
 
Subsequent to the enrolment of the initial 
group of 3 subjects in each of Cohort II and 
Cohort III, additional subjects will be enrolled in 
groups of at least 3. This is for operational and 
social reasons 
Subsequent to the enrolment of the initial group of 
3 subjects in each of Cohort II and Cohort III, additional 
subjects will be enrolled in groups of at least 3. This is 
for operational and social reasons (to ensure subjects 
have other children to spend their time with while in the 
research center so they don’t feel lonely because).  
Clarification of social reasons for 
enrolling additional subjects in groups. 


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Section  5.4 Study Sites 
(Study Areas) 
This will be a single center study. The study 
will be conducted at the School of Public 
Health, UHAS Research Centre, formerly the 
OCRC research facility, Volta Region, Ghana. 
This will be a single center study. The study will be 
conducted at the School of Public Health, UHAS 
Research Centre, formerly the OCRC research facility, 
Volta Region, Ghana, which was the site for the Phase 
II and Phase III studies of moxidectin. The Investigator 
was a co-investigator on the Phase II study and the 
principal investigator on the Phase III study and thus 
has substantial experience with moxidectin. 
Inclusion of rationale for site and 
investigator selection. 
Section  5.5 Estimated 
Duration of the Study 
The on-study period per subject is 
approximately 28 weeks total: up to 30 days for 
consent, including up to 7 days Screening (in-
clinic) prior to Baseline, 7 days in clinic stay 
and 23 weeks outpatient follow -up post-
treatment. 
 
The on-study period per subject is approximately 
28 weeks in total: up to 30 days for Pre-screening 
(including consent/assent) and Screening (including up 
to 7 days in the research center for Screening ) prior to 
Baseline (pre-treatment on Day 0) and 7 days stay in 
the research center and 23 weeks outpatient follow-up 
post-treatment. 
Clarification of study phases and 
timelines. 
 
It is anticipated that the total duration of the 
study will be up to 15 months, including 
6 months for recruitment in the event that more 
than one cohort per age is required and for 
data analysis and reporting. 
It is anticipated that the total duration of the study will 
be up to 15 months, including 6 months for recruitment 
in the event that more than one cohort per age group is 
required and for data analysis and reporting. 
Clarification that cohorts are defined by 
age group, not age. 


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Section 6.1 Selection of 
Subjects 
The nature of the study and the possible risks 
will be explained to all potential subjects and 
their families/guardians and communities. 
Written informed consent will be obtained from 
each child’s parents/guardian and, where 
possible, assent will be obtained from each 
child prior to performing any study related 
procedures. The consent process is described 
in Section 14.1.2.  
Study recruitment will occur in villages in the Kpassa 
sub-district of the Nkwanta North district, including Wii, 
Azua and Jagri-Do (for ethically relevant considerations 
relating to the choice of these villages see Section 
14.1.2).  
The nature of the study and the possible risks will be 
explained to all potential subjects and their 
parent(s)/guardian(s) (legally acceptable 
representative, LAR) and communities. Written 
informed consent will be obtained from each child’s 
parent(s)/guardian(s) and assent will be obtained from 
each child (as and if appropriate for age) prior to 
performing any study -related procedures. For children 
too young or immature to give assent, the investigator 
will search for indication of ‘deliberate objection’ as per 
commentary to the Council for International 
Organizations of Medical Sciences (CIOMS) Guideline 
17 (Council for International Organizations of Medical 
Sciences (CIOMS), 2016) (this is subsequently 
considered to be implied in the use of the term 
‘assent’). The consent/assent process is described in 
Section 14.1.2.  
Clarification of subject selection 
process, specifically:  
• relating to the selection of the 
villages from which participants will 
be recruited; and 
• reference to the fact that parental 
consent as well as participant 
assent will be obtained and that 
children too young or immature to 
provide assent will be assessed for 
signs of ‘deliberate objection’. 
 
After providing written informed consent and 
testing for OV16 IgG4, children will be admitted 
at the study site and enrolled for Screening 
assessments 
After obtaining written informed consent/assent and 
testing for OV16 IgG4, children who are positive for 
OV16 IgG4 will, where possible, be assessed in the 
village setting against other eligibility criteria not 
requiring medical or other laboratory examinations, as 
described in Section 6.2 and Section 6.3. This is 
intended to minimize the number of potentially 
ineligible children who travel to the study site to 
determine eligibility. Those who continue to be eligible 
for the study will receive transportation to the study site 
together with a parent or guardian for the remaining 
Screening assessments 
Clarification of subject selection 
process, specifically that screening in 
the communities can include evaluation 
of eligibility criteria other than Ov16 
IgG4 antibodies and the rationale for 
this. 


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Section 6.4.1 
Contraception 
Female subjects of child-bearing potential 
(post-commencement of menarche and 
physically able to bear children) must have a 
negative pregnancy test (with a sensitivity of at 
least 50 International Units (IU)/mL) performed 
at Screening (serum) and Day 0 (urine) and at 
Day 28, Week 12 and Week 24 (urine or 
serum) as indicated in Table 1. 
Female subjects of child-bearing potential (post-
commencement of menarche and physically able to 
bear children) must have a negative pregnancy test 
(with a sensitivity of at least 50 International Units 
(IU)/mL) performed at Screening (serum) and at 
Day 28, Week 12 and Week 24 (urine) as indicated in 
Table 1. 
Clarification of pregnancy testing 
requirements. 
 
The reliability of sexual abstinence needs to be 
evaluated for each subject on an ongoing 
basis. 
Compliance with the commitment to sexual abstinence 
will be evaluated at the Day 14, Day 28, Week 12 and 
Week 24 visits by asking subjects whether they have 
been abstinent. In addition, a pregnancy test will be 
carried out for all girls of child-bearing capacity as 
described above, regardless of the chosen method of 
contraception. 
Clarification of method for assessing 
compliance with commitment to sexual 
abstinence. 
 
Counselling and provision of contraceptives will 
be carried out by the staff of the Family 
Planning Unit of the Hohoe Municipal Hospital. 
Counselling and administration of contraceptives (if 
needed) will be carried out by the staff of the Family 
Planning Unit of the Hohoe Municipal Hospital. 
Clarification that administration of 
contraceptives will be by appropriately 
experienced staff. 
Section 7.2 Visit 
Windows 
Consent may be obtained up to 30 days prior 
to Screening. Screening must be conducted 
post-consent and in the window of Day -7 to 
Day 0. 
Consent/assent may be obtained up to 30 days prior to 
the day of planned study drug administration (Day 0) 
and before any study-specific procedures are 
conducted. Screening (with the exception of 
OV16 IgG4 testing and initial assessment of eligibility 
criteria not requiring medical or laboratory 
examinations, as described in Section 6.1) must be 
conducted in the window of Day -7 to Day -1. 
Clarification relating to: 
• assent being obtained; 
• reference time point for 
consent/assent; and 
• screening conducted in the 
communities prior to transport of 
participants and a parent/guardian 
to the research center. 
Section 7.3 Study 
Procedures / 
Assessment Periods 
Not applicable 
Study procedures will be conducted in the presence 
and with the help of the parent/guardian who 
accompanies the subject to the research center, as per 
the wishes of the accompanying parent/guardian and 
child. 
Clarification that the child’s 
parent/guardian will be present during 
all study procedures as per the wishes 
of parent/guardian and child.  


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Section 7.3.1 Consent 
and Assent 
Written informed consent may be obtained up 
to 30 days prior to Baseline. Informed consent 
must be obtained prior to any study related 
procedure. 
The process for obtaining informed consent 
and assent is described in Section 14.1.2. 
Further details may be described in an 
institutional Standard Operating Procedure 
(SOP). 
The process for obtaining informed consent and assent 
is described in Section 14.1.2.  
Removal of repetitious text.  
Section 7.3.2 Pre-
screening (Screening 
Conducted in the 
Community) 
Testing will be conducted between Day -30 
and Day -1. This test may be performed in the 
subject’s home village or at the clinic prior to 
Screening.  
An OV16 IgG4 rapid format card test will be 
used (see Section 7.4.3.1).  
Subjects for whom informed consent and assent has 
been obtained (as described in Section 14.1.2) are to 
be tested for exposure to O. volvulus infection using an 
OV16 IgG4 rapid format card test (see Section 7.4.3.1). 
Those testing positive for OV16 IgG4 may also be 
evaluated for other study eligibility criteria as described 
in Section 6.1. These evaluations will be conducted 
between Day -30 and Day -1 and may also be 
performed in the research center during Screening. 
Clarification of ‘Pre-screening’ 
assessments, including that eligibility 
criteria other than OV16 IgG4 may be 
evaluated in the community. 
Section 7.3.3 Screening 
Subjects and their parent, guardian or a trusted 
adult member of the community assigned by 
the subject’s parent/guardian will be invited to 
attend the clinic for Screening. 
Subjects who pass pre-screening and their parent or 
guardian will be invited to attend the research center 
for Screening 
Clarification that accompanying adult 
must be a parent or guardian. 
 
The dormitory will have separate rooms for 
males and females 
The dormitory ward has four separate rooms and each 
group of parents/guardians with their children can 
choose how to occupy these. A registered nurse will be 
on duty at all times.  
Clarification that dormitory has four 
rooms and that study participants and 
their accompanying parents/guardians 
will decide how these are allocated. 
 
Following confirmation of informed consent, the 
following will be performed and documented: 
• Medical history (see Section 7.4.1) 
• A complete physical examination including 
assessment of all appropriate body systems 
to determine study eligibility (see 
Section 7.4.1) 
Unless already conducted at Pre-screening, the 
following assessments / study requirements will be 
performed and documented: 
• Medical history, including medication history and 
evaluation of ability to swallow tablets (see 
Section 7.4.1) 
• A complete physical examination including 
assessment of all appropriate body systems and 
evaluation of venous access to determine study 
eligibility (see Section 7.4.1) 
Revised to allow for the fact that some 
eligibility criteria may have already 
been evaluated during Screening in the 
communities (referred to as Pre-
screening) and that 
consent/assent/evaluation for 
deliberate objection has been obtained 
in the villages before OV16IgG4 
evaluation. 
 
o 
Ov16 IgG4 (see Section 7.4.3.1) 
Deleted 
Since OV16IgG4 testing will have been 
conducted in the villages. 


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Section 7.3.3 Screening 
Not applicable 
The ability of children to swallow tablets will be 
assessed by the investigator based on discussion with 
the child and their parent(s)/guardian(s) of the child’s 
previous experience with taking tablets of a similar size 
(see Section 3.4.4.3). Parent(s)/guardian(s) and the 
child will be shown a tablet of a similar size to 
moxidectin as an example. 
Clarification of how ability to swallow 
tablets will be assessed. 
 
Not applicable 
Eligible girls of child-bearing potential and their 
accompanying parent/guardian will have a discussion 
with a family planning nurse about the need for 
contraception and the different options available, and 
will be provided with a contraceptive as needed, as 
described in Section 
Clarification that counselling relating to 
birth control will be conducted after 
eligibility has been assessed. 
 
Transport for the subject and their 
parent(s)/guardian(s) to return to their village 
will be arranged for the day following 
Screening. 
Transport for the subject and their parent/guardian to 
return to their village will be arranged for the day 
following Screening. 
Clarification that each child will be 
accompanied by only one parent or 
guardian. 
Section 7.3.4 Day -1 
Subjects will be required to fast overnight (from 
midnight) prior to dosing (See Section 8.5.1). 
Subjects will be required to fast overnight (from after 
dinner, which will be served at approximately 19:00) 
prior to dosing (see Section 8.5.1). 
Adjustment remove discrepancy 
between protocol body and information 
documents (since as per investigator 
the idea of having a meal after dinner 
and thus information of fasting after 
midnight would be alien to the study 
participants and their 
parents/guardians). 
Section 7.3.5.1 Pre-
dose 
• A targeted physical examination (see 
Section 7.4.1) 
• 12-lead safety ECG (see Section 7.4.2) 
• Vital signs measurement (see Section 7.4.1) 
• Final confirmation of eligibility. Only subjects 
continuing to meet all of the inclusion criteria 
and none of the exclusion criteria will be 
dosed with moxidectin 
The following will be performed and documented pre-
dose: 
• A targeted physical examination (see Section 7.4.1) 
• Vital signs measurement (see Section 7.4.1) 
• Final confirmation of eligibility. Only subjects 
continuing to meet all of the inclusion criteria and 
none of the exclusion criteria will be dosed with 
moxidectin 
Grammatical adjustment and deletion 
of 12 lead ECG, which is not required 
on Day 0 Pre-dose, per the schedule of 
assessments. 
Section 7.3.5.2 Dosing 
If a subject vomits after taking the dose of 
moxidectin, the subject will be assessed as 
described in Section 12.4. 
If a subject vomits within 30 minutes of taking the dose 
of moxidectin, the subject will be assessed as 
described in Section 12.2. 
Clarification of timing of vomiting and 
update of section with further details. 
Section 7.3.5.3 
Sections 7.3.6 – 7.3.14  
Not applicable 
Addition of procedures to be conducted if clinically 
indicated. 
To ensure consistency with the 
schedule of assessments. 


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Section 7.4.1 
Demographic Data, 
Medical History, 
Physical Examination, 
Vital Signs 
Demographic data will include sex, date of 
birth, height (in centimeters [cm]) and upper 
arm circumference (in cm) and weight (in kg). 
The medical history will include any significant 
diagnosed medical conditions or surgical 
history. 
A complete physical examination (including 
head, eyes, ears, nose, throat, lungs, lymph 
nodes, heart, abdomen and skin) will be 
conducted at Screening to determine study 
eligibility. A targeted physical examination 
based on prior findings and reported AEs will 
be performed on Day 0 pre-dose, Hour 1 and 
Hour 8 and at all subsequent visits. Weight will 
be repeated at the Week 24/Early Withdrawal 
visit. 
Demographic data will include sex, date of birth, height 
(in centimeters [cm]), upper arm circumference (in cm) 
and weight (in kg), as well as history of living in a Loa 
loa endemic area. 
The medical history will include any significant 
diagnosed medical conditions or surgical history and 
medication history. 
A complete physical examination (including head, 
eyes, ears, nose, throat, lungs, lymph nodes, heart, 
abdomen and skin) and body weight and height 
measurements will be conducted at Screening to 
determine study eligibility.  
A targeted physical examination based on prior 
findings and reported AEs will be performed on Day 0 
pre-dose and at all subsequent visits. Targeted 
physical examinations may also be performed at Hours 
1, 2, 4 and 8 on Day 0 and at unscheduled visits as 
clinically indicated.  
Body weight measurement will be repeated at the 
Day 28 and Week 24/Early Withdrawal visits and may 
be performed at unscheduled visits if clinically 
indicated. 
Provision of additional details to ensure 
consistency other sections and the 
schedule of assessments. 
Section 7.4.3 Blood and 
Urine Samples 
• a 0.5 mL sample of blood for hematology 
assessments and 1.5 mL for biochemistry 
assessments at each of Screening, Days 7 
and 28, and Week 12 (total 8 mL across all 
visits) (see Section 7.4.3.2) 
• up to 4 mL for serum pregnancy testing (see 
Section 7.4.3.5) 
• a 0.5 mL sample of blood for hematology 
assessments and 1.5 mL for biochemistry 
assessments at each of Screening, Days 7 and 28, 
and Week 12 (total 8 mL across all visits) and at 
other visits if clinically indicated (see Section 
7.4.3.2) 
• up to 4 mL for serum pregnancy testing at 
Screening (see Section 7.4.3.5) 
Clarification of blood volume that might 
be required in case of clinically 
indicated hematology or biochemistry 
assessments 


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Section 7.4.3 Blood and 
Urine Samples 
Planned blood sample collection will be no 
more than 33.5 mL for females requiring 
pregnancy testing and 29.5 mL for all other 
subjects. The maximum blood sample 
collection in any 4-week period for any subject 
is 30 mL (when pregnancy testing is required). 
For a child of 4 to 7 years weighing an 
allowable minimum 12 kg, the blood volume 
required in any 4 week period is less than the 
recommended maximum 3% of blood volume 
of 28 mL (2001/20/EC, 2008, Zisowsky et al., 
2010) 
Planned blood sample collection will be no more than 
33.5 mL for females requiring pregnancy testing (≥ 12 
years and ≥ 30 kg) and 29.5 mL for all other subjects. 
The maximum blood sample collection in any 4-week 
period for any subject is 30 mL (when pregnancy 
testing is required). For a child of 4 to 7 years weighing 
an allowable minimum 12 kg, the blood volume 
required in any 4 week period (26 mL) is less than the 
recommended maximum 3% of blood volume of 28 mL 
and the maximum amount drawn within a single day 
(8.5 mL) is less than the recommended maximum 1% 
of blood volume of 9.6 mL (2001/20/EC, 2008, 
Zisowsky et al., 2010) 
Addition of minimum reference weight 
for females requiring serum pregnancy 
test. 
Addition of assessment of maximum 
single blood draw relative to guidance. 
 
A single mid-stream urine sample will be 
collected from female participants of 
childbearing potential for pregnancy testing 
(See Section 7.4.3.5). 
A single mid-stream urine sample will be collected from 
female participants of childbearing potential for 
pregnancy testing at Day 28, Week 12 and Week 24 / 
Early Withdrawal visits and, if clinically required, at 
unscheduled visits as (See Section 7.4.3.5). 
Addition of timing of urine samples for 
consistency with the schedule of 
assessments and information provided 
for blood samples. 
Section 7.4.3.1 O. 
volvulus Exposure Test 
A Standard Diagnostics Bioline 
Onchocerciasis IgG4 Rapid Test will be 
performed at Screening to determine prior 
exposure to O. volvulus. Instructions on 
sample collection and testing will be provided 
in the SRM. 
A Standard Diagnostics Bioline Onchocerciasis IgG4 
Rapid Test will be performed at Pre-screening to 
determine prior exposure to O. volvulus, as per the 
manufacturer’s instructions. 
Clarification that test will be conducted 
as per manufacturer’s instructions. 
Section 7.4.3.2 Safety 
Laboratory Test 
Blood will be collected at scheduled time points 
for safety laboratory testing. Approximately 
2 mL per visit will be collected, at Screening, 
Days 7 and 28 and Week 12 (8 mL total). 
Blood will be collected at scheduled time points and, if 
clinically indicated, at unscheduled visits, for safety 
laboratory testing. A maximum of 2 mL per visit will be 
collected at the scheduled time points at Screening, 
Days 7 and 28 and Week 12 (8 mL total; see Section 
7.4.3 for evaluation of blood volumes collected relative 
to guidance on blood collection in children). 
Clarification of blood volume drawn  
Addition of cross reference to 
information on evaluation of volumes of 
planned blood sample collection 
relative to guidance to facilitate ethics 
committee review. 
Section 7.4.3.3 
Pharmacokinetic 
samples 
Plasma will be prepared from 1.5 mL blood 
collected (with samples for safety testing as 
appropriate) at Screening and post-dose at 
Hours 1, 2, 4, 8, 24 and 72, Days 7, 14 and 28 
and Week 12 (16.5 mL in total). 
Plasma will be prepared from 1.5 mL blood collected 
(with samples for safety testing as appropriate) at 
Screening and post-dose at Hours 1, 2, 4, 8, 24 and 
72, Days 7, 14 and 28 and Week 12 (16.5 mL in total; 
see Section 7.4.3 for evaluation of blood volumes 
collected relative to guidance on blood collection in 
children). 
Addition of cross reference to 
information on evaluation of volumes of 
planned blood sample collection 
relative to guidance to facilitate ethics 
committee review. 


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Section 7.4.3.4 
Laboratory Testing for 
Other Infections 
Testing for the presence of infection with HIV, 
chronic hepatitis B and C will be conducted at 
Screening.  
Testing for the presence of infection with HIV, chronic 
hepatitis B and C will be conducted at Screening using 
commercially available rapid test kits as per the 
manufacturer’s instructions.  
Clarification that commercial rapid 
diagnostic tests will be used according 
to the manufacturer’s instructions. 
 
Not applicable 
Testing for other infections (e.g. malaria) will be 
conducted as per investigator judgement in case of 
clinical suspicion. 
Clarification on how exclusion criterion 
12 will be evaluated. 
Section 7.4.3.5 
Pregnancy test 
At Day 28 and Week 12, a urine pregnancy 
test will be performed. 
At Day 28, Week 12 and Week 24 / Early Withdrawal, a 
urine pregnancy test will be performed.  
Commercially available rapid test kits will be used as 
per the manufacturer’s instructions. 
Clarification that urine pregnancy test 
will also be conducted at Week 24 or 
early withdrawal. 
Clarification of method to be used. 
Section 8.3 Treatment 
Allocation 
A Screening identification (ID) number will be 
allocated to each subject for whom informed 
consent is provided. 
A Screening identification (ID) number will be allocated 
to each subject for whom parental/guardian informed 
consent and child assent (as appropriate for the age 
group, see Section 14.1.2) is provided 
Clarification that child assent (as age 
appropriate, i.e. including evaluation for 
deliberate objection as specified in 
section 14.1.2) will also be required 
before a Screening ID is attributed. 
Section 8.5 Storage 
and Handling 
Only subjects enrolled in the study may receive 
moxidectin 2 mg tablets 
Only subjects enrolled in the study (i.e. those for whom 
eligibility has been confirmed on Day 0, see Section 
13.3) 
Clarification of when participants are 
considered enrolled. 
Section 10.2.1 
Assessment of Adverse 
Events 
AEs should be recorded, and severity graded 
according to the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 2.1, 
July 2017. This is provided in the SRM and 
available at: https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-
tables. 
AEs should be recorded, and severity graded 
according to the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.1, July 2017. This is provided in 
Appendix 16.5 and is available at: 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables. 
An additional appendix has been 
provided to facilitate availability of the 
AE grading scale. 
Section 10.3.2.1 All 
Serious Adverse events 
• send to the Safety Desk within 24 hours of 
the investigator’s knowledge of the event. 
Safety Desk contact details are in the SRM 
• send to the Safety Desk within 24 hours of the 
investigator’s knowledge of the event by emailing to: 
 
sae@medicinesdevelopment.com 
Provision of SAE reporting address. 
Section 10.5 Clinical 
Laboratory 
Abnormalities and 
Other Abnormal 
Assessments as AEs or 
SAEs 
Any laboratory test result that meets the criteria 
for a SAE (refer to Section 10.3) should be 
recorded as an AE, the AE page of the CRF 
completed and a SAE form also completed in 
order for the Sponsor to collect additional 
information about that abnormality, including 
information regarding relationship to 
investigational product or other causes, any 
action taken and resolution. 
Any laboratory test result that meets the criteria for a 
SAE (refer to Section 10.3) should be recorded as an 
AE, the AE page of the CRF completed and a SAE 
form also completed in order to provide the Sponsor 
with additional information about that abnormality, 
including information regarding relationship to 
investigational product or other causes, any action 
taken and resolution. 
Clarification text. 


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Section 10.7 Guidance 
for Dose Modification or 
Discontinuation of 
Treatment 
There will be no dose modification.  
There will be no dose modification for individual 
subjects, since this is a single dose study.  
Clarification of sentence in the context 
of this study (e.g. a second group 
within the Cohort II age group may be 
treated with a dose different from the 
initial dose depending on the outcome 
of Cohort II treated with 8 mg). 
Section 10.9 Risks for 
Women of Childbearing 
Potential or During 
Pregnancy 
The risks of treatment with moxidectin during 
pregnancy have not been evaluated. 
The risks of treatment with moxidectin during 
pregnancy have not been evaluated in humans. For 
information on the risk assessed in animal studies, see 
Section 3.3.1.2.2 and the Investigator’s Brochure for 
moxidectin. 
Clarification that the original statement 
only refers to humans (animal 
reproductive toxicology data are 
available). 
Section 10.10 
Procedures to be 
Followed in the Event of 
Pregnancy 
The subject must be instructed to inform the 
investigator IMMEDIATELY if she or, if male, 
their partner, becomes pregnant during the 
study period. The investigator should report all 
pregnancies to the Sponsor or designee within 
48 hours of becoming aware of the pregnancy. 
The subject and their parent(s)/guardian(s) must be 
instructed to inform the investigator IMMEDIATELY if 
the subject or, if male, their partner becomes pregnant 
during the study period. Contact information is provided 
on the study information sheet and the participant 
identification card each subject will receive. Subjects 
can also choose to ask the community coordinator (see 
Section 14.1.2.1) to contact the study team.  
Clarification that parents and guardians 
will also be requested to inform the 
investigator if the child becomes 
pregnant. 
Clarification that subjects and 
parents/guardians will be provided with 
contact information for the investigator 
and can also chose to inform 
investigator with the community-
selected coordinator. 


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Section 10.10 
Procedures to be 
Followed in the Event of 
Pregnancy 
Monitoring of the subject should continue until 
conclusion of the pregnancy. The outcome of 
the pregnancy should be reported to the 
Sponsor and a pediatrician will conduct follow-
up assessments of the health of the baby up to 
2 years of age.  
In the event of pregnancy in a subject, the investigator 
will advise the subject to attend all ante-natal visits and 
refer them to the appropriate GHS ante-natal service. 
Monitoring of the subject should continue until 
conclusion of the pregnancy (i.e. the investigator will 
ask the pregnant woman to contact him in case the 
GHS ante-natal service staff informs her about any 
abnormal findings). The outcome of the pregnancy 
should be reported to the Sponsor. Post-natal follow-up 
assessments of the health of the baby will be 
conducted by a pediatrician at least annually up to 2 
years of age.  
In the event of a pregnancy in the partner of a subject, 
the investigator should seek informed consent from the 
partner to monitor and report the outcome of the 
pregnancy to the Sponsor and to conduct post-natal 
follow-up assessments of the baby at least annually for 
2 years in the same way as for pregnant study 
participants).  
All abnormal GHS ante-natal service staff findings and 
results of follow-up assessments of babies will be 
reported to the Sponsor. 
Clarification of requirements for 
monitoring of a pregnancy in a study 
subject and that consent will also be 
sought for monitoring of pregnancies 
and follow-up of babies fathered by 
male study participants. 
Section 11 Data and 
Safety Monitoring 
Board (DSMB) 
The DSMB will review the safety and 
pharmacokinetic data following completion of 
enrolment and pharmacokinetic data analysis 
for both Cohorts I and II. 
The DSMB will review the safety and pharmacokinetic 
data following completion of enrolment and 
pharmacokinetic data analysis for both Cohorts I and II 
and recommend a starting dose for Cohort III. 
Clarification of the purpose of DSMB 
data review relating to the starting dose 
for Cohort III. 
Section 12.2 Criteria for 
Premature Withdrawal 
from Treatment or the 
Study 
Subjects also have the right to withdraw from 
the study at any time for any reason. The PI 
must make every reasonable effort to retain 
each subject in the study. 
Subjects (or their parent(s)/guardian(s)) also have the 
right to withdraw themselves (or their child/ward) from 
the study at any time for any reason. The PI must 
make every reasonable effort to understand the reason 
and, if possible, retain them in the study if their specific 
concerns can be addressed. 
To clarify that parents/guardians also 
have the right to withdraw their 
child/ward. 
To clarify that the investigator will make 
every effort to retain a subject in the 
study whilst still respecting the right of 
subjects and parents/guardians to 
withdraw themselves or their child. 
 
Not applicable 
If a subject vomits in the 30 minutes after taking the 
dose of moxidectin, all Day 0 assessments should be 
completed, and the subject should be withdrawn from 
the study. Any AEs or SAEs still ongoing at the time of 
withdrawal will be followed in accordance with Section 
10.  
Text moved here from section 12.4, 
which deals with procedures to be 
followed in case of withdrawal, but not 
criteria for withdrawal. 


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Section 12.2 Criteria for 
Premature Withdrawal 
from Treatment or the 
Study 
The PI also has the right to withdraw subjects 
from the study in the event of concurrent 
illness, AEs, pregnancy, protocol violations, 
administrative reasons or other reasons. 
The PI also has the right to withdraw subjects from the 
study for safety reasons (e.g. in the event of concurrent 
illness, AEs, or pregnancy), protocol non-compliance, 
or administrative or other reasons (see Section 12.6). 
Clarification that the PI has the right to 
withdraw the subject from the study for 
any reason related to subject safety, 
not only those listed. 
Addition of reference for administrative 
or other reasons. 
 
It is understood by all concerned that an 
excessive rate of withdrawals from the study 
can render the study difficult to interpret. In 
particular, missing data could significantly 
impact on the interpretation of the results; 
therefore, unnecessary withdrawal of subjects 
from the study should be avoided 
The reasons for withdrawal of the subject must 
be recorded on the CRF. 
An excessive rate of withdrawals from the study can 
render the study difficult to interpret. In particular, 
missing data could significantly impact on the 
interpretation of the results; therefore, unnecessary 
withdrawal of subjects from the study (e.g. based on 
misconceptions) should be avoided.  
The reasons for withdrawal of the subject must be 
recorded on the CRF (if given; if a reason is not given, 
this will be recorded). 
Clarification to avoid misconception 
that this paragraph is intended to 
motivate the investigator to minimize 
withdrawal even when this is in the 
interests of the subject’s safety and 
consistent with their and their 
parents/guardians rights to withdraw 
themselves or their child. 
Section 12.4 
Withdrawal of Subjects 
from the Study 
Should a subject decide to withdraw from the 
study, … 
Should a subject, and/or their parent(s)/guardian(s)) 
and/or the investigator decide on the withdraw of a 
subject from the study, 
Clarification that parents/guardians 
have the right to withdraw their child 
from the study. 
 
A complete final evaluation at the time of the 
subject withdrawal should be made with an 
explanation as to why the subject is 
withdrawing from the study. 
A complete final evaluation should be made at the time 
of the subject withdrawal, with an explanation for the 
withdrawal from the study. 
Clarification that this applies to subject 
withdrawing and investigator 
withdrawal of a subject. 
 
If a subject vomits up to 30 minutes after taking 
the dose of moxidectin, all Day 0 assessments 
should be completed and then the subject 
should be withdrawn from the study. Any AEs 
or SAEs still ongoing at the time of withdrawal 
will be followed in accordance with Section 10.  
Not applicable. 
Moved to section 12.2, since this is a 
criterion for withdrawal. 
Section 12.5 
Replacement of 
withdrawn subjects 
Any subjects who discontinue a clinical study 
of their own volition or by the PI are defined as 
“withdrawals”. 
Any subjects who discontinue a clinical study of their 
own and/or parent(s)/guardian(s) volition or are 
withdrawn by the PI are defined as “withdrawals”. 
Replacement subjects (up to a total study maximum of 
63 participants treated) 
Clarification that parents/guardians can 
also withdraw their child/ward and of 
the number of replacement subjects 
that may be enrolled in the study. 
Section 12.6 Premature 
Termination of the 
Study 
In the event that data obtained for Cohorts I or 
II does not enable determination of an optimal 
dose for Cohort III 
In the event that data obtained for Cohorts I or II does 
not enable determination of a starting dose for 
Cohort III or Cohorts I to III data does not enable 
determination of an optimal dose 
Clarification of requirements for study 
termination. 


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Section 13.3 Enrolment 
and Randomization 
Subject disposition will be described according 
to the numbers of subjects screened (not 
enrolled), enrolled (not treated) and treated. 
Screen failure data will not be databased. 
Subject disposition will be described according to the 
numbers of subjects screened (not enrolled), enrolled 
(not treated) and treated. Screen failure data will be 
included in the database only as necessary to 
determine the number of subjects screened but not 
enrolled and the reason(s) for ineligibility. 
Clarification of the extent of data to be 
entered into the database screen 
failures. 
Section 13.4 Analysis 
Populations 
As such, it is strongly recommended to adhere 
to the full pharmacokinetic sampling schedule 
as best as possible. 
As such, it is strongly recommended to adhere to the 
full pharmacokinetic sampling schedule as best as 
possible, unless non-adherence is required to 
safeguard subject safety. 
Clarification that subject safety is the 
prime consideration. 
 
Subjects in this population will be analyzed 
according to the dose received (actual drug 
amount). 
Subjects in this population will be analyzed according 
to the dose received (actual amount of investigational 
product swallowed). 
Clarification of how ‘actual drug 
amount’ will be determined. 
Section 13.5.4 Analysis 
of Safety 
AEs, concomitant medications and laboratory 
data will be listed and summarized by Cohort 
AEs, concomitant medications and laboratory data will 
be listed and summarized by Cohort, and/or by dose if 
more than one dose level is evaluated in an age group. 
Clarification of summarization in case 
more than one dose level is evaluated 
in Cohorts II and III. 
Section 13.6 
Pharmacokinetic 
Assessments for Dose 
Determinations 
The dose for children aged 4 to 7 years 
(Cohort III) will be selected following additional 
population pharmacokinetic modelling with 
allometric scaling including data obtained from 
Cohorts I and II. 
The first dose level to be proposed to the DSMB for 
administration in children aged 4 to 7 years (Cohort III) 
(and subsequent dose levels, if applicable, see Section 
5.3) will be selected following additional population 
pharmacokinetic modelling with allometric scaling 
including data obtained from Cohorts I and II. 
Clarification of DSMB role in dose 
selection for Cohort III. 
Section 14.1.3 
Compensation 
In addition, transportation will be provided to 
and from the study center, and accommodation 
and food will be provided for participants and 
their family/carers while at the study center. If 
the child is at the study center during school 
time, a teacher will be employed to provide 
educational activities and/or oversee 
homework during their stay to compensate for 
school time missed.   
In addition, transportation will be provided to and from 
the study center, and accommodation and food will be 
provided for each (potential) subject and their 
accompanying parent/guardian while at the study 
center 
Clarification that this applies to 
subjects and the accompanying 
parent/guardian.  
The Information on provision of 
teachers was extracted into a separate 
section since it is not a compensation. 
Section 14.1.4 
Provision for Study 
Visits During School 
Time 
Not applicable 
If the child is at the study center during school time, a 
teacher will be employed to provide educational 
activities and/or oversee homework during their stay to 
compensate for school time missed.   
Information on provision of teachers 
extracted from Section 14.1.3. 


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Section 14.1.5 Ethics 
Committees 
This protocol and any accompanying material 
provided to the subject (such as subject 
information sheets or descriptions of the study 
used to obtain informed consent) will be 
submitted by the investigator as described in 
Section 14.1.1 and to the Research Ethics 
Committee of the UHAS, the GHS Ethics 
Review Committee and the WHO Ethics 
Review Committee. Approval from all three 
ethics committees will be obtained before 
starting the study and must be documented in 
a letter to the investigator specifying the 
protocol number and version and the date on 
which the committee met and granted the 
approval. 
This protocol and any accompanying material provided 
to the potential subject and their parents/guardian 
(such as information sheets with descriptions of the 
study used to obtain informed consent/assent) will be 
submitted by the investigator to the Research Ethics 
Committee of the UHAS and the GHS Ethics Review 
Committee. Furthermore, the protocol will be submitted 
to the WHO Ethics Review Committee. Approval from 
all three ethics committees will be obtained before 
starting the study and must be documented in a letter 
to the investigator (or the WHO Responsible Officer 
submitting the protocol to the WHO Ethics Review 
Committee) specifying the protocol number and version 
and the date on which the committee met and the date 
it granted the approval.  
Section heading updated to accord 
with local terminology relating to ethics 
committees. 
Clarification that information 
documents are provided to potential 
study subjects and that this applies for 
both consent and assent.  
Modified to account for the fact that as 
per WHO ERC procedures, an 
investigator cannot submit a protocol or 
receive the WHO ERC response, and 
this will be done through the WHO 
Responsible Officer. 
Section 14.1.6 
Conditions for 
Modifying the Protocol 
The PI will then notify the ECs of such 
administrative changes. 
The PI (or WHO Responsible Officer) will then notify 
the ethics committees of such administrative changes. 
Clarification relating to WHO ERC 
procedures as outlined above.  
Section 14.1.8 Blood 
Volumes Sampled 
relative to the Maximum 
Recommended 
Volumes 
Not applicable 
Please refer to Section 7.4.3. 
Introduced to facilitate locating this 
ethically relevant information for 
reviewers. 
Section 14.4 
Confidentiality of Trial 
Documents and Subject 
Records 
All information concerning the study treatment 
and the Sponsor and its operation, 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 
All information concerning the study treatment shall 
remain the sole property of the Sponsor 
Elimination of language not applicable 
for the Sponsor as a not-for-profit 
organization. 


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Section 14.5 
Publication of Data 
(Dissemination of 
Results) 
The results of this study may be published or 
presented at scientific meetings. If this is 
envisaged, the PI agrees to submit all 
manuscripts or abstracts to the Sponsor prior 
to submission. This allows the Sponsor to 
protect proprietary information and to provide 
comments based on information from other 
studies that may not yet be available to the PI. 
Any formal publication of the study in which 
input of the Sponsor personnel exceeded that 
of conventional monitoring will be considered 
as a joint publication by the PI and the 
appropriate the Sponsor personnel. Authorship 
will be determined by mutual agreement prior 
to the completion of the study. 
The results of this study may be published or 
presented at scientific meetings. Sponsor-initiated 
publications and/or presentations will be agreed upon 
between the PI and Sponsor. PI-initiated publications 
and/or presentations will be provided for review by the 
Sponsor at least 30 days prior to submission to allow 
the Sponsor to provide comments based on 
information from other studies that may not yet be 
available to the PI. 
Any formal publication of the study in which input of the 
Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by 
the PI and the appropriate Sponsor personnel. 
Authorship will be determined by mutual agreement in 
accordance with International Committee of Medical 
Journal Editors recommendations. Additional authors 
will be agreed prior to journal submission 
Update of Section Heading given that 
the Sponsor is a not-for-profit 
organization 
Clarification for preparation of 
publications and criteria for determining 
authorship. 
Section 16.5 Division of 
AIDS (DAIDS) Table for 
Grading the Severity of 
Adult and Pediatric 
Adverse Events, 
Version 2.1, July 2017 
Not applicable 
Not applicable 
New appendix to facilitate access for 
protocol users and reviewers. 
 
Table 14: Details of Non-Administrative Protocol Amendments (Amendment 3) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 14.1.2 Informed 
Consent 
Not applicable 
Not applicable 
Section restructured to group together general 
principles relating to investigator responsibility 
and informing potential study participants and 
their parents/guardians in the presence of an 
independent witness. 
Information relating to informing potential 
participants and their parents/guardians 
previously provided in subsection 14.1.2.1 has 
been given its own subject heading for clarity. 


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Section 14.1.2 Informed 
Consent 
Not applicable 
Children who do not provide assent, including 
those aged 4-6 years and those 7-11 year old 
who may not be mature enough to give assent 
(as assessed by their parent(s)/guardian(s) 
and the person informing them about the 
study) will be assessed for expressions of 
‘deliberate objection’ (i.e. expressions of 
disapproval or refusal), as per CIOMS 
guidelines (Council for International 
Organizations of Medical Sciences (CIOMS), 
2016). Refusal to provide assent or an 
expression of ‘deliberate objection’ by a 
child/adolescent must be respected even if the 
parent(s)/guardian(s) have given consent for 
their participation in the study. The investigator 
will consider the child ineligible and record this 
on the informed consent provided by the 
parent(s)/guardian(s). 
Clarification that children who are not 
considered able to provide assent will be 
evaluated for expression of ‘deliberate 
objection’ as per CIOMS 2016.  
Section 14.1.2.1 
Informing Communities 
about the Study 
The council of elders will appoint a coordinator 
whom they think will best serve the 
community. Finally, the community will 
propose an impartial witness or witnesses for 
the informed consent procedure. 
During the community meeting, a ‘community 
coordinator’ will be selected. This will be a 
community member that the community thinks 
will best serve as a link between the subjects 
and the study team. Finally, the community will 
propose an impartial witness or witnesses for 
the informed consent/assent procedure 
Correction of the process for selection of the 
‘community coordinator’ and clarification that 
the witness(es) selected will also be 
witnessing the obtaining of assent. 
Section 14.1.2.2 
Informing Potential 
Subjects and their 
Parents/Guardians 
In order to address these factors, the following 
informed consent procedure is planned: 
In order to address these factors, recruitment 
will occur in communities from which 
participants in the Phase III study of 
moxidectin and another study conducted by 
the PI were recruited. Thus potential subjects 
and their parents/guardians themselves, or 
people they can talk to, are likely to have first-
hand experience in research study 
participation and procedures, the research 
center and moxidectin treatment, and 
therefore will be able to better understand the 
information provided about the study during 
the informed consent process.  
Clarification of factors inherent in selection of 
the villages for recruitment which will provide 
potential participants and their 
parents/guardians with additional sources of 
information about participation in clinical 
studies of moxidectin at the research center in 
Hohoe. 


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Section 14.1.2.2 
Informing Potential 
Subjects and their 
Parents/Guardians 
1. The process will take place in the 
community in order to remove any 
pressures imposed by its occurrence in the 
alien hospital environment;  
1. The process will take place in the 
community in order to remove any 
pressures imposed by its occurrence in the 
possibly unfamiliar research center 
environment.  
Clarification that the study will not be 
conducted at a hospital but at a research 
center. 
 
Not applicable 
2. Initial information will be provided at a 
community meeting, which will allow 
meeting participants to benefit from the 
questions asked by other meeting 
participants. This will be followed by 
discussions with individual 
parent(s)/guardian(s) and their child/ward.  
Clarification of the benefit of initial presentation 
of the study at a community meeting. 
 
2. Information will be conveyed in the local 
language. This means that the English 
version of the informed consent form (ICF) 
will be translated and authenticated by a 
reputable individual or agency and available 
for use as appropriate; 
3. Study information will be conveyed in the 
local language. The English version of the 
informed consent/assent information and 
forms will be translated and authenticated 
by a reputable individual or agency. Four 
different information documents have been 
generated. 
Introduction of four different consent/assent 
and/or information documents and 
characterization of the target audience for 
each. 
 
Not applicable 
i. the adolescent (12 to 17 years) and 
parent/guardian information sheet and 
assent and consent form is written in 
language that is understandable to a 12-
year-old (see Appendix 16.6);  
 
 
Not applicable 
ii. a separate parent/guardian information 
sheet and consent/assent form for parents 
of children aged 4 to 11 (see Appendix 
16.7), also written in language 
understandable to children aged 12 years 
and including two consent/assent forms:  
1. one for parents and children <12 years 
who are providing assent (includes 
written parent/guardian consent 
confirmation and child assent); 
2. one for parents/guardians of children 
considered too immature to provide 
assent (includes written parent/guardian 
consent and documentation of 
assessment of expression of “deliberate 
objection”);  
 


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Section 14.1.2.2 
Informing Potential 
Subjects and their 
Parents/Guardians 
Not applicable 
iii. a simpler study information sheet for 
children aged 7 to 11 years considered 
mature enough to provide assent (see 
Appendix 16.8);  
 
 
Not applicable 
iv. an even simpler information sheet for 
children 4 to 6 years or older children 
considered too immature to provide (see 
Appendix 16.9). 
 
 
3. Every effort will be made to ensure that all 
aspects of the study and all the elements 
regarded as essential to validate the 
informed consent process are specified in 
the ICF. These are presented in 
chronological order, and will be 
supplemented by a schematic diagram to 
facilitate comprehension and simplify the 
process for the parents/guardians and 
subjects; 
4. Every effort has been made to ensure that 
all aspects of the study and all elements 
regarded as essential for the informed 
consent/assent are specified in the 
information documents for consent/assent. 
These are presented in chronological order 
and supplemented by images and 
schematic diagrams to facilitate 
comprehension. 
To clarify that the focus is on obtaining 
informed consent/assent, not just validating 
the process. 
Addition of information that images have now 
been included in the information documents to 
aid comprehension and retention of 
information. 
 
4. Understanding of the study procedures will 
be assessed using a short test consisting of 
a series of open and closed questions in 
the local language for parents/guardians 
and subjects to answer. The questions to 
be asked are included at the end of Parent 
Information Sheet and Consent Form, with 
space provided for recording responses 
(refer to Appendix 16.5); 
5. Understanding of the information provided 
about the study will be assessed using a 
short questionnaire consisting of a series of 
open and closed questions in the local 
language for parents/guardians and 
adolescents and children considered 
mature enough to give assent to answer. 
The questions to be asked are included at 
the end of the informed consent/assent 
documents, with space provided for 
recording responses and any questions 
asked by the adolescent/child or 
parent(s)/guardian(s) (refer to Appendix 
16.6, Appendix 16.7, Appendix 16.8). 
Provision of information that age appropriate 
questionnaires have been added to the 
information sheets to examine the 
comprehension of adolescents 12 to 17 years 
and children 7 to 11 years and considered 
mature enough to provide assent. 


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Section 14.1.2.2 
Informing Potential 
Subjects and their 
Parents/Guardians 
5. An impartial, literate local resident agreed to 
by the subject (impartial witness) must 
countersign the document to attest to the 
fact that the information has been given to 
and understood by the parent/guardian; 
 
6. An impartial, literate local resident agreed to 
by the potential subject and their 
parent(s)/guardian(s) (impartial witness) 
must be present when study information is 
provided and discussed, and must 
countersign the consent/assent form to 
attest to the fact that the information has 
been given to and understood by the 
parent(s)/guardian(s) and child. 
Clarification of the role of the witness relating 
to adolescents/children providing assent.  
 
6. The ICF must be signed in 2 originals, one 
of which must be given to the 
parent(s)/guardian(s) in front of the impartial 
literate witness on the same day that the 
informed consent procedure takes place 
7. The informed consent/assent forms must be 
signed / thumbprinted in 2 originals, one of 
which must be given to the 
parent(s)/guardian(s) in front of the impartial 
literate witness on the same day that the 
informed consent/assent is given. 
Clarification that this process also applies for 
assent. 
 
7. At each subsequent study visit, the 
investigator should verbally confirm the 
continued consent / assent of the subject 
and that they are free to withdraw from the 
study at any time for any reason 
8. At each subsequent study visit, the 
investigator should verbally confirm the 
continued consent / assent / lack of 
deliberate objection of the subject and that 
they are free to withdraw from the study at 
any time for any reason. 
Clarification that continued lack of deliberate 
objection should also be evaluated. 


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Section 14.1.2.3 
Informing Children Too 
Young/Immature to Give 
Assent 
Not applicable 
Information about the study, primarily based 
on pictures (Appendix 16.9) will be presented 
to children 4-6 years old as well as older 
children considered not mature enough to 
provide assent in the joint judgement of the 
parent(s)/guardian(s) and the investigator.  
Early on in the presentation and discussion, a 
tablet similar in size and shape to moxidectin 
tablets will be shown and the child and their 
parent(s)/guardian(s) will be asked whether 
they think the child can swallow such tablets. If 
a child or their parent(s)/guardian(s) states 
that they cannot swallow a tablet of that size 
and shape, there will be no further discussion. 
Subsequently children will be told about the 
need to take blood and venous access will be 
assessed.  If a child has poor venous access, 
there will be no further discussion. 
It is acknowledged that this constitutes 
evaluation of exclusion criteria 7 and 8 before 
the child has been presented with all 
information about the study and had the 
opportunity to express ‘deliberate objection’ to 
all other elements of the study. This sequence 
was chosen since it does not include an 
invasive procedure or confidential health 
information and obtaining all other information 
about the study has no value for a child who 
will be excluded on the basis that they cannot 
swallow the tablets or have poor venous 
access.  
Addition of a new section to provide the 
rationale for the order in which information 
about the study will be provided to children 4 
to 6 years and older children considered too 
immature to provide assent to be evaluated for 
‘deliberate objection’. 


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Revised to Read 
Rationale for Change 
Section 16.6 Model 
Adolescent (12 to 17 
years) and 
Parent/Guardian 
Information Sheet and 
Assent and Consent 
Form  
Not applicable 
The document has been rewritten to: 
• address the adolescent (with clarification 
that this is also the information for their 
parent(s)/guardian(s)); 
• include relevant context (ivermectin mass 
drug administration in the villages, conduct 
of the Moxidectin Phase III study with 
participants from these villages); 
• provide more details on unwanted effects 
occurring after taking moxidectin and 
compare them with those occurring after 
taking ivermectin; 
• eliminate information applicable only to 
younger children and not relevant for 
adolescents and their parents; 
• add pictures of critical study elements; 
• simplify language; 
• add a short overview of all steps of the 
study primarily based on pictures; 
• provide separate questionnaires to assess 
comprehension of adolescents and of their 
parents/guardians; and 
• rearrange the consent and assent forms so 
that all required signatures/thumbprints 
(parents/guardians, subject, witness, 
person obtaining consent/assent) are on a 
single page. 
Provide information that is easier to 
understand and relevant for this age group 
and their parents/guardians  
Provide a basis for assessing comprehension 
of adolescents. 
Section 16.7. Model 
Information Sheet and 
Consent Form for 
Parents/Guardians of 
Children 4 to 11 Years, 
Including Assent Form 
for Children 7 to 11 
Years 
Not applicable 
This document has been newly generated 
since information relevant for the 
parents/guardians of children 4 to 11 years of 
age differs slightly from that which is relevant 
for parents/guardians of children aged 12 to 17 
years. 
The principles followed in this document are 
identical to those listed above for the 
document for adolescents 12 to 17 years and 
their parents/guardians. 
Provide information targeted to the parents of 
children aged 4 t0 11 years. 


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Revised to Read 
Rationale for Change 
Section 16.8 Model 
Information Sheet for 
Children 7 to 11 Years 
Mature Enough to 
Provide Assent 
Not applicable 
This document has been rewritten following 
the principles outlined above for the document 
for adolescents and their parents/guardians, 
including generation of an age-adapted 
questionnaire to assess potential subject 
comprehension. 
Provide information in a way that is that is 
understandable to children 7 to 11 years who 
are giving assent. 
Provide a basis for assessing comprehension 
of children 7 to 11 years. 
Section 16.9 Model 
Information Sheet for 
Children 4 to 6 Years and 
Older Children 
Considered Not Mature 
Enough to Provide 
Assent 
Not applicable 
This document has been newly generated  
Provide information about the study in a way 
that is understandable to children 4 to 6 years. 
Provide a basis for assessing these children 
for expressions of ‘deliberate objection’. 
 
 
 


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16.10.4 
Rationale for Protocol Amendment No. 4 
This amendment was made in response to comments received from the World Health Organization Research Ethics Review Committee following 
its review of the protocol at the meeting held on 12 December 2019.  
The amendments are all considered to be administrative in nature, since they do not change the conduct of the study or result in any increase in 
risk to subjects. Details of sections of the protocol amended are provided in Table 15. 
Table 15: Details of Administrative Protocol Amendments (Amendment 4) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Throughout document 
Not applicable 
Correction of minor grammatical and 
typographical errors.  
To improve readability and consistency 
within the document.  
Cover page, Investigator 
Statement page (page 2) and 
page footers 
Version 1.3 (incorporating Amendment 1, 2, 
and 3)  
27 Nov 2019 
Version 1.4 (incorporating Amendments 1, 2, 
3 and 4)  
21 Jan 2020 
Version number and date updated to 
indicate protocol amendment. 
Section 14.1.9 Informing Study 
Subjects and Community about 
the Study Results, page 86 
Not applicable – new text 
14.1.9 Informing Study Subjects and 
Communities about the Study Results 
Once the final data from the study are 
available and a decision on further 
evaluation of moxidectin has been made, 
each community will be visited. The 
study subjects and their parents, as well 
as other interested community members, 
will be informed about the study results 
and any future activities to be undertaken 
to enable the use of moxidectin for 
control and elimination of onchocerciasis 
in endemic countries. Age appropriate 
information documents to be used for 
this purpose will be submitted for review 
and approval by the responsible ethics 
committees. 
Addition of a new section (14.1.9) to the 
protocol, corresponding to the section in the 
participant information sheet describing the 
plan for sharing the results of the study with 
study subjects and their families and 
communities.  
14.1.3 Compensation, page 84 
All study-related costs, including study 
medication and provision, and medical care 
will be provided free of charge. 
All study-related costs, including study 
medication, laboratory tests, contraceptives 
counselling and provision, and medical 
care will be provided free of charge. 
Clarification that costs of counselling and 
provision of contraceptives, if required, will 
be borne by the study.  


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Revised to Read 
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Model Adolescent (12 to 17 
years) and Parent/Guardian 
Information Sheet and Assent 
and Consent Form, page 168 
If you change your mind about taking part in 
the study and don’t want to take part 
anymore, we will stop collecting information. 
We and the Sponsor will still use the 
information that we collected before you told 
us you want to stop being in the study. 
If you change your mind about taking part in 
the study and don’t want to take part 
anymore, we will stop collecting information. 
We and the Sponsor will still use the 
information that we collected before you told 
us you want to stop being in the study. 
However, if you have an unwanted effect 
that has not stopped, we will ask you to 
let us visit you to find out whether you 
need any treatment for this effect. Also, if 
you are pregnant, we will ask you if the 
doctor working with us who specializes 
in treating babies and children can come 
and examine the baby after birth and at 
least yearly for 2 years. If you are male 
and your partner becomes pregnant, we 
will ask you if we can contact your 
partner to ask her if we can examine the 
baby. You or your partner do not have to 
agree to this. 
Clarification that information will no longer 
be collected from subjects when they leave 
the study, unless they (or their partner, as 
appropriate) agree to follow-up of the baby 
in the event of a pregnancy (in the subject or 
their partner) or to follow-up of an ongoing 
adverse event. 
16.7 Model Information Sheet 
and Consent Form for 
Parents/Guardians of Children 
4 to 11 Years, Including Assent 
Form for Children 7 to 11 
Years, page 186 
If you change your mind about allowing your 
child or ward to take part in the study or the 
child doesn’t want to take part anymore, we 
will stop collecting information. We and the 
Sponsor will still use the information that we 
collected before you told us you wanted your 
child or ward to stop taking part in the study 
(or your child or ward told us they want to 
stop taking part in the study). 
If you change your mind about allowing your 
child or ward to take part in the study or the 
child doesn’t want to take part anymore, we 
will stop collecting information. We and the 
Sponsor will still use the information that we 
collected before you told us you wanted your 
child or ward to stop taking part in the study 
(or your child or ward told us they want to 
stop taking part in the study). However, if 
your child/ward has an unwanted effect 
that has not stopped, we will ask you to 
let us visit you and your child/ward to 
find out whether they need any treatment 
for this effect. You and your child/ward 
do not have to agree to this. 
Clarification that information will no longer 
be collected from subjects when they leave 
the study, unless the subject and their 
parents/guardians agree to follow-up for an 
ongoing adverse event. 
 
 


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Protocol Number: MDGH-MOX-1006 
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16.10.5 
Rationale for Protocol Amendment No. 5 
The Ghana Food and Drugs Authority in its feedback on review of the study (dated 18 May 2020) requested clarifications to the protocol which 
have resulted in the requirement for this amendment.  
In addition, the GHS Ethics Review Committee released guidelines for researchers during the COVID-19 pandemic, effective 7 May 2020, that 
require research protocols to take the current COVID-19 pandemic and public health measures into consideration by ensuring that the proposed 
research and methods for data collected can be conducted in a safe environment that also adheres to national directives on social distancing. As a 
result, the potential risks of conducting the study under the current circumstances have been assessed and risk mitigation strategies addressed in 
this amendment. 
Furthermore, the requirement for Ov16 IgG4 testing at Screening has been removed in this amendment based on recently-published results of a 
WHO external advisory committee review of large-scale evaluation of Ov16 IgG4 assays in various settings which has identified significant 
discrepancies between the results obtained with different assays and concerns about both false positive and false negative results. These concerns, 
together with the fact that the Ov16 IgG4 antibody test selected is designed to be a surveillance tool for onchocerciasis elimination programs in the 
late and post-control stages and not an individual diagnostic, suggested that it will not be possible to reliably identify individual children who have 
been exposed to O. volvulus. In addition, the Ov16 IgG4 antibody test is not registered in Ghana and is consequently an investigational diagnostic. 
The study presents a minor increase over minimal risk to the participating children but remains justified on the basis that it is not possible to gather 
the necessary data in adults and the study is being conducted in a region designated as endemic for O. volvulus, where children are at risk of O. 
volvulus infection. Consequently, the participants represent the population which will benefit from the identification of a paediatric dose that will 
allow children younger than 12 years to be included in moxidectin-based elimination strategies. 
The following sections of the protocol have been amended and details are provided in Table 16 and Table 17. 
Table 16: Details of Administrative Protocol Amendments (Amendment 5) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Throughout document 
Not applicable 
Correction of minor grammatical and 
typographical errors.  
To improve readability and consistency 
within the document. 
Cover page and footers 
Version 1.4 (incorporating Amendments 1, 2, 
3 and 4)  
21 Jan 2020 
Version 1.5 (incorporating Amendments 1, 2, 
3, 4 and 5)  
03 Jul 2020 
Version number updated to indicate protocol 
amendment. 
Abbreviations 
Not applicable 
Addition of definitions for abbreviated terms 
used within the document.  
To ensure clarity of meaning of abbreviated 
terms. 


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Protocol Number: MDGH-MOX-1006 
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Section 
Original Text 
Revised to Read 
Rationale for Change 
Section 15: References 
Not applicable 
Removal and addition of references. 
Revised to ensure completeness following 
updates and additions to the text. 
Section 16.10.5: Rationale for 
Protocol Amendment No. 5 
Not applicable 
Inclusion of Amendment 5 Summary of 
Protocol Amendment 
Provision of details of changes from version 
1.4.  
 
Table 17: Details of Non-Administrative Protocol Amendments (Amendment 5) 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Synopsis: Background 
However, to determine eligibility to the study, 
O. volvulus immunoglobulin G4 (Ov16 IgG4) 
testing will be performed to determine if the 
child is currently infected or has ever been 
exposed to O. volvulus infection and to 
exclude those with no evidence of prior 
systemic exposure to that infection. This is to 
balance risks in study participation with 
potential individual benefit from treatment,  
To balance risks in study participation with 
potential individual benefit from treatment, 
participants will be recruited from an area 
where onchocerciasis is endemic. 
Ov16 IgG4 testing for O. volvulus infection 
removed from protocol based on a recently 
published WHO report identifying significant 
discrepancies between different assays and 
concerns about both false positive and false 
negative results. See changes described for 
Section 3.4.3, below. 
Synopsis: Inclusion Criteria  
Section 6.2: Inclusion Criteria 
6. 
Test positive for Ov16 IgG4 antibody by 
rapid format antibody card test. 
Not applicable  
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Synopsis: Study Procedures 
After obtaining written informed consent from 
the parent(s)/guardian(s) and assent (or 
determining lack of expression of ‘deliberate 
objection’) from the child (see Section 14.1.2 
for details) the child will be tested for OV16 
IgG4 antibody. Children with a positive test 
result and meeting other eligibility criteria 
evaluated in the village, together with one 
parent or guardian, will be invited to attend 
the research center for further Screening. 
After obtaining written informed consent from 
the parent(s)/guardian(s) and assent (or 
determining lack of expression of ‘deliberate 
objection’) from the child (see Section 14.1.2 
for details), children meeting eligibility criteria 
that are able to be evaluated in the village 
will be invited to attend the research center 
for further Screening, together with one 
parent or guardian. 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Synopsis: Safety Parameters 
Table 1: Table of 
Assessments 
Section 7.3.3: Screening 
Tympanic temperature 
Temperature 
Removal of requirement for contact 
temperature measurement as part of 
measures taken to minimize risks associated 
with conduct of the study during the COVID-
19 pandemic. 


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Section 
Original Text 
Revised to Read 
Rationale for Change 
Synopsis: Specialized Tests 
and Analyses 
Prior exposure of each subject to O. volvulus 
infection will be determined by OV16 IgG4 
rapid format antibody card test prior to 
undertaking further screening assessments. 
Not applicable  
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Synopsis: Special Protocol 
Requirements or Issues 
Exposure to O. volvulus will be confirmed by 
OV16 IgG4 rapid format antibody card test. 
Not applicable  
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Table 1: Table of 
Assessments 
OV16 IgG4 test 
Footnote Abbreviations: OV16 IgG4 = O. 
volvulus 16 antigen immunoglobulin G4 
Not applicable  
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Table 1: Table of 
Assessments 
Footnote b: Blood pressure, and pulse, 
tympanic temperature and respiratory rate 
will be measured lying semi-supine for 5 
mins. 
Footnote b: Blood pressure, pulse, 
temperature and respiratory rate will be 
measured lying semi-supine for 5 mins.  
Clarification to ensure consistency with 
Section 7.4, Details of Scheduled 
Assessments. 
Table 1: Table of 
Assessments 
Section 7.3.3: Screening 
Not applicable 
Adverse events and concurrent medications 
assessments added to Consent and Pre-
screening and Screening visits. 
Clarification to ensure consistency between 
Table of Assessments, Section 7.4, Details 
of Scheduled Assessments and Section 
10.2, Adverse Events. 
Section 3.3.2.2.2: Overview of 
Safety and Efficacy in 
Patients with Onchocerciasis 
Table 2: Adverse Reactions Occurring in > 
10% of Moxidectin-treated Patients with 
Onchocerciasis in ONCBL60801 (Phase III) 
Adverse Reaction  
Table 2: Treatment-emergent Adverse 
Events Occurring in > 10% of Moxidectin-
treated Patients with Onchocerciasis in 
ONCBL60801 (Phase III) 
Adverse Event 
Correction of table caption and column 
heading to align with the updated 
Investigator’s Brochure v6 dated 12 Jun 
2020. 
Section 3.4.3: Design 
Rationale 
Additionally, O. volvulus infection risk on an 
individual participant basis will be determined 
by OV16 IgG4 testing to confirm if the child is 
currently infected or has ever been exposed 
to O. volvulus infection and to exclude those 
with no evidence of prior systemic exposure 
to that infection. This is to balance risks in 
study participation with potential individual 
benefit from treatment. 
Ov16 IgG4 antibody positivity determined 
using the Ov16 IgG4 antibody rapid format 
card test was originally included as an 
eligibility criterion in order to provide a benefit 
to study participants, since it was assumed 
that a positive test would indicate that the 
participant had been exposed to O. volvulus. 
However, this criterion has now been 
eliminated for the following reasons: 
• Recently-published results of a WHO 
external advisory committee review of 
large-scale evaluation of different assays 
for detecting Ov16 IgG4 antibodies in 
different settings and countries has 
Addition of rationale for removal of Ov16 
IgG4 testing for O. volvulus infection from the 
protocol. 


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Protocol Number: MDGH-MOX-1006 
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Original Text 
Revised to Read 
Rationale for Change 
identified significant discrepancies 
between the results obtained with different 
assays and concerns about both false 
positive and false negative results (WHO 
2020).   
• The concerns about false positive and 
false negative results, together with the 
fact that Ov16 IgG4 antibody testing is 
designed to be a surveillance tool for 
onchocerciasis elimination programs in 
the late and post-control stages and not 
an individual diagnostic (Abbott 2020), 
indicate that it will not be possible to 
reliably identify individual children who 
have been exposed to O. volvulus using 
the Ov16 IgG4 antibody test. In addition, 
the Ov16 IgG4 antibody test is not 
registered in Ghana and is consequently 
an investigational diagnostic. 
• While the study presents a minor increase 
over minimal risk to the participating 
children, it can be justified on the basis 
that it is not possible to gather the 
necessary data in adults and the study is 
being conducted in a region designated as 
endemic for O. volvulus, where children 
are at risk of O. volvulus infection. 
Consequently, the participants represent 
the population which will benefit from the 
identification of a paediatric dose that will 
allow children younger than 12 years to be 
included in moxidectin-based elimination 
strategies.  
Section 3.4.3: Design 
Rationale 
All enrolled children will have confirmed 
exposure to O. volvulus. 
Not applicable  
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Section 6.1: Selection of 
Subjects 
After obtaining written informed 
consent/assent, and testing for OV16 IgG4, 
children who are positive for OV16 IgG4 will, 
where possible, be assessed in the village 
After obtaining written informed 
consent/assent, children will, where possible, 
be assessed in the village setting against 
eligibility criteria not requiring medical or 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 


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Section 
Original Text 
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setting against other eligibility criteria not 
requiring medical or other laboratory 
examinations, as described in Section 6.2 
and Section 6.3. 
laboratory examinations, as described in 
Section 6.2 and Section 6.3, 
Section 6.2: Inclusion Criteria 
6. 
Tests positive for OV16 IgG4 antibody 
by rapid format antibody card test. 
Not applicable 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Section 7.2: Visit Windows 
Screening (with the exception of OV16 IgG4 
testing and initial assessment of eligibility 
criteria not requiring medical or laboratory 
examinations, as described in Section 6.1) 
must be conducted in the window of Day -7 
to Day -1. 
Screening (with the exception of initial 
assessment of eligibility criteria not requiring 
medical or laboratory examinations, as 
described in Section 6.1) must be conducted 
in the window of Day -7 to Day -1. 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Section 7.3.2: Pre-Screening 
(Screening Conducted in the 
Community) 
Subjects for whom informed consent/assent 
has been obtained as described in Section 
14.1.2 are to be tested for exposure to O. 
volvulus infection using an OV16 IgG4 rapid 
format card test (see Section 7.4.3.1). Those 
testing positive for OVG16 IgG4 may also be 
evaluated for other eligibility criteria as 
described in Section 6.1. 
Subjects for whom informed consent/assent 
has been obtained as described in Section 
14.1.2 will be evaluated for eligibility criteria 
not requiring medical or laboratory 
examinations, as described in Section 6.1. 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Section 7.3.3: Screening 
If the subject is ineligible to participate in the 
study due to a clinically significant laboratory 
abnormality or medical condition, a referral 
will be made to an appropriate GHS 
treatment facility for follow-up. 
If the subject is ineligible to participate in the 
study due to a clinically significant laboratory 
abnormality or medical condition, including a 
positive test for HIV, hepatitis B or hepatitis 
C, a referral will be made to an appropriate 
GHS treatment facility for follow-up. 
Clarification that potential subjects testing 
positive for HIV, hepatitis B or hepatitis C at 
Screening will be referred for appropriate 
follow-up. 
Section 7.4.2: 
Electrocardiograms 
Not applicable 
The following parameters will be reported: 
QRS, QT, QTcB (Bazett's correction 
formula), QTcF (Fridericia's correction 
formula), RR and PR intervals. 
Based on feedback from Ghana Food and 
Drugs Authority, both Bazett’s and 
Fridericia’s formulae will be used to calculate 
the corrected QT in order to make 
comparisons between the two calculations. 
Section 7.4.3: Blood and 
Urine Samples 
• 10 microliters (µL) for OV16 IgG4 testing 
(see Section 7.4.3.1) 
Not applicable 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 
Section 7.4.3.1: O. volvulus 
Exposure Test 
A Standard Diagnostics Bioline 
Onchocerciasis IgG4 Rapid Test will be 
performed at Pre-screening to determine 
Not applicable 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 


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prior exposure to O. volvulus, as per the 
manufacturer’s instructions. 
Section 8.5: Storage and 
Handling 
Unless otherwise labelled, the full contents of 
the container should be used within 24 hours 
or unused contents discarded. 
Unless otherwise labelled, the full contents of 
the container should be used within 7 days or 
unused contents discarded. 
Correction of the in-use period of the 
investigational product to align with the 
MDGH-MOX-1006 Investigational Product 
Dossier. 
Section 10.3.2.2: Investigator 
Reporting Requirements for 
SAEs 
An SAE may qualify for reporting to 
regulatory authorities if the SAE is 
considered to have a possible causal 
relationship to the investigational product and 
is unexpected (Suspected Unexpected 
Serious Adverse Reaction [SUSAR]) based 
upon the current Investigator’s Brochure. In 
this case, investigators will receive a formal 
notification describing the SAE. 
Where required by local regulations, and in 
accordance with the local institutional policy, 
the investigator should notify the EC of SAEs 
within the required timelines. 
Per Ghana Food and Drugs Authority 
guidelines, the investigator should report all 
SAEs to the Authority within 48 hours. 
Where required by local regulations, and in 
accordance with the local institutional policy, 
the investigator should also notify the EC of 
SAEs within the required timelines. 
Based on feedback from Ghana Food and 
Drugs Authority, investigator SAE reporting 
requirements revised to reflect regulatory 
guidelines. 
Section 13.5: Statistical and 
Analytical Plan 
Not applicable 
The SAP will be submitted to regulatory 
authorities prior to database lock, as 
required. 
Clarification that SAP will be submitted to 
regulatory authorities prior to database lock, 
as required. 
Section 14.1.10: 
Implementation of the Study 
in the Context of the COVID-
19 Pandemic 
Not applicable 
Addition of new section (Section 14.1.10) 
describing the review of protocol procedures 
and measures that will be taken to adhere to 
national public health directives in relation to 
COVID-19 to ensure the safety of 
participants, their communities and the study 
team during the pandemic. 
Per GHS Ethics Review Committee 
Guidelines for Researchers During the 
COVID-19 Pandemic (effective 7 May 2020), 
inclusion of information on procedures that 
will be put in place during the conduct of the 
study to minimize the risk of COVID-19 
infection. 
Section 14.5: Publication of 
Data (Dissemination of 
Results) 
Not applicable 
Per local regulatory guidelines, publication 
will only proceed 30 days after the Sponsor 
receives Ghana Food and Drug Authority's 
acknowledgement of receipt of the final study 
report. 
As requested by the Ghana Food and Drugs 
Authority, section updated in accordance 
with regulatory guidelines. 
Section 16.6: Model 
Adolescent (12 to 17 years) 
and Parent/Guardian 
What will happen in the study, where will 
it happen and how long will it take? 
What will happen in the study, where will 
it happen and how long will it take? 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 


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Information Sheet and Assent 
and Consent Form 
• We will take some drops of blood from a 
finger to see if you have ever had the 
oncho worms. If the test shows “no”, then 
you cannot take part in the study. 
 
• If the test shows “yes”, then we will ask 
questions about health problems you have 
had in the past, medicines you have 
taken, look closely at your arms to see if it 
will be easy to take blood. 
Help for your discussion with your 
parents/guardians, friends, family and 
others you want to talk this over with 
• Step 1 Screening in your community to 
see whether you have oncho and ask 
questions about your health (1-2 days). 
 
• We will ask questions about health 
problems you have had in the past, 
medicines you have taken, look closely at 
your arms to see if it will be easy to take 
blood. 
Help for your discussion with your 
parents/guardians, friends, family and 
others you want to talk this over with 
• Step 1 Screening in your community to 
ask questions about your health (1-2 
days). 
Section 16.7: Model 
Information Sheet and 
Consent Form for 
Parents/Guardians of 
Children 4 to 11 Years, 
Including Assent Form for 
Children 7 to 11 Years 
What will happen in the study, where will 
it happen and how long will it take? 
• We will take some drops of blood from a 
finger to see if the child has the oncho 
worms. If the test shows “no”, then the 
child cannot take part in the study. 
What will happen in the study, where will 
it happen and how long will it take? 
• We will ask questions about health 
problems you have had in the past, 
medicines taken, look closely at the child’s 
arm to see if it will be easy to take blood, 
and show an item that is the same size as 
the moxidectin tablets and ask the child 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 


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• If the test shows “yes”, then we will ask 
questions about health problems you have 
had in the past, medicines taken, look 
closely at the child’s arm to see if it will be 
easy to take blood, and show an item that 
is the same size as the moxidectin tablets 
and ask the child and you if they could 
swallow a tablet of that size. 
Help for your discussion with your 
parents/guardians, friends, family and 
others you want to talk this over with 
• Step 1 Screening in your community to 
see whether you have oncho and ask 
questions about your health (1-2 days). 
 
and you if they could swallow a tablet of 
that size. 
Help for your discussion with your 
parents/guardians, friends, family and 
others you want to talk this over with 
• Step 1 Screening in your community to 
ask questions about the health of your 
child (1-2 days). 
Section 16.8: Model 
Information Sheet for Children 
7 to 11 Years 
Where and when will this happen? 
Here in your community, we will take a few 
drops of blood from your finger to test 
whether you have the oncho worm. 
Where and when will this happen? 
Here in your community, we will ask your 
parents or guardians about your health. If we 
learn something about your health that 
makes us think it is better for you not to take 
part, we will tell you that you cannot take part 
in the study.  
If you are healthy and if you still want to take 
part, we will take you by car with one of your 
parents or guardians our place in Hohoe. 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 


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We will also ask your parents or guardians 
about your health. If you do not have the 
oncho worm or we learn something about 
your health that makes us think it is better for 
you not to take part, we will tell you that you 
cannot take part in the study.  
If you have the oncho worm and if you still 
want to take part, we will take you by car with 
one of your parents or guardians our place in 
Hohoe. 
Section 16.9: Model 
Information Sheet for Children 
4 to 6 Years and Older 
Children Considered Not 
Mature Enough to Provide 
Assent 
What will happen if you want to come to 
Hohoe? 
First, we will ask your parents to tell us about 
your health and take a bit of blood from one 
of your fingers to find our whether you have 
the oncho worms. 
 
If you don’t have the oncho worm, you will 
not go to Hohoe. 
Also, if your parents tell us that you have 
health problems you will not go to Hohoe 
since it will be better for you not to do that. 
What will happen if you can go to Hohoe? 
If you do have the oncho worm, you and one 
of your parents will ride in a car together with 
What will happen if you want to come to 
Hohoe? 
We will ask your parents to tell us about your 
health. 
If your parents tell us that you have health 
problems you will not go to Hohoe since it 
will be better for you not to do that. 
What will happen if you can go to Hohoe? 
If you do not have health problems, you and 
one of your parents will ride in a car together 
with other children and one of their parents to 
Hohoe. 
Removal of Ov16 IgG4 testing for O. volvulus 
from protocol. 


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other children and one of their parents to 
Hohoe.