A Multicentre Randomised, Double-Blind, Placebo-controlled, Study to Evaluate the efficAcy and Safety of Oral IVErmectin Tablets in the Prevention of COVID-19
Phase: PHASE2
Conditions: COVID-19
Sponsor: MedinCell S.A

 
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. 
 
 
 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
    Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
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 
 
 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD
2022-06-17 | 08:05:01 CEST
2022-06-17 | 11:08:22 CEST

MedinCell SA 
 
 
 
 
 
 
 
    Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
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 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
    Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
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. 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
    Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
Page 5 of 69 
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). 
 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
    Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
Page 6 of 69 
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: 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
    Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
Page 7 of 69 
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 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
    Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
Page 8 of 69 
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. 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
    Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
Page 9 of 69 
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. 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 10 of 69 
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 
 
 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD

MedinCell SA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Protocol 
SAIVE-mdc-TTG-CT-002 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 11 of 69 
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. 
DocuSign Envelope ID: 71C4A182-2161-43AB-A006-47D13B64E3CD