Clinical trial NCT05305560
Conditions: COVID-19
Keywords: Prophylaxis RT-PCR test
Sponsor: MedinCell S.A
Start date: 2022-03-25; Completion date: 2022-10-13
Enrollment: 400 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multicenter, randomized, double-blind, placebo-controlled, study to evaluate the efficacy and safety of oral ivermectin tablets versus placebo for COVID-19 prophylaxis

Detailed description:
This trial comprises a total observation period of up to 56 days (an on-treatment period of up to 28 days and a safety follow-up of up to 28 days).

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Ivermectin Tablets intervention 2: Matching placebo tablets
Intervention descriptions: intervention 1: Daily ivermectin tablets intake for 28 days ; 200 mcg/kg on D1 then 100 mcg/kg daily from D2 to D28. intervention 2: Daily placebo tablets intake for 28 days

Protocol documents:
Prot_000.pdf: 
 
Final version 3.0, 08 June 2022 
 
                                                          Page 1 of 69 
 
 
 
  
CLINICAL TRIAL PROTOCOL 
 
 
A multicentre randomised, Double-Blind, Placebo-controlled, Study to evaluate the 
efficAcy and safety of oral IVErmectin tablets in the prevention of COVID-19        
(the SAIVE Trial) 
 
 
 
Protocol Number: 
mdc-TTG-CT-002 
Investigational Medicinal Product: 
Ivermectin 
Indication: 
SARS-CoV-2 infection 
Phase: 
II 
Sponsor: 
MedinCell SA                                                 
3 rue des Frères Lumière                                
34830, Jacou, France 
Coordinating Investigator 
Dr. Anna Kostova 
EudraCT Number: 
2021-001938-19 
Protocol Version and Date: 
Final version 3.0, 08 June 2022
 
 
 
 
 
 
 
 
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki, and with other applicable 
regulatory requirements. 
 
 
CONFIDENTIAL INFORMATION 
This document contains confidential information of MedinCell SA. 
Do not copy or distribute without written permission from the Sponsor. 
 
 
 
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Page 2 of 69 
Final version 3.0, 08 June 2022 
Protocol Approval 
 
Sponsor: 
Dr. Richard Malamut, Chief Medical Officer 
MedinCell SA,  
3 rue des Frères Lumière, 34830, Jacou, France 
 
 
Phone: +33 4 30 29 70 85 
E-mail: richard.malamut@medincell.com 
 
__________________________________                      ________________________ 
Signature 
Date 
 
 
Coordinating Investigator: 
Dr. Anna Kostova 
University Hospital" Queen Joanna - ISUL", COVID-19 Department 
1527 Sofia Center, Sofia, Bulgaria 
__________________________________                      ________________________ 
Signature 
Date 
 
 
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2022-06-17 | 11:08:22 CEST


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Page 3 of 69 
Final version 3.0, 08 June 2022 
Site Principal Investigator Agreement 
 
I, _______________________________________________, (Investigator9s Name) 
have read this protocol and agree that it contains all necessary details for carrying out 
this trial. I will conduct the trial as outlined herein and will complete the trial within the 
time designated. 
The information contained in this protocol is provided to me in confidence, for review 
only by myself, the ethics committee authorised to review and approve the trial at this 
trial site, and designated trial staff participating in this clinical trial.  
I agree to the conditions as set out in this protocol and fully accept that any change 
requires prior approval by the trial sponsor. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this trial. I will discuss this material with 
them to ensure they are fully informed regarding the IMP and the conduct of the trial. 
I will use only the informed consent form approved by the sponsor or its representative 
and will fulfil all responsibilities for submitting pertinent information to the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) responsible for 
this trial. 
I agree to carry out all terms of this protocol in accordance with the ICH GCP (Good 
Clinical Practice) Guidelines, the Declaration of Helsinki and local regulations. I will 
ensure that the Investigational Medicinal Product is used only as described in the 
protocol or any subsequent amendment. 
I understand that the information/technology contained in this protocol is proprietary 
and may not be disclosed to any other party, in any form, without prior authorisation 
from the trial sponsor except to the extent necessary to obtain informed consent from 
potential trial participants.  
 
 
_________________________________________  
__________________ 
Investigator9s Signature 
 
 
 
 
 
Date 
 
_________________________________________ 
Clinical Trial Site Name 
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Page 4 of 69 
Final version 3.0, 08 June 2022 
PROTOCOL SYNOPSIS 
Title: 
A multicentre randomised, Double-Blind, Placebo-controlled, Study 
to evaluate the efficAcy and safety of oral IVErmectin tablets in the 
prevention of COVID-19 (the SAIVE Trial) 
Protocol Number: 
mdc-TTG-CT-002 
Study Phase: 
II 
Sponsor: 
MedinCell SA 
Coordinating Investigator: 
Dr. Anna Kostova 
Study Objectives: 
Primary objective:  
¥ 
To assess the efficacy of ivermectin compared to 
placebo in the prevention of laboratory-confirmed 
COVID-19 infection. 
Secondary objectives:  
¥ 
To assess the efficacy of ivermectin on Time to RT-
PCR positive testing. 
¥ 
To assess the efficacy of ivermectin on the occurence 
of severe COVID-19 symptoms. 
¥ 
To assess the efficacy of ivermectin on Time to first 
COVID-19 related clinical events. 
¥ 
To assess the efficacy of ivermectin on the rate of 
COVID-19 related hospitalisations. 
¥ 
To assess the efficacy of ivermectin on the rate of 
COVID-19 related mortality.  
¥ 
To assess the safety and tolerability of ivermectin given 
for a period of 28 days. 
Study Design: 
This is a randomised, double blind, placebo-controlled, multicentric 
Phase II clinical trial evaluating the efficacy and safety of ivermectin 
tablets in the prevention of COVID-19 infection.  
If a person tests positive for SARS-CoV-2 (index case), they can 
obtain details of this study, in leaflet form, at the clinic or laboratory 
where they received their positive result. The index case can then 
provide details of this study to their close contacts.  
A close contact is defined as: 
¥ 
Anyone who lives in the same household as another person 
who has tested positive for COVID-19. 
¥ 
Anyone who has had any of the following types of contact 
with someone who has tested positive for COVID-19: 
o 
Face-to-face contact including being coughed on 
or having a face-to-face conversation within one 
metre 
o 
Been within one metre for one minute or longer 
without face-to-face contact 
o 
Been within 2 metres for more than 15 minutes 
either as a one-off contact, or cumulatively over a 
24-hour period 
o 
A person may also be considered a close contact if 
they have travelled in the same vehicle or plane as 
a person who has tested positive for COVID-19. 
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Final version 3.0, 08 June 2022 
If the close contact wishes to participate in the study, they should ask 
the primary contact if they agree to give their informed consent by 
signing the form attached to the leaflet, through which primary cases 
agree that information related to their positive testing will be 
collected as evidence. Then, the contact case should get in touch with 
the study site and arrange for an appointment for the screening visit 
(within 5 days after the contact with the index case). At that 
appointment the contact will be screened, and they will provide the 
study staff with the index case9s signed consent form and positive 
PCR test result. In addition, informed consent from the close contact 
must be obtained. If all eligibility criteria are met, the participant 
(close contact) will be randomised and a loading treatment dose will 
be administered.  
Participants will be assigned in a 1:1 ratio to receive oral daily 
treatment with either ivermectin or placebo. 
The study requires two visits to the study centre, on Day 1 and Day 
28, the first and last days of treatment. In addition, there will be at 
least 3 remote visits that can be conducted by telephone. 
The treatment period lasts for 28 days in total, followed by a 28-day 
follow-up period, and there is a 2-day window period for visits. 
Therefore, total study duration for each participant is up to 58 
days.Erreur ! Source du renvoi introuvable. 
Study Population: 
Healthy volunteers between 18 and 65 years old, self-isolating after 
being in close contact with an individual who has had a documented 
exposure to COVID-19 within a maximum of 5 days prior to 
Screening. 
Inclusion Criteria: 
Individuals who meet all of the following criteria are eligible to 
participate in the study: 
1. Age between 18 and 65 years, inclusive. 
2. Body weight >45 kg. 
3. Body Mass Index >18.5. 
4. Close contact with a person who has a PCR-confirmed 
SARS-CoV-2 infection within 5 days before screening.  
5. Only one member in the same household will be enrolled. 
6. Participants must be able to give informed consent and 
comply with the study9s scheduled events/visits and study 
assessments. 
7. SARS-CoV-2 positive index case must be able to give 
consent to enable collection of the documented positive PCR 
test.  
8. Female participants of childbearing potential must use a 
highly effective method of contraception for the duration of 
the trial. Their male partners should also use a contraception 
method (i.e condom) unless vasectomized. (Refer to section 
4.5 Contraception Requirements). 
9. Male participants must use a contraception method (i.e 
condom) for the duration of the trial, unless vasectomized. 
Their female partners, if they are of childbearing potential, 
must use a highly effective method of contraception. (Refer 
to section 4.5 Contraception Requirements). 
 
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Final version 3.0, 08 June 2022 
Exclusion Criteria: 
Individuals who meet any of the following criteria are not eligible to 
participate in the study: 
1. Pregnant or breast-feeding. 
2. Participants who have been administered COVID-19 vaccine 
prior to the inclusion or have a planned vaccination during 
the duration of the study. 
3. A positive COVID-19 result (PCR or antigen test) within 8 
days of screening. 
4. Presence of typical COVID-19 symptoms (fever >38°C, 
SpO2 below 93%, dyspnoea, difficulty breathing, chills, 
repeated shaking with chills, ageusia, anosmia, cough, 
myalgia, headache) in the past 48 hours prior to screening. 
5. Presence of a known uncontrolled/unstable clinically 
significant medical condition, considered by the investigator 
as incompatible with study participation. 
6. Known history of HIV, HBV and/or HCV. 
7. Hypersensitivity to any component of ivermectin. 
8. Participants who have been administered ivermectin within 
30 days prior to screening. 
9. Participation in another interventional trial within the last 30 
days or 5 half-lives of the IMP of the other trial, whichever 
comes first. 
10. Having undergone extensive bowel resection which may 
alter ivermectin absorption. 
11. Participants with gastrointestinal erosions and ulcers (e.g. 
erosive esophagitis, stomach ulcers, ulcerative colitis etc.). 
12. Known or clinically suspected disturbance of the blood-
brain-barrier (e.g., ABCB-1 [=MDR1] mutation). 
13. History of neurotoxicity with ivermectin or other para-
glycoprotein (p-gp) substrates or inhibitors. 
14. Current use of P-gp inhibitor drugs such as amiodarone, 
azithromycin, 
ketoconazole, 
cyclosporine 
(listed 
in 
Appendix 3).   
15. Current use of monoclonal antibodies for the treatment of 
COVID-19. 
16. Known drug or alcohol abuse. 
17. Travel to endemic Loa loa regions within the past 3 months 
prior to screening (central and western Africa). 
18. Participants under legal guardianship or trusteeship. 
Number of Participants: 
400 participants. 
Countries/Number of 
Sites: 
Approximately 26 sites from a number of European countries will 
participate in this study. 
Investigational Medicinal 
Product: 
Ivermectine Substipharm and a matched placebo. 
Duration of Participation: 
Up to 58 days (28 days of treatment and 28 days of follow-up, with 
a 2-day window period for visits). 
Criteria for Evaluation: 
Primary endpoint analysis: 
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Final version 3.0, 08 June 2022 
¥ 
RT-PCR tests on D4, D7, D10, and D28, and at any 
unscheduled visits. 
Secondary endpoints analyses: 
¥ 
RT-PCR tests on D4, D7, D10, and D28, and at any 
unscheduled visits. 
¥ 
WHO COVID-19 and News 2 scales scoring on D1, 
D10, and D28, and at any unscheduled visits. 
¥ 
COVID-19 related AE notification by participants 
and/or investigators throughout the study. 
¥ 
COVID-19 related hospitalisations notified by the 
investigators. 
¥ 
Duration of hospitalisation as calculated from the 
associated SAE notification form (date of hospital 
admission through to date of hospital release). 
¥ 
COVID-19 related deaths notified by the investigators. 
¥ 
AE notification by participants or detection by 
investigators. 
Concomitant Medication: 
Prohibited medications: 
The following medications are prohibited:  
¥ 
Inhibitors of p-glycoprotien, e.g. amiodarone, 
azithromycin, ketoconazole, cyclosporine (listed in 
Appendix 3) up to 28 days prior to randomization and 
throughout the study. 
¥ 
Current pain medications such as acetylsalicylic acid or 
metamizol.  
Precautions: 
Some medications (listed in Appendix 3) may have moderate or 
minor interactions with ivermectin.  
Endpoints: 
Primary endpoint:  
 
¥ 
Proportion of laboratory-confirmed COVID-19 
infections between baseline and Day 28. 
 
Secondary endpoints:  
¥ 
Time to change from baseline in negative RT-PCR to 
positive RT-PCR. 
¥ 
Change from baseline in the WHO-COVID 19 and 
NEWS-2 scores. 
¥ 
Time to change from baseline to first COVID-19 
related clinical events. 
¥ 
Proportion of COVID-19 related hospitalisations. 
¥ 
Proportion of COVID-19 related mortality. 
¥ 
Safety and Tolerability of ivermectin based on 
treatment emergent adverse events (TEAE) and serious 
adverse events (SAE) according to Common 
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Final version 3.0, 08 June 2022 
Terminology Criteria for Adverse Events (CTCAE 
version 5.0). 
Statistical Methods: 
Sample size: 
Sample size was calculated to compare the proportion of participants 
who become positive to SARS-CoV-2 RT-PCR within 1 month after 
randomisation between the two groups: Placebo group and 
experimental group receiving ivermectin up to D28. Based on a study 
assessing the transmission of SARS-CoV-2 infections in households 
carried out in the US between April and September 2020, the 
proportion of randomised participants becoming infected in the 
placebo group is estimated to be 54% (Grijalva et al, 2020).. A 
difference of 20% is expected between the two groups (OR=2.28).  
With a power of 90% (1-³) and a significance level of 5% (³), 
according to the Casagrande & Pike formula the required sample size 
to detect such difference with a test of comparison of two proportions 
is equal to 138 participants per arm (Casagrande et al, 1978).  
A total of 396 participants (198 per arm),  rounded up to 400 
participants (200 per arm) is required to account for the primary 
analysis. This sample size also accounts for an estimated dropout rate 
of 30%.  
After approximately 40% of the targeted participants will have been 
randomised and will have completed 28 days of therapy (i.e. 160 
randomised participants), an independent Data Monitoring 
Committee (DMC) will review the data for further development 
pathway decisions. 
 
Primary endpoint analysis: 
The comparison of proportion of participants who were tested 
positive for SARS-CoV-2 up to D28: placebo group versus 
ivermectin group, will be performed using the Cochran-Mantel 
Haenszel (CMH) chi-squared test at the two-sided 0.05 level. Two-
sided 95% confidence intervals (95% CI) for the proportion 
differences between groups will be provided. Odds-ratio and 
corresponding 95% CI will also be reported.  
The primary endpoint will also be analysed using a logistic regression 
with treatment group and country as a covariate. Moreover, the 
analysis of the primary endpoint will be performed for the PP 
population. 
Secondary endpoints analysis: 
The statistical methodologies used to analyse the secondary 
endpoints will be detailed in the SAP. However only the primary 
endpoint will be statistically analysed, all other p-values are 
presented for information purposes only. 
Time to positive testing for PCR negative participants at 
randomisation will be assessed on the mFAS population. 
The rate and severity of COVID-19 identified symptoms, time to first 
COVID-19 related clinical event, rate and duration of COVID-19-
related hospitalisations and COVID-19-related mortality rate will be 
assessed on the FAS population, considering the following two-
subgroups separately: 
¥ 
Patients tested positive prior to receiving study drug (mFAS). 
¥ 
Patients tested negative prior to receiving study drug. 
Predictive factors that may affect the SARS-CoV-2 infection or 
COVID-19 disease will be assessed in exploratory analyses such as 
sex, age, BMI and SARS-CoV-2 variant type with specific statistical 
models (univariate or multivariate logistic regression up to D28 or 
Cox model). Such analyses will be detailed in the SAP. 
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Final version 3.0, 08 June 2022 
 
Safety analysis: 
Safety will be pooled analyses for the Safety set from all centres and 
countries. Placebo and ivermectin groups will be compared. 
All adverse events (AEs) will be coded according to coding 
dictionaries (MedDRA, applicable version) and summarised at 
System Organ Class (SOC) and Preferred Term (PT) levels. AEs will 
be classified according to period of occurrence: pre-treatment AEs, 
treatment-emergent AEs (TEAEs) and post-treatment AEs (PTAEs).  
AE reporting will focus on TEAEs and PTAEs. Incidence of TEAEs 
and PTEAEs will be summarised and detailed by seriousness, 
intensity, action taken with the study medication, other action taken 
and relationship to study treatment. 
The number/frequency of participants with TEAEs, related TEAEs, 
PTAE, the number/frequency of participants with related PTAEs, 
SAEs and CTCAE grade 3 or more will be displayed by system organ 
class and preferred term according to MedDRA classification. The 
frequency of participants with at least one TEAE, PTAE, related 
PTAE, SAE and/or AE of CTAE grade 3 or more will be compared 
between treatment groups using a chi-squared test or a Fisher exact 
test. 
All post-randomisation discontinuations will be summarised by main 
reason for discontinuation. The number of participants screened and 
not enrolled will be presented with the main reason for their non-
inclusion. 
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Final version 3.0, 08 June 2022 
Table 1: Schedule of Assessments 
  
Pre 
Screening 
Screening & 
Randomisation 
On-treatment period (i) 
EOS (J) 
D-1 or D1* 
D1 
D4  
(±1 day) 
D7 
(±1 day) 
D10 
(±1 day) 
EOT-D28** 
(+2 days) 
D56  
(±2 days) 
Remote 
On-site Visit*** 
Remote 
Remote 
Remote 
On-site 
Visit*** 
Remote 
Study participation suitability 
questionnaire (a)  
X  
 
 
 
 
 
 
ICF signature (b) 
 
X 
 
 
  
  
  
Demographics  
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
  
  
  
I/C criteria 
 
X 
 
 
  
 
  
Treatment dispensation 
 
X 
 
 
 
 
 
Treatment administration (c) 
  
 
  
RT-PCR test (d) 
  
X 
X 
X 
X 
X 
  
Antigen test (e) 
 
X 
 
 
 
 
 
Serology (f) 
  
X 
 
 
 
X 
X 
NEWS-2 scale  
 
X 
 
 
X 
X 
 
COVID-19 WHO scale 
 
X 
 
 
X 
X 
 
Laboratory tests (g) 
  
X  
 
 
  
X 
X 
Urine pregnancy test (g) 
 
X 
 
 
 
X 
X 
Randomisation (h) 
  
X 
 
 
  
  
  
Participant diary (i) 
 
 
 
ECG 
 
X 
 
 
 
X 
 
Vital signs 
  
X 
 
 
X 
X 
 
Adverse Events  
  
 
Concomitant medication 
 
 
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Final version 3.0, 08 June 2022 
* Pre-Screening corresponds to the time frame when the first positive case is detected in the cluster within 5 days prior to screening. The study is immediately proposed to the exposed 
cluster members who might potentially meet the eligibility criteria (Note: only one member in the same household will be enrolled). 
** Preferred on-site visit but can be performed remotely according to the investigator9s opinion. 
*** In case of on-site visit, participants should only use private transport. Moreover, a specific room for participants has to be available and restricted to participants in order to limit 
their contact with patients. 
a) Participants will be questioned about their close contact to the COVID-19 index case, their interest in participating in the study, and will be given information about the study (note 
that full eligibility inclusion/exclusion criteria will be confirmed once the participant has signed an ICF), 
(b) ICF signature for the participant and the index case to collect information regarding his/her SARS-CoV-2 RT-PCR test results, 
(c) IMP will be administered as follows: 200 ¿g/kg as the loading dose admisnistered on D1at the study site,  and then 100 ¿g/kg/day for 27 days taken by the participant at home. 
(d) PCR test to be performed on D1, D4, D7, D10 and D28: sequencing and viral load. In addition, any unscheduled test performed by the participant during the study will also be 
collected. Confirmed negative participants at baseline will continue RT-PCR testing, as per schedule of assessments, until they become positive or reach the planned end of study. 
When RT-PCR positivity is confirmed, participant will self-isolate according to local requirements. 
(e) Participants who have been tested positive at the screening with a quick antigen test will be screen failed. In addition, any unscheduled test performed by the participant during the 
study will also be collected, 
(f) Serology COVID-19 (antibodies levels). In addition, any unscheduled test performed by the participant during the study will also be collected). 
(g) Haematology, Biochemistry, Urine pregnancy test, please refer to Section 6.2.6.1, for details on the parameters evaluated. Pregnancy testing must be highly sensitive, at least 
before first administration.     
(h) Randomisation will be performed according to Section 8.1. 
(i) Participants will receive their diary on D1 and keep it for the duration of the treatment to record data collected between D1 and D28. They will bring it back to the site on D28. 
(J) Additional follow-up remote or on-site unscheduled visits, may be required if deemed necessary by the investigator, notably in case of emerging or prolonged adverse events. 
During the unscheduled visit, the investigator will evaluate the WHO COVID-19 scale and the NEWS-2 scale, in addition to any assessments deemed necessary. 
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SAP_001.pdf: 
FRM/BS/001.03 
Version 5.0, Effective Sep-2020 
 
 
Statistical Analysis Plan Version 1.0 
 
Page 1 of 25 
Sponsor 
MedinCell 
Protocol No 
mdc-TTG-CT-002 
 
 
CONFIDENTIAL 
 
Statistical Analysis Plan (SAP) 
Sponsor: 
MedinCell SA 
Study Title: 
A multicentre randomised, Double-Blind, Placebo-controlled Study 
to evaluate the efficAcy and safety of oral IVErmectin tablets in the 
prevention of COVID-19 (the SAIVE Trial) 
Protocol 
Version/Date: 
2.0; 2021-12-20 
SAP 
Version/Date: 
1.0; 2022-07-20 
Supersedes SAP Ver-
sion: 
NA 
Appendices 
(external documents): 1. 
List of Tables, Listing, Figures (TLFs) 
 
 
Approval 
 
The Trial Statistician hereby confirms that the SAP was prepared in conformance with the pro-
cedures and principles set forth in the indicated protocol version and all established relevant 
guidelines.  
Name 
Affiliation, Function 
Signature: 
Date: 
Wendy Sterenburg-Haveman 
Ergomed, Trial Statistician (Contracted) 
 
 
 
By signing hereafter, I confirm that this Statistical Analysis Plan adequately describes the sta-
tistical analyses to be performed in the context of this study. 
Name 
Affiliation, Function 
Signature: 
Date: 
Violaine Desort-Henin 
MedinCell, Head of Clinical Development 
 
 
 
 
 


FRM/BS/001.03 
Version 5.0, Effective Sep-2020 
 
 
Statistical Analysis Plan Version 1.0 
 
Page 2 of 25 
Sponsor 
MedinCell 
Protocol No 
mdc-TTG-CT-002 
 
 
CONFIDENTIAL 
Revision history 
 
SAP Version 
Version date 
Reason(s) for change 
0.1 
2022-03-04 
Not applicable. 
1.0 
2022-07-20 
Version 1.0 
 
 
 


FRM/BS/001.03 
Version 5.0, Effective Sep-2020 
 
 
Statistical Analysis Plan Version 1.0 
 
Page 3 of 25 
Sponsor 
MedinCell 
Protocol No 
mdc-TTG-CT-002 
 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ........................................................................................................................... 4 
1 Study information .......................................................................................................................................... 6 
1.1 Primary objective ..................................................................................................................................... 6 
1.2 Secondary objectives ................................................................................................................................ 6 
1.3 Study design ............................................................................................................................................ 6 
1.4 Planned sample size ................................................................................................................................. 7 
2 General Information ...................................................................................................................................... 7 
2.1 Background details ................................................................................................................................... 7 
2.2 Deviations from the trial protocol with regard to statistical analyses ......................................................... 7 
2.3 Individual protocol deviations .................................................................................................................. 8 
3 Analysis Populations ...................................................................................................................................... 8 
3.1 Randomized Set ....................................................................................................................................... 8 
3.2 Safety Set ................................................................................................................................................. 8 
3.3 Full Analysis Set ...................................................................................................................................... 9 
3.4 Modified Full Analysis Set ....................................................................................................................... 9 
3.5 Per-protocol Set ....................................................................................................................................... 9 
3.6 Subgroup analyses ................................................................................................................................... 9 
4 Statistical Analyses ......................................................................................................................................... 9 
4.1 Conventions ........................................................................................................................................... 10 
4.1.1 
Baseline definition ....................................................................................................................... 10 
4.1.2 
Missing data ................................................................................................................................ 10 
4.2 Demographic and other background data ................................................................................................ 12 
4.2.1 
Basic description.......................................................................................................................... 12 
4.2.2 
Homogeneity tests ....................................................................................................................... 12 
4.3 IMP exposure, compliance ..................................................................................................................... 12 
4.4 Medical history ...................................................................................................................................... 13 
4.5 Prior and concomitant medication .......................................................................................................... 13 
4.6 Efficacy ................................................................................................................................................. 13 
4.6.1 
Primary endpoint ......................................................................................................................... 13 
4.6.2 
Secondary endpoints .................................................................................................................... 14 
4.6.3 
Further Exploratory endpoints ...................................................................................................... 16 
4.7 Safety..................................................................................................................................................... 16 
4.7.1 
Adverse events............................................................................................................................. 16 
4.7.2 
Vital signs .................................................................................................................................... 17 
4.7.3 
ECG ............................................................................................................................................ 17 
4.7.4 
Laboratory variables .................................................................................................................... 18 
4.7.5 
Other safety variables .................................................................................................................. 18 
4.7.6 
Global assessments ...................................................................................................................... 18 
4.8 Other variables ....................................................................................................................................... 18 
4.9 Interim analyses ..................................................................................................................................... 18 
5 Quality Control ............................................................................................................................................. 19 
6 Derivations and Transformations................................................................................................................. 20 
6.1 Formulas for derived variables ............................................................................................................... 20 
6.2 Transformations to be applied ................................................................................................................ 20 
7 References ..................................................................................................................................................... 20 
8 Standards used in Preparation of Statistical Outputs ................................................................................. 21 
8.1 Programming ......................................................................................................................................... 21 
8.2 Layout ................................................................................................................................................... 21 
8.3 Headers, Titles and Footnotes ................................................................................................................ 21 
8.4 General Conventions .............................................................................................................................. 22 
Appendices ....................................................................................................................................................... 24 
1. 
List of Tables, Listings, Figures ............................................................................................................. 24 
2. 
Study flow chart ..................................................................................................................................... 24 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Description 
ADRs 
Adverse Drug Reactions 
AEs 
Adverse Events 
CA 
Competent Authority 
CDC  
Center for Disease Control 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
D 
Day 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECLS  
Extra Corporeal Life Support 
eCRF  
electronic Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End of study  
EOT 
End of treatment 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HBV 
Hepatitis B Virus  
HCV 
Hepatitis C Virus  
HIV 
Human Immunodeficiency Virus 
HR 
Hasard Ratio 
IB 
Investigator9s Brochure 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committees 
IMP 
Investigational Medical Product 
IRB 
Independent Review Board 
ITT 
Intention To Treat 
IVM 
Ivermectin 
IWRS 
Interactive Web Response System 
MDR-1 
Multi Drug Resistance-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified Full Analysis Set 
NCI-CTCAE  
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
PCR 
Poly Chain Reaction 
PP 
Per Protocol 
PT 
Preferred Term 
PTAEs 
Post-Treatment Adverse Events 
(r)SDV 
(remote) Source Data Verification 
SAEs 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SARS-CoV-
2 
Severe Acute Respiratory Syndrome Coronavirus-2 
SMP 
Safety Management Plan 


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Abbreviation 
Description 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Assessment 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SpO2 
Blood oxygen saturation level 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Temperature 
TS 
Trial Statistician 
TEAEs 
Treatment Emergent Adverse Events 
TMF 
Trial Master File 
WHO 
World Health Organization 
 
 
 


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1 STUDY INFORMATION 
The aim of the present Proof of Concept Phase II clinical study is to: 
" Demonstrate the efficacy of a continuous daily dosing for 28 days of ivermectin for the 
prevention of COVID-19 infection in humans,  
" Consolidate current knowledge on the ivermectin safety profile, 
" Collect data on potential ivermectin effects on COVID-19 clinical outcomes. 
 
A study flow chart is given in Appendix 2. 
Study flow chart. 
 
1.1 Primary objective 
The primary objective of this study is to assess the efficacy of ivermectin compared to 
placebo in the prevention of laboratory-confirmed COVID-19 infection. 
 
1.2 Secondary objectives 
The following secondary objectives will be investigated: 
" To assess the efficacy of ivermectin on Time to RT-PCR positive testing. 
" To assess the efficacy of ivermectin on the occurrence of severe COVID-19 symptoms. 
" To assess the efficacy of ivermectin on Time to first COVID-19 related clinical events. 
" To assess the efficacy of ivermectin on the rate of COVID-19 related hospitalisations. 
" To assess the efficacy of ivermectin on the rate of COVID-19 related mortality.  
" To assess the safety and tolerability of ivermectin given for a period of 28 days. 
 
1.3 Study design 
This is a randomised, double blind, parallel-group, placebo-controlled, multicentric Phase 
II clinical trial evaluating the efficacy and safety of ivermectin tablets in the prevention of 
COVID-19 infection. 
If all eligibility criteria are met, the participant will be randomised, and a loading treatment 
dose will be administered.  
Participants will be assigned in a 1:1 ratio to receive oral daily treatment with either iver-
mectin or placebo. Randomisation will be performed stratified by country. 
The study requires two visits to the study center, on Day 1 and Day 28, the first and last 
days of treatment. In addition, there will be 3 remote visits (day 4, day 7 and day 10) that 
can be conducted by telephone. 
The treatment period lasts for 28 days in total, followed by a 28-day follow-up period, and 
there is a 2-day window period for visits. Therefore, total study duration for each partici-
pant is up to 58 days. 
Ivermectin will be supplied as 3 mg tablets and will be administered orally, under fasting 
conditions, as follows: 200 ug/kg as the loading dose on Day 1 and then 100 ug/kg/day for 


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27 days. Control participants will receive placebo tablets, the number of tablets to be taken 
will match the number of IVM tablets taken by the active participants in the same body 
weight range.  
 
1.4 Planned sample size 
The sample size was calculated to compare the proportion of participants who become 
positive to SARS-CoV-2 RT-PCR within 1 month after randomisation between the two 
groups: Placebo group and ivermectin group. The assumptions are based on results of a 
study assessing the transmission of SARS-CoV-2 infections in households carried out in 
the US between April and September 2020. Thus it is expected that the proportion of par-
ticipants becoming infected in the placebo group is 54% or higher (Grijalva et al, 2020). 
Furthermore, a reduction by 20% is expected in the ivermectin group (OR=2.28).  
When requiring a power of 90% (1-³) and a significance level of 5% (³), then according 
to the Casagrande & Pike formula the required sample size to detect such difference with 
a test of comparison of two proportions is equal to 138 participants per treatment arm 
(Casagrande et al, 1978).  
A total of 396 participants (198 per arm), rounded up to 400 participants (200 per arm) is 
required to account for an estimated rate of randomised participants who won9t be valued 
for the primary analysis of 30%.  
After approximately 40% of the targeted participants will have been randomised and will 
have completed 28 days of therapy (i.e., 160 randomised participants tested PCR-negative 
at baseline), an independent Data Monitoring Committee (DMC) will review the data for 
further development pathway decisions. 
 
2 GENERAL INFORMATION 
2.1 Background details 
All study data will be transferred to a SAS database (version 9.4 or later, SAS institute, 
North Carolina, USA) for statistical analysis purposes. Data will be imported from a Data 
Capture System IBM Inform via validated SAS programs. 
The SAP will be finalized before the interim analysis, any changes needed after the DMC 
meeting will lead to an SAP amendment which needs to be finalized before database lock 
and unblinding after agreement with the Sponsor on subject disposition and coding. 
 
2.2 Deviations from the trial protocol with regard to statistical analyses 
In the protocol, subgroup analyses are planned for subjects tested PCR positive at base-
line and subjects tested PCR negative at baseline. However, the subjects tested PCR neg-
ative at baseline are also included in the mFAS population. The FAS population will 
have the subjects with a positive PCR test at baseline included together with the subjects 
in the mFAS population. It is expected that the number of subjects with a positive PCR 
test at baseline will be small, so it is decided to perform no subgroup analyses. If the 
number of subjects with a positive PCR test at baseline is not small, additional analyses 
for subjects with a positive PCR test at baseline may be performed. 


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The definition of the safety set in the protocol mentions that only subjects who are ran-
domized and received at least one dose of study drug should be included in the SS. In 
theory, a subject can also receive study drug while not being randomised, if this happens, 
the subject should also be included in the SS. Therefore, the definition in the SAP is 
adapted. 
 
Deviations from the protocol will be judged during the study and/or when an individual 
participant9s CRF is completed (monitored).   
Before unblinding the data, a blinded data review meeting (BDRM) will take place where 
protocol deviations will be classified (major/minor protocol deviations) for statistical  
analysis. Intake of pain medications such as acetylsalicylic acid and metamizole, will not 
be considered a major protocol deviation. 
 
2.3 Individual protocol deviations 
Apart from violations of in- or exclusion criteria, no individual protocol deviations have 
been determined a priori. 
A detailed review of all documented and derived deviations from protocol will be part of 
the blinded DRM before database lock. During this DRM the impact of protocol deviations 
on the analysis will be assessed and the conclusions recorded.  
A complete listing of documented and derived protocol deviations and the judgment for 
assessment of subject disposition will be signed before database lock. A description of 
protocol violations that led to exclusion from any analysis sets will be included in the table 
part of the CSR. 
 
3 ANALYSIS POPULATIONS 
In general, the disposition of subjects will be displayed for the subject populations defined 
below. 
Membership of subjects will be decided upon in a blind DRM with the Sponsor before 
database lock. The proper flag for analysis sets exclusion (e. g. exclusion from PP set), 
will be included in the analysis datasets. The protocol deviation list should be finalized 
before database lock. 
 
3.1 Randomized Set 
The randomized set includes all participants who were randomised. 
 
3.2 Safety Set 
The safety set (SS) includes all participants who received at least one tablet of the study drug (iver-
mectin or placebo). 
 


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3.3 Full Analysis Set 
The Full Analysis Set (FAS) includes all participants randomly assigned to a treatment 
group having received at least one tablet of the study drug (ivermectin or placebo) and 
having at least one efficacy assessment after randomisation. 
 
3.4 Modified Full Analysis Set 
Modified FAS (mFAS) includes all FAS participants with a confirmed negative SARS-
CoV-2 RT-PCR test at baseline. 
3.5 Per-protocol Set 
The Per-Protocol Set (PPS) is a subset of participants in the mFAS who did not present 
major deviations from the trial protocol. 
The primary efficacy endpoint will be analysed using the mFAS and the PP set. The PP 
analysis will be considered as a sensitivity analysis. 
Secondary efficacy endpoints will be analysed using the FAS or mFAS and PP set. 
In case of dispensation/randomisation major error (i.e. the participant did not receive the 
treatment planned by the randomisation), in agreement with the intention-to-treat (ITT) 
principle, participants in FAS and mFAS analyses will be analysed in the group planned 
by the randomisation and not <as treated=. As treated analyses will be performed as sensi-
tivity analyses only if the frequency of major dispensation/randomisation error is greater 
than 10%. 
The safety set will be used for safety analyses. In case of dispensation/randomisation ma-
jor error the safety analyses will be performed <as treated=, according to the real treatment 
received by the participant. 
 
 
3.6 Subgroup analyses 
No subgroup analyses are planned. It is expected that the number of subjects with a posi-
tive PCR test at baseline will be small. If this is not the case, additional analysis for sub-
jects with a positive PCR test at baseline may be performed.  
 
4 STATISTICAL ANALYSES 
All statistical analyses will be performed using the SAS¨ software (Version 9.4 or later, 
SAS institute, North Carolina, USA). 
All descriptive statistics will be given by treatment group. For baseline and basic variables, 
they will also be given for the entire analysis set. Screening failure data will not be ana-
lysed.  
If not stated otherwise the following standard types of descriptive analyses will be pre-
sented:  
2 Descriptive statistics for continuous data 


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N, mean, SD, min, lower quartile, median, upper quartile, and max will be presented. 
These descriptive statistics will be determined for measured values and optionally for 
differences to baseline. 
2 Descriptive statistics for categorical data 
Absolute frequencies and percentages will be presented. Percentage bases (denomina-
tors) will be identified in the table title or footnote (i.e. all subjects at risk, all cases). 
For changes from baseline, shift tables may be generated.  
2 Inferential statistics 
Unless otherwise stated, all statistical tests will be performed two-sided and at a type I 
error probability of ñ=0.05.  
Unless otherwise stated, all confidence intervals (CIs) will be derived two-sided and at 
a confidence probability of 1-³=0.95.  
2 Listings 
All recorded data will be listed by subject sorted by treatment group. Identification 
variables are centre number, participant number and treatment.  
Derived data will be stored in special analysis data sets and will be calculated as outlined 
in section 6.1. 
 
4.1 Conventions 
4.1.1 Baseline definition 
Results obtained on D1 (Screening/Randomization) of the study are considered as baseline 
results. In case of more than one result the closest to start of treatment will be used. 
 
4.1.2 Missing data 
In general, an observed cases approach will be applied in case of missing data, i.e., only 
the observed subject data at a given timepoint will be used. 
There will be one notable exception to this rule for the primary efficacy endpoint: if a 
subject discontinued the study without a confirmed negative test result on D28 (and on 
any day in between), then the missing data will be imputed using a multiple imputation 
(MI) method, under the assumption that the results are missing at random (MAR). Details 
on the MI method can be found in section 4.6.1. The MI method will only be used for the 
primary efficacy endpoint. 
Missing/incomplete information related to AEs and concomitant medications will be han-
dled as listed below, when applicable. Following these steps using temporary program-
ming will ensure that missing date imputation uses the most conservative approach. 
In case of a (partially) missing onset date, and the end date is determined to be after the 
first date of study drug administration, the onset date will be imputed as follows: 
" Partially missing onset date:  


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o If the day part is missing and month is equal to month of first study drug 
administration, then day will be set to day part of first study drug ad-
ministration date. 
o If the day part is missing and month is not equal to month of first study 
drug administration, then day will be set to the first day of that month. 
o If both day and month part are missing, and year is not the same as the 
year of the first study drug administration, then day and month will be 
set to 1 January. 
o If both day and month part are missing, and year is the same as the year 
of the first study drug administration, then day and month part will be 
set to day and month of first study drug administration. 
" Complete missing onset date: 
o If the end date is on or after date of first study drug administration, then 
the onset date will be set to the date of first study drug administration. 
o If the end date is prior to the date of first study drug administration, then 
the onset date does not need an imputation, and the event or medication 
is considered a pre-treatment AE or prior medication. 
In case of a (partially) missing end date, the end date will be imputed as follows: 
" In case end date is partially missing: 
o If the day part is missing, and the month and year present then day will 
be set to the last day of the month or the end of study date, whichever is 
earliest. 
o If both day part and month part are missing and year is the same as the 
year of the end of study date, then day and month will be imputed with 
the end of study date. 
o If both day part and month part are missing and year is prior to the year 
of end of study, then day and month will be set to 31 December. 
" Completely missing end date: 
o If the outcome of the AE is not marked as recovered/resolved: 
¯ The event will be assumed to be ongoing. 
o If the outcome of the AE is marked as recovered/resolved: 
¯ The end date will be imputed with the end of study date. 
In case both onset and end date are missing, the onset date will be imputed with the date 
of first study drug administration and the end date with the end of study date and the AE 
will be considered treatment emergent.  
AEs with missing severity/relatedness will be considered severe/related.  
Note that imputed dates will not be presented in the listings but will only be used in dura-
tion and onset time calculations, descriptive statistics and/or statistical analysis.  
 


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For additional standards and conventions applied in the generation of statistical outputs 
please refer to section 8. 
 
4.2 Demographic and other background data 
4.2.1 Basic description 
The disposition of subjects (cf. Section 3) will be tabulated by treatment and for the entire 
analysis set (pooled treatment groups). Frequencies of different reasons for exclusions 
(based on defined PD categories) from analysis sets will be listed. 
Similarly, discontinued subjects will be described by frequencies of reason for termination 
and in individual listings. 
Demographic data (e. g. age, sex, weight, height, and BMI as calculated) will be summa-
rized in frequency or sampling statistics tables. Tables will be split by treatment group and 
will show pooled groups as well.  
Descriptive summaries on other baseline or background data will be presented for the fol-
lowing variables: 
" Childbearing potential 
" Household composition 
" Medical/Surgery history 
" Country 
" Violation of in-/exclusion criteria 
" COVID-19 sign/symptoms 
" Result of RT-PCR test at baseline 
" Result of serology COVID-19 (antibody levels) at baseline 
" Pregnancy test result at baseline, if applicable 
 
The following background data will only be listed: 
" Details on medical/surgery history 
" Eligibility 
 
4.2.2 Homogeneity tests 
Homogeneity tests between treatment groups will be performed for age, sex, height, body 
weight and BMI. 
 
4.3 IMP exposure, compliance 
Treatment compliance will be described per visit by descriptive statistics on: 


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" Number of participants with modified, interrupted or missed study treatment with 
reasons 
" Number of missed doses 
" Number of days without medication 
" Number of tablets returned 
 
4.4 Medical history  
Medical history terms will be coded using the MedDRA dictionary, with version as docu-
mented in the Data Management Plan and presented descriptively by system organ class 
and preferred term. Details will be listed. 
 
4.5 Prior and concomitant medication 
"Concomitant" is defined as a medication which is taken during study treatment (starting 
before or during) and will be coded according to the WHO Drug Dictionary. Summary 
tables will be presented by international non-propriety name (INN) and WHO drug label. 
Prior medication is defined as medication taken prior to the first dosing of study drug, i.e., 
the end date is before the first study drug intake.  
Any medication with a missing start date will be considered 8concomitant9, unless a (par-
tial) end date shows that the medication is stopped prior to first study intake, then it will 
be considered as prior medication. 
Medication with a missing end date will be considered continued during the study and 
should be considered as concomitant, unless a (partial) end date shows that the medication 
was stopped before the first study intake.  
 
4.6 Efficacy 
4.6.1 Primary endpoint 
The primary endpoint is the proportion of laboratory-confirmed COVID-19 infections be-
tween baseline and Day 28. Frequency tables will be provided, and individual results will 
be listed. 
For missing results of the primary endpoint, the multiple imputation (MI) method will be 
used. MI is performed using 3 general steps: imputation, analysis, and pooling. A total of 
10 multiple imputations will be generated using a fully conditional specification (FCS) 
regression. This method conditions on observed values of the primary outcome measured 
at other time points (including baseline measurements) and possible other covariates that 
are related to the missing data pattern and/or primary endpoint. Furthermore, imputations 
will be performed in each treatment group separately and, if applicable, by stratification 
factor. The statistical model will be applied to each imputed dataset separately. The esti-
mated parameters from the models will then be pooled using Rubin9s combining rules. It 
should be noted that these combination rules rely on the assumption that the estimated 


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statistics are approximately normally distributed, which may not be the case for the un-
derlying data. Normalizing transformations will then be used on the estimated statistics 
prior to applying Rubin9s rules. 
The comparison between the two treatment groups of the proportion of participants will 
be performed using the Cochran Mantel Haenszel (CMH) chi-squared test. Odds-ratio, 
relative risk and risk differences and corresponding 95% CI will be reported. Country will 
be used as a stratification factor. In case the study was only performed in one country, the 
Chi-squared/Fisher9s exact test will be used.  
This analysis will be performed based on the mFAS and PP population using the planned 
treatment. 
Also under sensitivity aspects, the same analysis will be performed (mFAS and PP) based 
on the actual treatment received, but only if the frequency of major dispensation/random-
isation error is greater than 10%. 
 
As sensitivity analysis, the primary endpoint will also be analysed using a logistic regres-
sion with treatment group and country as a covariate based on the PP population. Odds 
ratios and 95% CI will be presented. 
In case the homogeneity tests show any significant differences between the two treatment 
groups, the relevant baseline characteristics will be added as a correction factor to a lo-
gistic regression model. 
In addition, a possible center effect will be investigated. If a center effect exists, appropri-
ate steps will be taken regarding the statistical analysis.  
Any deviations to the planned statistical analyses. will be described in the Clinical Study 
Report (CSR).  
 
4.6.2 Secondary endpoints 
Secondary endpoints will be considered for the FAS or mFAS and the PP populations: 
 The following results will be presented: 
" RT-PCR tests on D1, D4, D7, D10, and D28, and at any unscheduled visits 
(mFAS/PP). 
" Time to change from baseline from negative RT-PCR to positive RT-PCR 
(mFAS/PP). 
" WHO COVID-19 scales scoring on D1, D10, and D28, and at any unscheduled 
visits (FAS/PP). 
" Change from baseline in the WHO-COVID 19 scale at D10 and D28 (FAS/PP). 
" Number of participants per subject state based on WHO COVID-19 scale (refer to 
Appendix 2 of the protocol) (FAS/PP). 
" News-2 scales scoring on D1, D10, and D28, and at any unscheduled visits 
(FAS/PP) 


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" Change from baseline in the NEWS-2 scores at D10 and D28 (FAS/PP). 
" Categories of clinical risk (low, low-medium, medium, high) based on NEWS-2 
(refer to Appendix 1 of the protocol) (FAS/PP). 
" Time to change from baseline to first COVID-19 related clinical events (FAS/PP). 
" Proportion of COVID-19 related AE notification by participants and/or investiga-
tors throughout the study (FAS/PP). 
" Proportion of COVID-19 related hospitalisations notified by the investigator 
(FAS/PP). 
" Duration of COVID-19-related hospitalisations (FAS/PP) 
" Duration of hospitalisation as calculated from the associated SAE notification form 
(date of hospital admission through to date of hospital release) (FAS/PP). 
" Proportion of COVID-19 related deaths notified by the investigators (FAS/PP). 
" Time to death (FAS/PP) 
" Proportion of all AE notifications by participants and/or investigators throughout 
the study (SS). 
 
The analysis of the secondary endpoints is purely explorative. 
Results of RT-PCR tests and time to a positive test will be performed on the mFAS and 
PP population, while the analysis related to the occurrence of symptoms, (related) adverse 
events are performed on the FAS and PP population. 
Treatment comparisons on proportions will be done using Cochran Mantel Haenszel chi-
square test presenting odds-ratios, relative risk, and risk differences with 95% confidence 
intervals. Country will be used as a stratification factor. In case the study was only per-
formed in one country, the Chi-squared/Fisher9s exact test will be used. 
Comparisons between treatment groups on time to events will be done by using a Cox 
proportional hazard model, under the assumption of proportional hazards. Time-to event 
curves will be created for visualization. Hazard ratios with 95% CI will be presented, to-
gether with the P-values. Censoring will be at study completion or at discontinuation date 
(including date of death, if occurring). 
 
Treatment comparisons on mean score (WHO COVID-19 and NEWS-2) will be per-
formed per time point by means of the t-test. If normality cannot be assumed based on 
visual inspection, a non-parametric alternative will be used. 
 
Comparisons between treatment groups of clinical risk categories for NEWS-2 and subject 
state from WHO COVID-19 will be performed by Cochran Mantel Haenszel test. Country 
will be used as a stratification factor. In case the study was only performed in one country, 
the Chi-squared test will be used.  
 


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Treatment comparisons on durations will be examined by means of the non-parametric 
Wilcoxon-Rank-Sum test. If normality can be assumed based on visual inspection, a par-
ametric alternative will be used. 
 
4.6.3 Further Exploratory endpoints 
Factors that may affect the SARS-CoV-2 infection or COVID-19 disease such as sex, age, 
BMI, and SARS-CoV-2 variant type will be assessed with a logistic regression model with 
proportion of COVID-19 infections as dependent variable and treatment as independent 
variable and the factors as covariates. Odds-ratios, 95% CI and P-values will be presented.  
 
4.7 Safety 
All safety analyses will be based on the SS population according to the actual treatment 
the participant received. 
 
4.7.1 Adverse events 
Adverse events will be presented by MedDRA System Organ Class (SOC) and Preferred 
Term (PT). Coding of verbatim terms has been performed either by Ergomed or the Spon-
sor and that all relevant codes are stored in the database. 
Adverse events will be classified according to period of occurrence: pre-treatment AEs, 
treatment-emergent AEs (TEAEs) and post-treatment AEs (PTAEs). 
" Pre-treatment AEs are defined as adverse events starting before the first study drug 
intake. 
" TEAEs (i.e. during the treatment period) are defined as AEs starting from the first 
study drug intake until three days after the last study drug intake. 
" Post-treatment AEs are defined as AEs starting four days after the treatment period 
(last study drug intake). 
AE reporting will focus on TEAEs and PTAEs. Pre-treatment AEs will only be listed. 
Frequency tables of participants experiencing at least one occasion of the event while at 
risk (along with the number of different occurrences of the TEAE), will be presented for 
the following types of adverse events: 
" All TEAEs and PTAEs irrespective of the causality assessment 
" TEAEs and PTAEs by CTCAE grade 
" TEAEs and PTAEs by action taken with the study medication 
" Related TEAEs and PTAEs 
" Serious TEAEs and PTAEs (SAEs) 
" Related serious TEAEs and PTAEs 
" Fatal TEAEs or PTAEs 


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Participants will only be counted once within a PT or SOC. 
SOC terms will be presented according to the Internationally Agreed Sorting Order 
(MedDRA). 
Comparison between the treatment groups on the number of participants with 
TEAEs/PTAEs will be performed by means of a Fisher9s exact test. 
Detailed listings of all fatal and other serious events will be provided (for section 14.3.2). 
Narratives will not be included in section 14.3.3 but will be provided by medical writing 
in section 12.3.2 of the CSR. All adverse events (i.e. TEAEs as well as non-treatment 
emergent events) will be listed in section 16.2 of the CSR. However, only TEAEs and 
PTAEs will be summarized in the tables. 
 
4.7.2 Vital signs 
Vital signs are measured at baseline, D10 and end of treatment (D28). 
The following measurements are to be performed: temperature, systolic/diastolic blood 
pressure (in the sitting position under standardised conditions), heart rate will be measured 
at the time of the measurement of blood pressure, and Sp02 measurement. In addition, the 
level of consciousness will be recorded. 
Descriptive statistics will be calculated per time point, as well as changes to baseline for 
all metric parameters. Frequency tables will be presented for the level of consciousness. 
 
4.7.3 ECG 
ECG is taken at baseline and end of treatment (D28). Descriptive statistics will be calcu-
lated per time point, as well as changes to baseline. 
QTc will be recalculated, based on CRF entries according to both, the Fridericia and Bazett 
correction. 
QTc Frequencies will be calculated for following classified values and changes (according 
to ICH E14): 
" Absolute values:  
o <450 ms as normal,  
o >450-480 ms,  
o >480-500 ms,  
o >500 ms 
" Changes from baseline: decreases or increases  
o <30 ms as normal,  
o increases >30-60 ms,  
o increases >60 ms. 
 


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4.7.4 Laboratory variables 
Laboratory data (Haematology and Clinical Chemistry) and pregnancy test will be col-
lected at baseline, end of treatment (D28) and D56 (EOS). For a list of parameters (hae-
matology and clinical chemistry) refer to table 4 of section 6.2.6.1 of the study protocol. 
Since laboratory assessments will be performed locally at each site9s laboratory, all values 
and normal ranges will be transformed to standard SI units, but they need to be compliant 
with the controlled terminology of CDISC. 
All descriptive summary statistics and changes to baseline will be performed on the values 
based on standardized units. Original as well as transformed values will be presented in 
the listings in section 16.2. 
Figures on mean profiles with standard deviation will be displayed. 
Frequency tables of low (L), normal, or high (H) values will be presented as well as shift 
tables to baseline. 
Listing of abnormal safety laboratory values with clinical significance (CLS) as rated by 
the investigator will be presented. A frequency table will show the number of participants 
with clinically significant laboratory values. 
In the analysis only scheduled, common time points will be displayed. Results from un-
scheduled visits will only be used in listings. In such listings the normal ranges as well as 
an indicator of H/L and CLS will be given. 
The results of the urine pregnancy test (negative/positive) will only be listed. 
 
4.7.5 Other safety variables 
Concomitant medications will be summarized by preferred International Non-proprietary 
Name (INN; WHO Drug Dictionary). This summary will allow the detection of the use of 
prohibited medications. All prior and concomitant medications will also be listed. 
 
4.7.6 Global assessments 
Not applicable. 
 
4.8 Other variables 
Not applicable. 
 
4.9 Interim analyses 
An unblinded interim analysis will be performed when at least 160 participants will have 
completed the 28-day treatment period. This analysis will be carried out by an independent 
statistician, and results will only be presented to and discussed within the Data Monitoring 
Committee (DMC).  


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CONFIDENTIAL 
Interim analysis will be performed using the analysis methods described in this Statistical 
Analysis Plan. The TFLs to be provided to the DMC for the interim analysis are indicated 
with a 8Y9 in the IA column of the List of TFLs document to be used in conjunction with 
this SAP. 
Results of this interim analysis will be medically reviewed and evaluated for safety con-
cerns. No statistical tests will be performed for assessment of study endpoints and no de-
cisions will be made based on statistical decision theory. The type I-error levels and con-
fidence interval levels will not be multiplicity adjusted.  
Based on the descriptive statistics provided, the DMC wil make a risk/benefit assessment 
for their recommendation. Should the medical experts on the DMC recommend a discon-
tinuation of the trial or a modification of relevant aspects of the trial, this SAP will be 
amended as requested by the DMC for the final analysis. 
Upon request of the sponsor, the statistical analysis results of the primary efficacy end-
point will also be shared with the DMC. The DMC will report to the sponsor whether a 
relative risk reduction (RRR) of 63% or higher in favour of ivermectin has been reached. 
No futility assessment will be performed. 
 
5 QUALITY CONTROL 
The SAP will be reviewed by the trial statistician (TS) before signature. Particularly the 
TS has checked the consistency of the described methods and outputs with the actual ver-
sion of the study protocol. In addition, a sponsor representative has reviewed the SAP 
before final approval. 
Log files of all SAS¨ programs used in the analysis will be checked for errors, warnings 
and suspicious notes by the statistical programmer. All findings will be either eliminated 
or commented upon. The final version of each program will be stored along with its log 
file in the electronic archive. 
All programs will be validated by an independent statistician or statistical programmer 
depending on the requested validation level selected in the List of TLFs form 
(FRM/BS/001.02) for a particular program.  
The agreement of the program outputs with the SAP, their consistency and plausibility 
will be checked by the TS. Moreover, the TS will review the outputs regarding complete-
ness, readability and comprehensibility. 
The described process is associated with the 'normal' level of program validation. Addi-
tional levels of quality control can be specified in the List of TLFs (see Appendix, 1) for 
individual outputs. 
For the interim analysis, an unblinded statistician will be involved in the validation of the 
output and/or programs. 
 


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CONFIDENTIAL 
6 DERIVATIONS AND TRANSFORMATIONS 
6.1 Formulas for derived variables 
Variable 
Definition / Derivation 
BMI 
Weight [kg] / (height [m])**2 
QTc_B 
QTc [ms]/ (60 [bpm]/HR [bpm])**(1/2) 
QTc_F 
QTc [ms]/ (60 [bpm]/HR [bpm]) **(1/3) 
 
 
6.2 Transformations to be applied 
No transformations other than for laboratory data will be applied. 
 
7 REFERENCES 
No specific references were used.  
 
 
 
 


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CONFIDENTIAL 
8 STANDARDS USED IN PREPARATION OF STATISTICAL OUTPUTS 
The below conventions will be followed as agreed with the Sponsor. 
 
8.1 Programming 
" One SAS program should create only one output. 
" One output file can contain different output types (e. g. descriptive and inferential).  
" Individual output files will be created in MS Word format (Rich Text Format, 
RTF). 
" Once delivered to the client, numbering of TLFs will not be altered, unless agreed 
with the client. 
 
8.2 Layout 
" TLFs will be produced in landscape format 
" TLFs will have a minimum 2 cm on every side 
" TLFs will be produced using the Courier New font, size 8  
" Section numbering of TLFs will follow ICH E3 guideline. 
" Numbering of TLFs will follow the convention XXX-YY, where XXX stands for 
a (sub-)section number of the ICH E3 guideline and YY represents the sequence 
number of the output within the section. A dash (8-8) will always be used to sepa-
rate section numbers from output sequence numbers 
" Titles and footnotes for figures will also be in Courier New font, size 8. 
" Tables and listings will be in black and white (no colour), figures may include only 
colour that can be distinguished when printed on a grey-scale printer  
" Text styles, such as bolding, italics, borders, shading, and superscripted and sub-
scripted text, will be used sparingly in the TLFs 
" The ANSI character set will be used in the TLFs. Certain subscripts and super-
scripts (e.g., m2, AUCnorm) will be employed on a case-by-case basis. 
" Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, unless they are derived directly from the data 
 
8.3 Headers, Titles and Footnotes 
" All output will have the following header at the top left of each page showing the 
study ID, the date of output generation and an internal pagination, where Y stands 
for the total number of pages in the pertaining output. 
 
Study ID 
Study description 
ERGOMED, YYYY-MM-DD 
Page [ X / Y ] 


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CONFIDENTIAL 
" Also, all TLFs will have the following footer, identifying the generating SAS pro-
gram (XXX.SAS), a reference to the relevant subject listing and the date of the 
data snapshot: 
 
SAS program: <XXX>.sas 
Ref. list X.X.X-YY 
Data status: YYYY-MM-DD 
 
" Each TLF will bear a title which is repeated on each page of the output. 
" The title at the top of the page will be horizontally cantered in bold font. 
" A blank line will separate the title from the body of the output. 
" The title will consist of an Output number, a descriptive title and a description of 
the presented analysis set (if applicable).  
" The title will have the following general appearance: 
Table / Figure / List XX.X.X-YY 
Descriptive Title line 1 
Descriptive Title line 2 
 (All subjects in the FAS, N=nnn) 
 
" Each new footnote should start on a new line, where possible. 
" Preferably, footnotes should be left justified. When extending beyond a single line, 
a manual linefeed should be inserted to avoid meaning distortion. 
" An automatic footnote 8(continued)9 will appear at the bottom of TLFs that extend 
over more than one page. 
 
8.4 General Conventions 
" For measured variables column headers should include the unit in their description 
" The order of treatment arms in the TLFs will be consistent throughout the entire 
TLF presentation 
" Alphanumeric values are preferably displayed left-justified; 
" Dates are presented left-justified 
" Integer numbers (e.g., counts) can be centred or right-aligned 
" Numbers containing fractional portions will be decimal-aligned. 
" Fractional numbers with absolute value less than 1 will carry a leading zero, i.e. 
0.123 not .123. 
" Units of measured or derived variables will be included where appropriate 
" Unless otherwise warranted, the estimated mean, median and quartiles for a set of 
values will be displayed with 1 more significant digit than the original values, and 
standard deviations with 2 more significant digits. The minimum and maximum 
should report the same significant digits as the original values.  


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CONFIDENTIAL 
" P-values are output in the format: <0.xxxx=, where xxxx is the value rounded to 4 
decimal places. P-values less than 0.0001 will be presented as <0.0001. 
" Precision of percentages displayed will depend on the total study size. For studies 
with less than 1000 subjects values will be presented with one decimal place. For 
studies with more than 1000 subjects, values will be presented with two decimal 
places.  
" Tabular display of data for medical history, prior/concomitant medications and all 
tabular displays of adverse event data are generally presented by body system, 
treatment class, or SOC according to the Internationally Agreed Sorting Order of 
the MedDRA, unless otherwise agreed. 
" The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis (sub-) 
population presented.  
" For categorical summaries (number and percentage of subjects) where a subject 
can be included in more than one category, an explanatory text will be added to 
clarify that multiple answers were possible. 
" Missing values will be displayed either by a double-dash (<--=) or as <NA= (=9not 
available/applicable9), whichever is appropriate. 
" Dates are displayed in according to ISO date/time format as YYYY-MM-DD, e. 
g. 2010 03 24. Missing dates may be represented as <NA=, if not available/appli-
cable. 
" Clock times are displayed as HH:MM or HH:MM:SS based on 24-hour clock 
 
 
 


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CONFIDENTIAL 
APPENDICES 
1. 
List of Tables, Listings, Figures 
A complete List of tables, listings, figures (TLFs) will be given in a separate document 
which can be updated without updating the SAP. The List will serve as a reference for 
both the Sponsor, the TS and the SP and describes the entire set of statistical output to be 
produced. Therefore, this List will be versioned and approved by both Ergomed and Spon-
sor before commencing the statistical programming. 
All subject listings will contain in addition to the subject identification the analysis set and 
the treatment group. 
 
 
2. Study flow chart 
 
  
Pre 
Screening 
Screening 
& 
Randomisat
ion 
On-treatment period (i) 
EOS (i) 
D-1* 
D1 
D4  
(±1 day) 
D7 
(±1 day) 
D10 
(±1 day) 
EOT-
D28** 
(±2 days) 
D56  
(±2 days) 
Remote 
On-site 
Visit*** 
Remote 
Remote 
Remote 
On-site 
Visit*** 
Remote 
Study participation 
suitability 
questionnaire (a)  
X  
 
 
 
 
 
 
ICF signature (b) 
X 
 
 
  
  
  
Demographics  
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
  
  
  
I/C criteria 
 
X 
 
 
  
 
  
Treatment 
dispensation 
 
X 
 
 
 
 
 
Treatment 
administration (c) 
  
----------------------------------------------------------------------- 
  
RT-PCR test (d) 
  
X 
X 
X 
X 
X 
  
Antigen test (e) 
 
X 
 
 
 
 
 
Serology (f) 
  
X 
 
 
X 
X 
NEWS-2 scale  
 
X 
 
 
X 
X 
 
COVID-19 WHO 
 
X 
 
 
X 
X 
 
Laboratory tests (g) 
  
X  
 
 
  
X 
X 
Urine pregnancy test 
(g) 
 
X 
 
 
 
X 
X 
Randomisation (h) 
  
X 
 
 
  
  
  
ECG 
 
X 
 
 
 
X 
 
Vital signs 
  
X 
 
 
X 
X 
Adverse Events  
  
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Statistical Analysis Plan Version 1.0 
 
Page 25 of 25 
Sponsor 
MedinCell 
Protocol No 
mdc-TTG-CT-002 
 
 
CONFIDENTIAL 
  
Pre 
Screening 
Screening 
& 
Randomisat
ion 
On-treatment period (i) 
EOS (i) 
D-1* 
D1 
D4  
(±1 day) 
D7 
(±1 day) 
D10 
(±1 day) 
EOT-
D28** 
(±2 days) 
D56  
(±2 days) 
Remote 
On-site 
Visit*** 
Remote 
Remote 
Remote 
On-site 
Visit*** 
Remote 
Concomitant 
medication 
 
---------------------------------------------------------------------------------------