Clinical trial NCT04632706
Conditions: Covid19
Sponsor: MedinCell S.A
Start date: 2020-09-22; Completion date: 2021-03-09
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
An early stage trial to check how safe and tolerable, as well as how the body handles continuous daily use of Active IMP over 28 days in healthy volunteers.

Detailed description:
Detailed information restricted because this is a Phase 1 clinical trial.

Arms: arm 1: Ivermectin loading dose of 200 mcg/kg followed by daily doses of 50mcg/kg from D2 to D28 arm 2: Ivermectin loading dose of 200 mcg/kg followed by daily doses of 75mcg/kg from D2 to D28 arm 3: Ivermectin loading dose of 200 mcg/kg followed by daily doses of 100mcg/kg from D2 to D28 arm 4: Placebo using tablets identical to the Active IMP
Interventions: intervention 1: Ivermectin intervention 2: Placebo
Intervention descriptions: intervention 1: Ivermectin: Investigation of the safety, tolerability and the pharmacokinetic profile of the active IMP in an exploratory study intervention 2: Matching Placebo to the Active IMP.

Protocol documents:
Prot_000.pdf: 
 
 
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Clinical Study Protocol 
A Randomised, Double-Blind, Placebo-Controlled, 
Exploratory Phase I Trial Assessing the Pharmacokinetic 
Profile, Safety and Tolerability of a Continuous Daily Dosing 
Regimen of Ivermectin in Healthy Volunteers 
Investigational Medicinal Product: Ivermectin 
Sponsor Reference: 
 
MAC Number: 
 
EudraCT Number: 2020-002975-36 
 
Protocol Version: Final 2.0 
 Protocol Date: 16 December 2020 
Clinical Development Phase: I 
 
 
 
 
 
 
Sponsor: MedinCell 
 
3 rue des Frères Lumière 
 
34830, Jacou 
 
France 
CONFIDENTIALITY STATEMENT
The information provided in this document is strictly confidential and is available for review to Investigators, 
potential Investigators, appropriate ethics committees and other national authorities. No disclosure should take 
place without the written authorisation from the Sponsor, except to the extent necessary to obtain informed 
consent from potential subjects. 






 
 
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SUMMARY OF CHANGES: CLINICAL STUDY PROTOCOL AMENDMENT 1 
(VERSION 2.0) 
 
This version of the protocol will supersede the previous version (Version 1.0, dated 
27 August 2020). 
The rationale for this non-substantial amendment is to reduce the frequency of fundoscopy 
assessments performed during the study, and to only perform this procedure following receipt 
of a recent negative test for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-
CoV-2). This is to reduce the risk of exposure to SARS-CoV-2 in the current pandemic for the 
subject and the study team member performing the assessment, due to their close proximity 
when performing this procedure. The time window for pre-dose 12-lead ECG assessments has 
also been extended to 2 hours, to align with MAC Clinical Research Standard Operating 
Procedures. 
The changes to the protocol are detailed below: 
Section 
Description of Change 
Section 5.2 (Page 30) – Dose 
Administration (Table 4 footnote) 
Previous text: 
Not applicable. 
Amended text: 
Non-whole weight values will be rounded to the nearest whole 
number. For example, 95.1 to 95.4 kg would be rounded down to 
95 kg and 95.5 to 95.9 kg would be rounded up to 96 kg. 
Section 7.2 (Page 38) – 12-lead 
Electrocardiogram 
Previous text: 
The 12-lead ECG will be collected in triplicate, approximately 
1 minute apart, at Screening, Day -1 and within approximately 
1 hour pre-dose on Day 1. 
Amended text: 
The 12-lead ECG will be collected in triplicate, approximately 
1 minute apart, at Screening, Day -1 and within approximately 
1 hour 2 hours pre-dose on Day 1. 
Section 11.1 (Page 49) – Randomisation 
and Subject Allocation 
Previous text: 
The randomisation number will have 4 digital numbers, with the 
first being the cohort (i.e., 1 for Cohort 1, 2 for Cohort 2, etc), the 
second being whether a subject is a replacement (0 = original; 1 
= replacement), and the last 2 being the subject number from 01 
to 24; for example, 1011 means the 11th subject in the originally 
randomised Cohort 1, whereas 1111 is the replacement of 1011. 
All screened subjects should be identifiable throughout the study. 
Amended text: 
The randomisation number will have 4 digital numbers, with the 
first being the cohort (i.e., 1 for Cohort 1, 2 for Cohort 2, etc), the 
second being whether a subject is a replacement (0 = original; 1 
= replacement), and the last 2 being the subject number from 01 
to 24; for example, 10111001 means the 11th1st subject in the 
originally randomised Cohort 1, whereas 11111101 is the 
replacement of 10111001. All screened subjects should be 
identifiable throughout the study. 




 
 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................ 2 
INVESTIGATOR SIGNATURE PAGE................................................................................ 3 
SUMMARY OF CHANGES: CLINICAL STUDY PROTOCOL AMENDMENT 1 
(VERSION 2.0)......................................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................ 6 
LIST OF TABLES ................................................................................................................... 9 
LIST OF FIGURES ................................................................................................................. 9 
SYNOPSIS .............................................................................................................................. 10 
LIST OF ABBREVIATIONS ............................................................................................... 12 
1. 
INTRODUCTION....................................................................................................... 14 
1.1. 
Background and Study Rationale .............................................................................. 14 
1.2. 
Ivermectin.................................................................................................................. 14 
1.3. 
Non-Clinical Experience ........................................................................................... 15 
1.3.1. Non-Clinical Pharmacology ................................................................................... 15 
1.3.2. Pharmacokinetics in Animals ................................................................................. 15 
1.3.3. Toxicology............................................................................................................... 16 
1.4. 
Clinical Experience ................................................................................................... 16 
1.4.1. Clinical Experience from the Treatment of Strongyloidiasis ................................. 17 
1.4.2. Clinical Experience from the Treatment of Onchocerciasis................................... 17 
1.4.3. Post-Marketing Experience .................................................................................... 18 
1.5. 
Risk/Benefit Assessment........................................................................................... 18 
2. 
OBJECTIVES AND ENDPOINTS ........................................................................... 22 
2.1. 
Objectives .................................................................................................................. 22 
2.1.1. Primary Objective................................................................................................... 22 
2.1.2. Secondary Objectives(s) ......................................................................................... 22 
2.1.3. Exploratory Objective............................................................................................. 22 
2.2. 
Endpoints................................................................................................................... 22 
2.2.1. Primary Endpoint ................................................................................................... 22 
2.2.2. Secondary Endpoint(s)............................................................................................ 22 
2.2.3. Exploratory Endpoints ............................................................................................ 22 
3. 
STUDY DESIGN......................................................................................................... 23 
3.1. 
Rationale for Study Design ....................................................................................... 24 
3.2. 
Dose Rationale .......................................................................................................... 24 
3.2.1. Safety Review Committee........................................................................................ 26 
3.2.2. Dose Escalation and Adjustment Criteria .............................................................. 27 


 
 
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4. 
STUDY SETTING ...................................................................................................... 29 
5. 
STUDY TREATMENTS ............................................................................................ 30 
5.1. 
Name and Description of Investigational Products................................................... 30 
5.2. 
Dose Administration ................................................................................................. 30 
5.3. 
Concomitant Medication ........................................................................................... 31 
5.4. 
Assessment of Compliance with Treatment.............................................................. 31 
5.5. 
Blinding ..................................................................................................................... 31 
5.6. 
Emergency Unblinding ............................................................................................. 31 
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................... 32 
6.1. 
Inclusion Criteria ....................................................................................................... 32 
6.2. 
Exclusion Criteria...................................................................................................... 32 
6.3. 
Study Restrictions ..................................................................................................... 34 
6.3.1. Contraception Restrictions ..................................................................................... 34 
6.3.2. Lifestyle Restrictions............................................................................................... 35 
6.3.3. Meals and Dietary Restrictions .............................................................................. 35 
6.4. 
Subject Withdrawal Criteria ...................................................................................... 36 
6.5. 
Follow-up Procedures ............................................................................................... 36 
7. 
SAFETY ASSESSMENTS ......................................................................................... 37 
7.1. 
Clinical Laboratory Evaluations................................................................................ 37 
7.2. 
12-lead Electrocardiogram ........................................................................................ 38 
7.3. 
Vital Signs and Oral Temperature............................................................................. 38 
7.4. 
Physical Examinations .............................................................................................. 38 
7.5. 
Neurological Examinations ....................................................................................... 38 
7.6. 
Adverse Event Reporting .......................................................................................... 39 
7.6.1. Definition and Criteria ........................................................................................... 39 
7.6.2. Evaluating Adverse Events and Serious Adverse Events........................................ 42 
7.6.3. Reporting Procedures and Requirements ............................................................... 43 
7.6.4. Prompt Reporting of Serious Adverse Events......................................................... 44 
7.6.5. Special Considerations ........................................................................................... 44 
7.7. 
Other Assessments .................................................................................................... 45 
8. 
PHARMACOKINETIC ASSESSMENTS................................................................ 46 
8.1. 
Pharmacokinetic Sampling........................................................................................ 46 
8.2. 
Storage and Analysis of Clinical Samples ................................................................ 46 
 
 
 
 
 
 




 
 
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LIST OF TABLES  
Table 1: Risk/Benefit Assessment ........................................................................................... 19 
Table 2: Planned Dose Levels.................................................................................................. 23 
Table 3: Summary of the Main Toxicokinetic Parameters from Selected Preclinical Studies 
and the corresponding HED at the NOAELs12 ........................................................................ 25 
Table 4: Number of Ivermectin Tablets Per Cohort by Body Weight ..................................... 30 
Table 5: Clinical Laboratory Evaluations ................................................................................ 37 
Table 6: Pharmacokinetic Parameters...................................................................................... 51 
LIST OF FIGURES 
 
Figure 2: SARS-CoV-2 Tests and Outcomes .......................................................................... 47 
 
 




 
 
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Subsequent daily doses of ivermectin or placebo will be administered in the morning in the CRU from Day 2 
to Day 7, following an overnight fast. Subjects will reside in the CRU until at least 4 hours post-dose on Day 7 
for the collection of safety assessments and PK blood samples but may reside for longer if deemed necessary 
by the Investigator. From Day 8 to Day 27, subjects will self-administer their daily dose of ivermectin or 
placebo at home following an overnight fast, with the exception of outpatient visits on Day 14 and Day 21 
which will be administered in the CRU. Subjects will be readmitted to the CRU on Day 28 to receive their final 
dose of ivermectin or placebo and will be discharged on Day 29 following safety assessments and PK blood 
samples. Subjects will return to the CRU for outpatient visits on Days 32, 35 and 42 for safety assessments and 
PK blood samples.  
Treatment Duration: Once daily dosing for 28 days 
Study Participants:  
Healthy male subjects, with a body mass index of 18.5 to 32.0 kg/m2 (inclusive), of any ethic origin. Subjects 
should be aged between 18 to 45 years, inclusive. 
Dose and Route of Administration:  
The ivermectin or matched placebo will be orally administered in the morning from Day 1 to Day 28 following 
an overnight fast. Each dose will be taken with 240 mL of water at room temperature. Water will be allowed 
ad libitum and breakfast can be eaten between 1 to 2 hours after dosing.  
 
The planned dose levels are presented in the table below. 
Cohort 1 
Loading dose of 200 µg/kg on Day 1, then 50 µg/kg/day from Day 2 to Day 28 
Cohort 2 
Loading dose of 200 µg/kg on Day 1, then 75 µg/kg/day from Day 2 to Day 28 
Cohort 3 
Loading dose of 200 µg/kg on Day 1, then 100 µg/kg/day from Day 2 to Day 28 
Criteria for Evaluation: 
Pharmacokinetics will be assessed by blood sampling. Safety will be assessed through AE reporting, 12-lead 
ECG, vital signs, physical examinations, comprehensive neurological examinations and clinical laboratory 
evaluations. Efficacy will be assessed through the occurrence of SARS-CoV-2 infection, as confirmed by 
serology. 
Statistical Analysis:  
Pharmacokinetic parameters will be derived from individual plasma concentration data of ivermectin by 
noncompartmental analysis. The PK parameters derived to assess the multiple dose PK of ivermectin are 
provided below. 
 
Abbreviation 
Definition  
Cmax 
Maximum plasma concentration 
 
 
tmax 
Time of maximum plasma concentration 
AUC0-24h 
Area under the plasma concentration-time curve from zero to 24 hours 
 
 
 
 
t1/2 
Apparent terminal half-life 
RA 
Accumulation ratio 
 
Steady state will be assessed from visual examination of the data. In addition, dose proportionality will be 
determined using a suitable statistical model. 
 
Safety and efficacy parameters will be listed and summarised using descriptive statistics. 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-24h 
area under the plasma concentration-time curve from zero to 24 hours 
 
 
BMI 
body mass index 
 
 
CDC 
Centers for Disease Control and Prevention 
Cmax 
maximum plasma concentration 
COVID-19 
Coronavirus Disease 2019 
CRU 
Clinical Research Unit 
 
 
CYP 
cytochrome P450 
ECG 
electrocardiogram  
eCRF 
electronic case report form 
FAS 
Full Analysis Set 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HCV 
anti-hepatitis C antibody 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IgM 
immunoglobulin 
IMP 
Investigational Medicinal Product 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
NOAEL 
no observed-adverse-effect level 


 
 
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OTC 
over-the-counter 
PK 
pharmacokinetic(s) 
PT 
preferred term 
PV 
Pharmacovigilance Vendor 
RA 
accumulation ratio 
REC 
research ethics committee 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus-2 
SOC 
system-organ class 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
t1/2 
apparent terminal half-life 
tmax 
time to reach the maximum plasma concentration  
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 


 
 
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1. 
INTRODUCTION 
1.1. 
Background and Study Rationale 
Coronavirus Disease 2019 (COVID-19) is a highly contagious disease, caused by a novel 
enveloped RNA beta-coronavirus, also known as Severe Acute Respiratory Syndrome 
Coronavirus-2 (SARS-CoV-2). Following an initial outbreak in the Chinese city of Wuhan at 
the end of 2019, it became a pandemic, with more than 21.2 million cases and 761 000 deaths 
reported worldwide as of August 16 2020.1 Since its isolation and identification in January 
2020, the exact pathogenic mechanism(s) of this virus is (are) to be clearly established. While 
the majority of patients with COVID-19 develop mild or uncomplicated illness, approximately 
20% to 30% of hospitalised patients have required intensive care support and 5% of those have 
multi-organ failure or shock. The case fatality rate ranges from 1% to 4% and it is higher among 
those with pre-existing comorbid conditions. To date, treatments for COVID-19 in high risk 
individuals remain experimental and therapeutic strategies to deal with the infection are at best 
supportive, with prevention aimed at reducing transmission in the community as the best 
strategy. 
Despite its apparent low lethality (<2%), its high infectivity and fast spread has prompted the 
repurposing of existing drugs developed for other indications. These drugs may have a specific 
antiviral activity (antiviral agents) and/or can be host-targeted agents meaning that they impact 
host specific targets playing a role in the SARS-CoV-2 infectivity or in the COVID-19 
physiopathology.2 
1.2. 
Ivermectin 
Ivermectin tablets will be the study drug to be administered to healthy volunteers in this study 
in the context of the development of a product containing ivermectin for pre-exposure 
prophylaxis against SARS-CoV-2 infection. 
Ivermectin is a drug that is well known in Africa and Latin America and some experts regard 
it as one of the greatest health interventions of the past 50 years. It is used to treat a variety of 
internal nematode infection including Onchocerciasis, Strongyloidiasis, Ascariasis, cutaneous 
larva migrans, filariases, Gnathosto-miasis and Trichuriasis, as well as for oral treatment of 
ectoparasitic infections, such as Pediculosis (lice infestation) and scabies (mite infestation).  
Alongside penicillin and aspirin, it lays claim to the title of ‘Wonder drug’, based on its 
versatility, safety and the beneficial impact that it has had, and continues to have. It was initially 
commercialised for multi-purpose use in animal health in 1981 as it kills a wide range of 
internal and external parasites in commercial livestock and companion animals. It was quickly 
discovered to be ideal in combating two of the world’s most devastating and disfiguring 
diseases, Onchocerciasis and Lymphatic filariasis, and 6 years later it was registered for human 
use. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases 
globally.3 New roles in other human diseases, including the management SARS-CoV-2, are 
continually being found.4  
Ivermectin causes death of parasites, primarily through binding selectively and with high 
affinity to glutamate-gated chloride channels, which occur in invertebrate nerve and muscle 
cells. This leads to an increase in the permeability of the cell membrane to chloride ions with 
hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. 
Compounds of this class may also interact with other ligand-gated chloride channels, such as 
those gated by the neurotransmitter gamma-aminobutyric acid (GABA). The selective activity 
of compounds of this class is attributable to the fact that some mammals do not have 


 
 
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glutamate-gated chloride channels, that avermectins have a low affinity for mammalian 
ligand-gated chloride channels, and that they do not readily cross the blood-brain barrier in 
humans.  
Recently, ivermectin has been shown to be a potent inhibitor of Importin α/β-mediated nuclear 
transport and exhibits antiviral activity towards several RNA and DNA viruses by blocking the 
nuclear trafficking of viral proteins.5,6,7,8 In Flaviviruses, ivermectin was also shown to inhibit 
the viral helicase, a key enzyme involved in viral replication that has also been identified in 
SARS-CoV-2.9,10 The pharmacological mechanism may explain the inhibitory effect of 
ivermectin on the SARS-CoV-2 replication observed in vitro in Vero cells.11 Several clinical 
trials are currently testing ivermectin as a treatment for COVID-19. By its actions on Importin 
α/β and on viral helicase, ivermectin may present a combined antiviral and host-targeted effect 
against SARS-CoV-2, and its wide use and clearly established safety profile justify further 
clinical investigations as a possible treatment against COVID-19. 
The aim of this study is to evaluate the safety, tolerability and pharmacokinetic (PK) profile of 
daily dosing of ivermectin for 28 days, using 3 different dosing regimens, as a potential 
long-term prophylaxis for COVID-19.  
1.3. 
Non-Clinical Experience 
1.3.1. Non-Clinical Pharmacology 
In vitro, ivermectin has an antiviral action against the SARS-CoV-2 clinical isolate, with a 
single dose able to control viral replication within 24 to 48 hours in Vero cells (IC50: ~2 μM).11 
Ivermectin may exert its antiviral activity through the direct inhibition of the nuclear transporter 
importin α/β, limiting the entry of key viral protein into the host’s nucleus, as described with 
other RNA and DNA viruses.5,6,7,8 Additionally, ivermectin has been shown to efficiently 
inhibit the flaviviral helicase, a non-structural protein essential for subsequent viral replication 
and proliferation that is also present in SARS-CoV-2.9,10  
Safety pharmacology studies data originate from the New Drug Application (NDA) 206255 of 
Soolantra (Ivermectin).12 In safety pharmacology studies, no treatment-related effects on 
spontaneous activity, central nervous system excitability, sensory, motor, autonomic or 
neuromuscular function or body temperature were noted in rats at single oral doses up to 5 
mg/kg ivermectin. In a second study, a dose-dependent decrease in motor activity was noted at 
single oral doses of 7 and 20 mg/kg in rats (no observed-adverse-effect level [NOAEL]: 3 
mg/kg). Single oral doses of ivermectin up to 20 mg/kg had no effects on intrinsic convulsive 
activity or pentylenetetrazole-induced convulsive activity and on intrinsic analgesic activity or 
pentobarbital-induced anaesthesia. Ivermectin had no significant effects on the delayed 
rectifier potassium current in an in vitro hERG assay at concentrations up to 10 μM. In 
conscious beagle dogs, single oral doses of ivermectin at 1.5 mg/kg was slightly hypotensive. 
Ivermectin reduced the gastrointestinal transit in rats at a single oral dose of 20 mg/kg and 
dose-dependently reduced gastric emptying from 7 mg/kg. Ivermectin at single oral doses up 
to 20 mg/kg had no significant effects on urinary volume, urinary pH, potassium, sodium, or 
creatinine excretion in rats. 
1.3.2. Pharmacokinetics in Animals 
Oral bioavailability of ivermectin is low in rats and dogs (25% to 41%). Ivermectin is widely 
distributed to tissues and no blood brain barrier passage is noted after either oral or intravenous 
administration in rats.12,13 After administration to pregnant rats, transfer of ivermectin through 
the placenta is low and ivermectin was found to be quantitatively transferred to milk. 


 
 
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Ivermectin is highly bound to plasma proteins (99.9%) in mouse, rat, rabbit, dog, minipig and 
human, with low in vitro partitioning into red blood cells. The fraction of ivermectin that is 
metabolised is higher after oral administration indicating a hepatic first-pass effect. 
Demethylation and hydroxylation appear to be the main metabolic reactions and no significant 
gender differences in metabolism are noted in rats. Cytochrome P450 (CYP)3A4 was identified 
as the enzyme primarily responsible for the metabolism of ivermectin. CYP2D6 and CYP2E1 
were also shown to be involved in the metabolism of ivermectin but to a significantly lower 
extent compared to CYP3A4. Ivermectin is slowly eliminated, the primary route of excretion 
being in the faeces. The majority of radioactivity associated with ivermectin is excreted within 
48 hours after oral administration to rats. 
1.3.3. Toxicology 
Ivermectin appears to be neurotoxic at high oral doses, indicated by signs of mydriasis, tremors, 
and ataxia, presumably through an effect on GABA neurons.  
In single dose oral toxicity studies, the signs of toxicity were ptosis, bradypnea, ataxia, tremors, 
and loss of the righting reflex (in rodents); mydriasis (in dogs [5 to 80 mg/kg studied]); 
vomiting (in monkeys [0.2 to 24 mg/kg studied]).  
In repeat dose oral toxicity studies, enlarged spleens with extramedullary haematopoiesis and 
minimal decreased secretion in seminal vesicles was noted in rats (up to 12 mg/kg/day studied); 
salivation, mydriasis, anorexia, dehydration, tremors and ataxia were noted in dogs (0 to 
2.5 mg/kg/day studied); no significant toxicities were noted in a study in immature monkeys 
(0 to 1.2 mg/kg/day studied) or in a study in neonatal monkeys (0 to 0.1 mg/kg/day studied).  
Ivermectin is not genotoxic in the Ames test, mouse lymphoma assay, or in vivo rat 
micronucleus assay.  
Carcinogenicity (hepatocellular adenoma) of ivermectin has been detected at high dose 
(9 mg/kg/day) in a 104-week study in rats. There were no significant test article-related 
neoplastic findings in males treated with 1 or 3 mg/kg/day ivermectin. 
Ivermectin is teratogenic in mice, rats, and rabbits. Cleft palate, wavy ribs, and clubbed 
forepaws were seen in these studies. The teratogenic effects were found at or near oral doses 
that produced maternal toxicity. 
Further details regarding the preclinical data can be found in the Investigator Brochure (IB). 
1.4. 
Clinical Experience 
Ivermectin is a potent anthelminthic drug with a good and well described safety profile. 
Ivermectin has been used in clinical practice for over 30 years, since 1987 with an estimated 
1.3 billion treatments for river blindness.14 This good safety profile may be attributed to its 
high affinity to invertebrate neuronal glutamate-coupled chloride channels and its inability to 
cross the blood–brain barrier in humans and other mammals.15 In addition, ivermectin has been 
administered to healthy patients at doses 7 to 10 times the maximum approved therapeutic dose, 
with no severe adverse events (AEs) being reported.16,17  
Tolerance to the compound has been assessed in healthy volunteers and in patients; adverse 
effects are usually mild and transient. but their severity may be increased in patients infected 
with more than one parasite, particularly in the case of infestation with Loa loa.  
Following oral administration of ivermectin to healthy volunteers, plasma concentrations are 
relatively proportional to the dose level in the 30 to 120 mg dose range (i.e., 333-2000 µg/kg).16 


 
 
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The mean peak plasma concentration of the major component (H2B1a), observed 
approximately 4 hours after oral administration of a single 12 mg dose of ivermectin in tablet 
form is 46.6 (± 21.9) ng/mL. Ivermectin plasma concentration increases with increasing doses 
in a generally proportional manner. Ivermectin is absorbed and metabolised in the human body 
and ivermectin and/or its metabolites are excreted almost exclusively in faeces, whilst less than 
1% of the administered dose is excreted in urine.18 The plasma half-life of ivermectin is about 
12 hours (range in human healthy volunteers: 11.1 to 36.6 hours) and that of the metabolites is 
about 3 days. 
1.4.1. Clinical Experience from the Treatment of Strongyloidiasis  
In 4 clinical studies19 involving a total of 109 patients given either one or two doses of 170 to 
200 µg/kg of ivermectin, the following AEs were reported as possibly, probably, or definitely 
related to ivermectin: 
Body as a Whole: asthenia/fatigue (0.9%), abdominal pain (0.9%) 
Gastrointestinal: anorexia (0.9%), constipation (0.9%), diarrhoea (1.8%), nausea (1.8%), 
vomiting (0.9%) 
Nervous System/Psychiatric: dizziness (2.8%), somnolence (0.9%), vertigo (0.9%), tremor 
(0.9%) 
Skin: pruritus (2.8%), rash (0.9%), and urticaria (0.9%). 
The following laboratory abnormalities were seen regardless of drug relationship: 
Elevation in alanine aminotransferase (ALT) and/or aspartate aminotransferase AST (2%), 
decrease in leukocyte count (3%). Leukopenia and anaemia were seen in one patient. 
In comparative trials, patients treated with ivermectin experienced more abdominal distention 
and chest discomfort than patients treated with albendazole. However, ivermectin was better 
tolerated than thiabendazole in comparative studies involving 37 patients treated with 
thiabendazole. 
1.4.2. Clinical Experience from the Treatment of Onchocerciasis  
In clinical trials19 involving 963 adult patients treated with 100 to 200 µg /kg ivermectin, 
worsening of the following Mazzotti reactions during the first 4 days post-treatment were 
reported: arthralgia/synovitis (9.3%), axillary lymph node enlargement and tenderness (11.0% 
and 4.4%, respectively), cervical lymph node enlargement and tenderness (5.3% and 1.2%, 
respectively), inguinal lymph node enlargement and tenderness (12.6% and 13.9%, 
respectively), other lymph node enlargement and tenderness (3.0% and 1.9%, respectively), 
pruritus (27.5%), skin involvement including oedema, papular and pustular or frank urticarial 
rash (22.7%), and fever (22.6%). 
Ophthalmological conditions were examined before treatment, at Day 3, and months 3 and 6 
after treatment with 100 to 200 µg /kg ivermectin. Changes observed were primarily 
deterioration from baseline 3 days post-treatment. Most changes either returned to baseline 
condition or improved over baseline severity at the month 3 and 6 visits. The percentages of 
patients with worsening of the following conditions at Day 3, month 3 and 6, respectively, 
were: limbitis: 5.5%, 4.8%, and 3.5% and punctate opacity: 1.8%, 1.8%, and 1.4%. The 
corresponding percentages for patients treated with placebo were: limbitis: 6.2%, 9.9%, and 
9.4% and punctate opacity: 2.0%, 6.4%, and 7.2%. 


 
 
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The following clinical adverse reactions were reported as possibly, probably, or definitely 
related to the drug in ≥1% of the patients: facial oedema (1.2%), peripheral oedema (3.2%), 
orthostatic hypotension (1.1%), and tachycardia (3.5%). Drug-related headache and myalgia 
occurred in <1% of patients (0.2% and 0.4%, respectively). However, these were the most 
common adverse experiences reported overall during these trials regardless of causality (22.3% 
and 19.7%, respectively). 
A similar safety profile was observed in an open study in paediatric patients ages 6 to 13. 
The following ophthalmological side effects do occur due to the disease itself but have also 
been reported after treatment with ivermectin: abnormal sensation in the eyes, eyelid oedema, 
anterior uveitis, conjunctivitis, limbitis, keratitis, and chorioretinitis or choroiditis. These have 
rarely been severe or associated with loss of vision and have generally resolved without 
corticosteroid treatment. 
The following laboratory adverse experiences were reported as possibly, probably, or definitely 
related to the drug in ≥1% of the patients: eosinophilia (3%) and haemoglobin increase (1%). 
1.4.3. Post-Marketing Experience  
Hypotension (mainly orthostatic hypotension), worsening of bronchial asthma, toxic epidermal 
necrolysis, Stevens-Johnson syndrome, seizures, hepatitis, elevation of liver enzymes, and 
elevation of bilirubin have been reported. 19 Conjunctival haemorrhage has been reported in the 
treatment of Onchocerciasis.  
Further details regarding the clinical data can be found in the IB or the Summary of Product 
Characteristics.19 
1.5. 
Risk/Benefit Assessment  
Further information about the known and expected benefits and risks and reasonably expected 
AEs of ivermectin may be found in the current IB and the Summary of Product 
Characteristics.19  
Details of these risks and the proposed strategy to mitigate/monitor these risks are detailed in 
Table 1.  
In this study, safety will be monitored closely both by subjective reporting and by objective 
means i.e., serial assessments of vital signs, clinical laboratory evaluations data, physical 
examinations, 
12-lead 
electrocardiogram 
(ECG) 
and 
comprehensive 
neurological 
examinations. This study will be run in a Clinical Research Unit (CRU) with immediate access 
to hospital facilities for the treatment of medical emergencies. Subjects will remain monitored 
in the clinic for the first 7 days of dosing and will only be discharged from the CRU at the end 
of Day 7 if the Investigator deems it safe to do so. 
 
 


 
 
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Table 1: Risk/Benefit Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy  
Skin rashes and pruritus 
SmPC 
Physical examinations will be performed regularly 
throughout the study to identify any rashes and overall 
TEAEs will be monitored. 
Cardiovascular changes 
SmPC 
Heart rate and blood pressure will be frequently 
monitored during the study by supine and standing 
vital signs. 
CNS changes 
SmPC 
Comprehensive neurological examinations will occur 
frequently during the study to identify any changes. 
Gastrointestinal system effects 
SmPC 
Clinical monitoring of body weight and standard safety 
laboratory parameters, as well as overall TEAEs will 
be monitored. Subjects will be withdrawn if effects are 
severe. 
Respiratory system changes; exacerbation of asthma 
SmPC 
Asthmatic subjects will be excluded. 
Ophthalmologic changes 
SmPC; IB 
Comprehensive neurological examinations will occur 
frequently during the study to identify any changes. 
Haematological changes 
SmPC 
Subjects will be closely monitored with frequent blood 
tests during the study. Haematology parameters will be 
closely monitored throughout the course of the study 
as dose escalation proceeds. Escalation to higher doses 
and exposures will only occur if emerging data 
indicates this is safe and appropriate. Stopping criteria 
have been added for clinically significant lab results. If 
indicated, no further dose escalation will occur. 
Liver dysfunction: elevation in ALT, AST and/or 
bilirubin; acute hepatitis. 
SmPC 
Subjects will be closely monitored with frequent blood 
tests during the study. Liver function test parameters 
must be entirely normal for study eligibility and no 
alcohol will be allowed from 48 hours prior to Day -1. 
Clinical chemistry parameters will be closely 
monitored throughout the course of the study as dose 
escalation proceeds. Escalation to higher doses and 
exposures will only occur if emerging data indicates 
this is safe and appropriate. Stopping criteria have 


 
 
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been added for clinically significant lab results. If 
indicated, no further dose escalation will occur.  
Drug-drug interaction 
In pre-clinical studies, ivermectin has been shown to 
be most likely hepatically metabolised through the 
CYP3A4 system.  
In pre-clinical studies, a subpopulation of CF-1 mice 
with P-gp deficiency presented with a 10 to 100-fold 
increase in ivermectin sensitivity and increased 
concentration of ivermectin were found in the intestine 
and in the brain. 
Concomitant medication restrictions; co-administration 
of ivermectin and drugs known to be CYP3A4 or P-gp 
substrates will be avoided. 
Risk of local or systemic allergic response. 
SmPC and risk from multiple dose accumulation 
This study will be performed in a CRU equipped to 
deal with allergic responses and anaphylaxis with 
access to hospital emergency facilities, if needed. 
Sentinel subjects will be dosed in each cohort. During 
outpatient periods there will be close contact with the 
CRU to ensure any type of local or systemic reaction is 
highlighted. 
Exposure to SARS-CoV-2 
Exposure to other infections is always a risk when 
study subjects attend a clinical research facility, but 
increased risk due to SARS-CoV-2 pandemic. 
A SARS-CoV-2 test (according to the current UK 
standard testing) screen will be performed at Screening 
and prior to any inpatient stays. Additional SARS-
CoV-2 tests will be carried out, as required, if any 
subject displays any of the signs and symptoms. 
The subject’s temperature will be taken at the start of 
every visit to help assess SARS-CoV-2 status. In 
addition to temperature checks, subjects will be asked 
SARS-CoV-2 standard questions prior to all visits to 
the CRU. 
The CRU has been in operation throughout the 
lockdown period and will continue to monitor the 
situation and adhere to current UK Government advice 
around social distancing and personal protective 
equipment to protect site staff and study subjects. The 
requirement for, and duration of, inpatient stays has 
been minimised where safely possible. Distancing is in 
place within the CRU to ensure the least amount of 
contact possible, with both staff and subjects wearing 
face coverings. Any communal areas have been put out 


 
 
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of use with restrictions on use of bathrooms and 
showers to ensure safety. 
Abbreviations: ALT – alanine aminotransferase; AST – aspartate aminotransferase; CNS – Central Nervous System; CRU – Clinical Research Unit; CYP – cytochrome P450; IB – Investigator Brochure; P-gp  – 
P-glycoprotein; SARS-CoV-2 – severe acute respiratory syndrome coronavirus-2; SmPC – summary of product characteristics; TEAE – treatment emergent adverse event.




 
 
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3. 
STUDY DESIGN 
This is a Phase I, double-blind, placebo-controlled, randomised study to determine the PK 
profile, safety and tolerability of multiple oral doses of ivermectin in healthy male subjects 
 
 
Up to 24 subjects are planned to be enrolled into 3 cohorts comprising 8 subjects each. In each 
cohort, 6 subjects will be randomised to receive ivermectin and 2 subjects will be randomised 
to receive placebo. Multiple-dose oral administration of once daily ivermectin or placebo will 
occur for 28 days. All cohorts will consist of 2 sentinel subjects, of whom 1 subject will receive 
ivermectin and 1 subject will receive matched placebo. The remaining subjects in each cohort 
(6 subjects; 5 subjects ivermectin and 1 subject placebo) will commence treatment after 
satisfactory review of the safety data up to a minimum of 4 hours post-dose on Day 7 from the 
sentinel subjects, if deemed safe to do so by the Principal Investigator. 
The planned dose levels are presented in Table 2. 
Table 2: Planned Dose Levels 
Cohort 1 
Loading dose of 200 µg/kg on Day 1, then 50 µg/kg/day from Day 2 to 
Day 28 
Cohort 2 
Loading dose of 200 µg/kg on Day 1, then 75 µg/kg/day from Day 2 to 
Day 28 
Cohort 3 
Loading dose of 200 µg/kg on Day 1, then 100 µg/kg/day from Day 2 to 
Day 28 
 
The dose levels will be administered in an ascending order; progression to the next dose level, 
and dose selection, will be based on the safety, tolerability and available PK data from the 
preceding dose cohort(s) (safety, tolerability and PK data [up to Day 14] from a minimum of 


 
 
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4 ivermectin and 1 placebo subjects in the preceding dose cohort). Except for the starting dose, 
the doses outlined in the protocol are preliminary, with actual subsequent doses determined 
based on an ongoing evaluation of the safety, tolerability, and PK data by the Safety Review 
Committee (SRC; described in Section 3.2.1). 
Subjects will be required to attend the CRU for a Screening visit within 28 days prior to first 
dosing to ensure they meet the inclusion/exclusion criteria and are in good health. Subjects will 
be admitted to the CRU 1 day prior to first dosing (Day -1) for collection of baseline safety 
assessments and will receive their first dose of ivermectin or placebo in the morning of Day 1, 
following an overnight fast. Subsequent daily doses of ivermectin or placebo will be 
administered in the morning in the CRU from Day 2 to Day 7, following an overnight fast. 
Subjects will reside in the CRU until at least 4 hours post-dose on Day 7 for the collection of 
safety assessments and PK blood samples but may reside for longer if deemed necessary by 
the Investigator. From Day 8 to Day 27, subjects will self-administer their daily dose of 
ivermectin or placebo at home following an overnight fast, with the exception of outpatient 
visits on Day 14 and Day 21 which will be administered in the CRU. Subjects will be 
readmitted to the CRU on Day 28 to receive their final dose of ivermectin or placebo and will 
be discharged on Day 29 following safety assessments and PK blood samples. Subjects will 
return to the CRU for outpatient visits on Days 32, 35 and 42 for safety assessments and PK 
blood samples.  
A detailed plan of study assessments is provided in Appendix 1. 
3.1. 
Rationale for Study Design 
This study is designed to evaluate the PK profile, safety and tolerability of multiple (28-day) 
ascending doses of ivermectin in healthy male subjects. This information will help to establish 
the dose and regimen suitable for administration in future studies. 
In line with the European Medicines Agency Guideline on strategies to identify and mitigate 
risks for first-in-human and early clinical trials with Investigational Medicinal Products 
(IMPs)20, all cohorts will consist of 2 sentinel subjects; 1 receiving ivermectin and 1 receiving 
placebo. The remaining 6 subjects in each cohort (5 receiving ivermectin and 1 receiving 
placebo) will be dosed only if safe to do so based on the safety data from up to a minimum of 
4 hours post-dose on Day 7 from the sentinel subjects. 
To mitigate risk to subjects in this study, the cohorts will be recruited sequentially with 
progression through the cohorts dependent on adequate safety and PK data from the previous 
cohort and approval by the SRC. The SRC findings at each review will be documented. 
To ensure compliance with the dosing regimen whilst outside the CRU, subjects will be 
contacted regularly by phone or text message to ensure that the correct number of tablets are 
being taken, and that doses have been following an overnight fast. 
Since the safety profile in humans over 28 days of consecutive dosing has not yet been 
investigated, all subjects will be closely monitored. Standard assessments to evaluate safety 
and tolerability, including vital signs, physical examinations, neurological examination, 
12-lead ECGs, clinical laboratory evaluations and AE collection will be utilised in this study. 
3.2. 
Dose Rationale 
Ivermectin has been used in clinical practice for over 30 years, since 1987 with an estimated 
1.3 billion treatments for river blindness.14 The standard approved dose of 200 μg/kg is taken 
once to three times a year14 but much higher doses, up to 2,000 μg/kg taken in split doses over 


 
 
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one week found ivermectin to be  generally well tolerated, with no difference in AEs between 
placebo and these highest doses.16 However, despite these high doses no study has investigated 
continuous daily dosing for one month which would have the potential for a prophylaxis 
treatment of COVID-19.  
In healthy volunteers receiving oral doses of ivermectin up to 120 mg (equivalent to a dose per 
body weight of 1404 to 2000 μg/kg), the Cmax was 247.8. ± 158.9 ng/ml with no significant 
increase in AEs recorded compared to the placebo treated group.16 This value is equivalent to 
approximately 2.2 times the minimum mean Cmax after 13 weeks of repeated daily oral 
treatment at the lowest NOAEL in rats and is similar to the lowest mean Cmax after 13 weeks 
of repeated daily oral treatment at the NOAEL in dogs Table 3. 
After 3 repeated administrations of 30 mg ivermectin three times in a week (equivalent to 347 
to 594 μg/kg every fourth day or 149 to 232 μg/kg/day) in healthy volunteers, the mean Cmax 
and AUC0-∞ were 87.0 ng/ml and 2819.4 ng.h/mL, respectively.16 When compared to the 
animal data after 13 weeks daily oral treatments with ivermectin at the NOAELs, these values 
are 1.2 to 6.4 lower than the mean Cmax values found in rats and dogs, and 2 times higher to 2 
times lower than the mean AUC0-24h values found in rats and dogs, respectively dogs Table 3. 
Table 3: Summary of the Main Toxicokinetic Parameters from Selected Preclinical 
Studies and the corresponding HED at the NOAELs12 
Study 
Type 
Species 
NOAEL 
HED at 
the 
NOAEL 
Cmax at the 
NOAEL (ng/ml) 
AUC0-24h. at the 
NOAEL (ng h/ml) 
Dose Effect 
Accumulation 
Males 
Females 
Males 
Females 
13-
weeks 
DRF 
study 
in rats 
Wistar 
rats 
1  
161 
μg/kg/day 
Day 1: 
81.6 
Day 
91: 128  
Day 1: 
91.5 
Day 91: 
112 
Day 1: 
1417 
Day 
91: 
1629  
Day 1: 
1337 
Day 91: 
1431 
More than 
dose 
proportional 
increase 
Slight 
accumulation 
(dose 
≥ 1mg/kg/day) 
13-
week 
oral 
toxicity 
study 
in rats 
Wistar 
rats 
3  
484 
μg/kg/day 
Day 1: 
417 
Day 
88: 558  
Day 1: 
367 
Day 88: 
508 
Day 1: 
4770 
Day 
88: 
7786 
Day 1: 
4803 
Day 88: 
7470 
More than 
dose 
proportional 
increase in 
the 1-3 
mg/kg/day 
range 
Slight 
accumulation 
13-
week 
oral 
toxicity 
study 
in dogs 
Beagle 
dogs 
0.5 
278 
μg/kg/day 
Day 1: 
195 
Day 
90: 365 
Day 1: 
209 
Day 90: 
282   
Day 1: 
2282 
Day 
90: 
5629 
Day 1: 
2494 
Day 90: 
4166 
Dose 
proportional 
increase in 
exposure at 
doses below 
the NOAEL 
Accumulation 
Abbreviations: AUC0-24h – area under the plasma concentration-time curve from zero to 24 hours; Cmax – maximum plasma concentration; 
DRF – dose range finding; HED – human equivalent dose; NOAEL – no observed-adverse-effect level. 
In cases of severe crusted scabies, the Centers for Disease Control and Prevention (CDC) 
recommends a dosing regimen of 200 μg/kg up to 7 times for a 28-day period (dosing on Day 1, 
Day 2, Day 8, Day 9, Day 15, Day 22 and Day 28).21 This gives a total dose per month of 
1400 μg/kg. These recommendations are also endorsed by the European Academy of 
Dermatology and Venerology22 as well as the Department of Health and Families of the 
Northern Territory Government of Australia.23  
The proposed dosing regimen is over a 28-day period consisting of a first loading dose of 
200 μg/kg for the first day followed by once daily dosing of either 50, 75 or 100 μg/kg/day for 


 
 
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27 days. The loading dose of 200 μg/kg in all cohorts is within the approved dose range of the 
summary of product characteristics19 with the first cohort then having continuous daily dosing 
of 50 μg/kg/day for 27 days, the equivalent of a 200 μg/kg loading dose plus cumulative 
continuous daily dose of 1350 μg/kg (which is less than the CDC crusted scabies dose over a 
month, 1400 μg/kg) and combined dose would be less than 2000 μg/kg taken in split doses 
over one week.  
The study has been designed to ensure the safety of the subjects by careful monitoring of 
individual subjects and review of safety data before dose escalation. The study design has the 
following features: 
• Sentinel dosing for each cohort 
• Safety data review before dose escalation  
• Careful monitoring of the subjects with a one-week inpatient stay followed by once 
weekly on-site visits during the dosing phase and a final visit 2 weeks after the last 
dose.  
In conclusion, for the proposed dosing regimen over 28-day period consisting of a first loading 
dose of 200 μg/kg followed by once daily dosing of either 50, 75 or 100 μg/kg/day for 27 days, 
in healthy volunteers, is expected to be well tolerated due to: 
• Substantial exposure to Ivermectin since 1987 
• Shorter duration of the study (4 weeks in humans vs 13 weeks in rats/dogs) 
• Known safety profile of ivermectin at doses much higher than the approved dosages 
(up to 2000 μg/kg was tested in healthy volunteers with no significant increase in 
adverse events recorded compared to placebo) and the one-month treatment regimen 
for crusted scabies 
• Study design, allowing for close monitoring of subjects and careful dose escalations 
after SRC reviews. 
3.2.1. Safety Review Committee 
Decisions for dose escalation between dose cohorts will be taken during an SRC meeting. The 
objectives of the SRC meetings are to review data from the current and previous cohort(s) and 
define the dose to be tested in the next cohort.  
The SRC will comprise at a minimum: 
• The Principal Investigator 
• The Sponsor Medical Monitor 
• MAC Project Manager for purpose of recording meeting minutes 
Safety Review Committee meetings will be scheduled to occur once quality-controlled safety, 
tolerability and plasma PK data up to at least Day 14 are available from a minimum of 4 active 
and 1 placebo subjects. For the Cohort 2 data SRC meeting onwards, available safety, 
tolerability and plasma PK data up to Day 28 from previous cohorts will be reviewed. 


 
 
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The safety and tolerability data to be reviewed will include, at a minimum, AEs, physical 
examinations, comprehensive neurological examinations, 12-lead ECGs, vital signs and 
clinical laboratory evaluation results, summarised by the Investigator in an Interim Safety 
Report. 
Further details on the operation of the SRC will be defined in a standalone supporting 
document. Details regarding the safety stopping criteria are provided in Section 3.2.2. 
3.2.2. Dose Escalation and Adjustment Criteria 
3.2.2.1. Criteria for Stopping Dose Escalation 
• PK Stopping Criteria: based on review of the accumulation ratio (RA).  Dose 
escalation will not proceed if this is deemed to pose a clinically significant risk to 
subjects by the SRC members. 
• Safety Stopping Criteria: Dose escalation will not proceed if any of the following 
occur in ivermectin-treated subjects: 
o One or more Hy’s Law cases in subjects who have been administered 
ivermectin. Hy’s Law is defined as AST or ALT ≥3 x upper limit of 
normal (ULN) and bilirubin ≥2 x ULN, in the absence of a significant 
increase in alkaline phosphatase (ALP) and in the absence of an 
alternative diagnosis that could explain the increase in bilirubin. 
o A ‘serious’ adverse reaction (see Section 7.6.1.2 for definition of 
‘serious) in 1 subject, i.e., a serious adverse event (SAE) that is 
considered at least possibly related to ivermectin administration. 
o ‘Severe’ non-serious adverse reaction, i.e., a severe non-serious AE 
considered as at least possibly related to ivermectin administration, in 
2 subjects in the same cohort, independent of within, or not within, the 
same system-organ class (SOC). 
o Clinically significant abnormalities in laboratory parameters in 2 or 
more subjects within the same cohort indicating dose-related 
intolerance, considered related to ivermectin. 
o Other findings that indicate dose escalation should be halted, e.g., if 
there is an unacceptable tolerability profile based on the nature, 
frequency and intensity of observed AEs and/or clinical safety 
monitoring. 
If any of these stopping criteria are met, the SRC should stop further dose escalation. The SRC 
will determine whether the dose level should be repeated, whether a lower dose should be 
tested, or whether the study should be terminated. Progression to subsequent cohorts (which 
may include lower doses) may be approved by the SRC subject to satisfactory review of the 
available PK, safety and tolerability data. Alternatively, the SRC may conclude it is 
inappropriate to continue to another cohort, in which case the study will be terminated. If 
significant safety concerns arise during dosing of a cohort, the SRC will review all available 
data and, considering the criteria above, decide whether it is appropriate to continue. 


 
 
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3.2.2.2. Individual Stopping Criteria 
• Any subject who experiences any of the criteria listed in Section 3.2.2.1. 
• Investigator discretion based on clinical safety grounds.  
 


 
 
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4. 
STUDY SETTING 
A single clinical research facility will be selected for this study. 
 
 


 
 
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5. 
STUDY TREATMENTS 
5.1. 
Name and Description of Investigational Products 
Ivermectin will be provided as 3 mg tablets
 
Matching placebo will be manufactured by 
 and supplied with a 
certificate of analysis. 
Further supportive information will be provided in the Pharmacy Manual.  
The IMP supplied by the Sponsor is to be used exclusively in the clinical study according to 
the instructions in this Protocol and the Pharmacy Manual. Until the IMP is dispensed to the 
subjects, it should be stored at a controlled room temperature below 25°C. At home, subjects 
IMP will be stored at room temperature and kept out of the reach and sight of children.  
The Principal Investigator will be responsible for storage and accountability of the IMP. Safety 
information regarding the IMP is provided in the IB. 
5.2. 
Dose Administration 
The active IMP or matched placebo will be orally administered in the morning from Day 1 to 
Day 28 following an overnight fast. Each dose will be taken with 240 mL of water at room 
temperature. Water will be allowed ad libitum and breakfast can be eaten between 1 to 2 hours 
after dosing. Dosing will be observed by CRU staff whilst resident in the CRU. 
Body weight at Screening will be used to calculate the dose administered. For each dose level 
administered, the number of 3 mg tablets shown in Table 4 will be administered. 
Table 4: Number of Ivermectin Tablets Per Cohort by Body Weight 
 
Loading 
Dose 
(Day 1) 
50 µg/kg Daily Dose  
(Cohort 1; Day 2 to 
Day 28) 
75 µg/kg Daily Dose  
(Cohort 2; Day 2 to 
Day 28) 
100 µg/kg Daily Dose  
(Cohort 3; Day 2 to 
Day 28) 
50 to ≤65 kg 
4 tablets 
1 tablet 
1.5 tablets (first day 
1 tablet, the next day 
2 tablets, etc.) 
2 tablets 
≥66 to ≤79 kg 
5 tablets 
1 tablet 
1.5 tablets (first day 
1 tablet, the next day 
2 tablets, etc.) 
2.5 tablets (first day 
2 tablets, the next day 
3 tablets, etc.) 
≥80 to ≤95 kg 
6 tablets 
2 tablets 
2.5 tablets (first day 
2 tablets, the next day 
3 tablets, etc.) 
3 tablets 
≥96 to ≤110 kg 
7 tablets 
2 tablets 
2.5 tablets (first day 
2 tablets, the next day 
3 tablets, etc.) 
3.5 tablets (first day 
3 tablets, the next day 
4 tablets, etc.) 
Non-whole weight values will be rounded to the nearest whole number. For example, 95.1 to 95.4 kg would be rounded down to 95 kg and 
95.5 to 95.9 kg would be rounded up to 96 kg. 
Before leaving the CRU on Day 7, subjects will be provided with a paper diary to record their 
daily dose of ivermectin or placebo (number of tablets taken, what time they took their dose 
and what time they had breakfast). Whilst outside the CRU, subjects will be contacted regularly 
by phone or text message to ensure that they are taking the correct number of tablets and to 
ensure that they are taking their dose following an overnight fast. 


 
 
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If a subject forgets to take their daily dose of ivermectin or placebo in the morning and has 
already eaten, they should not take their dose for that day.  
The number of tablets to be taken can vary day-to-day. If a subject misses their daily dose of 
ivermectin or placebo then, on the following day, they should take the number of tablets they 
missed the day previously (e.g., if they are alternating between 1 tablet and 2 tablets per day 
and they missed 2 tablets, they should take 2 tablets the following day and 1 tablet the day 
after).  
For the Day 14, Day 21 and Day 28 doses, subjects will NOT take their daily dose of ivermectin 
or placebo. Instead they will bring their remaining tablets to the clinic and will take their daily 
dose (overnight fasted) after any applicable pre-dose assessments have been performed by 
CRU staff. Dosing will be observed by CRU staff on all study visit days. 
5.3. 
Concomitant Medication 
The Investigator and study team may review medication use on a case-by-case basis to 
determine if its use would compromise subject safety or interfere with study procedures or data 
interpretation (exclusion criteria relating to concomitant medication are presented in 
Section 6.2). By exception, the subject may take paracetamol (less or equal 2 g/day) for up to 
48 hours prior to first dosing. All concomitant medications used (including over-the-counter 
[OTC] medications and herbal supplements) will be recorded in the source documents and on 
the appropriate electronic case report form (eCRF). 
5.4. 
Assessment of Compliance with Treatment 
All doses will be administered by study staff under direct observation whilst resident in the 
CRU. The administration of the study drug will be recorded within the appropriate pages of the 
eCRF. Subjects will be asked to return all unused medication including empty and partially 
used containers. For the time when subjects administer at home (Day 8 to Day 27), study 
medication dispensed at the previous visit will be retrieved by the Investigator and compliance 
assessed by regular contact with the subject whilst outside the CRU, returned medication count 
and subject diary completion. 
Any deviations from the planned dosing procedure will be recorded within the eCRF. 
5.5. 
Blinding  
This study will be double-blinded (Investigator- and subject-blinded). The randomisation list 
will be kept in a secure location until the end of the study. Only the Pharmacy staff involved in 
handling the study drug and laboratory staff responsible for analysing the PK blood samples 
will be unblinded during the study and will have access to the randomisation list.  
5.6. 
Emergency Unblinding  
The study blind should not be broken except in a medical emergency where knowledge of the 
IMP would inform treatment of an emergency. The Investigator has the sole responsibility for 
determining if unblinding of treatment is necessary for medical management of an event. The 
Investigator will inform the Medical Monitor and Sponsor of this decision as soon as is 
reasonably practicable. The applicable Standard Operating Procedures (SOPs) will be followed 
to break the blind. 
After database lock, the overall randomisation code will be broken only for reporting purposes.  


 
 
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6. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The study population includes 24 healthy male subjects. Each subject should meet all the 
inclusion criteria and none of the exclusion criteria for this study. Under no circumstances can 
there be exceptions to this rule.  
6.1. 
Inclusion Criteria 
Subjects meeting the following criteria will be included in the study: 
1. Subject is male, of any ethnic origin. 
2. Subject is aged between 18 to 45 years, inclusive. 
3. Subject has a body mass index (BMI) of 18.5 to 32.0 kg/m2, inclusive. 
4. Subject is ≥50 kg. 
5. Negative RT-PCR Test for SARS-CoV-2 at Screening and negative lateral flow 
immunoassay test for SARS-CoV-2 at Day -1. 
6. Willing and able to comply with scheduled visits, treatment plan, and other study 
procedures 
7. Healthy as determined by a responsible physician, based on medical evaluation 
including medical history, physical examinations, neurological examinations, 
concomitant medication, vital signs, 12-lead ECG and clinical laboratory evaluations.  
8. Male subjects must use a condom during the study and for 3 months after their final 
dose of study medication, if their partner is a woman of childbearing potential. In 
addition, their female partner of childbearing potential must use an additional method 
of highly effective contraception (see Section 6.3.1) from first dosing until 3 months 
following final dosing. 
9. Provision of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. 
6.2. 
Exclusion Criteria  
Subjects with any of the following will be excluded from study participation: 
1. Clinically relevant history of abnormal physical or mental health (defined as any subject 
requiring medical, psychological or pharmacotherapeutic intervention for mental 
illness) interfering with the study as determined by medical history and physical 
examinations obtained during Screening and Day -1 as judged by the Investigator 
(including [but not limited to], neurological, psychiatric, endocrine, cardiovascular, 
respiratory, gastrointestinal, hepatic, or renal disorder). 
2. Clinically relevant abnormal laboratory results (including hepatic and renal panels, 
complete blood count, chemistry panel and urinalysis), 12-lead ECG and vital signs, or 
physical findings at Screening and/or Day -1 (as judged by the Investigator). In case of 
uncertain or questionable results, tests performed during Screening may be repeated 
once to confirm eligibility or judged to be clinically irrelevant for healthy subjects. 


 
 
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3. Refractory nausea, vomiting, or chronic gastrointestinal disorders, inability to swallow 
the study drug or having undergone extensive bowel resection which may affect 
adequate absorption of ivermectin 
4. Any other concomitant disease or condition that could interfere with, or for which the 
treatment might interfere with, the conduct of the study as outlined in this Protocol, or 
that would, in the opinion of the Investigator, pose an unacceptable risk to the subject 
in this study. 
5. Subjects with Gilbert’s syndrome or AST, ALT, gamma-glutamyl transferase (GGT) 
or total bilirubin levels greater than the ULN at Screening or Day -1. These laboratory 
evaluations may be repeated once at the discretion of the Investigator. If the repeat test 
is within the reference range, the subject may be included only if the Investigator 
considers that the previous finding will not introduce additional risk factors and will 
not interfere with interpretation of safety data. 
6. Known hypersensitivity or allergy to any component of the ivermectin drug product or 
placebo. 
7. Evidence of previous SARS-CoV-2 infection from medical history. 
8. Ophthalmologic disorder (moderate and severe retina or optic nerve pathology; 
cataracts excluded). 
9. Subjects with a diagnosis of asthma or any other respiratory condition. 
10. A neurologic disorder that may compromise blood brain barrier permeability (stroke 
within 90 days, brain tumour, multiple sclerosis, or other neuroinflammatory condition, 
a neurodegenerative disorder, epilepsy) or history of seizures. 
11. QTcF >450 msec at Screening or at check-in on Day -1, following triplicate ECG 
readings. 
12. Positive test for hepatitis B surface antigen (HBsAg), anti-hepatitis C antibody (anti-
HCV) or human immunodeficiency virus I and II (anti-HIV I/II) at Screening. 
13. Positive urine test for drugs of abuse, urine cotinine test or alcohol breath test at 
Screening or Day -1.  
14. History of drug and/or alcohol abuse within the last 2 years, or intake of >21 units of 
alcohol weekly, and the inability to refrain from alcohol use from 48 hours before 
Screening and from 48 hours before Day -1 until the end of the study. One unit is 
equivalent to a 285 mL glass of full-strength beer or 1 (30 mL) measure of spirits or 
1 glass (100 mL) of wine. 
15. Use of tobacco and/or nicotine containing products (including e-cigarettes) within 
3 months of Screening.  
16. Habitual and heavy consumption of caffeinated beverages (>8 cups of coffee or 
equivalent per day) at Screening; and/or unable to refrain from use of (methyl) xanthine 
(e.g., coffee, tea, cola, chocolate) from 48 hours prior to each clinic visit until the end 
of the study.  


 
 
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17. The subject has participated in a clinical study and has received a medication or a new 
chemical entity within 3 months or 5 half-lives (whichever is longer) prior to first 
dosing of current study medication. 
18. Use of any prescription or non-prescription medications, including herbal and 
nutritional supplements, or OTC medications (e.g., ibuprofen, aspirin) within 14 days 
of first dosing and throughout the study. By exception, the subject may take 
paracetamol (less or equal 2 g/day) for up to 48 hours prior to first dosing. The 
Investigator and study team may review medication on a case-by-case basis to 
determine if its use would compromise subject safety or interfere with study procedures 
or data interpretation. 
19. Use of any drugs that are known substrates of CYP3A4, P-glycoprotein (P-gp) from 
within 4 weeks of Screening and unable to refrain from them until the end of the study 
(e.g., rifampicin, quinidine, amiodarone, diltiazem, spironolactone, verapamil, 
clarithromycin, erythromycin, itraconazole, ketoconazole, cyclosporine, tacrolimus, 
indinavir, ritonavir or cobicistat). Use of critical CYP3A4 substrate drugs such as 
warfarin or coumarin anticoagulants.  
20. Recent or expected microfilaricidal drug use, including ivermectin, or travel history to 
areas that are endemic for Loa loa or onchocerciasis (Angola, Cameroon, Central 
African Republic, Chad, Democratic Republic of Congo, Ethiopia, Equatorial, Guinea, 
Gabon, Republic of Congo, Nigeria and Sudan). 
21. Use of medications having potential activity against SARS-CoV-2 such as 
hydroxychloroquine, chloroquine, lopinavir, ritonavir, remdesivir, azithromycin, in the 
30 days prior to Screening and unable to refrain from them until the end of the study. 
22. History of severe adverse reactions or allergies, or history of an anaphylactic reaction 
to prescription or non-prescription medication or food (non-active hay-fever is 
acceptable). 
23. Consumption of any food or drinks containing cranberry, pomegranate, starfruit, 
grapefruit, pomelos, exotic citrus fruits or Seville oranges (including marmalade and 
juices made from these fruits) within 14 days prior to first dosing until the end of the 
study. 
24. Strenuous exercise within 48 hours prior to each blood collection for clinical laboratory 
tests.  
25. Donation of blood or plasma of >400 mL within 4 weeks prior to first dosing until 
4 weeks after final dosing. 
26. Male subject who will not abstain from sperm donation between first dosing and 
3 months after final dosing. 
6.3. 
Study Restrictions 
6.3.1. Contraception Restrictions 
Male subjects with a female sexual partner of child-bearing potential must wear a condom 
(from first dosing until 3 months after final dosing) in addition to their female partner using a 
highly effective method of contraception, from first dosing until 3 months following final 
dosing. Contraceptive methods that can achieve a failure rate of less than 1% per year when 


 
 
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used consistently and correctly are considered as highly effective birth control methods. Such 
methods 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 or intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Surgical sterilisation 
If the male subject is vasectomised then this will be accepted as a second form of highly 
effective contraception, in addition to the subject also wearing a condom. Sexual abstinence is 
considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with study treatment and must be part of 
the preferred and usual lifestyle of the subject. 
6.3.2. Lifestyle Restrictions 
Subjects should abstain from strenuous exercise for 48 hours prior to each visit for blood 
collection for clinical laboratory tests, and while in the CRU. Subjects should not start any new 
exercise regimes during their participation in the study. 
6.3.3. Meals and Dietary Restrictions 
The subjects are required to adhere to the following restrictions: 
• Subjects should refrain from consumption of any food or drinks containing cranberry, 
pomegranate, starfruit, grapefruit, pomelos, exotic citrus fruits or Seville oranges 
(including marmalade and juices made from these fruits) within 14 days prior to first 
dosing until the end of the study.  
• Subjects should abstain from alcohol for 48 hours prior to Screening and no alcohol 
should be consumed from 48 hours prior to Day -1 until the end of the study.  
• Subjects should abstain from tobacco and nicotine-containing products for 3 months 
prior to Screening, throughout the study until completion of the study.  
• Subjects should abstain from (methyl) xanthine- and caffeine-containing products for 
48 hours prior to each clinic visit until the end of the study.  


 
 
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• Subjects will be fasted overnight before dosing. Water will be allowed ad libitum and 
breakfast can be eaten between 1 to 2 hours after dosing. Standard meals and drinks 
will be provided while resident in the CRU. In addition, subjects should fast at least 
4 hours prior to any visit where clinical laboratory evaluations will be carried out. 
• Subjects should refrain from consuming poppy seeds 48 hours prior to Screening, 
Day -1, Day 14, Day 21 and Day 28 to avoid a positive result on the drugs of abuse 
screen.  
6.4. 
Subject Withdrawal Criteria 
For all subjects withdrawn from the study, discontinuation procedures as described in 
Appendix 1 should be conducted prior to discharge in the study. Subjects will be replaced if 
there are insufficient evaluable subjects in each dose cohort. A minimum of 4 ivermectin and 
1 placebo subjects in each cohort are required for dose escalation and a minimum of 
5 ivermectin and 1 placebo subjects are required for completion of a dose cohort.  
Reserve subjects will be screened and admitted to the CRU on Day -1. They will undergo the 
Day -1 and pre-dose assessments but will not be dosed on Day 1, unless replacing another 
subject who fails inclusion/exclusion criteria. 
Reasons for withdrawal or discontinuation at any time during the study may include any of the 
following reasons: 
• Adverse event: Clinical or para-clinical events occurred that, in the medical 
judgement of the Investigator for the best interest of the subjects, are grounds for 
discontinuation. This includes serious and non-serious AEs regardless of relation to 
the study medication.  
• Withdrawal of consent: The subject desired to withdraw from further participation in 
the study in the absence of an Investigator determined medical need to withdraw. If 
the subject gave a reason for withdrawing it should be recorded in the eCRF.  
• Investigator decision. 
• Compliance: any subject who fails to take their daily dose for 2 consecutive days, 
misses 3 doses in a week (7 days), or misses greater than 1 dose of study drug per 
week (>4 in total during 4-week study). 
• Lost to follow-up: The subject stopped coming for visits and study personnel were 
unable to contact the subject. 
• Other: The subject was discontinued for a reason other than those listed above, such 
as termination of the study by the Sponsor. The reason(s) should be recorded in the 
eCRF.  
6.5. 
Follow-up Procedures 
The Investigator will make diligent attempts to contact subjects who fail to return for a 
scheduled visit or were otherwise unable to attend the follow-up visit. All discontinuations and 
the reason for early discontinuation will be documented by the Investigator, and if appropriate 
on the AE form.  
 


 
 
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7. 
SAFETY ASSESSMENTS 
Baseline safety data assessments for all parts of the study will be collected pre-dose at the 
nearest timepoint to dosing as shown in Appendix 1. The subjects will attend a Follow-up visit 
14 days after the final dose for safety follow-up procedures 
 
 
7.1. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed including clinical chemistry, haematology, 
coagulation and urinalysis as indicated in the table below (Table 5). Serology, drugs of abuse, 
cotinine and alcohol screen will be performed as indicated in the table below (Table 5). 
 
All blood and urine analyses will be conducted at the sampling times 
 
. The clinical laboratory evaluation results will be collected at 
Day -1, in time for results to be reviewed prior to dose administration. For abnormal values, 
additional testing may be performed, or clinical laboratory evaluations may be added to 
evaluate the abnormal values. Clinically significant values should be followed until resolution 
or until they reach a stable state.  
Table 5: Clinical Laboratory Evaluations 
Blood Chemistry 
BUN 
Creatinine 
Glucose 
Sodium 
Potassium 
Phosphate 
Chloride 
Calcium 
AST 
ALT 
GGT 
Alkaline phosphatase 
Total bilirubin 
Uric acid 
Albumin 
Total protein 
Lactate dehydrogenase 
Urinalysis (dipstick)  
Glucose 
Bilirubin 
Ketone 
Specific Gravity 
Blood 
pH 
Protein 
Urobilinogen 
Nitrite 
Leukocyte Esterase 
 
Microscopic analysis if dipstick is abnormal 
Haematology 
Haemoglobin  
Haematocrit 
RBC count 
RBC indices (MCV, MCH, MCHC) 
Platelet count 
White blood cell count with differential 
Drugs of abuse 
Amphetamines  
Barbiturates 
Benzodiazepines 
Cocaine 
Cannabinoids  
Opiates 
Coagulation 
Prothrombin time 
International normalization ratio 
Activated partial thromboplastin time 
Serology 
Anti-HIV I/II 
SARS-CoV-2 (performed only if lateral flow 
immunoassay testing is positive) 
Anti-HCV 
HBsAg  
Other Screens 
Alcohol (breath)  
Cotinine (urine) 
SARS-CoV-2 RT-PCR test 


 
 
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Abbreviations: ALT – alanine aminotransferase; Anti-HIV I/II – Anti-human immunodeficiency virus I and II; Anti-HCV – anti-hepatitis C 
antibody; AST: aspartate aminotransferase; BUN – blood urea nitrogen; GGT – gamma-glutamyl transferase; HBsAG – hepatitis B surface 
antigen; MCV – mean corpuscular volume; MCH - mean corpuscular haemoglobin; MCHC – mean corpuscular haemoglobin concentration; 
RT-PCR – reverse transcription polymerase chain reaction. 
 
7.2. 
12-lead Electrocardiogram 
A 12-lead ECG will be collected at the timepoints indicated in the Schedule of Assessments 
 The 12-lead ECG will be collected in triplicate, approximately 1 minute apart, 
at Screening, Day -1 and within 2 hours pre-dose on Day 1.  Single readings will be collected 
at all other timepoints. 12-lead ECGs should be obtained after the subject has rested in the 
supine position for at least 5 minutes. In the event of an abnormal finding, recordings should 
be performed in triplicate. The ECG machine used should automatically calculate the heart rate 
and PR, RR, QRS, QT and QTcF intervals.  
For timepoints with multiple assessments: 
• collect the ECG first,  
• then vital signs, 
• then the PK blood draw. The PK sample should be collected at the scheduled time 
post-dose.  
7.3. 
Vital Signs and Oral Temperature 
Supine and standing vital signs (2 minutes apart), including heart rate, blood pressure and oral 
temperature will be collected at the timepoints in the Schedule of Assessments 
 
Pre-dose vital signs should be collected within 30 minutes pre-dose.  
For timepoints with multiple assessments: 
•  collect the ECG first,  
• then vital signs,  
• then the PK blood draw. The PK sample should be collected at the scheduled time 
post-dose. 
7.4. 
Physical Examinations 
A full physical examination, including height, BMI, and body weight, and assessments of the 
head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular system, 
abdomen (liver and spleen), lymph nodes and extremities will be conducted at the times 
indicated in the Schedule of Assessments 
 A symptom-guided physical 
examination will also be conducted at the times indicated in the Schedule of Assessments 
 
7.5. 
Neurological Examinations 
A comprehensive neurological examination will be conducted at the times specified in the 
Schedule of Assessments 
 The comprehensive neurological examination will 
include assessment of mental status and cognitive function, cranial nerve examination, motor 
function, sensation and proprioception (light touch, vibration), deep tendon reflexes of all 
4 limbs, balance, co-ordination, gait and visual assessments. Visual assessments will include 


 
 
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visual inspection of the eyes, pupil response, eye movements, fundoscopy, visual acuity 
(Snellen chart) and visual fields. 
7.6. 
Adverse Event Reporting 
Adverse event monitoring will be conducted at the times specified in the Schedule of 
Assessments 
 Adverse events will be elicited through non-leading questions and 
spontaneous reporting by subjects. The Investigator is responsible for evaluating AEs and for 
the appropriate medical care of subjects during the study. 
7.6.1. Definition and Criteria 
7.6.1.1. Adverse Event  
An AE is any untoward medical occurrence in a study subject which either emerges, or worsens 
from Screening, during the clinical study, regardless of its potential relationship to the 
medicinal product. An AE, therefore, can be any unfavourable or unintended sign, including a 
clinically significant abnormal laboratory finding, symptom, or disease temporally, whether or 
not it is considered to be study medication related.  
Examples of an AE include: 
• Exacerbation of a pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• New conditions detected or diagnosed. 
• Signs or symptoms of a drug interaction. 
• Signs or symptoms of a suspected overdose of either IMP or a concurrent medication 
(overdose per se should not be reported as an AE/SAE) 
• A new laboratory abnormality occurring after the start of the study (i.e., after 
Screening) that results in subject withdrawal from the study or medical treatment or 
further follow-up.  
o Note: abnormal laboratory or other values obtained during Screening that 
preclude a subject from entering the study are not considered AEs but will be 
recorded.  
Adverse events may include pre- or post-treatment events that occur as a result of Protocol-
mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic 
regimen).  
A medical intervention to address an AE is an “action taken” and not an AE itself. 
7.6.1.2. Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death, 
• Is life-threatening, 
o Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event 
in which the subject was at risk of death at the time of the event. It does not refer 


 
 
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to an event, which hypothetically might have caused death, if it were more 
severe. 
• Requires hospitalisation or prolongation of existing hospitalisation,  
o Note: In general, hospitalisation signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or out setting. Complications that occur during hospitalisation 
are AEs. If complication prolongs hospitalisation or fulfils any other serious 
criteria, the event is serious. When in doubt whether ‘hospitalisation’ occurred 
or was necessary, the AE should be considered serious.  
• Results in persistent or significant disability or incapacity, 
o Note: The term ‘disability’ means a substantial disruption of a person’s ability 
to conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhoea, influenza and accidental trauma (e.g., 
sprained ankle) which may interfere or prevent everyday life functions but do 
not constitute a substantial disruption.  
• Is a congenital abnormality or birth defect, 
• Is an important medical event.  
o Note: Medical or scientific judgement should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events 
that may not be immediately life threatening, or result in death or 
hospitalisation, but may jeopardise the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These should also be considered serious. Examples of such events 
are invasive or malignant cancers, intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalisation, or development of drug dependency or drug abuse. 
o Note: The terms “serious” and “severe” ARE NOT synonymous. The term 
“severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate or severe myocardial infarction); the event itself, however, 
may be of relatively minor medical significance (such as severe headache). This 
is NOT the same as “serious”, which is based on subject/event outcome or action 
criteria described above and are usually associated with events that pose a threat 
to a subject’s life or functioning. A severe AE does not necessarily need to be 
considered serious. For example, persistent nausea of several hours duration 
may be considered severe nausea but not an SAE. On the other hand, a stroke 
resulting in only a minor degree of disability may be considered mild but would 
be defined as an SAE based on the above criteria. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations.   


 
 
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7.6.1.3. Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events 
Abnormal laboratory findings (e.g., clinical chemistry and haematology) or other abnormal 
assessments (e.g., ECGs, vital signs) that are judged by the Investigator as clinically significant 
will be recorded as AEs or SAEs if they meet the definition of an AE or SAE. Clinically 
significant abnormal laboratory findings or other abnormal assessments that are detected during 
the study or are present at baseline and significantly worsen following the start of the study 
will be reported as AEs or SAEs. The Investigator will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory finding, or other abnormal assessment 
is clinically significant. Liver chemistry thresholds have been designed to assure subject safety. 
When subjects meet the hepatic transaminase threshold criteria (AST or ALT ≥3 x ULN), the 
subject should undergo close observation, including monitoring for symptoms (clinical 
symptoms of hepatitis, or hypersensitivity, fatigue, decreased appetite, nausea, vomiting, 
abdominal pain, jaundice, fever, or rash) and hepatic function (AST, ALT, ALP), and 
fractionated bilirubin at least every 48 hours, until symptoms and/or hepatic function 
abnormalities resolve, stabilise, or return to baseline values. This event should be reported to 
MedinCell within 24 hours of learning of its occurrence.  Appendix 4 represents the decision 
tree for whether or not study medication will be discontinued. A specialist or hepatology 
consultation should be considered in cases of protocol-mandated study medication 
discontinuation. 
In addition, every attempt should be made to obtain the following for any subject who meets 
the hepatic transaminase threshold criteria:  
• Viral hepatitis including: hepatitis A immunoglobulin (IgM) antibody, hepatitis B 
surface antigen and hepatitis B core antibody (IgM), HCV RNA, cytomegalovirus 
IgM antibody, Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophil antibody or monospot testing), and hepatitis E antibody (if subject 
resides outside UK or has travelled outside UK in past 3 months).  
• Serum creatine phosphokinase and lactate dehydrogenase. Record the appearance or 
worsening of clinical symptoms of hepatitis, or hypersensitivity, fatigue, decreased 
appetite, nausea, vomiting, abdominal pain, jaundice, fever, or rash as relevant on the 
AE report form.  
• Record use of concomitant medications, including paracetamol, herbal remedies, 
other OTC medications, putative hepatotoxins, or alcohol on the concomitant 
medications report form. 
• The following are required for subjects with AST or ALT ≥3 x ULN and bilirubin ≥2 
x ULN, but are optional for other abnormal liver chemistries:  
o Anti-nuclear antibody, anti-smooth muscle antibody, and type 1 anti-liver 
kidney microsomal antibodies.  
o Liver imaging (ultrasound, magnetic resonance, or computerised tomography) 
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7.6.1.4. Pharmacokinetic Sampling Associated with Serious Adverse Events or Severe 
Adverse Events 
Every possible attempt will be made to collect an unscheduled PK sample if a subject 
experiences an SAE or a severe AE. As the determination of an SAE or a severe AE is 
sometimes retrospective, unscheduled PK samples obtained when an event that is suspected to 
be serious or severe are also permitted. 
7.6.2. Evaluating Adverse Events and Serious Adverse Events 
All AEs will be assessed on 2 descriptive parameters: intensity (severity) and relationship to 
the study medication: 
• Intensity refers to the severity of an event and references impact on a subject’s 
functioning. 
• Relationship refers to the likelihood that the event being assessed was caused by the 
study medication.  
The intensity of each AE (including SAEs) will be recorded in the eCRF and assigned to one 
of the following categories: 
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities. 
• Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. 
For AEs and SAEs, the relationship to the study treatment is to be assessed according to the 
following definitions: 
Not related: There is no reasonable association between the study treatment and the suspected 
event. 
Unlikely related: It is doubtful that there is an association between the study treatment and the 
suspected event. The event could have been produced by the subject’s clinical state or other 
modes of therapy administered to the subject. 
Possibly related: The suspected AE may or may not follow a reasonable temporal sequence 
from study drug administration. The event could have been produced or mimicked by the 
subject’s clinical state or by other modes of therapy concomitantly administered to the subject. 
Probably related: The suspected AE follows a reasonable temporal sequence from study 
treatment administration, abates upon discontinuation of the treatment; and cannot be 
reasonably explained by the known characteristics of the subject’s clinical state.  
When assessing the relationship to the study medication, the following criteria will be 
considered: 
• Known class effect 
• Positive rechallenge 


 
 
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• Positive dechallenge (resolution upon stopping the suspect study medication, in 
absence of other interventional treatment] 
• Biological plausibility  
• Lack of alternative explanation – concomitant drug or disease 
7.6.3. Reporting Procedures and Requirements 
7.6.3.1. Adverse Events 
Events meeting the criteria in Section 7.6.1.1 occurring from the time of signed informed 
consent will be considered as AEs. All AEs between Screening to the Follow-up visit will be 
recorded in source and eCRF, whether or not considered study medication related. All AEs that 
are possibly or probably related to study medication will be followed until resolution or 
database lock, whichever occurs first. Also, the sign, symptom, or disease present before the 
baseline AE assessment are only considered AEs if they worsen after this point. Any AEs 
already documented at a previous assessment and designated as ongoing should be reviewed 
at subsequent visits as necessary. If these have resolved, this should be documented. Changes 
in intensity or frequency of AEs should be recorded as separate events (i.e., a new record 
started). The Investigator should report all AEs on the AE page(s) of the eCRF and source 
documents, regardless of seriousness, severity, and causality. Whenever possible, an AE will 
be reported using a diagnostic term, (e.g., “common cold” or “upper respiratory infection” 
rather than “runny nose, cough, mild fever”) and should be described with the attributes 
described in Section 7.6.1.1.  
7.6.3.2. Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria (Section 7.6.1.2). 
If the AE is considered serious the Investigator should report this event to the Sponsor. The 
Sponsor will report the event to the research ethics committee (REC) according to its SOPs. 
Serious adverse events occurring from the time of signed informed consent to the follow-up 
visit or 7 days after the last dose of study medication (whichever occurs later) will be recorded 
in source and electronic data capture; ongoing SAEs after this time frame will be followed until 
the Investigator, Medical Monitor, and Sponsor agree that the SAE is satisfactorily resolved, 
or stably unresolved. Serious adverse events considered by the Investigator to be related to 
study medication, regardless of the time of onset after treatment, should be reported. All 
information about SAEs will be collected and reported via the SAE form and sent by email 
message (contact information will be contained in the Investigator site file). The Investigator 
should send the initial report within 24 hours of becoming aware of the SAE. At a minimum, 
the initial report should include the following information: 
• Event 
• Seriousness criteria 
• Protocol number 
• Subject number, initials and date of birth 
• Study medication 
• Reporter name and contact information 


 
 
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In the case of a “minimum report” (one that solely comprises the information bulleted above), 
a more detailed follow-up report should be sent as soon as more information becomes available 
but no later than 7 calendar days after the date of the initial report. Each SAE should be 
followed up until resolution or stabilisation and for reported deaths, the Investigator should 
supply MedinCell or its designee and the REC with any additional requested information (e.g., 
autopsy reports and terminal medical reports), if available. The original SAE form should be 
kept at the study site. The Investigator will be responsible for determining and in turn, reporting 
SAEs to the Sponsor. MedinCell or its designee will be responsible for reporting SAEs to 
regulatory authorities according to the applicable regulatory requirements. MedinCell or its 
designee will be responsible for completing the safety report and for notifying the relevant 
authorities of any SAE as outlined in the International Council for Harmonisation (ICH) 
Guidelines and per local regulatory requirements.  
7.6.4. Prompt Reporting of Serious Adverse Events 
Any SAE, occurring in a subject receiving treatment or if the Investigator becomes aware of 
any SAE post-treatment during the follow-up visit, should be reported by the Investigator to 
the Medical Monitor within 24 hours even if the SAE does not appear to be medication-related. 
An emailed copy of the SAE form, in addition to other related information should be sent to 
the appropriate Pharmacovigilance Vendor (PV). Additionally, it may be necessary for the 
Medical Monitor or Sponsor to directly communicate with the Investigator if additional 
information is required. 
All additional follow-up evaluations should be reported to MedinCell or its designee. Such data 
should be emailed to the PV within 10 calendar days. Serious adverse events occurring from 
the time of signed informed consent to the follow-up visit or 7 days after the last dose of study 
medication (whichever occurs later) will be recorded in source and electronic data capture; 
ongoing SAEs after this time frame will be followed until the Investigator, Medical Monitor, 
and Sponsor agree that the SAE is satisfactorily resolved, or stably unresolved. Serious adverse 
events considered by the Investigator to be related to study medication, regardless of the time 
of onset after treatment, should be reported. 
MedinCell or its designee is responsible for the reporting of SUSARs. An AE will be 
considered unexpected if the nature, severity, frequency of the event is not consistent with the 
risk information previously described for the IMP. The process for recording and reporting 
SUSARs is defined in the Sponsor or its designee SOPs in accordance with regulatory 
guidelines. 
A list of expected serious adverse reactions are provided in the IB. 
7.6.5. Special Considerations 
7.6.5.1. Pregnancy of Female Partner of Male Subject  
If the female partner of a male subject becomes pregnant between dosing and 3 months after 
dosing, the Investigator should report pregnancy within 72 hours after learning of the 
pregnancy. The Investigator should contact the designated individual(s) following the SAE 
notification process and record information related to the pregnancy on the designated 
pregnancy form provided by MedinCell or its designee. Early discontinuation visit assessments 
are required as soon as possible after learning of the pregnancy. The Investigator is also 
responsible for following any pregnancy following admission until delivery or termination if 
possible. These findings should be reported on the pregnancy form and forwarded to the 
designated individual(s). The event meets the SAE criterion only if it results in a spontaneous 


 
 
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abortion, congenital anomaly or reports of suspected adverse reactions in the neonate that are 
classified as serious. 
7.7. 
Other Assessments 
Assessments to be performed at Screening only and Day -1 only are detailed in the Schedule 
of Assessments
 
 
 


 
 
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8. 
PHARMACOKINETIC ASSESSMENTS 
8.1. 
Pharmacokinetic Sampling 
Baseline PK blood samples will be collected within 15 minutes before first dosing.  
Blood samples for determination of plasma concentrations of ivermectin will be taken at the 
timepoints stated in 
  
The actual times of collection will be recorded.  
Plasma concentration-time data will be analysed by noncompartmental methods. Nominal 
times may be used for interim decisions, however actual sampling times will be used for final 
calculations.  
8.2. 
Storage and Analysis of Clinical Samples  
Approximate sampling volumes are provided in
 Samples will be collected, 
labelled, stored and shipped as detailed in the Sample Handling Sheets.  
Pharmacokinetic blood (collected in K2EDTA tubes) samples will be collected and ivermectin 
will be quantified using a validated liquid chromatography-tandem mass spectrometry 
(LC/MS-MS) method. Further details will be provided in a standalone document. 
 
 






 
 
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11. 
STATISTICS AND DATA ANALYSIS 
11.1. Randomisation and Subject Allocation 
A randomisation scheme will be produced by MAC Clinical Research. After informed consent 
is obtained, subjects will be allocated a unique screening number. 
Only subjects who comply with all the inclusion criteria, and none of the exclusion criteria will 
be randomised onto the study. The subjects will be assigned to a randomisation number in the 
order of recruitment. The randomisation number will have 4 digital numbers, with the first 
being the cohort (i.e., 1 for Cohort 1, 2 for Cohort 2, etc), the second being whether a subject 
is a replacement (0 = original; 1 = replacement), and the last 2 being the subject number; for 
example, 1001 means the 1st subject in the originally randomised Cohort 1, whereas 1101 is 
the replacement of 1001. All screened subjects should be identifiable throughout the study. 
11.2. Sample Size Determination 
It is planned to enrol 24 subjects. An appropriate sample size cannot be determined statistically 
as no previous human data are available for continuous daily dosing. A sample size of 
8 subjects (6 active:2 placebo) per dose level of ivermectin, with 3 dose levels was selected to 
be able to characterise the PK profile and produce safety information which can be compared 
with the known safety profile of ivermectin. 
11.3. Statistical Analysis Plan  
A Statistical Analysis Plan (SAP) will be prepared after finalising the Protocol and before 
database lock. The specifications in this document will detail the implementation of all the 
planned statistical analyses in accordance with the principal features stated in the Protocol. The 
SAP will provide full details of the analyses, data displays, and algorithms to be used for data 
derivation. 
11.4. Analysis Sets 
The following analysis sets are defined for this study.  
11.4.1. Safety Set 
The Safety Analysis Set will consist of all subjects who received at least 1 dose of study drug(s). 
Subjects in the Safety Analysis Set will be classified according to study drug(s) they actually 
received. Safety data will not be formally tested but will be summarised using descriptive 
statistics. 
11.4.2. Pharmacokinetic Analysis Set 
All subjects who receive at least 1 dose of IMP per the protocol for whom any post-dose data 
are available and who do not violate or deviate from the protocol in ways that would 
significantly affect the PK analyses will be included in the PK Analysis Set. The population 
will be defined by the Study Physician, Pharmacokineticist and Statistician prior to any 
analyses being performed. 
11.4.3. Per-protocol Analysis Set 
The Per-protocol Set will include all randomised subjects that have completed the 28-day 
dosing period of the trial without major protocol deviations. Subjects withdrawn due to 
non-compliance (see Section 6.4) will not be included in the Per-protocol Set. Subjects will be 
classified according to study drug(s) they actually received. 


 
 
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11.5. Statistical Analysis 
Statistical analyses will be performed using SAS 9.4.  
11.5.1. Safety Statistical Analysis 
Safety assessments will include standard laboratory safety evaluations (haematology, 
biochemistry, coagulation and urinalysis), vital signs (blood pressure, heart rate and oral 
temperature), physical examinations, neurological examinations, 12-lead ECG and AE 
monitoring. 
11.5.1.1. Adverse Events 
All AEs will be listed according to SOC and preferred term (PT) assigned to the event using 
Medical Dictionary for Regulatory Activities (MedDRA; highest version). Number and 
percentage of subjects who experienced any AEs will be summarised by cohort and treatment. 
Furthermore, AEs will be summarised by causality and the maximum intensity. Any SAEs 
and/or AEs that led to withdrawal will be listed.  
11.5.1.2. Clinical Laboratory Evaluations 
Clinical Laboratory evaluation results will be listed and compared to laboratory reference 
ranges, with those values outside of the applicable range flagged as high (H) or low (L). The 
quantitative laboratory data will be summarised using descriptive statistics (n, arithmetic mean, 
median, minimum and maximum) for each parameter by treatment, time and cohort. Urinalysis 
data will be listed only. 
11.5.1.3. Vital Signs 
Vital signs (supine and standing systolic blood pressure, diastolic blood pressure, heart rate and 
body temperature) will be listed for individual subjects. Summary statistics (n, arithmetic mean, 
median, minimum, and maximum) will be calculated for each parameter by treatment, time, 
and cohort. 
11.5.1.4. 12-Lead Electrocardiogram 
Standard 12-lead ECG parameters (RR, PR, QRS, QT, QTcB, QTcF intervals and heart rate) 
will be listed for individual subjects. Out-of-range ECG values will be flagged as high (H) or 
low (L). Summary statistics (n, arithmetic mean, median, minimum, and maximum) will be 
calculated for each parameter by treatment, time, and cohort. Where multiple values are 
recorded at a timepoint for a subject, the mean of the values will be used in the summary 
statistics. 
11.5.1.5. Neurological Examination 
Neurological examination parameters will be listed for individual subjects. Frequency tables 
will be calculated for each parameter (percentage normal/abnormal) by treatment, time, and 
cohort.  
11.5.1.6. Physical Examination 
Physical examination data will be listed only.  
11.5.2. Pharmacokinetic Statistical Analysis 
Ivermectin plasma concentrations and PK parameters will be summarised using all subjects in 
the Pharmacokinetic Set. Full details of the PK analysis will be included in the PK Analysis 
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12. 
DATA HANDLING AND RECORD KEEPING 
12.1. Collection of Data 
Data collected from each completed subject will be recorded on source documents, which will 
be entered into an eCRF. The Investigator is responsible for ensuring that all sections of the 
eCRF are completed correctly and that entries can be verified against the source documents. If 
certain data are not available or not applicable this will be indicated as such within the 
appropriate area of the eCRF. 
Screening failures (subjects who signed consent to take part in the study but were not dosed) 
will not be entered into the clinical study database. 
Data produced by automatic devices with original printouts (i.e., clinical laboratory evaluation 
results, ECG traces) will be attached to the source documents. Clinical laboratory parameters 
will be provided in laboratory printouts which are to be signed by the Investigator. Comments 
on all clinically significant abnormal values will be provided and documented by the 
Investigator or appropriately recorded within the eCRF. 
Adverse Events and Medical History will be reported by the MedDRA SOC and PT; the latest 
version will be applied to all terms. All Medical History and AEs will be included in the data 
listings. Furthermore, all Prior Medications and Concomitant Medications will be reported 
using the WHODRUG categorization; the latest version will be applied to all terms. 
All Prior Medications and Concomitant Medications will be summarised within the data 
listings. 
Any missing, implausible or inconsistent recordings within the eCRFs will be referred to the 
Investigator using data query validation procedures; will be documented and resolved for each 
individual subject before database lock is declared. 
All processes pertaining to the Data Management activities will be detailed within the Data 
Management Plan. 
12.2. Inspection of Records 
Authorised representatives of MedinCell will be allowed to conduct site visits to the CRU for 
the purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability and subject records, 
study source documents and any other pertinent records relative to study conduct.  
12.3. Retention of Records 
The Investigator should maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the IMP for investigation. If it becomes necessary for MedinCell or a 
regulatory authority to review any documentation relating to the study, the Investigator must 
permit access to such records.  
 
 


 
 
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13. 
MONITORING, AUDIT AND INSPECTION 
13.1. Study Monitoring 
During the study, a monitor from MedinCell or representative will have regular contacts with 
the CRU, for the following: 
• Provide information and support to the Investigator. 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the Protocol, that data are being 
accurately recorded in the eCRFs, and that IMP accountability checks are being 
performed.  
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (e.g., clinic charts). 
• Record and report any Protocol deviations not previously sent to MedinCell 
• Confirm AEs and SAEs have been appropriately documented within eCRFs and 
confirm any SAEs have been communicated to MedinCell and those SAEs that met 
criteria for reporting have been provided to the REC. 
The monitor will be available between visits if the Investigator or other staff needs information 
or advice. 
13.2. Audits and Inspections 
Authorised representatives of MedinCell, a regulatory authority, or the REC may visit the site 
to perform audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents. The inspection determines whether these activities were conducted, in addition to 
data being recorded, analysed, and accurately reported according to the Protocol; ICH-GCP 
and any applicable regulatory requirements. The Investigator is responsible for making contact 
with MedinCell immediately, if approached by a regulatory agency regarding an inspection. 
13.3. Quality Control and Quality Assurance 
To ensure compliance with GCP and all regulatory requirements, MedinCell, may conduct a 
Quality Assurance Audit. 
13.4. Research Ethics Committee 
The Investigator should obtain REC approval for the study. Initial REC approval, and all 
materials approved by the REC for this study including the subject consent form and 
recruitment materials, should be maintained by the Investigator and made available for 
inspection. 
 
 


 
 
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14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. Ethical Conduct of the Study 
The study will be conducted in accordance with the EU Clinical Trial Directive 2001/20/EC, 
the ICH guideline for GCP E6(R2) dated December 2016, and the ethical principles laid down 
in the Declaration of Helsinki. Current regulatory requirements will be followed, as applicable. 
14.2. Ethics Review 
The final study Protocol, including the final version of the Informed Consent Form (ICF), must 
be approved or given a favourable opinion in writing by a REC as appropriate. The Investigator 
should submit written approval to MedinCell before enrolling any subject into the study.  
The Investigator is responsible for informing the REC of any amendment to the Protocol in 
accordance with local requirements. In addition, the REC must approve all advertising used to 
recruit subjects for the study. The Protocol must be reapproved by the REC upon receipt of 
substantial amendments, as local regulations require. 
The Investigator is also responsible for providing the REC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the IMP. MedinCell will 
provide this information to the Investigator.  
Progress reports and notifications of serious adverse drug reactions will be provided to the REC 
according to local regulations and guidelines.  
14.3. Written Informed Consent 
Potential subjects will have a detailed verbal presentation of the nature, purpose, risks and 
requirements, in addition to receiving detailed written information provided in the Participant 
Information Sheet. They will have adequate opportunity to ask the physician presenting the 
study about any aspect of the study. Subjects must also be notified that they are free to 
discontinue from the study at any time. The subject should be given the opportunity to ask 
questions and allowed time to consider the information provided. Once the subject is satisfied 
that they are willing to participate in the study, they will be asked to sign a copy of the study 
ICF. The subject’s signed and dated informed consent must be obtained before conducting any 
study procedures. The Investigator must maintain the original, signed ICF. A copy of the signed 
ICF will be provided to the subject. 
Data and samples collected up to the point of withdrawal can only be used after withdrawal if 
the subject has consented for this. Any intention to utilise such data should be outlined in the 
consent literature.  
A subject may be rescreened for the study once, if: 
• They were ineligible at the first screen due to a transient reason, such as an upper 
respiratory tract infection, which impacted the clinical laboratory results. 
• They were eligible at first screen, but unable to take part in the study dates within the 
Screening window.  
• The subject was finally not enrolled in the initial group, e.g., reserve subjects 
In the case of rescreening, only the assessments that were performed more than 28 days before 
the new dosing date will be repeated. The CRU will maintain a record of all subjects screened 


 
 
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(i.e., who signed the ICF) and any subject who is rescreened will be allocated a new screening 
number. Records up to the time of premature termination should be completed. In the event 
that a subject does not receive a study treatment, the primary reason will be recorded. A list of 
the procedures conducted at Screening are presented in the Schedule of Assessments 
 
Informed consent will be obtained prior to the subject undergoing procedures that are 
specifically for the purposes of the study. 
14.4. End-of-Study 
The end-of-study is defined as completion of the clinical activities relating to the follow-up 
visit by the last subject.  
14.5. Notification of Serious Breaches to Good Clinical Practice 
A “serious breach” is a breach which is likely to affect to a significant degree: 
• the safety or physical or mental integrity of the subjects of the study; or, 
• the scientific value of the study. 
The Sponsor will be notified immediately of any case where the above definition applies during 
the study conduct phase. The Sponsor of a clinical study will notify the licensing authority in 
writing of any serious breach of: 
•  the conditions and principles of GCP in connection with that study; or  
• the Protocol and/or any Protocol amendments relating to the study, within 7 days of 
an awareness of the breach. 
 


 
 
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15. 
REFERENCES 
1. 
WHO Coronavirus disease (COVID-19) Situation report #209, 16 August 2020. 
2. 
Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus 
(2019-nCoV). Nat Rev Drug Discov. 2020; 19(3);1 49-150. 
3. 
Crump A, Ōmura S. Ivermectin, 'wonder drug' from Japan: the human use 
perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2011; 87(2); 13-28. 
4. 
Kumar BS, Jeyaraman M, Jain R, Anudeep TC. A Wonder Drug in the Arsenal against 
COVID - 19: Medication Evidence from Ivermectin. Journal of Advances in Medicine 
and Medical Research. 2020; 32(10); 30-37. 
5. 
Yang SNY, et al. The broad spectrum antiviral ivermectin targets the host nuclear 
transport importin α/β1 heterodimer. Antiviral Res. 2020; 177; 104760. 
6. 
Raza S, et al. Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear 
Import and Interferes with Viral Replication. Microorganisms. 2020; 8(3); 409. 
7. 
Lee YJ, Lee C. Ivermectin inhibits porcine reproductive and respiratory syndrome virus 
in cultured porcine alveolar macrophages. Arch Virol. 2016; 161(2); 257-268. 
8. 
Lv C, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance 
into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res. 2018; 
159; 55-62. 
9. 
Mastrangelo E, et al. Ivermectin is a potent inhibitor of flavivirus replication 
specifically targeting NS3 helicase activity: new prospects for an old drug. 
J Antimicrob Chemother. 2012; 67(8); 1884-1894. 
10. 
Mirza MU, Froeyen M. Structural elucidation of SARS-CoV-2 vital proteins: 
Computational methods reveal potential drug candidates against main protease, Nsp12 
polymerase and Nsp13 helicase [published online ahead of print, 2020 Apr 28]. 
J Pharm Anal. 2020; 10; 1016. 
11. 
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug 
ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020; 178; 
104787.  
12. 
NDA. 2013. Soolantra (Ivermectin) Cream, 1%. Pharmacology Review(S). Center for 
drug 
evaluation 
and 
research, 
Application 
number: 
NDA 
206255. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206255Orig1s000PharmR
.pdf 
13. 
NDA. 2012. Sklice (ivermectin) Lotion, 0.5%. Pharmacology Review(S). Center for 
drug 
evaluation 
and 
research, 
Application 
number: 
NDA 
202736. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202736Orig1s000PharmR
.pdf 
14. 
Badhan R, Zakaria Z, Olafuyi O. The Repurposing of Ivermectin for Malaria: A 
Prospective Pharmacokinetics-Based Virtual Clinical Trials Assessment of Dosing 
Regimen Options. J Pharm Sci. 2018; 107(8); 2236-2250. 
15. 
Kircik LH, Del Rosso JQ, Layton AM, Schauber J. Over 25 Years of Clinical 
Experience With Ivermectin: An Overview of Safety for an Increasing Number of 
Indications. J Drugs Dermatol. 2016; 15(3); 325-332. 


 
 
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16. 
Guzzo CA, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of 
ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10); 1122-1133. 
17. 
Muñoz J, Ballester MR, Antonijoan RM, et al. Safety and pharmacokinetic profile of 
fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers. PLoS 
Negl Trop Dis. 2018;12(1); e0006020. 
18. 
González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, 
Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin 
in humans - a mini-review. AAPS J. 2008; 10(1); 42-46. 
19. 
Stromectol Summary of Product Characteristics available at: 
https://www.merck.com/product/usa/pi_circulars/s/stromectol/stromectol_pi.pdf. 
20. 
Committee for Medicinal Products for Human Use. Guidelines on strategies to identify 
and mitigate risks for first-in-human and early clinical trials with investigational 
medicinal products. 2017 Jul; 1. 
21. 
https://www.cdc.gov/parasites/scabies/health_professionals/meds.html. 
22. 
Salavastru CM, Chosidow O, Boffa MJ, Janier M, Tiplica GS. European guideline for 
the management of scabies. J Eur Acad Dermatol Venereol. 2017; 31(8); 1248-1253. 
23. 
https://www.cdc.gov/parasites/resources/pdf/CrustedScabiesNT.pdf. 
 
 
 


 
 
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16. 
APPENDICES 


 
 
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16.4. Appendix 4 – Liver Function Abnormalities Flowchart  
 
 
 
Abbreviations: ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; IMP: investigational 
medicinal product; Q48H: every 48 hours; ULN: upper limit of normal.  
* The following tests are required for subjects/patients with AST or ALT ≥3 x ULN and bilirubin ≥2 x ULN: Anti-nuclear antibody, anti-
smooth muscle antibody, and type 1 anti-liver kidney microsomal antibodies, in addition to liver imaging (ultrasound, magnetic resonance, 
or computerised tomography) to evaluate liver diseases. 

SAP_001.pdf: 




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and special terms are used in this document. 
Abbreviation 
Explanation 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
BP 
Blood Pressure 
BMI 
Body Mass Index 
eCRF 
Electronic Case Report Form 
CI 
Confidence Intervals 
Cmax 
Maximum Concentration 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure  
ECG 
Electrocardiogram 
GLMM 
Generalised Linear Mixed Model 
HR 
Heart Rate  
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetics 
PRO 
Patient reported outcome 
PT 
Preferred Term 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAS 
Statistical Analysis system 
SBP 
Systolic Blood Pressure  
SRC 
Safety Review Committee 
SOC 
System Organ Class 


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Abbreviation 
Explanation 
SD 
Standard Deviation  
TFL 
Tables, Figure and Listing 
TEAEs 
Treatment-Emergent Adverse Events  
Tmax 
Time taken to reach Cmax 
 
 






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2 
ANALYSIS SETS 
2.1 
PER PROTOCOL ANALYSIS SET 
The Per-Protocol Set will include all randomised subjects that have completed the 28-
day dosing period of the trial without major protocol deviations. Subjects withdrawn due 
to non-compliance (see Section 6.4 of study protocol) will not be included in the Per-
Protocol Set. Subjects will be classified according to study drug(s) they actually 
received. 
2.2 
SAFETY ANALYSIS SET 
The Safety Analysis Set will consist of all subjects who received at least 1 dose of study 
drug(s). Subjects in the Safety Analysis Set will be classified according to study drug(s) 
they actually received. Safety data will not be formally tested but will be summarised 
using descriptive statistics. 
2.3 
PHARMACOKINETIC ANALYSIS SET 
All subjects who receive at least 1 dose of investigational medicinal product (IMP) per 
the Protocol for whom any postdose data are available and who do not violate or deviate 
from the protocol in ways that would significantly affect the PK analyses will be included 
in the PK Analysis Set. The population will be defined by the Study Physician, 
Pharmacokineticist and Statistician prior to any analyses being performed. 
2.4 
PROTOCOL DEVIATIONS 
Protocol deviations will be categorised as minor/major and deviation category in a 
blinded manner prior to the database lock for each study part. The sponsor will review 
protocol deviations throughout the course of the study. All deviations will be listed. 
3 
DERIVED VARIABLES 
3.1 
EXPLORATORY ENDPOINT - OCCURRENCE OF SARS-COV-2 INFECTION 
Occurrence of SARS-CoV-2 infection will be defined as either a positive PCR or positive 
serology test result at any point after first dose of the IMP. 
4 
ANALYSIS METHODS 
4.1 
GENERAL PRINCIPLES 
All summary tables, figures and data listings will be produced using SAS software 9.4 or above. 
Summaries will be performed by treatment group and overall.  
Descriptive statistics will be used for all variables, as appropriate. Continuous variables will be 
summarised by the number of observations, mean, standard deviation, median, minimum, and 
maximum. For log-transformed data, the geometric mean, coefficient of variation (CV), 
median, minimum and maximum will be presented. 


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Categorical variables will be summarised by frequency counts and percentages for each 
category.  
For AE summaries, the n and % of subjects with event, as well as the number of events, will 
be shown.  
For all endpoints the last observation before the first dose of study treatment will be considered 
the baseline measurement unless otherwise specified. However, if an evaluable assessment is 
only available after randomisation but before the first dose of randomised treatment then this 
assessment will be used as baseline.   
Assessments on the day of the first dose where neither time nor a nominal predose indicator 
are captured will be considered prior to the first dose if such procedures are required by the 
protocol to be conducted before the first dose.  
In all summaries change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The percentage change from baseline will be calculated as: 
(post-baseline value - baseline value) / baseline value x 100. 
All listings will be ordered by treatment group (ivermectin or placebo), cohort and subject 
number and will include all available data including unscheduled data. 
Unscheduled values will be mapped to the closest prior nominal visit/timepoint. If multiple 
values exist for a nominal visit/timepoint then the worst value of available results will be used 
in the summary.   
Listings will show the original visit and timepoint as collected on the electronic case report 
form (eCRF) as well as the mapped visit and timepoint for unscheduled values. An indicator 
will be included in the listings to indicate which value is utilised in the analysis. 
4.2 
SUBJECT ACCOUNTABILITY 
Summaries of analysis populations and subject disposition will be summarised and listed using 
all subjects who have signed informed consent. The data summaries will contain the following 
information: 
• 
Number of subjects randomised 
• 
Number and percent of subjects who received ivermectin/placebo 
• 
Number and percent of subjects who completed the study 
• 
Number and percent of subjects who discontinued early from the study and reason for early 
discontinuation 
• 
Number and percent of subjects in each of the analysis populations 
4.3 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS  
All randomized subjects  will be used for all demographic and baseline characteristics 
summaries. All demographics and baseline characteristics data will be included in listings. The 
actual treatment (ivermectin / placebo) received will be utilised in these analyses. 






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For the incidence at the subject level by SOC, PT and severity; if a subject experiences more 
than one event within the same SOC and PT, only the most severe occurrence will be included 
in the incidence. 
4.6.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluation results (chemistry, haematology, and coagulation) will be listed 
for individual subjects and compared to laboratory reference ranges and those values outside 
of the applicable range will be flagged as high (H) or low (L) and categorised by clinical 
significance (clinically significant/non-clinically significant). This classification of high, low 
and normal will be summarised by panel (i.e., chemistry, haematology, and coagulation), 
laboratory test, visit and timepoint. 
For all laboratory variables, baseline value will be calculated as last laboratory value prior to 
dosing. Change from baseline values at each assessment will be calculated as the assessment 
value minus the baseline value. The quantitative laboratory data, along with changes from 
baseline will be summarised using descriptive statistics by timepoint, cohort and treatment.  
Urinalysis data will be listed only. 
4.6.3 
Vital Signs 
Vital signs data and oral temperature will be listed for individual subjects.  
Vital signs include heart rate (HR), supine and standing systolic blood pressure (SBP), diastolic 
blood pressure (DBP), respiration rate and body temperature.  
Vital signs data along with changes from baseline will be summarised using descriptive 
statistics by position and timepoint. For each vital sign variable, baseline value will be 
calculated from the mean of the available triplicate (if collected) predose values. 
4.6.4 
Electrocardiogram (ECG) 
Standard 12-lead ECG parameters (PR, RR, QRS, QT, QTcF and HR) and ECG abnormal 
assessment will be listed for individual subjects.  
For each ECG variable, baseline value will be calculated from the means of the available data 
prior to dose, if multiple values are recorded. Change from baseline values will be calculated 
as the assessment values minus baseline values.  
Descriptive statistics will be calculated for absolute value of each parameter, together with the 
corresponding changes from baseline overall and by dose and timepoint. Where multiple values 
are recorded at a timepoint for a subject, the mean of the available values will be used in the 
summary statistics.  
4.6.5 
Physical examination 
A summary table will be produced for each physical examination test reporting PI 
interpretation category (n and %) by cohort, timepoint and arm.  
Physical examination data will be listed for individual subjects. 


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4.6.6 
Neurological examination 
A summary table will be produced for each neurological examination test reporting PI 
interpretation category (n and %) by cohort, timepoint and arm.  
Neurological examination data will be listed for individual subjects. 
4.7 
SAFETY REVIEW COMMITTEE 
SRC analysis is out of scope of this SAP and details are contained within the SRC charter. 
5 
HANDLING OF MISSING OR INCOMPLETE DATA 
Unrecorded values will be treated as missing. Efforts will be made to prevent this from 
occurring. For complete missing visits the missing efficacy, safety will be treated as missing at 
random and will not be imputed in the statistical analysis except for partial dates. 
 
For the exploratory efficacy analysis, frequency of missing data will be reported in a separate 
table as described within the analysis section. 
5.1 
PRIOR AND CONCOMITANT MEDICATION DATES 
Partial dates for any prior and concomitant medications recorded in the eCRF will be imputed 
using the following convention: 
• 
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will be used for the 
month. 
• 
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day (dependent on the 
month and year) and ‘Dec’ will be used for the month. 
The recorded partial date will be displayed in listings. No imputation will be performed for 
completely missing start and end dates. 
5.2 
AE START AND END DATES 
The eCRF allows for the possibility of partial dates (i.e. only month and year) to be recorded 
for AE start and end dates; that is the day of the month may be missing. In such a case, the 
following conventions will be applied for calculating the time of onset and the duration of the 
event: 
• 
Missing Start Day: First of the month will be used unless this is before the start date of first 
study treatment; in this case the study treatment start date will be used and hence the event is 
considered treatment emergent. 
• 
Missing Stop Day: Last day of the month will be used, unless this is after the stop date of study 
completion; in this case the study stop date will be used. 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.  


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6 
TABLE AND LISTING SHELLS 
Tables, figures and listing (TFL) Shells will be provided as a separate document. The TFLs 
listed and the corresponding numbering may be subject to alteration. Tables and figures may 
be presented as in-text tables and figures in the CSR body.