Clinical trial NCT04390022
Conditions: Covid-19 Coronavirus Infection SARS-CoV-2 Infection
Keywords: ivermectin
Sponsor: Clinica Universidad de Navarra, Universidad de Navarra
Start date: 2020-07-31; Completion date: 2020-10-09
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
SAINT is a double-blind, randomized controlled trial with two parallel groups that evaluates the efficacy of ivermectin in reducing nasal viral carriage at seven days after treatment in SARS-CoV-2 infected patients who are at low risk of progression to severe disease. The trial is currently planned at a single center in Navarra.

Detailed description:
SAINT is a double-blind, randomized controlled trial with two parallel groups that evaluates the efficacy of ivermectin in reducing nasal viral carriage at seven days after treatment in SARS-CoV-2 infected patients who are at low risk of progression to severe disease. The trial is currently planned at a single center in Navarra.

Participants will be randomized to receive a single dose of 400 mcg/kg ivermectin or a placebo. The randomization code will be generated by the trial statistician using blocks that ensure balance between the groups.

The allocation will be made by the investigator after obtaining informed consent, and confirmation of fulfillment of all inclusion and none of the exclusion criteria. The investigational product will be administered by a researcher not involved in patient care or participant follow up.

Participants will remain in the trial for a period of 28 days.

In the interests of public health and containing transmission of infection, trial visits will be conducted in the participant's home by a clinical trial team comprising nursing and medical members.

Subsequent visits will be to assess clinical and laboratory parameters.

A final study visit will be made for participants who withdraw prematurely from the study or are withdrawn by the investigator.

Arms: arm 1: Participants on this arm will receive a single, oral dose of ivermectin 400 mcg/kg at the enrolment visit. arm 2: Participants on the arm will receive a single, oral dose of placebo tablets at the enrollment visit.
Interventions: intervention 1: Ivermectin intervention 2: Placebo
Intervention descriptions: intervention 1: Single dose of STROMECTOL® tablets at 400mcg/kg intervention 2: Placebo tablets will not match ivermectin but they will be administered by staff not involved in the clinical care.

Protocol documents:
Prot_001.pdf: 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
Code: SAINT 
Title of trial: Pilot study to evaluate the potential of ivermectin to reduce 
COVID-19 transmission 
Phase: IIa 
Date of protocol: 12 of August 2020 - Version 2.0 
EudraCT number: 2020-001474-29 
Sponsor: Clínica Universidad de Navarra 
Written by: Carlos Chaccour MD PhD 
 
Principal Investigator:   
Dr. Carlos Chaccour 
Department: División of Infectious Diseases 
Clínica Universidad de Navarra 
 
 
 
 
 
CONFIDENTIAL MAY NOT BE USED, DIVULGED OR PUBLISHED WITHOUT TRIAL SPONSOR'S CONSENT. 
 


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PROTOCOL SIGNATURES SHEET 
 
Protocol:  Pilot study to evaluate the potential of ivermectin to reduce COVID-19 transmission 
 
 
 
 
 
 
 
 
 
 
 
 
 
I have read this protocol and accept the obligation to direct this trial in accordance with all the 
stipulations of the protocol and with the Helsinki Declaration. 
 
 
Dr. Carlos Chaccour  
12 agosto 2020 
 
Principal investigator/ 
 
 
Signature 
 
 
Date 
trial coordinator 
 
 
 
Dr. Enrique Aubá Guedea 
12 agosto 2020 
Deputy Chief Medical Officer 
 
    Sponsor's Signature  
 
Date 
Clínica Universidad de Navarra 
  
 


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CONTENTS 
1. 
GENERAL INFORMATION ....................................................................................................... 7 
1.1. Identification of trial .................................................................................................... 7 
1.2. Details of sponsor ........................................................................................................ 7 
1.3. Person responsible for monitoring ............................................................................. 7 
1.4. Coordinating investigator ............................................................................................ 7 
1.5. Details of trial investigators ........................................................................................ 7 
1.6. Centers where study takes place ................................................................................ 8 
1.7. Expected duration of trial ........................................................................................... 8 
1.8. Number of patients ..................................................................................................... 8 
2. 
BACKGROUND AND JUSTIFICATION OF THE STUDY .............................................................. 9 
2.1. Investigational drug ................................................................................................... 11 
2.2. Disease under study .................................................................................................. 16 
2.3. Evaluation of benefit/risk ratio for the participants in the clinical trial .................... 16 
2.4. References from literature ........................................................................................ 16 
3. 
OBJECTIVES OF TRIAL .......................................................................................................... 16 
3.1     Main objective ........................................................................................................... 16 
3.2     Secondary objectives ................................................................................................. 17 
4. 
DESIGN OF TRIAL ................................................................................................................. 17 
4.1. Global design ............................................................................................................. 17 
5. 
SELECTION OF STUDY SUBJECTS.......................................................................................... 19 
5.1. Inclusion criteria ........................................................................................................ 19 
5.2. Exclusion criteria ....................................................................................................... 19 
5.3.     Criteria for withdrawal ............................................................................................. 20 
6. 
DESCRIPTION OF TRIAL TREATMENT ................................................................................... 21 
6.1. Method of treatment assignment ............................................................................. 21 
6.2     Pharmaceutical information ...................................................................................... 21 
6.3.    Drug Identity .............................................................................................................. 22 
6.4.    Potential Risks............................................................................................................ 23 
6.5.    Administration ........................................................................................................... 23 
6.6.    Packaging and Labeling .............................................................................................. 23 
6.7.    Handling and Storage ................................................................................................ 24 
6.8.    Dispensing.................................................................................................................. 24 
6.9.    Accountability ............................................................................................................ 25 
6.10.    Study Intervention Compliance ............................................................................... 25 
6.11.  Disposal and Destruction........................................................................................... 25 
6.12.  Concomitant Therapy/Devices .................................................................................. 25 
6.13.  Dose Escalation ......................................................................................................... 26 
6.14.  Dose Modification and Delay .................................................................................... 26 
6.15.  Dose-Limiting Toxicity ............................................................................................... 26 
6.16.  Overdose ................................................................................................................... 27 


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6.17.  Treatment Discontinuation ....................................................................................... 27 
6.18.  Maintenance of the randomization codes and the procedures for opening ............ 27 
7. 
EVALUATION OF RESPONSE ................................................................................................ 27 
7.1. Study plan and procedures ....................................................................................... 27 
7.2. Efficacy variables ....................................................................................................... 30 
8. 
SAFETY APPRAISAL .............................................................................................................. 31 
8.1. Definitions ................................................................................................................. 31 
8.2. Recording and communicating adverse events ........................................................ 32 
8.3. SAEs that do not require communication to the person responsible for 
pharmacovigilance .................................................................................................... 33 
8.4. Procedure for reporting SAEs .................................................................................... 33 
8.5. Expedited reports of an USAR to the medical authorities ........................................ 34 
8.6. Expedited report of other relevant safety information ............................................ 34 
8.7. Annual safety reports ................................................................................................ 35 
8.8. Reports to investigators ............................................................................................ 35 
8.9. Discontinuation of investigational drugs due to adverse events .............................. 35 
9. 
STATISTICS ........................................................................................................................... 35 
9.1. Description of the statistical methods to be used .................................................... 35 
9.2.  Planned number of subjects to be included and study power ................................ 36 
9.3. The level of significance to be used .......................................................................... 36 
9.4. Criteria for terminating the trial ................................................................................ 36 
9.5. Procedure used to account for lost, unused and incorrect data .............................. 37 
10. ETHICAL ASPECTS ................................................................................................................ 38 
10.1. Good Clinical Practice ................................................................................................ 38 
10.2. Ethical considerations ............................................................................................... 38 
10.3. Information for the patient and informed consent .................................................. 38 
10.4. Confidentiality of patients ......................................................................................... 39 
10.5. Compensation for the patient ................................................................................... 39 
10.6. Insurance policy......................................................................................................... 39 
10.7. Reports to medical authorities .................................................................................. 39 
10.8. Compliance with protocol ......................................................................................... 39 
10.9. Premature termination of study ............................................................................... 40 
11. PRACTICAL CONSIDERATIONS ............................................................................................. 40 
11.1. Direct access to source data/documents .................................................................. 40 
11.2. Responsibilities of all the participants in the trial ..................................................... 40 
11.3. Quality control and assurance .................................................................................. 42 
11.4. Audit/Inspections ...................................................................................................... 42 
12. DATA MANAGEMENT .......................................................................................................... 42 
12.1. Case Report Forms (CRF) ........................................................................................... 42 
12.2. Documents to be kept by the investigator ................................................................ 43 
12.3. Study archive ............................................................................................................. 43 


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12.4. Monitoring................................................................................................................. 43 
12.5. Final report ................................................................................................................ 43 
13. PUBLICATION OF RESULTS OF TRIAL AND USE OF INFORMATION ..................................... 43 
14. REFERENCES ........................................................................................................................ 44 
ANNEX 1: SCHEDULE OF VISITS AND EVALUATIONS ................................................................... 47 
ANNEX 2: DISCRETE DOSING TABLE ............................................................................................ 48 
 
 


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LIST OF ABBREVIATIONS 
AE: adverse event 
AEMPS: Agencia Española de Medicamentos y Productos Sanitarios 
AR: adverse reaction 
CEIm: Comités de Ética de la Investigación con Medicamentos 
CIOMS: Council for International Organizations of Medical Sciences  
CRF: case report form 
Ct: cycle threshold 
CUN: Clínica Universidad de Navarra 
DENV: dengue virus 
DOT: direct observed therapy 
EMA: European Medicines Agency 
ER: emergency room 
FDA: Federal Drug Administration 
GCP: good clinical practice 
ICF: informed consent form 
IP: investigational product 
LFU: lost to follow-up 
MDA: mass drug administration 
NTDs: neglected tropical diseases 
PI: principal investigator 
PIN: participant identification number  
PK: pharmacokinetics 
RRP: records reported by patients  
SAE: serious adverse event 
SUSAR: suspected unexpected serious adverse reaction 
USAR: unexpected and serious adverse reaction  
  


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1. 
GENERAL INFORMATION 
1.1. Identification of trial 
Protocol code: SAINT (SARS-CoV-2 Ivermectin Navarra-ISGlobal Trial) 
EUDRACT:   2020-001474-29 
Version and date:   v2.0 dated: 12 August 2020  
Title of trial: Pilot study to evaluate the potential of ivermectin to reduce COVID-19 transmission
 
 
1.2. Details of sponsor 
CLÍNICA UNIVERSIDAD DE NAVARRA / UNIVERSIDAD DE NAVARRA 
Avenida de Pío XII, 36 
31008 Pamplona 
Email: ucicec@unav.es 
1.3. Person responsible for monitoring 
Jose Manuel Enciso Gadea 
1.4. Coordinating investigator  
Dr. Alejandro Fernández Montero 
Clínica Universidad de Navarra 
Avda. Pío XII 36 
31008 Pamplona 
Tel.: 948 255 400 
1.5. Details of trial investigators 
Clínica Universidad de Navarra 
PI: Carlos Chaccour 
Study coordinator: Alejandro Fernández Montero 
José Luis Del Pozo 
Francisco Carmona 
José Ramón Yuste Ara  
Belen Sadaba  
José Ramón Azanza  


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Miriam Fernández 
Gabriel Reina 
Miriam Giráldez 
Felipe Prosper 
Susana Inoges 
Ascensión López 
ISGlobal 
Carlota Dobaño  
Gemma Moncunill 
Regina Rabinovich 
Mary Ann Richardson 
Paula Ruiz Castillo 
Aina Casellas  
External collaborators 
Felix Hammann, University of Bern. 
Joe Brew, Databrew 
1.6. Centers where study takes place  
Clínica Universidad de Navarra (CUN) and ISGlobal, Barcelona Institute for Global Health 
1.7. Expected duration of trial 
It is estimated that patients shall be recruited over 1 month, after the initial visit, which shall 
take place once authorization is obtained from the Spanish Agency of Medicines and Health Care 
Products (AEMPS). 
Each patient shall participate in the clinical for a maximum of 28 days, including the selection 
phase (1 day), the treatment phase (single dose) and the monitoring phase (28 days). 
1.8. Number of patients 
24 


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2. 
BACKGROUND AND JUSTIFICATION OF THE STUDY  
As of April 11, 2020, there were a more than 1.6 million cases of COVID-19 and more than 
100,000 deaths worldwide.  
Drug-based strategies are widely used in the control of infectious diseases at the population 
level. Notably, mass drug administration (MDA) for malaria has been used to reduce the impact 
and transmission of the disease. Mass distribution has also been carried out for other tropical 
diseases [1].  
In the case of COVID-19, three different drug strategies could be considered: 
a) Early treatment. Assuming that an effective drug is available, this approach requires the 
identification of patients and targets people with suspected or early confirmed disease. It 
involves the use of antivirals or immunomodulators that reduce the progression to severe 
disease and deaths from COVID-19. This strategy would relieve pressure on the health system 
and decrease indirect deaths due to other diseases requiring intensive care.  
(b) Reducing or blocking transmission. Assuming that an effective drug is available, this 
approach involves treating confirmed or suspected cases with a drug that reduces viral excretion 
in the airway or in the stool. The use of such a drug at Community level could reduce 
transmissibility and "flatten the curve" of cases, including those that would progress to severe 
disease, thus allowing a better functioning of the health system.   
(c) Prophylaxis. This approach consists of providing a drug capable of preventing infection to 
vulnerable non-immune populations, following the same strategy as currently used to protect 
travelers from malaria.  
A combination drug strategy may also be feasible, for example, a drug that provides early 
treatment may also reduce the excretion of the virus and decrease transmission.  
Coronaviruses, including SARS-CoV-2, are positive, single-stranded RNA viruses that encode a 
variable number of structural and non-structural proteins. The virus responsible for the former 
SARS epidemic (SARS-CoV-1) uses transport proteins on the surface of the endoplasmic 
reticulum to enter the nucleus [2]. In SARS-CoV-2, it has four structural and several nonstructural 
proteins [3].  
The nonstructural helicase plays a central role in the replication of the virus RNA by unwinding 
the target nucleic acids [4], in the same way as SARS-CoV-1 [5].   
Because SARS-CoV-2 is a new pathogen for our species, infections with this virus are associated 
with a hyperinflammatory state and hypercytokinemia that can cause lung damage and multiple 
organ failure [6]. This inflammatory profile is well described and includes increased interleukin 
(IL)-2, IL-7, granulocyte colony-stimulating factor, interferon-inducible protein-10, monocyte 
chemotractant protein-1, macrophage inflammatory protein-1-9, and tumor necrosis factor-α 
(TNFa) [7].   


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Ivermectin is a widely used drug for the treatment and control of certain neglected tropical 
diseases (NTDs). The drug has an excellent safety profile, with more than 2.5 billion doses 
distributed in the last 30 years [8]. There are two possible mechanisms by which ivermectin 
could be useful against COVID-19. 
Firstly, ivermectin inhibits the in vitro replication of several similar positive, single-stranded RNA 
viruses that cause disease in humans and animals, such as dengue (DENV) [9-11], Zika [10, 12] 
and yellow fever [13, 14], West Nile [10], chikungunya [13], Venezuelan equine encephalitis [15], 
Semliki Forest virus [13], Sindbis virus [13], porcine reproductive and respiratory syndrome virus 
[16] and recently SARS-CoV-2 [17]. 
This inhibition has been observed in an in vitro system with Vero cells at micromolar 
concentrations of ivermectin (2.5 uM in SARS-CoV-2 and 17-25 uM in DENV).  Mastrangelo et al 
showed that inhibition of DENV NS-3 helicase, an enzyme responsible for unwinding flavivirus 
dsRNA, occurs at concentrations of 0.5 uM in DENV [14]. No such data yet exists for SARS-CoV-
2. While micromolar concentrations are not achievable using approved doses, ivermectin may 
still be druggable if NS-3 helicase data are any indication.  
Strikingly, a clinical trial in Thai Dengue patients showed a reduction in circulating molecular 
markers following three consecutive daily administrations of ivermectin 400 ug/kg [18]. This 
cannot be explained by the concentrations obtained from the Vero cell in vitro system. If Vero 
cells offer any quantitative guidance on ivermectin effect, it would actually give reason to expect 
a stronger effect in SARS-CoV-2 than in DENV. It is therefore conceivable  that a microbiological 
or clinical effect in vivo may be seen with a single dose of 400 mcg/kg (dose included in the 
European Union, EU, Drug Factsheet), also given the three-fold levels achieved in pulmonary 
tissue respective to plasma one week after oral administration [19, 20], the adjuvant role of the 
immune response and the potential impact of active ivermectin metabolites [20].  
However, this trial did not demonstrate a clinical effect, probably because of the long 15-day 
incubation period of dengue fever, which allows much of the viral replication to occur before 
the onset of symptoms and treatment with ivermectin.  
Second, ivermectin has been shown to have immunomodulatory effects by decreasing TNFa 
production in vitro [21, 22] and in vivo [21], IL-1 production in vitro [21, 22] and in vivo [21], and 
IL-10 production in vitro [22]. In addition, ivermectin may also act on T cells by increasing surface 
receptors in vivo [23]. 
For this trial we propose to test the use of ivermectin, a safe anti-parasitic drug with broad-
spectrum antiviral activity and immunomodulatory properties, against a disease classified as a 
global public health emergency and for which there is no proven treatment.  
We propose a first pilot trial at the Clínica Universidad de Navarra. The trial will use a dose of 
ivermectin included in its EU drug specification in a population of patients with mild disease and 
no risk factors for progression to severe disease. The results of this trial could be available as 
soon as one month after completion of recruitment. In case the trial results are positive and viral 


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transport is reduced at day 7 post-treatment, it could be used in the short term to reduce 
transmission at community level.  
2.1. Investigational drug 
The product under investigation is ivermectin in 3mg tablets manufactured by Merck under the 
name Stromectol®. 
The human ivermectin regimen proposed for SAINT is a single dose of 400 mcg/kg at the 
enrolment visit. Note that this dose is included in the European Medicines Agency (EMA) 
approved ivermectin label for the Merck product (Stromectol®) in the Netherlands and France, 
and for the InfectoPharm product (Scabioral®) in Germany.  
The dose will be administered using scales at the site for tailored administration. Given that 
dosing is limited by the size of the tablet (3mg) the participants will receive a discrete number 
of tablets according to their weight band as shown in Table 1. The individual dose will range 
from 400 mcg/kg to a maximum of 457 mcg/kg. See annex 2 for a full color-coded table.  
 
Weight 
in kg 
Number of 
3 mg tablets 
Total 
dose in 
mg 
Dose range 
45 
6 
18 
400 
46-52 
7 
21 
404-457 
53-60 
8 
24 
400-453 
61-67 
9 
27 
403-443 
68-75 
10 
30 
400-441 
76-82 
11 
33 
402-434 
83-90 
12 
36 
400-434 
91-97 
13 
39 
402-429 
98-100 
14 
42 
420-429 
Table 1. Discrete doses based on table size and weight. 
 
The ivermectin dose chosen for the SAINT trial is included in the EU approved label of Stromectol 
[24] and Scabioral [25]. The only difference in the ivermectin administration for this trial is the 
evaluation of the drug’s activity against SARS-CoV-2, an unknown indication, rather that the 
direct treatment of other infections for which ivermectin is active.  
 
The elimination of ivermectin is biliary and via metabolic processes, presumably by Cytochrome 
𝑃450 3A4 (CYP3A4). In healthy volunteers, the reported half-life after oral administration ranged 
between 12 and 36 hours. This may increase for up to 54 hours in onchocerciasis patients [26]. 
In addition, it is conceivable that elimination is prolonged when the relevant metabolic pathways 
are inhibited, such as with co-administration of CYP3A4 inhibitors such as ritonavir (this is 
incorporated into exclusion criteria). 
 


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The ivermectin label has been modified extensively over 30 years of use for treatment and for 
public health campaigns. The FDA-approved ivermectin dosing regimen for onchocerciasis MDA 
is 150-200 mcg/kg (every 12 months), although the possibility of quarterly use in individual 
patients is also included in the label [27]. For moderate to severe crusted scabies, three doses 
of 200 mcg/kg within two weeks are recommended in the Australian label [28]. 
The main PK parameters of the dose and regimen proposed dose for SAINT are compared with 
actual or modelled parameters for the currently label-approved doses of ivermectin in Table 2.  
See Appendix 1 for a table summarizing trials where ivermectin 400mcg/kg was used.  
 
Table 2. Main PK parameters of the ivermectin dose proposed for SAINT as compared with the same 
parameters for currently approved doses for other indications. PK model by Hammann. All parameters in 
median [range]. Cmax: ng/ml, AUC ng·h/ml, Tmax: hours 
 
At least six published trials have administered ivermectin at doses above 400 mcg/kg. Table 3 
summarizes the available data from those trials. These encompass 2,662 independent 
administrations of cumulative 800 mcg/kg within one week and 2,103 independent 
administration at 800 mcg/kg (single dose). Only Kamgno [30] and Smit et al [31] report side 
effects associated with the drug administered at this high doses. Side effects consisted of mild, 
transient (hours) visual disturbances without eye structural changes. 
 
SAINT 
400 mcg/kg single 
dose 
Onchocerciasis 
150-200 mcg/kg single 
[29] 
Moderate to severe scabies 
200 mcg/kg, 3 doses within 2 
weeks [modelled] 
Cmax 
63.8 
[44- 88.5] 
38 
[35 - 41] 
38.3 
[27.8 - 52.1] 
AUC 
2353 
[1313-4169] 
1032 
[874-1210] 
3532 
[1970 – 6266] 
Tmax 
5.3 
[3.9 – 7] 
5.6 
29 
[27.8 - 30.3] 


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Ref 
Highest 
single 
dose 
Max. freq. 
Max. 
number 
of doses 
Maximum 
total dose 
(period) 
Population 
Sample by dose 
AEs 
Awadzi et 
al 1995 
[32] 
 
800 
mcg/kg 
Single 
Single 
800 mcg/kg 
(once) 
Males with 
moderate to 
heavy 
Onchocerca 
infection 
600 mcg/kg x 1:  24 patients 
800 mcg/kg x 1:  17 patients 
No difference with controls taking the 150 mcg/kg dose 
Awadzi et 
al 1999 
[33] 
800 
mcg/kg 
Days 
1 and 4 
2 
1.600 mcg/kg 
(4 days) 
Adult males 
infected with 
Onchocerca 
400-550 mcg/kg x 2: 25 patients 
600-750 mcg/kg x 2: 23 patients 
800-950 mcg/kg x 2: 24 patients 
1600       mcg/kg x 2: 12 patients 
No difference with controls taking the 150 mcg/kg dose 
Guzzo et 
al 2002 
[34] 
2.000 
mcg/kg 
Days 
1, 4 and 7 
3 
3.273 mcg/kg 
(one 
week) 
68 male and 
female healthy, 
adult 
volunteers 
347-594     mcg/kg x 3: 15 volunteers 
713-1091   mcg/kg x 3: 12 volunteers 
1031-1466 mcg/kg x 1: 12 volunteers 
1404-2000 mcg/kg x 1: 12 volunteers 
347-541      mcg/kg x 1 (fed): 11 volunteers 
No difference with controls 
Kamgno 
et al 
2002 
[30] 
800 
mcg/kg 3-monthly 
13 
8.950 mcg/kg 
(3 years) 
657 adult 
males infected 
with 
Onchocerca 
150 mcg/kg yearly: 166 participants 
400 then 800 mcg-kg yearly: 161 participants 
150 mcg/kg 3-monthly: 161 participants 
400 then 800 mcg-kg 3-monthly: 158 
participants 
The high dose group reported a statistically higher rate of 
transitory mild and subjective visual side effects. 
(No structural explanation). 
For all other AE comparable rates reported in all groups. 
Munoz 
et al 2018 
[35] 
705 
mcg/kg 
(single 
36 mg 
dose) 
Single 
Single 
705 mcg/kg 
(once) 
54 male and 
female healthy 
adult 
volunteers 
276-352 mcg/kg x 1: 18 volunteers 
227-272 mcg/kg x 1: 19 volunteers 
157-225 mcg/kg x 1: 20 volunteers 
553-705 mcg/kg x 1: 18 volunteers 
455-545 mcg/kg x 1: 19 volunteers 
315-450 mcg/kg x 1: 20 volunteers 
No significant difference compared to weight-adjusted 
dose of 200 mcg/kg 
Smit 
et al 2018 
[31] 
600 
mcg/kg 
Days 1, 2 
and 3 
3 
1.800 mcg/kg 
(3 days) 
141 male and 
female adults 
with 
uncomplicated 
malaria 
300 mcg/kg x 3: 48 participants 
600 mcg/kg x 3: 47 participants 
No difference in SAE. Ivermectin 600 x 3 had 15% more 
AEs predominantly reflecting transient minor visual 
disturbances. One case of anaphylaxis was reported in the 
trial 
Table 3. Ivermectin studies assessing the safety of doses above 400 mcg/kg 


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Adverse reactions 
All data in this section is taken from the FDA-approved Merck Stromectrol® 2009 label [27]. 
When ivermectin is used in patients with strongyloidiasis (dose of 200 mcg/kg) the following 
side effects classified by body system have been described: 
 
Body as a Whole: Asthenia/fatigue (0.9%), abdominal pain (0.9%) 
 
Gastrointestinal: anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea (1.8%), 
vomiting (0.9%) 
 
Nervous System/Psychiatric: dizziness (2.8%), somnolence (0.9%), vertigo (0.9%), tremor 
(0.9%) 
 
Skin: pruritus (2.8%), rash (0.9%), and urticaria (0.9%). 
When ivermectin is used in patients with onchocerciasis (dose 150-200 mcg/kg) the following 
side effects have been described (note this disease is not endemic in Spain): 
 
Mazzoti reactions during the first 4 days after treatment including arthralgia/synovitis 
(9.3%), lymph node enlargement or tenderness (up to 13.9%), pruritus (27.5%), urticarial 
rash (22.7%) and fever (22.6) 
 
Worsening of pre-existing ophthalmological conditions: limbitis (5.5%), punctate opacity 
(1.8%).  
 
Additionally, the following clinical adverse reactions were reported as possibly, probably, or 
definitely related to the drug in ≥1% of the patients: facial edema (1.2%), peripheral edema 
(3.2%), orthostatic hypotension (1.1%), and tachycardia (3.5%). Drug-related headache and 
myalgia occurred in <1% of patients (0.2% and 0.4%, respectively).  
Note these side effects have been associated with parasite lysis rather with ivermectin itself. 
In patients receiving cumulative doses above 800 mcg/kg in a week, unspecific, mild (not 
impeding daily activities), transient (lasting less than 24 hours), visual disturbances (blurred 
vision, tunnel vision) have been described. When ivermectin is used in patients with 
concomitant Loa with high parasite burden (> 15.000 mf/ml) the following side effects have 
been described in relationship with rapid parasite lysis: 
 
Encephalopathy in 0.01-0.11% of the treated population [36] 
 
The syndrome includes confusion, lethargy and coma 
 
This disease is not endemic in Spain. Note that travel to Loa loa endemic areas is an exclusion 
criterion for SAINT. 
Laboratory test findings reported as possibly, probably or definitely associated with ivermectin: 
 
Elevation in liver enzymes (ALT and/or AST) (2%) 
 
Decrease in leukocyte count (3%).  
 
Leukopenia and anemia (<1%). 
 


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The following adverse reactions have been reported since FDA marketing authorization: 
 
Hypotension (mainly orthostatic hypotension) 
 
Worsening of bronchial asthma 
 
Toxic epidermal necrolysis 
 
Stevens-Johnson syndrome 
 
Seizures 
 
Hepatitis 
 
Elevation of liver enzymes 
 
Elevation of bilirubin 
Pregnancy 
Information from the Stromectol® label [27]. 
At high doses, well above (ranging from 10-80 fold human therapeutic doses and regimens), 
ivermectin is a known teratogen in mammals and is classified by FDA as a category C drug (these 
categories are no longer in use, as FDA now recommends considering risk/benefit on an 
individual basis). During onchocerciasis MDA campaigns with lower dose within the EMA label, 
visually pregnant women are excluded but no formal testing is routinely performed on women 
of childbearing age. There are several reports of inadvertent treatment during pregnancy, a 
recent metanalysis by Nicolas et al [37] analyzed data from 893 inadvertently exposed 
pregnancies (97 in the first trimester) and concluded there is insufficient evidence to understand 
the safety of ivermectin during pregnancy.  
Note that pregnancy is an exclusion criterion for SAINT. 
Dose justification 
SAINT is proposed as a proof of concept pilot trial. Ivermectin has proven antiviral and 
immunomodulatory activity. There is uncertainty as whether the immunomodulatory effect 
could increase symptoms. The study has been designed to maximize safety. 
 
The 400 mcg/kg single dose scheme will result in full excretion in 5-7 days. This manages risks 
related to immunomodulation. The participants will only include those with non-severe disease 
and no risk factors for severity.  
 
By treating patients within 72 hours of symptoms we aim at reducing early viral replication and 
improving the potential efficacy of ivermectin. The primary outcome measure is microbiological 
which makes assessment objective. Secondary objectives including surrogates of viral load and 
assessment of the immune response will reduce the risk type II error and ensure appropriate 
evaluation of a drug with potential beneficial effects. 
 
Placebo 
The placebo will not be visibly identical, but will be administered by a researcher not involved in 
the clinical care or participant follow up, helping secure the blind. Placebo is an acceptable 
control for this trial as there is currently no approved drug for the treatment of SARS-CoV-2, and 


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the efficacy of ivermectin is to be determined. Placebo tablets will be supplied by Idifarma, and 
manufactered under GMP. 
 
Other drugs allowed 
Supportive measures such as use of antipyretics and hydration as long as they do not interfere 
with exclusion criteria. Participants may continue to take any drugs and non-pharmacological 
therapies that are not on the excluded list for the trial 
 
2.2. Disease under study 
COVID-19 is the disease caused by infection with SARS-CoV-2, currently classified as a pandemic 
that can cause severe hyperinflamatory state associated with pneumonia, respiratory and multi-
organ failure, particularly in patients over 60 years of age and with comorbidities. There is 
currently no specific treatment for COVID-19. 
 
The population for the study will be patients with a positive nasopharyngeal swab PCR test for 
SARS-CoV-2, with non-severe COVID-19 disease and no risk factors for progression to severity 
(see exclusion criteria). Vulnerable populations such as pregnant women, minors (i.e.; under 18 
years old), and seniors (i.e.; over 60 years old) will be excluded.  
 
The control group will receive placebo. There is no current data on the efficacy of ivermectin 
against the virus in vivo, so the use of placebo in the control group is ethically justified. 
Participants of the study will have non-complicated COVID-19 disease and will not have risk 
factors to develop severe disease so they would not be receiving any alternative treatment for 
the disease.  
2.3. Evaluation of benefit/risk ratio for the participants in the clinical trial 
Ivermectin has a well-documented safety profile at the proposed dose and the potential 
immunomodulatory and antiviral activity of ivermectin against SARS-CoV-2, outweighs the risk 
of drug-related adverse events. It is possible, though, that participants will not obtain a direct 
benefit from taking ivermectin.  
2.4. References from literature 
See section 14 for all references 
3. 
OBJECTIVES OF TRIAL  
3.1 Main objective  
To determine the efficacy of a single dose of ivermectin, administered to low risk, non-severe 
COVID-19 patients in the first 72 hours after symptoms onset to reduce the proportion of 
patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day seven post-
treatment. 
 


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Primary outcome measure 
Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 
post-treatment 
3.2 Secondary objectives 
1. To assess the efficacy of ivermectin to reduce the SARS-CoV-2 viral load in the 
nasopharyngeal swab at day seven post treatment 
2. To assess the efficacy of ivermectin to improve symptom progression in treated patients 
3. To assess the proportion of seroconversions at day 21 post-treatment in treated patients 
4. To assess the safety of ivermectin at the proposed dose 
5. To determine the magnitude of immune response against SARS-CoV-2  
6. To assess the early kinetics of immunity against SARS-CoV-2 
 
Secondary outcome measures 
1. Mean viral load as determined by PCR cycle threshold (Ct) at baseline and on days 4, 7, 14 
and 21 post-treatment 
2. Proportion of patients with fever and cough at days 4, 7, 14 and 21 post-treatment as well 
as proportion of patients progressing to severe disease or death during the trial 
3. Proportion of patients with seroconversion at day 21 post-treatment 
4. Proportion of drug-related adverse events  
5. Levels of IgG, IgM, IgA measured by Luminex, frequencies of innate and SARS-CoV-2-specific 
T cells assessed by flow cytometry, levels of inflammatory and activation markers measured 
by Luminex and transcriptomics. 
6. Kinetics of IgG, IgM, IgA levels till day 28 post-treatment 
4. 
DESIGN OF TRIAL 
The SAINT trial is a double-blind, randomized controlled trial with two parallel groups that 
evaluates the efficacy of ivermectin in reducing nasal viral carriage at seven days after treatment 
in SARS-CoV-2 infected patients who are at low risk of progression to severe disease. The trial is 
currently planned at a single center in Navarra. 
 
4.1. Global design 
Participants will be randomized to receive a single dose of 400 mcg/kg ivermectin or a placebo 
equivalent. The randomization code will be generated by the trial statistician using blocks that 
ensure balance between the groups.  
The allocation will be made by the investigator using opaque envelopes, after obtaining 
informed consent (note that this might be done verbally during the screening and paper forms 


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will only be signed after a negative PCR), and confirmation of fulfillment of all inclusion and none 
of the exclusion criteria. The investigational product will be administered by a researcher not 
involved in patient care or participant follow up.  
Participants will remain in the trial for a period of 28 days.  
Trial visits will be conducted either at the COVID-19 department of the Clínica Universidad de 
Navarra or in the participant's home. 
Subsequent visits will be to assess clinical and laboratory parameters. 
A final study visit will be made for participants who withdraw prematurely from the study or are 
withdrawn by the investigator.  A summary of the study visits and procedures is provided in 
Table 4 below.  
 
Table 4. Visit procedures 
 
Serious adverse events related to ivermectin will be followed until resolved or 30 days after the 
participant's final visit, whichever occurs first.  All other serious adverse events will be followed 
through to the participant's final visit or for a specified period at the investigator's discretion. 
 
Recruitment 
Day 0 
Visit 2 
Day 4 post treatment 
Visit 3 
Day 7 post treatment 
Visit 4 
Day 14 post treatm. 
Visit 5 
Day 21 post treatm. 
Final visit   
Day 28 post treatm. 
Informed consent# 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Clinical data collection 
X 
X 
X 
X 
  X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
Laboratory test* 
X 
 
X 
X 
 
 
Urine pregnancy test 
X 
 
 
 
 
 
Nasopharyngeal swab (PCR for SARS-CoV-2) 
X 
X 
X 
X 
X 
 
Serology for SARS-CoV-2 
X 
X 
X 
X 
X 
X 
Proinflammatory and activation markers 
X 
X 
X 
X 
X 
X 
Cell responses (PBMC) 
X 
 
X 
 
 
X 
Chest x-ray 
X 
 
 
 
 
 
Administration of IP 
X 
 
 
 
 
 
Daily self-assessment of symptoms 
X-----------------------------------------X 
Evaluation of adverse events 
X-----------------------------------------X 
# verbal consent initially, in writing when isolation is concluded  
* C reactive protein, Procalcitonin, Ferritin, IL-6 
, Renal function: urea, creatinine, electrolytes, FBC,    
   Troponin T, CPK, DD, LDH  


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The study shall end when the final randomized patient has completed the study, all the planned 
visits have been carried out and any inconsistencies have been resolved. 
A patient (or their family or legal representative) may interrupt their participation in the study 
at any time and for whatever reason. The principal investigator may also withdraw a patient 
from the study if he/she considers that it is in the best interest of the patient. 
5. 
SELECTION OF STUDY SUBJECTS  
5.1. Inclusion criteria 
1. Patients diagnosed with COVID-19 in the emergency room of the Clínica Universidad de 
Navarra with a positive SARS-CoV-2 PCR. 
2. Residents of the Pamplona basin (“Cuenca de Pamplona”) 
3. The patient should be between the ages of 18 and 60 years of age 
4. Negative pregnancy test for women of child bearing age* 
5. The patient or his/her representative, have given consent to participate in the study. 
6. The patient should, in the investigator's opinion, be able to comply with all the 
requirements of the clinical trial. 
5.2. Exclusion criteria 
1. Known history of Ivermectin allergy 
2. Hypersensitivity to any component of Stromectol® 
3. COVID-19 Pneumonia 
 
Diagnosed by the attending physician 
 
Identified in a chest X-ray 
4. Fever or cough present for more than 72 hours 
5. Positive IgG against SARS-CoV-2 by rapid test 
6. Age under 18 or over 60 years 
7. The following co-morbidities (or any other disease that might interfere with the study in 
the eyes of the investigator): 
 
Immunosuppression  
 
Chronic Obstructive Pulmonary Disease 


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 
Diabetes 
 
Hypertension 
 
Obesity 
 
Acute or chronic renal failure 
 
History of coronary disease 
 
History of cerebrovascular disease 
 
Current neoplasm 
8. Recent travel history to countries that are endemic for Loa loa (Angola, Cameroon, Central 
African Republic, Chad, Democratic Republic of Congo, Ethiopia, Equatorial, Guinea, 
Gabon, Republic of Congo, Nigeria and Sudan) 
9. Current use of CYP 3A4 or P-gp inhibitor drugs such as quinidine, amiodarone, diltiazem, 
spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, 
cyclosporine, tacrolimus, indinavir, ritonavir or cobicistat. Use of critical CYP3A4 substrate 
drugs such as warfarin. 
*Women of child bearing age may participate if they use a safe contraceptive method for the 
entire period of the study and at least one month afterwards. A woman is considered to not 
have childbearing capacity if she is post-menopausal (minimum of 2 years without 
menstruation) or has undergone surgical sterilization (at least one month before the study). 
5.3. Criteria for withdrawal 
Patients will be informed that they may be withdrawn from the study at any time without 
providing any explanation. Withdrawal may also take place for any of the following reasons:  
 
Adverse reaction that puts the patient's life at risk, according the principal investigator's 
judgment. 
 
Decision made by the patient or the legally authorized person. 
 
Documented progression of the disease requiring hospitalization in a different center. 
 
The patient cannot complete the trial visits due to unforeseen circumstances. 
 
Development of other disorders that, in the opinion of the investigator and in the patient's 
best interest, make it advisable for him/her to leave the study. 
 
Administration of treatment with a non-permitted drug. 
 
The investigator believes that the patient may benefit from a different treatment. 
 
Loss of monitoring  
The investigator shall strive to ensure that the patient agrees to the final trial visit. The data of 
the withdrawn patients shall be collected up to this final visit. If the withdrawal is the outcome 
of a Serious adverse event related to ivermectin or SARS-CoV-2, the data shall be collected until 
the patient recovers or stabilizes.  


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The subjects shall be replaced if the withdrawal is for a reason different from lack of efficacy of 
the treatment or appearance of adverse events. All efforts will be made to maintain the total 
number of assessable patients as per the protocol.  
The withdrawal shall be documented in the patient's clinical history, giving the reasons for the 
decision. A final trial visit should be conducted by the clinical team if possible.  
6. 
DESCRIPTION OF TRIAL TREATMENT 
6.1. Method of treatment assignment 
This is a single center, randomized, double-blind clinical trial with two parallel groups that 
evaluates the efficacy of ivermectin in reducing nasal viral carriage at seven days after treatment 
in SARS-CoV-2 infected patients who are at low risk of progression to severe disease.   
Eligible patients shall be enrolled in the study under the supervision of the investigator or 
designated sub-investigators. 
Participants will be randomized to receive a single 400 mcg/kg oral dose of ivermectin or a 
placebo equivalent.  The person administering the drug will observe the participant take it under 
directly observed treatment (DOT). The placebo will not match ivermectin in appearance. The 
clinical team will remain blinded to the treatment received by all participants. 
6.2 Pharmaceutical information 
The investigator shall take responsibility for and take all steps to maintain appropriate records 
and ensure appropriate supply, handling, storage, distribution, and usage of these materials in 
accordance with the protocol and any applicable laws and regulations. Please refer to Table 5 
for ivermectin pharmaceutical information. 
 
 
Ivermectin (STROMECTOL®) 
Dose formulation 
Tablets 
White, round, flat tablet with a beveled edge, engraved with MSD on 
one side and 32 on the other side. 
Unit dose strength(s) 
400mcg /kg 
Route of administration 
Oral. Ivermectin will administered as a single oral dose. 
Storage 
Below 30°C 
Packaging and labeling 
As required per country requirement according to Annex 13 of GMP. 
Dosing instructions(a): 
The IP will be administered in accordance with the labeling instructions 
of a single dose of 400mcg /kg following the discrete dosing described in 
table 1. 


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List of excipients 
Microcrystalline cellulose 
Pregelatinized starch 
Magnesium stearate 
Butylated hydroxyanisole 
Citric acid powder (anhydrous). 
Incompatibilities 
Very rarely, post-marketing reports of increased INR (International 
Normalised Ratio) have been reported when ivermectin was co-
administered with warfarin. Please refer to exclusion criteria and table 6. 
Label example 
 
 
Manufacturer/ Source of 
Procurement: 
Manufacturer : Merck Sharp & Dohme BV Waarderweg 39 2031 BN 
Haarlem Netherlands  
Source of Procurement: MSD France 
The tablets are packaged in aluminum foil blister packs in cardboard 
cartons. Pack size: 4 tablets. 
Table 5 Ivermectin (STROMECTOL®) pharmaceutical information  
 (a) The Pharmacist or Delegate will prepare the treatment dose required for each patient, 
according to body weight (400 μg/kg). The Pharmacist or qualified designee completes on site’s 
electronic system. Individual treatment dose is prepared in the dedicated facilities of the 
pharmacy department by the Pharmacist or designee at a workstation free from unrelated items 
and in aseptic conditions, as per local rules. Safety measures for preparation and handling 
include protective clothing, gloves, and the use of safety cabinets. 
6.3. Drug Identity 
The following information has been taken from the Stromectrol® package insert. 
Ivermectin is a semisynthetic, antihelmintic agent derived from the soil bacterium Streptomyces 
avermitilis. Ivermectin is the mixture of 22,23-dihydro-avermectin B1a (at least 90%) and 22,23-
dihydro-avermectin B1b (less than 10%). 
Ivermectin is a member of the avermectin class of broad-spectrum antiparasitic agents which 
have a unique mode of action. Compounds of the class bind selectively and with high affinity to 
glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This 
IVERMECTINA/PLACEBO 3 mg 
____COMPRIMIDOS 
C. Estudio: SAINT 
Caducidad:__________ Lote:_______ 
SUJETO xxxxxxxx                Vía oral 
Promotor: CUN     Conservar 15 a 25ºC 
Investigador: Dr. Chaccour 
USO EXCLUSIVO ENSAYO CLÍNICO 


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leads to an increase in the permeability of the cell membrane to chloride ions with 
hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. 
Compounds of this class may also interact with other ligand-gated chloride channels, such as 
those gated by the neurotransmitter gamma-aminobutyric acid (GABA). 
The selective activity of compounds of this class is attributable to the facts that some mammals 
do not have glutamate-gated chloride channels and that the avermectins have a low affinity for 
mammalian GABA-gated chloride channels. In addition, ivermectin does not readily cross the 
intact blood-brain barrier in humans. 
6.4. Potential Risks 
Please refer to section 2.1 
6.5. Administration 
Treatment will be administered in the designated area for COVID-19 patients. 6.6. 
Packaging and Labeling 
Experimental drugs will be supplied by the Department of Pharmacy of the Clínica Universidad 
de Navarra packaged and labeled according to the standard requirements for clinical trials. 
Investigational products will be packaged according to the participants’ weight (table1). They 
will be manually introduced in opaque flasks by the study pharmacist. The study medication will 
be labelled in accordance with annex 13 of the European Good Manufacturing Practices. 
Each flask will be clearly marked with the following information:  
 
Investigational site study code / Sponsor study code:    
 
Product code: 
 
Route of administration: For oral administration  
 
Treatment No: XXXXXXX  
 
Patient number: 
 
Theoretical day and time of administration: 
 
Preparation Date and Time:   
 
Dose: XXX unit (g, mg, ml…)  
 
Number of units:  XXX tablets  
 
For clinical trial use only  
 
Storage conditions: below 30 °C 
 


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6.7. Handling and Storage 
Ivermectin and placebo will be received at the Pharmacy department following local regulation, 
with receipt acknowledged by signing the receipt confirmation list that will be filed at site 
pharmacy file. Lot, batch and manufacturer information of the investigational product will be 
recorded in the pharmacy records. 
All study treatment supplies must be stored in accordance with the manufacturer’s instructions 
and package labeling. Until dispensed to the participants, the study treatment will be stored in 
a securely locked area, accessible to authorized personnel only.  All study interventions must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
Upon receipt, ivermectin as well as placebo tablets will be stored under 30°C. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
If a temperature excursion occurs:  
• The affected products will be placed in quarantine immediately with a clear sign of 
“quarantined” and clearly separated from the rest of the supplies. In addition, the affected 
products will be stored under proper conditions as per storage requirements.   
• The Site Monitor will be informed about the temperature excursion within the same business 
day. 
6.8. Dispensing 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. The investigator agrees that study drug will 
be dispensed by the investigator or sub-investigator(s) named on the Investigator Agreement or 
their qualified designees. The investigator, sub-investigators, or qualified designees also agree 
that the study drug(s) will be dispensed only to study subjects who have provided informed 
consent and have met all entry criteria and in accordance with the instructions provided in the 
storage and handling manual.  
The investigational product dispensation is not managed by IVRS/IWRS. The treatment 
allocation for ivermectin/placebo will be recorded on site using an electronic system. 


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6.9. Accountability 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
The Investigator or designee is responsible for maintaining accurate dispensing records of the 
study treatment throughout the clinical study. The study treatment accountability log includes 
information including investigational product, number of assigned vials, of IMP used, batch and 
expiration date of such tablets, dose, patient’s identification, quantity of tablets dispensed, 
person responsible for the accountability register.  
Site accountability electronic logs will be available for monitoring visits. All dispensing and 
accountability records should be stored in accordance to the Sponsor institution regulations.  
An accurate accountability record of products received and dispensed, or destroyed by the 
pharmacy at the investigator site will be maintained on pharmacy file and electronic system. 
 
6.10. Study Intervention Compliance 
Participants will receive study intervention directly from a designated nurse. The date and time 
of each dose administered in the clinic will be recorded in the source documents and reported 
in the case report form (CRF).  
Ivermectin or placebo tablets will be taken orally at the site.  
 
6.11. Disposal and Destruction 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. Approvals for drug destruction at site will be filed in the pharmacy folder in 
addition to the Certificate of Destruction according to the destruction policy that is in place 
6.12. Concomitant Therapy/Devices  
Any important concomitant medication that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose and frequency 


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The Medical Monitor should be contacted if there are any questions regarding concomitant 
therapy. 
Drugs or treatments that are permitted (including rescue medication) and not permitted 
before and/or during the trial 
Participants may continue to take any drugs and non-pharmacological therapies that are not 
on the excluded drug list for the trial. 
Treatment with inhibitors of CYP3A or the P-gp or other drugs that can interfere with the study 
drug is an exclusion criterion. See table 6 for details. 
 
Class 
Drug 
Rationale 
Antiarrhytmic/ 
Antihypertensive 
Quinidine 
May increase ivermectin exposure by inhibiting its 
metabolism and excretion or competing with CYPs 
or the P-gp. 
Amiodarone 
Diltiazem 
Spironolactone 
Verapamil 
Antibiotic- Macrolides 
Clarithromycin 
Erythromycin 
Antifungal agents 
Itraconazole 
Ketoconazole 
Inmunosupressants 
Cyclosporine 
Tacrolimus 
Anti HIV therapy 
Indinavir 
Ritonavir 
Cobicistat 
Anticoagulant 
Warfarin 
Steroids 
Dexamethasone 
Table 6 Concurrent treatment used as exclusion criteria 
 
6.13. Dose Escalation 
Not applicable. One single dose will be administered. 
6.14. Dose Modification and Delay 
 Not applicable. One single dose will be administered. 
6.15. Dose-Limiting Toxicity 
Not applicable. One single dose will be administered. 


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6.16. Overdose 
In the event of an overdose, the patient should be closely monitored, treated symptomatically, 
and supportive measures instituted as required. 
6.17. Treatment Discontinuation 
Not applicable. One single dose will be administered. 
6.18. Maintenance of the randomization codes and the procedures for opening  
On occasion, and where an SAE is deemed to be unexpected, related and life threatening at 
the time, the investigator may ask the Sponsor for unblinding of that participant to identify the 
treatment received in relation to the SUSAR experienced by the participant. Unblinded 
participants will be withdrawn from the study and followed through to study end.  
Regulatory Authorities and institutional ethics committees will receive unblinded Council for 
International Organizations of Medical Sciences (CIOMS 1) reports from the trial.  
Before the trial begins, the sponsor will assign named independent individuals to code break 
activity to avoid introducing any bias for the designated safety physician, clinical team, sponsor 
and statistician teams.   
Procedures for code breaking at the end of study 
a. Unblinding of the study can only occur after all participants have completed the final visit 
and the database has been cleaned and locked. 
b. The coordinating investigator documents the date of the last trial visit and the data lock. 
c. The coordinating investigator gives approval for the statistician to break the code and 
documents the breaking of the code in the study folder 
d. The coordinating investigator informs the PI of the treatment status of each group only 
after all the data analysis is complete.   
7. 
EVALUATION OF RESPONSE 
7.1. Study plan and procedures 
7.1.1. Obtaining consent 
During this SARS-CoV-2 pandemic period, documented verbal consent in lieu of patient 
signature should be obtained. Once the entire study is explained, a verbally informed consent 
shall be obtained from the patient before their participation in the study may be made effective. 
Investigator must fully inform the patient of what they are consenting to, and must document 
consent was verbally received. 


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Subsequent efforts will be made to ratify the written consent or to obtain a written informed 
consent from their relatives or representative.  
The method used to obtain and document the informed consent and the contents of same 
should comply with the EMA recommendations: “Guidance on the Management of Clinical Trials 
during the COVID-19 (Coronavirus) pandemic Version 2 (27/03/2020)” [38].  
Part of the process of the informed consent consists of clearly explaining the purposes, methods, 
objectives and risks of the study to the patient, their family or legal representative. A copy of 
the informed consent, also signed by the investigator, will be kept with the clinical 
documentation. Another copy will be given to the patient. 
The attending physician will record the patient's consent to participate in the study in his/her 
clinical documentation.  
7.1.2. Screening, enrollment and first visit 
Once the informed consent process has been completed, the information required for the trial 
may be obtained, and the evaluations to confirm trial inclusion and exclusion criteria conducted. 
At this visit the following procedures will take place: 
 
Appropriately trained and delegated trial staff will explain the study objectives, methods 
and procedures to patients who will be invited to participate in the study. The trial staff will 
explain the inclusion and exclusion criteria and offer to answer questions as part of the 
informed consent process.  
 
During the consent procedure, women of child-bearing age will be informed of the hazards 
to an unborn child and will be asked about the current contraceptive method they are using.  
They will be informed that if their pregnancy test is positive, they cannot participate in the 
trial. 
 
A site visit template containing visit related questions will be completed by the trial staff as 
it is answered by each participant   
 
Trial staff will document the participant’s medical history and all concomitant medication to 
confirm eligibility to participate in the trial 
 
A urine-based pregnancy test will be administered to all women of child bearing age 
 
Participants will be given a chest x-ray to rule out pneumonia. 
 
Eligible participants will be randomized to the trial and allocated a Participant Identification 
Number (PIN). 
 
The trial staff will perform a physical examination including anthropometric assessment. 


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 
Approximately 20ml of blood will be drawn to record baseline laboratory values for C 
reactive protein, Procalcitonin, Renal function: urea, creatinine, electrolytes, FBC, Troponin 
T, CPK, DD, LDH. 
 
Approximately 4mL of blood will be drawn for serological assays and assess proinflammatory 
and activation markers. 
 
Approximately 10 mL of blood will be drawn for cellular assays. 
 
A nasopharyngeal swab will be taken to confirm the presence of SARS-CoV-2 RNA. 
 
A rapid serology test for SARS-CoV-2will be conducted to assess the current immune status. 
 
The investigational product will be administered following a weight-band table. Immediate 
tolerance will be monitored. 
 
A link to the trial website with a self-assessment questionnaire will be given to each 
participant with brief instructions for daily completion and an explanation of the review 
process with the clinical team at all subsequent trial visits. 
7.1.3. Subsequent trial visits 
Subsequent visits will be conducted at the COVID-19 department of the Clínica Universidad de 
Navarra or at the participant´s home until obtaining a negative PCR in the nasopharyngeal swab 
after which the patient may attend te conventional ambulatory clinic. 
In SAINT, patients will self-monitor symptoms daily. A study physician will visit the participants 
five times during the trial to assess symptoms and potential side effects as well as to perform a 
physical examination. 
At the trial visits on post-treatment days 4, 7, 14 and 21: 
 
The clinical trial team will confirm that the participant is still willing to participate in the trial. 
 
A member of the clinical trial team will ask the participant about symptoms progression and 
document the information in the visit template. 
 
A member of the clinical trial team will review the information that the participant has 
recorded in the daily online self-assessment with the participant and ask whether the 
participant has taken any medication or sought healthcare since the last trial visit. 
 
The trial staff will perform a physical examination.  
 
A nasopharyngeal swab will be taken to confirm the presence of SARS-CoV-2 RNA. 
 
A serology test for SARS-CoV-2 will be conducted to assess the current immune status. 


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 
4mL of blood will be drawn for serological assays and assess proinflammatory and activation 
markers. 
Additional procedure at the trial visit on post-treatment days 7 and 14: 
 
A blood sample will be drawn to assess any changes in laboratory parameters since the 
recruitment visit 
Additional procedure at the trial visit on post-treatment days 7 and 28: 
 
10 mL of blood will be drawn for cellular assays. 
Final trial visit on post-treatment day 28: 
 
A member of the clinical trial team will ask the participant about symptoms progression and 
document the information in the visit template 
 
A member of the clinical trial team will review the information that the participant has 
recorded in the daily online self-assessment with the participant and ask whether the 
participant has taken any medication or sought healthcare since the last trial visit 
 
The trial staff will perform a physical examination 
 
A serology test for SARS-CoV-2 will be conducted to assess the current immune status 
 
4mL of blood will be drawn for serological assays and assess proinflammatory and activation 
markers. 
 
10 mL of blood will be drawn for cellular assays. 
 
7.2. Efficacy variables 
Primary 
Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 
post-treatment 
 
Secondary 
1. Mean viral load as determined by PCR cycle threshold (Ct) at enrollment and days 4, 7, 14 
and 21 post-treatment 
2. Proportion of patients with fever and cough at days 4, 7, 14 and 21 post-treatment 
3. Proportion of patients with seroconversion at day 21 post treatment 
4. Levels of IgG, IgM, IgA measured by Luminex, frequencies of innate and T cell responses 
assessed by flow cytometry, levels of inflammatory and activation markers measured by 
Luminex and transcriptomics. 


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5. Kinetics of IgG, IgM, IgA levels till day 28 post-treatment. 
8. 
SAFETY APPRAISAL 
All the adverse events reported by patients or observed by the investigating team shall be 
evaluated, including any clinically relevant analytical alterations. 
Any AE spontaneously referred by a patient or that appears as a result of the investigator's 
anamnesis shall be noted in the patient's clinical history, specifying the time it appeared, 
evolution, duration, intensity, therapy required and relation to the investigational drug.  
Common Terminology Criteria for Adverse Events (CTCAE 5.0) will be used. 
8.1. Definitions 
Adverse event: defined as any incident that is hazardous to the health of a patient or subject of 
a clinical trial treated with a drug, even when there is not necessarily a causal relationship with 
said therapy. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporarily associated with the use of an investigational drug, 
regardless of whether or not it is related to the investigational drug. 
Serious adverse event: defined as any adverse event or adverse reaction that, at any dose: 
 
Causes the death of the patient. 
 
Threatens the patient's life 
 
Requires the patient to be hospitalized or his/her hospitalization to be extended 
 
Causes permanent or major invalidity or incapacity  
 
Gives rise to a congenital abnormality or deformation 
For the purposes of notification, any suspicions of an adverse event or reaction regarded as 
potentially important from a medical point of view shall also be considered to be serious, even 
when they do not comply with the above criteria, including important medical events that 
require an intervention to prevent any of the above-mentioned consequences from taking place. 
Likewise, all suspicions of transmission of an infectious agent via a drug shall also be reported as 
serious events. 
 
Adverse reaction (AR)  
Any toxic and unintended reaction to an investigational drug is considered to be an adverse 
reaction, independently of the dose administered. 
Unlike an AE, there is a suspected causal relationship between the investigational drug and the 
adverse event. 


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The possible relationship with the therapy of the study shall be established in accordance with 
the following definitions: 
Relation 
Definition 
UNRELATED 
There is no evidence of any causal relationship. 
UNLIKELY 
There is little evidence to suggest a causal relationship (e.g. the 
event did not present in a reasonable time frame after the 
administration of the drug/procedure under study). There is 
another explanation for the event (e.g. the patient's clinical 
conditions, other concomitant therapies). 
POSSIBLE 
There is evidence that suggests a possible causal relationship (e.g. 
because the event took place in a reasonable time frame after 
administration of the investigational drug). However, the influence 
of other factors may have contributed to the event (e.g. the 
patient's clinical condition, other concomitant therapies). 
PROBABLE 
There is evidence that suggests a causal relationship and the 
influence of other factors is unlikely. 
CERTAIN 
There is clear evidence to suggest a causal relationship and a 
possible contribution from other factors can be dismissed. 
 
An adverse reaction should be considered as any adverse event that is possibly, probably or 
certainly linked to the therapy under study. 
The principal investigator of the research center or person appointed by same is responsible for 
establishing the possible relationship with the therapy under study. 
Unexpected and Serious Adverse Reaction (USAR) 
Any serious adverse reaction whose nature, intensity or consequences does not match the 
reference information for the drug (e.g. the Investigator's Brochure in the case of an 
unauthorized investigational drug or the Summary of Product Characteristics in the case of an 
authorized drug). 
The unexpected nature of an adverse reaction is based on the fact that it was not previously 
observed and shall not be based on what could be anticipated in view of the pharmacological 
properties of the drug. 
8.2. Recording and communicating adverse events 
All the reported adverse events shall be recorded, either spontaneously by the patients or during 
the interviews held with them in the study visits. The AE from when the patient received the 
first dose of the investigational drug until the end of his/her participation shall be collected. 


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The patient should be requested to give all the information about the AEs that took place in the 
time period between the previous visit and the current one. 
All the AE should be documented in the patient's clinical history and in the CRF. 
When the investigator considers an adverse event to be a serious one, he/she should 
immediately notify the sponsor as soon as he/she is aware of it. 
8.3. SAEs that do not require communication to the person responsible for 
pharmacovigilance 
The investigator should immediately report all the SAEs, as per the above-mentioned definitions, 
with the exception of the following serious adverse events: 
- 
SAEs occurring after 5 days of treatment (as the half-life of ivermectin is 17 hours) 
- 
Hospitalization or death due to progression of the disease. 
All SAEs shall be recorded in the patient's clinical history and the CRF. 
The other SAEs should be reported as per the procedure described in point 8.4. 
8.4. Procedure for reporting SAEs 
If there is an SAE that should be reported to the person responsible for pharmacovigilance, a 
member of the investigating team shall complete and sign an SAE, which shall be sent scanned 
by email, immediately and always within the 24 hours following the moment when the event 
was known of. 
The person responsible for pharmacovigilance shall check the form received and, if necessary, 
shall ask the investigator for additional information. 
When additional information about the SAE is obtained, or the situation is resolved or is unlikely 
to change, a monitoring report should be completed and likewise sent scanned by email to the 
appointed person responsible for pharmacovigilance. 
If it is suspected that the SAE may be a SUSAR, the investigator should provide any monitoring 
information that might be requested. 
Any SAE that is discovered and that takes place in the month following the end of the trial should 
be reported (with no time limit), if the investigator considers that the SAE is related to the 
investigational therapy (i.e. if it is a serious adverse reaction) or is medically important.  
Pregnancy 
All women of child bearing potential will have a urine pregnancy test to confirm 
inclusion/exclusion criteria.  As the IP is only administered at the first visit there will be no further 
pregnancy tests during the trial. 


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During onchocerciasis MDA campaigns with lower doses within the EMA label, visually pregnant 
women are excluded but no formal testing is routinely performed on women of childbearing 
age. There are several reports of inadvertent treatment during pregnancy, a recent metanalysis 
by Nicolas et al [37]. analyzed data from 893 inadvertently exposed pregnancies (97 in the first 
trimester) and concluded there is insufficient evidence to understand the safety of ivermectin 
during pregnancy 
8.5. Expedited reports of an USAR to the medical authorities  
The person responsible for pharmacovigilance is responsible for reporting to the AEMPS (Clinical 
testing department of the General Sub-directorate for Medicines for Human Use) and to the 
Spanish autonomous communities, about all the USARs contained in the study, following the 
procedures indicated by legislation currently in force. 
8.5.1. Report deadlines  
The maximum period for reporting an individual case of a suspected USAR shall be 15 calendar 
days dating from when the sponsor was aware of same. When the suspected USAR has caused 
a patient's death, or put his/her life in danger, the sponsor shall send the information within 7 
calendar days dating from when the sponsor was made aware of same. He shall complete the 
report whenever possible in the following 8 days. 
8.6. Expedited report of other relevant safety information 
Expedited reports shall also be issued of any information that might change the risk/benefit 
balance of the investigational drug, or determine changes in its administration schedule or in 
carrying out the test, such as: 
 
A qualitative change or increase in the percentage of expected serious ADRs considered to 
be clinically important. 
 
New developments related to the trial and that may affect the patients' safety, such as: 
o SAEs that may be associated with the trial procedures and that might modify how it is 
carried out. 
o A significant risk to subjects, such a lack of efficacy of a drug used to treat a life-
threatening disease. 
o New important findings about safety that come from new animal trials (such as 
carcinogenicity). 
o Any premature termination or temporary halt of a clinical trial with the same 
investigational drug for safety reasons, carried out in another country by the same 
sponsor 
This relevant information shall be reported as soon as possible and no later than the 15 days 
from when the sponsor was made aware of same. 
The additional information shall also be reported as soon as possible. 


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8.7. Annual safety reports 
The annual reports that include the SUSARs and SAEs in the study shall be sent to the AEMPS 
(Clinical testing department of the General Subdirectorate for Medicines for Human Use), the 
autonomous communities and the CEIm, within the deadlines established by legislation 
currently in force. This will be included as an appendix of the study report as the study is 
expected to be completed within two months. 
8.8. Reports to investigators 
The investigators shall be given any safety information that might affect the safety of the trial 
subjects as soon as possible. 
Information shall also be issued throughout the study of any aspect of safety that might have an 
impact on the clinical trial, including modifications to the protocol that are linked to safety. 
8.9. Discontinuation of investigational drugs due to adverse events 
The investigational will be administered as a single dose.  
9. 
STATISTICS 
9.1. Description of the statistical methods to be used 
Baseline data from patients enrolled in both arms will be described. This descriptive analysis will 
use frequency, median and interquartile range for qualitative and quantitative variables 
respectively.  
All analyses will be done using the STATA and R program.  
EVALUATION OF EFFICACY 
The primary outcome measure will be assessed using Fisher´s exact test. This will allow for 
comparing the proportion of participants with positive PCR at day seven post treatment.  
The analysis will be done per protocol, including all randomized participants for whom there is 
a PCR result at day seven. Randomized patients without day seven results Will be described to 
verify there is no common pattern.  
SAFETY EVALUATION 
The analysis of safety will be done using a modified intention to treat approach considering all 
randomized and treated participants. AEs experienced by treated participants in each study 
arm will be described separately.  
All the adverse events that occur during the study will be included in the data lists and organized 
according to each patient. Events that are considered to be related to the treatment (possibly, 
probably or definitely related to it) will also be included in a table. A table will with the list the 


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adverse events according to maximum intensity will be provided. The deaths and serious 
adverse events will also be classified in a separate table. 
9.2.  Planned number of subjects to be included and study power 
The study will enroll 24 participants, 12 per arm. The sample size has been calculated for 
comparing two proportions. This sample provides 80% power at 5% significance level using 
fisher´s unilateral test to determine a difference of 45% (100% vs 55%) in the proportion of 
participants with positive PCR at day 7 post-treatment. This includes up to one participant lost 
to follow up (LFU) per arm. We estimated this low LFU level given that the patients will be 
isolated at home and will have a low risk of progression to severe disease. The 100% positivity 
rate at day seven is based on the clinical experience at the Clínica Universidad de Navarra. Figure 
1 provides the relationship power-outcome measure for the full sample and one scenario 
considering LFU of up to two patients per arm. 
 
 
Figure 1. Trial power scenarios for different effect size and loss to follow up levels. 
9.3. The level of significance to be used 
The significance level has been established at 5% 
9.4. Criteria for terminating the trial 
The study will normally end when the planned number of patients has been recruited, the last 
patient has completed the study and all the inconsistencies and adverse events have been 


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resolved. The sponsor is entitled to terminate the study and withdraw all the study materials at 
any time. 
The reason for which it may be necessary to terminate the study: 
 
The incidence and/or severity of adverse events in this or other studies indicates a possible 
risk to health from treatment with the experimental or reference drug. 
In all these cases a final examination should be carried out on each patient who remains in the 
study at the time it is closed or prematurely terminated. The investigator shall complete the 
Case Report Forms in as much detail as possible. The completed Case Report Forms and the 
study materials shall be collected by the sponsor. 
9.5. Procedure used to account for lost, unused and incorrect data 
All the available data on safety and efficacy shall be included in the data lists and tables. No 
values shall be allocated for unavailable data. 
Any confusing or incorrect data shall be examined in accordance with the standardized data 
control procedures. 
In the analysis of the records reported by patients (RRP) the omitted data shall be allocated by 
using the last observation carried over. The omitted standard shall be examined before any 
allocation. If the omitted standard is clearly informative, the repercussion of the non-random 
data shall be evaluated using sensitivity analysis. 
For the RRP analysis, if a section of subscale from several is missing, the average of the remaining 
sections shall be used as a scoring scale, as long as at least half of the sections of the scale are 
available. 
9.6. Procedure for reporting all the deviations from the original statistical plan 
All the deviations from the original statistical analysis plan will be included in the final report of 
the clinical trial. 
9.7. Selection of the subjects to be included in each analysis 
The efficacy analysis will be done per protocol, including all randomized participants for whom 
there is a PCR result at day seven. 
The analysis of safety will be done using a modified intention to treat approach considering all 
randomized and treated participants.  


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10. ETHICAL ASPECTS 
10.1. Good Clinical Practice 
The study shall be carried out in accordance with the International Conference on 
Harmonization (ICH) regarding good clinical practice and the corresponding regulatory 
requirements. The investigator shall be completely familiar with the correct use of the 
investigational drug as described in the protocol. The essential clinical documents shall be kept 
to demonstrate the validity of the study and the integrity of the collected data. The main files 
should be established when the study starts, shall be kept over the course of the study and 
stored in accordance with the relevant legislation. 
10.2. Ethical considerations 
The study will be carried out in accordance with the ethical principles of the latest revision of 
the Helsinki Declaration and with legislation currently in force. The CEIm shall examine all the 
documentation relating to the study in order to protect the patients' rights, safety and 
wellbeing. The study shall only be carried out at the centers for which approval has been 
obtained from the CEIm. The protocol shall be submitted to the CEIm, along with the informed 
consent, advertising, the written information given to patients, updates linked to safety, annual 
progress reports and any changes made to the above documents.  
This study may only start after a favorable decision in writing is received from the CEIm and 
approval is given by the AEMPS. 
10.3. Information for the patient and informed consent 
During this SARS-CoV-2 pandemic period, documented verbal consent in lieu of patient 
signature should be obtained. Once the entire study is explained, a verbal informed consent 
shall be obtained from the patient before their participation in the study may be made effective. 
Investigator must fully inform the patient of what they are consenting to, and must document 
consent was verbally received. 
Subsequent efforts will be made to ratify the written consent or to obtain a written informed 
consent from their relatives or representative.  
The method used to obtain and document the informed consent and the contents of same 
should comply with the EMA recommendations: “Guidance on the Management of Clinical Trials 
during the COVID-19 (Coronavirus) pandemic Version 2 (27/03/2020)”[38].  
The investigator (or person delegated by same) shall sign and date the Consent Form. The 
investigator shall file the original consent form in the Investigator's File in the center. 
The patient shall receive the Informed Consent Form and shall be informed that participation in 
the study is voluntary and may be withdrawn at any time without prejudice to the prior medical 
care. Neither the Patient Information Sheet or the Informed Consent can be modified without 
agreement from the CEIm and the sponsor. 


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A copy of the Informed Consent Form will be kept by the patient. 
The Consent Form includes information about the need to inspect the Clinical Histories and to 
enable basic data to be obtained in the event that the patient decides to suspend participation 
for reasons different from the withdrawal of consent. 
10.4. Confidentiality of patients 
With a view to respecting patients' privacy, the patients will be identified with an assigned 
patient number in all the case report forms, investigational drug accountability records, reports 
and communiqués of the study. The investigator shall provide inspectors and any possible 
auditors or collaborators appointed by the sponsor and the regulatory authorities with access 
to original records of the patients so that they can verify the data in the case report forms and 
audit the data collection process. Confidentiality shall be maintained and the patient's identity 
shall not be made public, to the extent permitted by relevant legislation and regulations. 
Confidentiality shall be maintained and the patient's identity shall not be made public, to the 
extent permitted by relevant legislation and regulations (Law 03/2018). 
10.5. Compensation for the patient 
The investigational drug and the tests deriving from the study will be financed by the sponsor. 
The sponsor will not bear the costs of the habitual care of the patient, in other words, any 
procedures that would be practiced or treatments that would be received independently of their 
participation in the study.  
10.6. Insurance policy 
The sponsor has taken out an insurance policy that covers, in its terms and conditions, the legal 
liability for damages caused to participants and deriving from the investigation, carried out 
strictly in accordance with the scientific protocol and legislation currently in force (RD 
1090/2015). 
10.7. Reports to medical authorities 
This trial requires an application to be sent to the Director of the Spanish Agency of Medicines 
and Health Care Products (AEMPS) for its approval. The study must be approved by the AEMPS 
before it can start. 
10.8. Compliance with protocol 
The investigator will carry out the study in accordance with the protocol provided by the sponsor 
and once approval or a favorable decision is obtained from the CEIm and the relevant regulatory 
authorities. The protocol should not be changed without the consent of the investigator and the 
sponsor. Any relevant changes to the protocol require approval or a favorable decision in writing 
from the CEIm prior to its implementation unless the modification is necessary to prevent 
immediate risks to patients. The sponsor shall present all the changes made in the protocol to 
the regulatory authorities in accordance with legislation currently in force. 


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When an immediate deviation of the protocol is required to prevent immediate risks to patients, 
the investigator shall contact the sponsor, if the circumstances so permit, to consider the 
measures to be adopted. Any deviation from the protocol should be documented in detail in the 
CRF and the original documentation. 
10.9. Premature termination of study 
This study may be prematurely interrupted if the sponsor or the regulatory authorities consider 
that there is sufficient cause to do so. The investigator shall receive written notification in which 
the transferring party documents the reason for suspending the study. 
The circumstances that can justify the suspension of the study include but are not limited to: 
 
Establishment of unexpected risks that are considerable or unacceptable for patients 
 
Insufficient number of patients registered  
 
Insufficient compliance with protocol requirements. 
The reason for which it may be necessary to terminate the study: 
 
The incidence and/or severity of adverse events in this or other studies indicates a possible 
risk to health from treatment with the experimental or reference drug. 
In all these cases a final examination should be carried out on each patient who remains in the 
study at the time it is closed or prematurely terminated. The investigator shall complete the 
Case Report Forms in as much detail as possible. The completed Case Report Forms and the 
study materials shall be collected by the sponsor. 
11. PRACTICAL CONSIDERATIONS 
11.1. Direct access to source data/documents 
The sponsor shall guarantee in the protocol or other written agreement that the investigator or 
the institution shall permit direct access to the source data or documents for monitoring, 
auditing, revision by the CEIm, and for inspection of the trial by the medical authorities. 
11.2. Responsibilities of all the participants in the trial  
Investigator 
The investigator should agree with this protocol and have an in-depth knowledge of the 
properties of the products used in the clinical trial. 
The investigator should give the information sheet to the patient and collaborate with him/her 
to help them understand the explanation provided in the document. It is important for him/her 
to inform patients that their participation in the study is totally voluntary and that it does not 
affect the doctor/patient relationship, and to assure them that all the persons involved in the 
study shall respect the confidential nature of any information relating to the patient. 


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The Principal Investigator or one of his/her collaborators shall be responsible for correctly 
collecting, recording and reporting the data and shall ensure that any serious or unexpected 
adverse events shall be reported within 24 hours. 
It is the duty of the investigator to regularly inform the CEIm of the progress of the study and 
he/she shall be jointly responsible with the sponsor in preparing the final report. 
Monitor  
The monitor is responsible for directly monitoring the trial process in line with the directive of 
Good Clinical Practices (GCP) and legislation currently in force. He/she will carry out a kick-off 
visit to the study centers to check the qualifications of each investigator, inspect the facilities of 
the study center and inform the investigator about the responsibilities and procedures to 
guarantee adequate and correct documentation of the study. This meeting shall include an 
inventory of the materials and a detailed revision of the protocol and the CRF. 
The investigator is obliged to prepare and maintain adequate and exact records of the patients, 
designed to log all the observations and other relevant data to the study of each participant in 
the study. All the information recorded in the CRFs for this study should match the patients' 
original documentation. 
All the study data recorded in the original documents shall be transcribed in the CRFs. The study 
data shall be entered in a data processing system that is validated and secure and backup copies 
shall be kept. Any changes to the study data shall be documented. 
Over the course of the study the monitor shall check for compliance with the protocol, compare 
the CRFs and the medical histories of individual patients, evaluate the accountability of the drugs 
and ensure that the study is being developed in accordance with the relevant legal 
requirements. The CRFs shall be verified by comparing to the original documentation. The 
medical histories shall be checked in such a way as to ensure the patients' confidentiality. A copy 
of the final CRF shall be left in the investigator's study file and the original shall be collected by 
the study monitor.  
The investigator shall permit monitoring and audits of the study by personnel authorized by the 
sponsor, along with revision by the CEIm and medical authorities, and shall provide them with 
direct access to the source data/documents. 
Sponsor 
The sponsor of the clinical trial is the natural person or legal entity that has an interest in 
completing it, signs the applications for authorization sent to the CEIm and/or the Spanish 
Agency of Medicines and Health Care Products (AEMPS) and is responsible for same, including 
its execution, commencement and completion. The sponsor shall also be responsible for 
ensuring compliance with the relevant legal standards. 


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The sponsor takes on the obligations of a sponsor contained in legislation currently in force, 
providing all the resources and collaborators required to fulfill said responsibility with full 
guarantees. 
The sponsor shall provide the investigator with an Investigator's File. This file shall be used for 
all the relevant documents related to the study. The investigator shall be responsible for 
updating the Investigator's File, checking that all the required documents are included during 
and after the study. The file shall be inspected during the monitoring visits and shall be kept by 
the investigator after the study. 
11.3. Quality control and assurance 
The study shall be regularly monitored. A representative of the sponsor shall analyze the 
protocol with the investigators and their staff during the kick-off visit at the study center or in a 
meeting with the investigators. 
The investigator should provide the monitor with access to the appropriate hospital record or 
the clinical histories to confirm the accuracy of the data entered in the CRF. None of the 
information contained in said records about the identity of the patients shall leave the study 
center. The monitor shall check that all the patients have duly given their consent and that the 
signed informed consent is available after the last study visit. He/she shall also review the 
inclusion and exclusion criteria to ensure that all the patients are duly included in the study. 
The monitor shall ensure that all the AEs, SAEs and deviations from the protocol are 
appropriately noted and documented. Other verifications shall be carried out on the match 
between the original data and the CRFs in accordance with the specific monitoring plant of the 
study. 
11.4. Audit/Inspections 
The regulatory authorities, the CEIm and the sponsor or an appointed representative may ask 
for access to all the original documents, case report forms of the patients and other 
documentation of the study in order to carry out an audit or inspection at the center. The 
investigator should guarantee direct access to these documents and collaborate at all times in 
said activities. 
12. DATA MANAGEMENT 
12.1. Case Report Forms (CRF) 
  
CRFs shall be completed by the investigation team, transcribing the data from the original 
documents that form the patient's clinical history. The investigator shall sign the CRF to 
guarantee its authenticity and accuracy. The CRF may be completed by any authorized person, 
whose signature is recognized. The completed CRF shall be checked during the monitoring visit. 


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Daily self-assessment of symptoms will be written in XLSform, entered via web the enketo web 
application, transferred securely via https, and stored in an encrypted PostgreSQL database. 
Back-ups of the database will be generated daily in the form of a SQL “dump” file, and a paper 
back-up will be generated weekly. Only the PI and his/her designated deputies will have access 
to the database. Any changes to the database will be logged in a change ledger, along with 
information pertaining to why the change was made, who it was made by, and a timestamp. 
Upon completion of the study, an encrypted CD-ROM storing the digital CRFs will be generated 
for archiving. 
Any outcome outside the range of normality shall be duly commented. 
12.2. Documents to be kept by the investigator 
The investigator shall keep all the records of the study which includes all the original documents 
of the clinical history and a copy of all the CRFs and the identification list of the subjects in 
accordance with the good clinical practices of the International Conference on Harmonization 
(ICH) and the corresponding regulatory requirements.  
12.3. Study archive 
The Clínica Universidad de Navarra shall keep a Principal Archive of the Study for the lifetime of 
the product. 
12.4. Monitoring 
The sponsor shall assign monitoring staff to the clinical trial. Their functions shall include 
assisting the investigator and the sponsor in keeping the data completely legible, well organized 
and easy to recover. They shall also explain and make sure that the investigator understands 
and interprets all the sponsor's applicable SOPs and the relevant provisions regarding the clinical 
evaluation of an investigational drug. They shall also ensure that the protocol is correctly 
understood, and they shall give information about responsibilities and the validity of the data. 
The initial notes (raw data) about the key points of their status, such as the AEs and laboratory 
trials, shall be kept in the Clinical History. 
12.5. Final report  
The investigation team shall draw up a report suitable for presentation to the relevant 
authorities. 
13. PUBLICATION OF RESULTS OF TRIAL AND USE OF INFORMATION 
The results of this clinical trial shall be published in scientific journals and shall mentioned the 
CEIm, which approved the study. 


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Basic regulations of the trial 
The Principal Investigator is obliged not to use, transmit to third parties, divulge and/or publish 
the results obtained in this trial without prior written consent from the Clínica Universidad de 
Navarra, sole sponsor of the trial. They should in any case respect the following conditions: 
The results of this study may not be published until the end of the trial or before if both parties 
agree to do so. 
a) The results of the trial and any proposal for publication shall be sent to the sponsor, at least 
30 days before it is sent for publication. The sponsor should reply in writing within said 
period, granting said authorization or giving reasons for denying it. If no reply is received in 
this period, it shall be assumed that publication has been authorized. 
b) The sponsor shall not cite the names of the investigators without their authorization, except 
when referring to work that is already published. 
c) The sponsor shall permit publication of the data obtained in this trial in journals of 
recognized scientific prestige and the divulgation of its contents in seminars and conferences 
in the professional medical sphere, as long as the conditions in paragraphs a) and b) of this 
section are respected and if the final draft of the article may be may be reviewed within a 
maximum of thirty days. In any case, the legitimate interests of the trial sponsor shall be 
protected, such as in obtaining optimal protection of patients, coordination in the 
presentation of documents to medical authorities or other studies in progress in the same 
field, protection of confidential data and information, etc. 
d) These regulations are understood to be applicable to information obtained in uncompleted 
trials or studies that were suspended before termination. 
14. REFERENCES 
 
1. 
Richards FO, Jr.: Upon entering an age of global ivermectin-based integrated mass drug 
administration for neglected tropical diseases and malaria. Malar J 2017, 16:168. 
2. 
Frieman M, Yount B, Heise M, Kopecky-Bromberg SA, Palese P, Baric RS: Severe Acute 
Respiratory Syndrome Coronavirus ORF6 Antagonizes STAT1 Function by Sequestering 
Nuclear Import Factors on the Rough Endoplasmic Reticulum/Golgi Membrane. 
Journal of Virology 2007, 81:9812-24. 
3. 
Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F: Network-based drug repurposing 
for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery 2020, 6:14. 
4. 
Jang K-J, Jeong S, Kang DY, Sp N, Yang YM, Kim D-E: A high ATP concentration enhances 
the cooperative translocation of the SARS coronavirus helicase nsP13 in the unwinding 
of duplex RNA. Scientific Reports 2020, 10:4481. 
5. 
Adedeji AO, Marchand B, Te Velthuis AJ, Snijder EJ, Weiss S, Eoff RL et al: Mechanism 
of nucleic acid unwinding by SARS-CoV helicase. PLoS One 2012, 7:e36521. 
6. 
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ et al: COVID-19: 
consider cytokine storm syndromes and immunosuppression. Lancet 2020. 


Sponsor: Clínica Universidad de Navarra   
 
 
                 
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7. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al: Clinical features of patients infected 
with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395:497-506. 
8. 
Omura S, Crump A: Ivermectin: panacea for resource-poor communities? Trends 
Parasitol 2014, 30:445-55. 
9. 
Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C et al: Nuclear 
localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 
4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res 2013, 99:301-6. 
10. 
Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA et al: The broad 
spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 
heterodimer. Antiviral Res 2020:104760. 
11. 
Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA: Ivermectin is a specific 
inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of 
HIV-1 and dengue virus. Biochem J 2012, 443:851-6. 
12. 
Barrows NJ, Campos RK, Powell ST, Prasanth KR, Schott-Lerner G, Soto-Acosta R et al: A 
Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. Cell Host Microbe 
2016, 20:259-70. 
13. 
Varghese FS, Kaukinen P, Glasker S, Bespalov M, Hanski L, Wennerberg K et al: 
Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya 
and other alphaviruses. Antiviral Res 2016, 126:117-24. 
14. 
Mastrangelo E, Pezzullo M, De Burghgraeve T, Kaptein S, Pastorino B, Dallmeier K et al: 
Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 
helicase activity: new prospects for an old drug. J Antimicrob Chemother 2012, 
67:1884-94. 
15. 
Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM et al: Nuclear 
import and export inhibitors alter capsid protein distribution in mammalian cells and 
reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res 2013, 100:662-
72. 
16. 
Lee YJ, Lee C: Ivermectin inhibits porcine reproductive and respiratory syndrome virus 
in cultured porcine alveolar macrophages. Arch Virol 2016, 161:257-68. 
17. 
Caly L, Druce J, Catton M, Jans D, KM W: The FDA-approved Drug Ivermectin inhibits 
the replication of SARS-CoV-2 in vitro. Antiviral Research 2020, In Press, Journal Pre-
proof. 
18. 
Yamasmith, E; et al. Efficacy and Safety of Ivermectin against Dengue Infection: A 
Phase III, Randomized, Double-blind, Placebo-controlled Trial, in he 34th Annual 
Meeting The Royal College of Physicians of Thailand- ‘Internal Medicine and One 
Health'. 2018: Chonburi, Thailand. Registry available at: 
https://clinicaltrials.gov/ct2/show/NCT02045069 (accessed Aplri 5, 2020). 
19. 
Lespine A, Alvinerie M, Sutra JF, Pors I, Chartier C: Influence of the route of 
administration on efficacy and tissue distribution of ivermectin in goat. Vet Parasitol 
2005, 128:251-60. 
20. 
Chiu SH, Lu AY: Metabolism and Tissue Residues. In: WC Campbell (ed),Ivermectin and 
Abamectin. New York: Springer-Verlag; 1989: 131–43. 
21. 
Zhang X, Song Y, Ci X, An N, Ju Y, Li H et al: Ivermectin inhibits LPS-induced production 
of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res 
2008, 57:524-9. 
22. 
Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N et al: Avermectin exerts anti-inflammatory effect 
by downregulating the nuclear transcription factor kappa-B and mitogen-activated 
protein kinase activation pathway. Fundam Clin Pharmacol 2009, 23:449-55. 
23. 
Blakley BR, Rousseaux CG: Effect of ivermectin on the immune response in mice. Am J 
Vet Res 1991, 52:593-5. 


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24. 
MSD: Stromectol label approved in The Netherlands. Available at 
https://www.geneesmiddeleninformatiebank.nl/smpc/h28341_smpc.pdf. 2015. 
25. 
Infectopharm: Scabioral 3mg package insert available here: 
https://www.infectopharm.com/images/newsletter/1216/fi-scabioral.pdf (accessed 
JUly 2019). 
26. 
Gonzalez Canga A, Sahagun Prieto AM, Diez Liebana MJ, Fernandez Martinez N, Sierra 
Vega M, Garcia Vieitez JJ: The pharmacokinetics and interactions of ivermectin in 
humans--a mini-review. AAPS J 2008, 10:42-6. 
27. 
Merck_&_Co.: Stromectrol. FDA approved Package insert 2009. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050742s026lbl.pdf 
(Accessed February 2018). 
28. 
Merck_&_Co.: Stromectrol. TGA-Australia approved Package insert 2014. 
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-
2011-PI-02659-3&d=2016071016114622483 (Accessed February 2018). 
29. 
Elkassaby MH: Ivermectin uptake and distribution in the plasma and tissue of 
Sudanese and Mexican patients infected with Onchocerca volvulus. Trop Med Parasitol 
1991, 42:79-81. 
30. 
Kamgno J, Gardon J, Gardon-Wendel N, Demanga N, Duke BO, Boussinesq M: Adverse 
systemic reactions to treatment of onchocerciasis with ivermectin at normal and high 
doses given annually or three-monthly. Trans R Soc Trop Med Hyg 2004, 98:496-504. 
31. 
Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Chen T et al: Safety and 
mosquitocidal efficacy of high-dose ivermectin when co-administered with 
dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria 
(IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 
2018, 18:615-26. 
32. 
Awadzi K, Opoku NO, Addy ET, Quartey BT: The chemotherapy of onchocerciasis. XIX: 
The clinical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol 1995, 
46:131-7. 
33. 
Awadzi K, Attah SK, Addy ET, Opoku NO, Quartey BT: The effects of high-dose 
ivermectin regimens on Onchocerca volvulus in onchocerciasis patients. Trans R Soc 
Trop Med Hyg 1999, 93:189-94. 
34. 
Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM et al: Safety, 
tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy 
adult subjects. J Clin Pharmacol 2002, 42:1122-33. 
35. 
Munoz J, Ballester MR, Antonijoan RM, Gich I, Rodriguez M, Colli E et al: Safety and 
pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in 
healthy adult volunteers. PLoS Negl Trop Dis 2018, 12:e0006020. 
36. 
Gardon J, Gardon-Wendel N, Demanga N, Kamgno J, Chippaux JP, Boussinesq M: 
Serious reactions after mass treatment of onchocerciasis with ivermectin in an area 
endemic for Loa loa infection. Lancet 1997, 350:18-22. 
37. 
Nicolas P, Maia MF, Bassat Q, Kobylinski KC, Monteiro W, Rabinovich NR et al: Safety 
of oral ivermectin during pregnancy: a systematic review and meta-analysis. Lancet 
Glob Health 2020, 8:e92-e100. 
38. 
European Medicines Agency. Guidance on the Management of Clinical Trials during the 
COVID-19 (Coronavirus) pandemic Version 2. Available at: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf (Accessed April 11, 2020). 


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ANNEX 1: SCHEDULE OF VISITS AND EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
Day 0 
Visit 2 
Day 4 post treatment 
Visit 3 
Day 7 post treatment 
Visit 4 
Day 14 post treatm. 
Visit 5 
Day 21 post treatm. 
Final visit   
Day 28 post treatm. 
Informed consent# 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Clinical data collection 
X 
X 
X 
X 
  X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
Laboratory test* 
X 
 
X 
X 
 
 
Urine pregnancy test 
X 
 
 
 
 
 
Nasopharyngeal swab (PCR for SARS-CoV-2) 
X 
X 
X 
X 
X 
 
Serology for SARS-CoV-2 
X 
X 
X 
X 
X 
X 
Proinflammatory and activation markers 
X 
X 
X 
X 
X 
X 
Cell responses (PBMC) 
X 
 
X 
 
 
X 
Chest x-ray 
X 
 
 
 
 
 
Administration of IP 
X 
 
 
 
 
 
Daily self-assessment of symptoms 
X-----------------------------------------X 
Evaluation of adverse events 
X-----------------------------------------X 
# verbal consent initially, in writing when isolation is concluded  
* C reactive protein, Procalcitonin, Ferritin, IL-6 
, Renal function: urea, creatinine, electrolytes, FBC,    
   Troponin T, CPK, DD, LDH  


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ANNEX 2: DISCRETE DOSING TABLE 
# of 3mg 
tablets-->
6
7
8
9
10
11
12
13
14
15
Dose in 
mg -->
18
21
24
27
30
33
36
39
42
45
45
400
467
533
600
667
733
800
867
933
1000
46
391
457
522
587
652
717
783
848
913
978
47
383
447
511
574
638
702
766
830
894
957
48
375
438
500
563
625
688
750
813
875
938
49
367
429
490
551
612
673
735
796
857
918
50
360
420
480
540
600
660
720
780
840
900
51
353
412
471
529
588
647
706
765
824
882
52
346
404
462
519
577
635
692
750
808
865
53
340
396
453
509
566
623
679
736
792
849
54
333
389
444
500
556
611
667
722
778
833
55
327
382
436
491
545
600
655
709
764
818
56
321
375
429
482
536
589
643
696
750
804
57
316
368
421
474
526
579
632
684
737
789
58
310
362
414
466
517
569
621
672
724
776
59
305
356
407
458
508
559
610
661
712
763
60
300
350
400
450
500
550
600
650
700
750
61
295
344
393
443
492
541
590
639
689
738
62
290
339
387
435
484
532
581
629
677
726
63
286
333
381
429
476
524
571
619
667
714
64
281
328
375
422
469
516
563
609
656
703
65
277
323
369
415
462
508
554
600
646
692
66
273
318
364
409
455
500
545
591
636
682
67
269
313
358
403
448
493
537
582
627
672
68
265
309
353
397
441
485
529
574
618
662
69
261
304
348
391
435
478
522
565
609
652
70
257
300
343
386
429
471
514
557
600
643
71
254
296
338
380
423
465
507
549
592
634
72
250
292
333
375
417
458
500
542
583
625
73
247
288
329
370
411
452
493
534
575
616
74
243
284
324
365
405
446
486
527
568
608
75
240
280
320
360
400
440
480
520
560
600
76
237
276
316
355
395
434
474
513
553
592
77
234
273
312
351
390
429
468
506
545
584
78
231
269
308
346
385
423
462
500
538
577
79
228
266
304
342
380
418
456
494
532
570
80
225
263
300
338
375
413
450
488
525
563
81
222
259
296
333
370
407
444
481
519
556
82
220
256
293
329
366
402
439
476
512
549
83
217
253
289
325
361
398
434
470
506
542
84
214
250
286
321
357
393
429
464
500
536
85
212
247
282
318
353
388
424
459
494
529
86
209
244
279
314
349
384
419
453
488
523
87
207
241
276
310
345
379
414
448
483
517
88
205
239
273
307
341
375
409
443
477
511
89
202
236
270
303
337
371
404
438
472
506
90
200
233
267
300
333
367
400
433
467
500
91
198
231
264
297
330
363
396
429
462
495
92
196
228
261
293
326
359
391
424
457
489
93
194
226
258
290
323
355
387
419
452
484
94
191
223
255
287
319
351
383
415
447
479
95
189
221
253
284
316
347
379
411
442
474
96
188
219
250
281
313
344
375
406
438
469
97
186
216
247
278
309
340
371
402
433
464
98
184
214
245
276
306
337
367
398
429
459
99
182
212
242
273
303
333
364
394
424
455
100
180
210
240
270
300
330
360
390
420
450

SAP_000.pdf: 
Sponsor: Clínica Universidad de Navarra   
 
 
                 
 EUDRACT No.: 2020-001474-29 
Statistical Analysis Plan: SAINT 
Version 1.0 
           Page 1 of 31 
5 of October 2020 
 
 
 
 
CLINICAL TRIAL STATISTICAL ANALYSIS PLAN 
 
Code: SAINT 
Title of trial: Pilot study to evaluate the potential of ivermectin to reduce 
COVID-19 transmission 
Phase: IIa 
Date of statistical analysis plan: 5 of October 2020 - Version 1.0 
EudraCT number: 2020-001474-29 
Sponsor: Clínica Universidad de Navarra 
Written by: Aina Casellas, ISGlobal 
 
Principal Investigator:   
Dr. Carlos Chaccour 
Clínica Universidad de Navarra 
 
 
 
 
 
 
CONFIDENTIAL MAY NOT BE USED, DIVULGED OR PUBLISHED WITHOUT TRIAL SPONSOR'S CONSENT. 
 
 


Sponsor: Clínica Universidad de Navarra 
                
EUDRACT No.: 2020-001474-29
Statistical Analysis Plan: SAINT 
Version 1.0 
           Page 2 of 31 
5 of October 2020 
 
 
 
 
 
 
Approval Page 
The signatures below confirm that the signatories have reviewed and approved this document 
which shall govern the stipulated statistical analysis tasks of the specified research study. 
 
Aina Casellas 
 
Head of Statistics 
Name 
 
Designation 
 
 
 
5 of October 2020 
Signature 
 
Date 
 
 
 
Sergi Sanz 
 
Reviewer  
Name 
 
Designation 
 
 
 
5 of October 2020 
Signature 
 
Date 
 
 
 
Carlos Chaccour 
 
Approver 
Name 
 
Designation 
 
 
 
5 of October 2020 
Signature 
 
Date 
 
 
 
 
 
 
 


Sponsor: Clínica Universidad de Navarra   
 
 
                 
 EUDRACT No.: 2020-001474-29 
Statistical Analysis Plan: SAINT 
Version 1.0 
           Page 3 of 31 
5 of October 2020 
 
 
1 Table of Contents 
1 
Table of Contents .................................................................................................................. 3 
2 
Abbreviations and Definitions ............................................................................................... 5 
3 
Introduction .......................................................................................................................... 5 
3.1 
Preface........................................................................................................................... 5 
3.2 
Purpose of the analyses ................................................................................................ 6 
4 
Study Objectives and Endpoints ............................................................................................ 6 
4.1 
Main Study Objective .................................................................................................... 6 
4.2 
Secondary Study Objectives .......................................................................................... 6 
4.3 
Endpoints....................................................................................................................... 6 
4.3.1 
Primary .................................................................................................................. 6 
4.3.2 
Secondary .............................................................................................................. 6 
5 
Study Methods ...................................................................................................................... 7 
5.1 
General Study Design and Plan ..................................................................................... 7 
5.2 
Equivalence or Non-Inferiority Studies ......................................................................... 7 
5.3 
Inclusion-Exclusion Criteria and General Study Population .......................................... 8 
5.3.1 
Inclusion criteria .................................................................................................... 8 
5.3.2 
Exclusion criteria ................................................................................................... 8 
5.3.3 
Criteria for withdrawal .......................................................................................... 9 
5.4 
Randomisation and Blinding ......................................................................................... 9 
5.5 
Study Variables .............................................................................................................. 9 
5.5.1 
Baseline information (day 1) ............................................................................... 10 
5.5.2 
Previous medical history (day 1) ......................................................................... 10 
5.5.3 
Visit information .................................................................................................. 11 
5.5.4 
Concomitant medication (during follow up) ....................................................... 15 
5.5.5 
Adverse Events (during follow up) ...................................................................... 15 
6 
Sample Size .......................................................................................................................... 18 
7 
General Considerations ....................................................................................................... 19 
7.1 
Timing of Analyses ....................................................................................................... 19 
7.1.1 
Full Analysis Population ....................................................................................... 19 
7.1.2 
Safety Population ................................................................................................ 19 
7.2 
Covariates and Subgroups ........................................................................................... 19 
7.3 
Missing Data ................................................................................................................ 19 


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7.4 
Multiple Testing .......................................................................................................... 19 
8 
Summary of Study Data ....................................................................................................... 19 
8.1 
Subject Disposition ...................................................................................................... 20 
8.2 
Derived variables ......................................................................................................... 21 
8.3 
Concurrent Illnesses and Medical Conditions ............................................................. 21 
8.4 
Prior and Concurrent Medications .............................................................................. 21 
8.5 
Treatment Compliance ................................................................................................ 21 
9 
Efficacy Analyses ................................................................................................................. 21 
9.1 
Primary Efficacy Analysis ............................................................................................. 21 
9.2 
Secondary Efficacy Analyses........................................................................................ 22 
10 
Safety Analyses ................................................................................................................ 22 
10.1 
Extent of Exposure ...................................................................................................... 22 
10.2 
Adverse Events ............................................................................................................ 22 
10.3 
Deaths, Serious Adverse Events and other Significant Adverse Events ...................... 22 
10.4 
Pregnancies ................................................................................................................. 22 
10.5 
Clinical Laboratory Evaluations ................................................................................... 22 
11 
Pharmacokinetics ............................................................................................................ 23 
12 
Reporting Conventions .................................................................................................... 23 
13 
Technical Details .............................................................................................................. 23 
14 
References ....................................................................................................................... 24 
15 
Listing of Tables, Listings and Figures ............................................................................. 25 
15.1 
Tables .......................................................................................................................... 25 
15.2 
Listings ......................................................................................................................... 29 
15.3 
Figures ......................................................................................................................... 30 
 
 
 


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2 Abbreviations and Definitions 
AE
Adverse Event
BMI
Body Mass Index
CI
Confidence interval
CRF
Case Report Form
Ct
Cycle threshold
CUN
Clínica Universidad de Navarra
ENT
Ear, Nose, Throat
FU
Follow-up
LFU
Lost to follow-up
mITT
Modified Intention to treat
NTDs
Neglected tropical diseases
PP
Per Protocol
RR
Relative risk ratio
RRP
Reports reported by patients
SAE
Severe Adverse Event
SAP
Statistical Analysis Plan
3 Introduction 
3.1 Preface 
As of May 8, 2020, there were a more than 4 million cases of COVID-19 and more than 270,000 
deaths worldwide. There is currently no proven treatment for this disease, so drug-based 
strategies to control COVID-19 are urgently needed. Among the potential approaches to be 
considered for COVID-19 are early treatment of patients to reduce progression to severe 
disease, treatment to block or reduce transmission with a drug that reduces viral excretion in 
the airway, prophylaxis or combinations of either. These strategies could significantly relieve 
pressure on the health system and decrease indirect deaths due to other diseases requiring 
intensive care.  
Ivermectin is a widely used anti-parasitic drug for the treatment and control of neglected 
tropical diseases (NTDs) which has shown an excellent safety profile, with more than 2.5 billion 
doses distributed in the last 30 years. Based on previous evidence, ivermectin could be active 
against COVID-19 by inhibiting the replication of the virus or by having immunomodulatory 
effects. 


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3.2 Purpose of the analyses 
These analyses will assess the efficacy and safety of ivermectin as a treatment for COVID-19 
patients to reduce virus spread. 
4 Study Objectives and Endpoints 
4.1 Main Study Objective 
To determine the efficacy of a single dose of ivermectin, administered to low risk, non-severe 
COVID-19 patients in the first 48 hours after symptoms onset to reduce the proportion of 
patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day seven post-
treatment. 
4.2 Secondary Study Objectives 
1. To assess the efficacy of ivermectin to reduce the SARS-CoV-2 viral load in the 
nasopharyngeal swab at day seven post treatment 
2. To assess the efficacy of ivermectin to improve symptom progression in treated patients 
3. To assess the proportion of seroconversions at day 21 in treated patients 
4. To assess the safety of ivermectin at the proposed dose 
5. To determine the magnitude of immune response against SARS-CoV-2  
6. To assess the early kinetics of immunity against SARS-CoV-2 
4.3 Endpoints 
4.3.1 
Primary 
Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 
post-treatment. 
4.3.2 
Secondary 
1. Mean viral load as determined by PCR cycle threshold (Ct) at baseline and on days 4, 7, 14 
and 21. 
2. Proportion of patients with fever and cough at days 4, 7, 14 and 21 as well as proportion of 
patients progressing to severe disease or death during the trial. 
3. Proportion of patients with seroconversion at day 21. 
4. Proportion of drug-related adverse events during the trial. 
5. Median levels of IgG, IgM, IgA measured by Luminex, frequencies of innate and SARS-CoV-
2-specific T cells assessed by flow cytometry, median levels of inflammatory and activation 
markers measured by Luminex and transcriptomics. 
6. Median kinetics of IgG, IgM, IgA levels till day 28. 
The analysis of objectives 5 and 6 will be addressed in a supplementary SAP. 
 


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5 Study Methods 
5.1 General Study Design and Plan 
The SAINT trial is a single center, randomized, double-blind, placebo-controlled, parallel arm, 
superiority clinical trial.  
Participants will be randomized to receive a single dose of 400 mcg/kg ivermectin or a placebo 
equivalent and followed up for 28 days.  
A final study visit will be made for participants who withdraw prematurely from the study or are 
withdrawn by the investigator. A summary of the study visits and procedures is provided in Table 
1Table 1. Visit Procedures below. 
 
Table 1. Visit Procedures 
 
5.2 Equivalence or Non-Inferiority Studies 
Not Applicable 
 
Recruitment 
Day 1 
Visit 2 
Day 4 
Visit 3 
Day 7 
Visit 4 
Day 14 
Visit 5 
Day 21 
Final visit 
Day 28 
Informed consent#
X
Randomization
X
Clinical data collection
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
Laboratory test*
X
X
X
Urine pregnancy test 
X 
 
 
 
 
 
Nasopharyngeal swab (PCR for SARS-CoV-2) 
X 
X 
X 
X 
X 
 
Serology for SARS-CoV-2 
X 
X 
X 
X 
X 
X 
Proinflammatory and activation markers 
X 
X 
X 
X 
X 
X 
Cell responses (PBMC) 
X 
 
X 
 
 
X 
Chest x-ray 
X 
 
 
 
 
 
Administration of IP 
X 
 
 
 
 
 
Daily self-assessment of symptoms 
X--------------------------------------------X 
Evaluation of adverse events 
X--------------------------------------------X 
# verbal consent initially, in writing when isolation is concluded  
* C reactive protein, Procalcitonin, Renal function: urea, creatinine, electrolytes, FBC,    
   Troponin T, CPK, DD, LDH 


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5.3 Inclusion-Exclusion Criteria and General Study Population 
5.3.1 
Inclusion criteria 
 
Patients diagnosed with COVID-19 in the emergency room of the Clínica Universidad de 
Navarra with a positive SARS-CoV-2 PCR. 
 
 
 
The patient should be between the ages of 18 and 60 years 
 
Negative pregnancy test for women of child bearing age* 
 
The patient or his/her representative have given consent to participate in the study. 
 
The patient should, in the investigator's opinion, be able to comply with all the requirements 
of the clinical trial (including home follow up during isolation) 
*Women of child bearing age may participate if they use a safe contraceptive method for the 
entire period of the study and at least one month afterwards. A woman is considered to not 
have childbearing capacity if she is post-menopausal (minimum of 2 years without 
menstruation) or has undergone surgical sterilization (at least one month before the study). 
5.3.2 
Exclusion criteria 
 
Known history of Ivermectin allergy 
 
Hypersensitivity to any component of Stromectol® 
 
COVID-19 Pneumonia 
 
Diagnosed by the attending physician 
 
Identified in a chest X-ray 
 
Fever or cough present for more than 72 hours 
 
Positive IgG against SARS-CoV-2 by rapid test 
 
Age under 18 or over 60 years 
 
The following co-morbidities (or any other disease that might interfere with the study in the 
eyes of the investigator): 
 
Immunosuppression  
 
Chronic Obstructive Pulmonary Disease 
 
Diabetes 
 
Hypertension 
 
Obesity 
 
Acute or chronic renal failure 
 
History of coronary disease 
 
History of cerebrovascular disease 
 
Current neoplasm 
 
Recent travel history to countries that are endemic for Loa loa (Angola, Cameroon, Central 
African Republic, Chad, Democratic Republic of Congo, Ethiopia, Equatorial, Guinea, Gabon, 
Republic of Congo, Nigeria and Sudan) 
 
Current use of CYP 3A4 or P-gp inhibitor drugs such as quinidine, amiodarone, diltiazem, 
spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, 
cyclosporine, tacrolimus, indinavir, ritonavir or cobicistat. Use of critical CYP3A4 substrate 
drugs such as warfarin. 


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5.3.3 
Criteria for withdrawal 
Patients will be informed that they may be withdrawn from the study at any time without 
providing any explanation. Withdrawal may also take place for any of the following reasons:  
 
Adverse reaction that puts the patient's life at risk, according the principal investigator's 
judgment. 
 
Decision made by the patient or the legally authorized person. 
 
Documented progression of the disease requiring hospitalization in a different center. 
 
The patient cannot complete the trial visits due to unforeseen circumstances. 
 
Development of other disorders that, in the opinion of the investigator and in the patient's 
best interest, make it advisable for him/her to leave the study. 
 
Administration of treatment with a non-permitted drug. 
 
The investigator believes that the patient may benefit from a different treatment. 
 
Loss of monitoring  
The investigator shall strive to ensure that the patient agrees to the final trial visit. The data of 
the withdrawn patients shall be collected up to this final visit. If the withdrawal is the outcome 
of a Serious adverse event related to ivermectin or SARS-CoV-2, the data shall be collected until 
the patient recovers or stabilizes.  
The subjects shall be replaced if the withdrawal is for a reason different from lack of efficacy of 
the treatment or appearance of adverse events. All efforts will be made to maintain the total 
number of assessable patients as per the protocol.  
The withdrawal shall be documented in the patient's clinical history, giving the reasons for the 
decision. A final trial visit should be conducted by the clinical team if possible. 
5.4 Randomisation and Blinding 
Participants will be randomized to receive a single dose of 400 mcg/kg ivermectin or a placebo 
equivalent. The randomization code will be generated by the trial statistician using blocks of four 
individuals that ensure balance between the groups. This randomization will be performed with 
the module ralloc [1] for Stata software [2]. 
-
 that the 
randomization number does not match the subject identifier. 
The sequence and code used will be kept in an encrypted file accessible only to the trial 
statistician. A physical copy will be kept on a locked cabinet at the CUN, accessible only to the 
staff administering the drug who will not enroll or attend to patient care. 
This is a double-blind study; the participants and the clinical team will be blinded. The placebo 
will not be visibly identical, but it will be administered by a researcher not involved in the clinical 
care or participant follow up. 
5.5 Study Variables 
The list of variables collected at each study timepoint is provided in the following subsections. 


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All study visits must be on the planned days, so no visits out of the specified visit days (1, 4, 7, 
14, 21 and 28) will be taken into account in the analysis. 
5.5.1 
Baseline information (day 1) 
The variables listed below will be assessed on the first visit. 
Variable name 
Description 
Data type 
Coding or 
range 
Demographics
Age
Age (years)
Integer
18-60
Sex
Gender
Integer
1: Female
2: Male 
V1_VSHeight
Height (in m)
Real
1.2-2.2
V1_VSWeight
Weight (in kg)
Real
40-100
V1_VSBMI
BMI (in kg/m2)
Real
18-30
Smoking habits and alcohol consumption
Smoke
Smoker or tobacco products user
Integer
0: No
1: Yes 
Cigarettes
Number of cigarettes per day
Integer
0-40
SmokeYears
Smoking duration (in years)
Integer
??
Alcohol
Alcohol consumption
Integer
0: No
1: Yes 
AlcoholUnits
Weekly alcohol consumption (in units)
Integer
0-20
Medication
MedicationTaken
Taking medication
Integer
0: No
1: Yes 
5.5.2 
Previous medical history (day 1) 
For each preexisting medical condition, the list of variables given below will be collected. 
Variable name 
Description 
Data 
type 
Coding or range 
RELEVANT_HISTORY_MEDICAL
Relevant History Medical 
Integer
0: Other 
1: Cardiovascular 
2: Respiratory 
3: Hepato-biliary 
4: Gastro-intestinal 
5: Genito-urinary 
6: Endocrine 
7: Hematological 
8: Musculo-skeletal 
9: Neoplasia 
10: Neurological 
11: Psychological 


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12: Immunological 
13: Dermatological 
14: Allergies 
15: Eyes, ear, nose, 
throat 
Details
Details 
(Diagnosis 
/ 
Procedure) 
String
StartDate
Start Date
Date
Ongoing
Is the medical condition 
ongoing? 
Integer
0: No
1: Yes 
EndDate
End Date
Date
5.5.3 
Visit information  
The list below contains those variables assessed recurrently during follow up. Note that not all 
variables are collected every visit. A superscript indicating the days when the information is 
collected is provided for those variables not collected at every study visit. 
Variable name
Description 
Data 
type 
Coding or range 
VIVisitDate
Visit Date
Date
ASAnySymptoms
Does the patient have any of 
the symptoms suggestive of 
COVID-19? 
Integer
0: No
1: Yes 
ASAnyNewSymptoms
Does the patient have any 
new symptom suggestive of 
COVID-19? 
Integer
0: No
1: Yes 
SYMPTOM 
Symptom 
Integer 
1: General 
2: ENT 
3: Respiratory 
4: Digestive 
5: Other 
VSHeartRate 
Heart rate (beats per minute) 
Integer 
50-120 
VSBloodPressSystolic 
Systolic 
blood 
pressure 
(mmHg) 
Integer 
90-160 
VSBloodPressDiastolic 
Diastolic 
blood 
pressure 
(mmHg) 
Integer 
50-100 
VSTemperature 
Temperature (ºC) 
Real 
35-41 
VSOxygenSaturation 
Oxygen saturation (%) 
Real 
85- 
VSRespiratoryRate 
Respiratory rate (breaths per 
minute) 
Integer 
8-24 
VSHeight 
Height (m) 
Real 
1.2-2.2 
VSWeight 
Weight (kg) 
Real 
40-100 
VSBMI 
BMI (kg/m2) 
Real 
18-30 


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PHEAnyAbnormalPhyExam 
Does the patient show any 
abnormal signs on physical 
examination? 
Integer 
0: No 
1: Yes 
PHEAnyNewAbnormalPhyExam
Does the patient show any 
new 
abnormal 
signs 
on 
physical examination? 
Integer
0: No
1: Yes 
Xray 1
X-RAY Result
Integer
0: Normal
1: Abnormal 
ChestXrayDescription 1
X-RAY Description:
String
PregnancyTestConducted 1
Was 
a 
pregnancy 
test 
conducted? 
Integer
0: No
1: Yes 
2: NA 
PregnancyTestResult 1
Pregnancy test result
Integer
0: Negative
1: Positive 
PCRSwabResults 1,4,7,14,21
Swab result
Integer
0: Negative
1: Positive 
RSCompleteSelfAssessment
4,7,14,21,28 
Did the participant complete 
the 
self-assessment 
daily 
since the last visit? 
Integer
0: No
1: Yes 
RSParticipantReportAE 4,7,14,21,28
Did the participant report any 
negative changes? 
Integer
0: No
1: Yes 
RSParticipantReportCM
4,7,14,21,28 
Did the participant report any 
new medications? 
Integer
0: No
1: Yes 
Nasopharyngeal swab (PCR for SARS-CoV-2) 1,4,7,14,21
PCRPCR_gen_N 
Gene N (PCR sample)  Result 
Integer 
1: Detected 
2: Not detected 
3: Not done 
PCRPCR_muestra_CT_N 
Gene N (PCR sample)  Ct  
Real 
12-40 (41 if not 
detected) 
PCRPCR_muestra_Q_N 
Gene N (PCR sample) 
Quantity (Copies/ml) 
Integer 
0-1012 
PCRPCR_gen_E 
Gene E (PCR sample)  Result 
Integer 
1: Detected 
2: Not detected 
3: Not done 
PCRPCR_muestra_CT_E 
Gene E (PCR sample)  Ct  
Real 
12-40 (41 if not 
detected) 
PCRPCR_muestra_Q_E 
Gene E (PCR sample) 
Quantity (Copies/ml) 
Integer 
0-1012 
PCRPCR_gen_ab1 
Gene ab1 (PCR sample) 
Result 
Integer 
1: Detected 
2: Not detected 
3: Not done 
PCRPCR_muestra_CT_ab1 
Gene ab1 (PCR sample)  Ct 
Real 
12-40 (41 if not 


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detected) 
PCRPCR_muestra_Q_ab1
Gene ab1 (PCR sample) 
Quantity (Copies/ml) 
Integer
0-1012
PCRPCR_cul_N
Gene N (PCR culture) Result 
Integer
1: Detected
2: Not detected 
3: Not done 
PCRPCR_cultivo_CT_N
Gene N (PCR culture) Ct
Real
12-40 (41 if not 
detected) 
PCRPCR_cultivo_Q_N
Gene N (PCR culture) 
Quantity (Copies/ml) 
Integer
0-1012
PCRPCR_cul_E
Gene E (PCR culture) Result 
Integer
1: Detected
2: Not detected 
3: Not done 
PCRPCR_cultivo_CT_E
Gene E (PCR culture) Ct
Real
12-40 (41 if not 
detected) 
PCRPCR_cultivo_Q_E
Gene E
(PCR culture) 
Quantity (Copies/ml) 
Integer
0-1012
PCRPCR_cul_ab1
Gene ab1 (PCR culture) 
Result  
Integer
1: Detected
2: Not detected 
3: Not done 
PCRPCR_cultivo_CT_ab1
Gene ab1 (PCR culture) Ct
Real
12-40 (41 if not 
detected) 
PCRPCR_cultivo_Q_ab1
Gene ab1 (PCR culture) 
Quantity (Copies/ml) 
Integer
0-1012
Laboratory test 1,7,14
BIOCHEMCreatinine 
Blood creatinine (mg/dL) 
Real 
Male: 0.7-1.2 
Female: 0.5-0.9 
BIOCHEMUreaBlood 
Urea blood (mg/dL) 
Integer 
16.6-48.5 
BIOCHEMMDRD 
MDRD (mL/min/1.73m2) 
Real 
60- 
BIOCHEMLDH 
LDH (Ul/L) 
Real 
135-225 
BIOCHEMCRP 
CRP (mg/dL) 
Real 
0-0.5 
BIOCHEMTroponin 
Troponin T (ng/L) 
Real 
0-13 
BIOCHEMProcalcitonin 
Procalcitonin (ng/mL) 
Real 
0-0.5 
 
 
 
 
BIOCHEMSodium 
Sodium (mEq/L) 
Real 
136-145 
BIOCHEMPotassium 
Potassium (mEq/L) 
Real 
3.5-5 
BIOCHEMChlorine 
Chlorine (mEq/L) 
Real 
98-107 
BIOCHEMBicarbonate 
Bicarbonate (mEq/L) 
Real 
22-29 
BIOCHEMRemAnion 
Remaining anion (mEq/L) 
Real 
8-16 
BIOCHEMFerritin 
Ferritin (ng/mL) 
Real 
Male: 30-400 
Female: 15-150 
BIOCHEMCPK 
CPK (Ul/L) 
Real 
Male: 0-190 


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Female: 0-170 
BIOCHEMIL6
IL-6 (pg/mL)
Real
0-7
COAGDimero
D-Dimer (ng/mL)
Real
150-500
BCRBC 
Red blood cells (1012/L) 
Real
Male: 4.7-5.1
Female: 4.2-5.4 
BCHb 
Haemoglobin (g/dL) 
Real
Male: 14-17
Female: 12-16 
BCHto 
Hto (%) 
Real
Male: 42-49
Female: 37-48 
BCVCM
VCM (fL)
Real
80-95
BCHCM
HCM (pg)
Real
27-31
BCCMHC
CMHC (g/dL)
Real
33-35
BCRDW
RDW (%)
Real
11.5-14.5
BCPlaquetas
Platelets (109/L)
Integer
150-450
BCVPM
VPM (f/L)
Real
7.2-11.1
BCPDW
PDW (%)
Real
25-65
BCPTC
PTC (%)
Real
0.12-0.36
BCWBC
White blood cells (109/L)
Real
4.8-10.8
BCNeutrophils
Neutrophils (%)
Real
45-75
BCTotalNeutrophils
Total Neutrophils (109/L)
Real
1.5-6.5
BCLymphocytes
Lymphocytes (%)
Real
20-50
BCTotalLymphocytes
Total Lymphocytes (109/L)
Real
1.2-4
BCMonocytes
Monocytes (%)
Real
2-9
BCTotalMonocytes
Total Monocytes (109/L)
Real
0.4-0.8
BCEosinophils 
Eosinophils (%) 
Real 
0-6 
BCTotalEosinophils 
Total Eosinophils (109/L) 
Real 
0-0.4 
BCBasophils 
Basophils (%) 
Real 
0-4 
BCTotalBasophils 
Total Basophils (109/L) 
Real 
0-0.2 
Serology  
SEROLOGYSerSarsCoV2 1,21 
SARS-CoV-2 (COVID-19) 
Serology result 
Integer 
0: Negative 
1: Positive 
BIOBANKEDTA5 
EDTA 5 Biobank collected 
Integer 
0: No 
1: Yes 
BIOBANKEDTA5_PBMC 
EDTA 5 Biobank (PBMC) 
collected 
Integer 
0: No 
1: Yes 
BIOBANKSerumBiobank 
Serum 10 Biobank collected 
Integer 
0: No 
1: Yes 
BIOBANKHeparinBiobank 
Heparin 10 Biobank collected 
Integer 
0: No 
1: Yes 


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Superscripts indicate the days in which each variable is collected. Variables with no superscripts 
are collected at all visits. 
ENT: Ear, Nose, Throat. 
5.5.4 
Concomitant medication (during follow up) 
Details on concomitant treatments will be collected during the study. 
Variable name 
Description 
Data 
type 
Coding or range 
Medication
Medication
String
Units
Units
String
FREQ
Frequency
String
TotalDailyDose
Todal daily dose
Integer
Reason
Reason
String
StartDate
Start Date
Date
EndDate
End Date
Date
CMContinuing
Continuing at end of trial?
Integer
0: No
1: Yes 
5.5.5 
Adverse Events (during follow up) 
For each Adverse Event occurred, the following details will be recorded. 
Variable name 
Description 
Data 
type 
Coding or range 
AE
Adverse Event name
String
 
StartDate 
Start Date 
Date 
 
TimeStart 
Start Time 
Date 
 
Ongoing 
Is the Adverse Event ongoing? 
Integer
0: No 
1: Yes 
EndDate 
End Date 
Date 
 
TimeEnd 
End Time 
Date 
 
Outcome 
Outcome 
Integer
1: Recovered 
2: Recovered with sequelae 
3: Continuing 
4: Patient Died 
5: Change in AE 
6: unknown 
Severity 
Severity 
Integer
1: Mild 
2: Moderate 
3: Severe 
RelationshipStudyDrug1 
Plausible relationship to Study 
Drug 
Integer
0: No 
1: Yes 
ActionTaken 
Action taken with Study Drug 
Integer
1: None 


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2: 
Dose 
Reduction 
Temporarily 
3: Dose Reduced 
4: Discontinued Temporarily 
5: Discontinued 
WithdrawnDueAE
Withdrawn due to an adverse 
event? 
Integer
0: No
1: Yes 
SAE
Serious adverse event (SAE)?
Integer
0: No
1: Yes 
SAEReporting
If 
SAE 
does 
it 
require 
immediate reporting? 
Integer
0: No
1: Yes 
1: An event will be considered as related to the study drug if it appears within 5 days after its 
administration. 
5.5.6 
Daily self-assessment of symptoms 
Each patient will give information on the variables below each day during follow up. 
Variable name 
Description 
Data 
type 
Coding or range 
day
Follow up day
Integer
1-28
como_se_encuentra
How do you fell today?
Integer
1: Better than yesterday
2: Same as yesterday 
3: Worse than yesterday 
malestar_si_no
Are you feeling generally unwell 
or tired? 
Integer
0: No
1: Yes 
malestar_mejor 
If feeling generally unwell or tired, 
is it:  
Integer
1: Better than yesterday 
2: Same as yesterday 
3: Worse than yesterday 
temp_si_no 
Have 
you taken your body 
temperature? 
Integer
0: No 
1: Yes 
temp 
What has been your highest 
temperature since yesterday? (in 
ºC) 
Real 
35-41 
fiebre 
Have you had a fever since 
yesterday? 
Integer
0: No 
1: Yes 
tos_si_no 
Do you have a cough? 
Integer
0: No 
1: Yes 
tos_es 
Your cough is: 
Integer
1: Dry 
2: Productive 
tos_expectoracion 
Your expectoration: 
Integer
1: Is whitish 
2: Is yellowish 
3: Is greenish 
4: Has blood 


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tos_esta 
Your cough is: 
Integer
1: Better than yesterday 
2: Same as yesterday 
3: Worse than yesterday 
tos_esta
Does your cough make it difficult 
for you to eat, drink or talk? 
Integer
0: No
1: Yes 
olores
Can you perceive odours well?
Integer
0: No
1: Yes 
mal_sabor
Do you have a bad taste in your 
mouth? 
Integer
0: No
1: Yes 
cefalea
Cephalea
Integer
0: No
1: Yes 
dolor_cabeza
Do you have a headache?
Integer
0: No
1: Yes 
dolor_garganta
Do you have a sore throat?
Integer
0: No
1: Yes 
congestion_si_no
Do you have a stuffy nose?
Integer
0: No
1: Yes 
fatiga_si_no
Do you have fatigue? (Shortness
of breath?) 
Integer
0: No
1: Yes 
fatiga
You 
are 
fatigated: 
(multiple 
choice) 
Integer
1: Resting
2: When talking 
3: When walking 
4: When climbing stairs 
vomitos_si_no
Do you have vomiting?
Integer
0: No
1: Yes 
casados_por_tos 
Is it caused by coughing? 
Integer
0: No 
1: Yes 
veces_vomitado 
How many times have you 
vomited since yesterday? 
Integer
1- 
diarrea_si_no 
Do you have diarrhea? 
Integer
0: No 
1: Yes 
deposiciones 
How many bowel movements 
have you had since yesterday? 
Integer
1- 
medicacion_si_no 
Have you taken any medication 
for these symptoms in the last 24 
hours? 
Integer
0: No 
1: Yes 
medicacion_cual 
If yes, which one? 
String 
 
sintomas_1 
Since 
yesterday, 
have 
you 
experienced 
any 
of 
these 
symptoms? (multiple choice) 
Integer
1: Confusion / difficulty 
concentrating on something 
2: Dizziness 
3: Drowsiness 
4: Vertigo 


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5: Tremors 
sintomas_2
Since 
yesterday, 
have 
you 
experienced 
any 
of 
these 
symptoms? (multiple choice) 
Integer
1: Blurry vision
2: Difficulty focusing on 
objects or reading 
3: Tunnel vision 
4: Abnormal colors or shapes
5: Blind spots 
6: Floating points 
sintomas_3
Since 
yesterday, 
have 
you 
experienced 
any 
of 
these 
symptoms? (multiple choice) 
Integer
1: Pruritus (itching)
2: Rash  
6 Sample Size  
The study will enroll 24 participants, 12 per arm. The sample size has been calculated for 
comparing two proportions. This sample provides 80% power at 5% significance level using 
Fisher´s unilateral test to determine a difference of 45% (100% vs 55%) in the proportion of 
participants with positive PCR at day 7. This includes up to one participant lost to follow up (LFU) 
per arm. We estimated this low LFU level given that the patients will be isolated at home and 
will have a low risk of progression to severe disease. The 100% positivity rate at day seven is 
based on the clinical experience at the Clínica Universidad de Navarra. Figure 1 provides the 
relationship power-outcome measure for the full sample and one scenario considering LFU of 
up to two patients per arm. 
 
Figure 1 Trial power scenarios for different effect size and loss to follow up levels. 


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7 General Considerations 
7.1 Timing of Analyses 
Data will be collected using the ShareCRF platform [3], which uses automatic rules to provide 
high quality data. No additional cleaning process will be needed. Daily self-assessment of 
symptoms will be recorded by each participant in an ODK platform. The final analysis will take 
place after all subjects have completed the final visit or dropped out and after the finalization 
and approval of this SAP document. 
7.1.1 
Full Analysis Population 
The efficacy analysis will be done per protocol (PP), including all randomized participants for 
whom there is a PCR result at day seven. 
7.1.2 
Safety Population 
The safety analysis will be done using a modified intention to treat (mITT) approach considering 
all randomized and treated participants. 
7.2 Covariates and Subgroups 
No covariate nor subgroup analyses planned. 
7.3 Missing Data 
All the available data on safety and efficacy shall be included in the data lists and tables. No 
values shall be allocated for unavailable data. 
Any confusing or incorrect data shall be examined in accordance with the standardized data 
control procedures. 
In the analysis of the records reported by patients (RRP), the omitted data shall be allocated by 
using the last observation carried forward. The omitted standard shall be examined before any 
allocation. If the omitted standard is clearly informative, the repercussion of the non-random 
data shall be evaluated using sensitivity analysis. 
For the RRP analysis, if a section of subscale from several is missing, the average of the remaining 
sections shall be used as a scoring scale, as long as at least half of the sections of the scale is 
available. 
7.4 Multiple Testing 
Adjustment for multiple testing will not be necessary as there is only one primary outcome. 
8 Summary of Study Data 
Descriptive analyses will use frequency and percentage (based on the non-missing sample size) 
for qualitative variables and median, interquartile range and n (non-missing sample size) for 
quantitative variables. Summary tables will be structured using one column per study arm and 
overall in the order: Placebo, Ivermectin, All subjects.   


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8.1 Subject Disposition 
The number of subjects reaching each study stage will be defined as: 
 
 
Assessed for eligibility if any information available o
baseline visit CRF. 
 
Randomized if study identifier given and recorded in the baseline visit CRF. 
 
Reached visit 2, 3, 4, 5 or final if any information available on the CRF corresponding to 
that visit. 
 
Analyzed if PCR result at day 7. 
A skeleton CONSORT flow diagram is provided below. 
 
 
Analysed 
 
(n= 
 
) 
 Excluded from analysis (give reasons) 
(n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Allocated to ivermectin (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention 
(give reasons) (n=  ) 
Analysed 
 
(n= 
 
) 
 Excluded from analysis (give reasons) 
(n=  ) 
Analysis
Follow-Up
Assessed for eligibility (n=  ) 
Not included  (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
   Other reasons (n=  ) 
Allocated to placebo (n=  ) 
 Received allocated placebo (n=  ) 
 Did not receive allocated placebo (give 
reasons) (n=  ) 
Allocation
Randomized (n=  ) 


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8.2  Derived variables 
The following table contains the list of derived variables that will be used in the analysis. 
Variable name 
Description 
Calculation 
Data 
type 
Coding 
or range 
any_symptom 
Any symptom 
reported 
General OR ENT OR 
Respiratory OR Digestive OR 
Others 
Integer
0: No 
1: Yes 
platelet_lymphocyte 
Platelet-Lymphocyte 
index 
Platelet / Lymphocyte 
Real 
0- 
neutrophil_lymphocyte
Neutrophil-
Lymphocyte index 
Neutrophil / Lymphocyte 
Real 
0- 
severity_pred
Severity predictor
N/L*CRP*D-dimer
Real
0-
vload_change 
Viral load change 
(viral load [n] viral load [1]) / 
viral load [1] 
Real 
- 
A list of variables with 
 
Primary parameters 
of viral kinetic 
Individual curve fits and non-
linear mixed effects models 
Real 
- 
 
8.3 Concurrent Illnesses and Medical Conditions 
No standard coding system will be used for concurrent illnesses and medical conditions. Each 
condition will be classified according to the affected system (Cardiovascular, Respiratory, 
Hepato-biliary, Gastro-intestinal, Genito-urinary, Endocrine, Hematological, Musculo-skeletal, 
Neoplasia, Neurological, Psychological, Immunological, Dermatological, Allergies, Eyes, ear, 
nose, throat  or Other). The summary statistics will be produced in accordance to section 7. 
8.4  Prior and Concurrent Medications 
No standard coding system will be used for medications. The summary statistics will be produced 
in accordance to section 7. 
8.5 Treatment Compliance 
Study treatment is administered using the directly observed therapy (DOT) method. With this 
method, treatment adherence is ensured as a health care professional watches the study 
participants while they take their medication.  
No treatment compliance measures will be calculated. 
9 Efficacy Analyses 
9.1 Primary Efficacy Analysis 
The proportion of participants with positive PCR at day seven post treatment will be calculated. 
Proportions will be compared between study arms 
sented as a 
relative risk ratio (RR), or reduction of the RR (1- RR) if RR lower than 1, and 95% Confidence 


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Interval (CI). Differences will be considered statistically significant if the p-value obtained is 
lower than 0.05. 
9.2 Secondary Efficacy Analyses 
Secondary endpoints will be analyzed using descriptive methods as explained in section 8. 
Graphics such as alluvial diagrams and boxplots will be also employed to assess evolution along 
follow up for qualitative and quantitative variables, respectively. For each symptom and for all 
as a composite outcome, Kaplan-Meyer survival curves will be used to show time to 
improvement. The effect of study treatment on the presence of symptoms will be estimated 
using mixed effect logistic regression models with subject as a random intercept. These models, 
will be adjusted by day of follow up as symptoms are expected to disappear over time. 
We will attempt to fit viral load profiles as quantified by rt-PCR to standard viral kinetics models 
(e.g. target cell limited models or eclipse models). Fitting strategies will comprise individual 
curve fits and non-linear mixed effects models. For successful fits, primary parameters of viral 
kinetic can be derived and compared between treatment arms. Examples include virion 
clearance rate, cell death rate, cellular infectivity, and acquired immune effects. Given sufficient 
data, secondary parameters such as peak viral load, time to peak viral load, and exposure as 
quantified by area under the curve can be calculated. 
10 Safety Analyses 
All the adverse events that occur during the study will be included in the data lists and sorted by 
patient and order of occurrence. Events that are considered to be related to the treatment 
(possibly, probably or definitely related to it) will also be included in a table. A table will with the 
list the adverse events according to maximum intensity will be provided. The deaths and serious 
adverse events will also be classified in a separate table. 
Summary statistics on the number of observed events and their relatedness with the study drug 
will be presented by study arm and overall.  
10.1  Extent of Exposure 
The summary statistics will be produced in accordance to section 7. 
10.2  Adverse Events 
The summary statistics will be produced in accordance to section 7. 
10.3  Deaths, Serious Adverse Events and other Significant Adverse Events 
The summary statistics will be produced in accordance to section 7. 
10.4  Pregnancies 
Pregnant women will not be included in the trial. Pregnancy tests will be administered before 
recruitment to all women of child bearing age. 
10.5  Clinical Laboratory Evaluations 


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The summary statistics will be produced in accordance to section 7. 
11  Pharmacokinetics 
Not applicable. 
12 Reporting Conventions 
P-values greater or equal to 0.001 will be reported to 3 decimal places. P-values less than 0.001 
same number of decimal places as the original data. 
13 Technical Details 
The analyses will be conducted using Stata version 16 [2]. Graphs will be produced using the 
packages ggplot2 [4] and ggalluvial [5] for R version 4.0.2. [6]. The operating system of the 
computer will be Windows 10. 
 
 


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14 References 
 
[1] P. Ryan, RALLOC: Stata module to design randomized controlled trials, revised 28 Jan 2018 
ed., Statistical Software Components S319901, Boston College Department of Economics, 
1997.  
[2] StataCorp, Stata Statistical Software: Release 16, College Station, TX: StataCorp LLC, 2019. 
[3] "ShareCRF," [Online]. Available: www.ShareCRF.com.
[4] H. Wickham, ggplot2: Elegant Graphics for Data Analysis, Springer-Verlag New York, 2016. 
[5] J. C. Brunson, ggalluvial: Alluvial Plots in 'ggplot2', 2020. 
[6] R Core Team, R: A Language and Environment for Statistical Computing, Vienna, Austria: R 
Foundation for Statistical Computing, 2020.  
 
 
 
 


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15  Listing of Tables, Listings and Figures 
15.1 Tables  
Table 1. Baseline description of study participants 
Variable 
Study arm
All subjects 
Placebo
Ivermectin
Demographics
Gender: female 1
Age 2
Height (in m) 2
Weight (in kg) 2
BMI (in kg/m2) 2
Smoking habits and alcohol consumption
Smoker or tobacco products user 1
Number of cigarettes per day 2
Smoking duration (in years) 2
Alcohol consumption 1
Weekly alcohol consumption (in units) 2
Medication
Taking medication 1, 3
Previous medical history
Cardiovascular 1
Respiratory 1
Hepato-biliary 1 
 
 
 
Gastro-intestinal 1 
 
 
 
Genito-urinary 1 
 
 
 
Endocrine 1 
 
 
 
Hematological 1 
 
 
 
Musculo-skeletal 1 
 
 
 
Neoplasia 1 
 
 
 
Neurological 1 
 
 
 
Psychological 1 
 
 
 
Immunological 1 
 
 
 
Dermatological 1 
 
 
 
Allergies 1 
 
 
 
Eyes, ear, nose, throat 1 
 
 
 
Others 1 
 
 
 
1: n/N (Percentage) 
2: Median (IQR) [n] 
3: includes OTC, vitamins and supplements 
 


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Table 2. Baseline clinical description of study participants 
Variable 
Study arm
All subjects 
Placebo
Ivermectin
Symptoms
General 1, 3
ENT 1,4
Respiratory 1
Digestive 1
Others 1
Physical examination results, system affected
General appearance 1
Heart 1
Lungs 1
Abdomen 1
Extremities 1
Others 1
Vital signs
Heart rate (in bmp) 2
Blood pressure (in mmHg)
Systolic 2
Diastolic 2
Temperature (in ºC) 2
Oxygen saturation (in %) 2
Respiratory rate (in breaths per minute) 2
Chest X-Ray 
Abnormal result 1 
 
 
 
Pregnancy test 
Test conducted 1, 5 
 
 
 
Positive test result 1 
 
 
 
Laboratory results 
Positive nasopharyngeal swab for SARS-CoV-2 1 
 
 
 
Positive for IgG antibodies 1 
 
 
 
IgG antibodies (in mg/dL) 2 
 
 
 
Positive for IgM antibodies 1 
 
 
 
IgM antibodies (in mg/dL) 2 
 
 
 
Positive for IgA antibodies 1 
 
 
 
IgA antibodies (in mg/dL) 2 
 
 
 
Blood creatinine (in mg/dL) 2 
 
 
 
Urea blood 2 
 
 
 
MDRD 2 
 
 
 
LDH (in U/L) 2 
 
 
 
CRP (in mg/L) 2 
 
 
 


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Troponin T (in ng/mL) 2 
 
 
 
Procalcitonin (in ng/mL) 2
Sodium (in mEq/L) 2
Potassium (in mEq/L) 2
Chlorine (in mEq/L) 2
Bicarbonate (in mEq/L) 2
Remaining anion (in mEq/L) 2
Ferritin (in ng/mL) 2
CPK (in Ul/L) 2
D-Dimer (in ng/mL) 2
IL-6 (in pg/mL) 2
Hemogram
Red blood cells (in 1012/L)
Haemoglobin (in g/dL)
Hto (in %)
VCM (in f/L)
HCM (in pg)
CMHC (in g/dL)
RDW (in %)
Platelets (in 109/L)
VPM (in f/L)
PWD (in %)
White blood cells (in 109/L)
Neutrophil (in %)
Neutrophil absolute value (in 109/L) 
 
 
 
Lymphocyte (in %) 
 
 
 
Lymphocyte absolute value (in 109/L) 
 
 
 
Monocytes (in %) 
 
 
 
Monocytes absolute value (in 109/L) 
 
 
 
Eosinophil (in %) 
 
 
 
Eosinophil absolute value (in 109/L) 
 
 
 
Basophiles (in %) 
 
 
 
Basophiles absolute value (in 109/L) 
 
 
 
Platelet-Lymphocyte index 
 
 
 
Neutrophil-Lymphocyte index 
 
 
 
Severity predictor?? (N/L*CRP*D-dimer) 
 
 
 
1: n/N (Percentage) 
2: Median (IQR) [n] 
3: includes General malaise, Myalgia, Appetite, Headache 
4: ENT: Ear, Nose, Throat (includes anosmia and dysgeusia) 
5: only women considered in this section 
 


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Table 3. PCR positivity  
Variable 
Study arm
RR (95% CI) 
p-value 2 
Placebo
Ivermectin
Positive PCR at day 7 1
Positive PCR culture at day 4 1
Positive PCR culture at day 7 1
1: n/N (Column percentage) 
 
RR: risk ratio, CI: confidence interval 
 
Table 4. Seroconversion at day 21 
Variable 
Study arm
All subjects 
Placebo
Ivermectin
Seroconversion at day 21 1
1: n/N (Column percentage) 
 
Table 5. Seroconversion at day 21 in patients taking ivermectin 
Variable 
PCR at day 7
Negative
Positive
Seroconversion at day 21 1
1: n/N (Column percentage) 
 
Table 6. AEs description 
Variable 
Study arm 
All subjects 
Placebo 
Ivermectin 
Number of AEs observed 
 
 
 
Number of SAEs observed 
 
 
 
Drug-related SAEs 2 
 
 
 
Observed serious adverse events (per subject) 
 
Number of SAEs during FU 1 
 
 
 
Death 2 
 
 
 
Body as a whole 2 
 
 
 
Gastrointestinal 2 
 
 
 
Nervous System/Psychiatric 2 
 
 
 
Skin 2 
 
 
 
 
 
 
 
1: Median (IQR) [n] 
2: n/N (Percentage) 


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Table 7. Treatment effect on symptom presence 
Variable 
OR (95% CI) 
p-value 1 
Treatment
Day
1: Mixed effect logistic regression model with subject as a random intercept 
 
15.2 Listings 
List 1. Patient baseline information 
Patient
Study arm
Ct
Vital signs
Symptoms 
Lab results + immuno
1
Placebo
value
2
Placebo
3
Placebo
4
Placebo
5
Placebo
6
Placebo
7
Placebo
8
Placebo
9
Placebo
10
Placebo
11
Placebo
12 
Placebo 
 
 
 
 
13 
Ivermectin 
 
 
 
 
14 
Ivermectin 
 
 
 
 
15 
Ivermectin 
 
 
 
 
16 
Ivermectin 
 
 
 
 
17 
Ivermectin 
 
 
 
 
18 
Ivermectin 
 
 
 
 
19 
Ivermectin 
 
 
 
 
20 
Ivermectin 
 
 
 
 
21 
Ivermectin 
 
 
 
 
22 
Ivermectin 
 
 
 
 
23 
Ivermectin 
 
 
 
 
24 
Ivermectin 
 
 
 
 
 
 
 
 


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List 2. List of all AEs occurred  
Study arm
AE diagnosis
Drug relatedness
Severity
Action taken
Withdrawal due to AE
 
List 3. List of all SAEs occurred  
Study arm
AE diagnosis
Drug relatedness
Severity
Action taken
Withdrawal due to AE
 
15.3 Figures 
Figure 1. Viral load evolution during FU (days 1, 4, 7, 14 and 21) by study arm 
This figure will contain a boxplot for each day and study arm. 
[boxplots] 
 
Figure 2. Viral load change during FU (days 1, 4, 7, 14 and 21) by study arm 
A boxplot for each day and study arm. 
 [boxplots] 
 
Figure 3. Viral load evolution during FU (days 1, 4, 7, 14 and 21) by study participant 
 
 [line plots] 
 
Figure 4. Symptom presence during FU (days 1, 4, 7, 14 and 21) by study arm 
One diagram for each symptom considered: General (General malaise, Myalgia, Appetite, 
Headache), ENT (includes anosmia and dysgeusia), Respiratory and Digestive. 
[Alluvial diagram] 
 
 


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Figure 5. System abnormalities identified during FU (days 1, 4, 7, 14 and 21) by study arm 
One diagram for each system considered: General Appearance, Heart, Lungs, Abdomen and 
Extremities. 
[Alluvial diagram] 
 
Figure 6. Time to symptom improvement by study arm 
General (General malaise, Myalgia, Appetite, Headache), ENT (includes anosmia and dysgeusia), 
Respiratory and Digestive. 
 [Kaplan-Meier curve] 
 
Figure 7. Time to severe disease or death by study arm 
[Kaplan-Meier curve]