A Phase 2/3, Adaptive, Randomized, Controlled, Double-blind Study to Investigate the Pharmacokinetics, Efficacy and Safety of the Hyperimmune Equine Serum (INM005) in Adult Patients With Moderate to Severe Confirmed SARS-CoV-2 Disease.
Phase: PHASE2
Conditions: COVID-19
Sponsor: Inmunova S.A.

 
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DRUG: 
INM005 
 
STUDY NUMBER(S): 
CT-INM005-01 
 
PROTOCOL TITLE: 
A phase II/III, adaptive, randomised, controlled, 
double-blind 
study 
to 
investigate 
the 
pharmacokinetics, 
efficacy and safety 
of the 
hyperimmune equine serum INM005 in adult patients 
with moderate to severe confirmed SARS-CoV-2 
disease. 
SPONSOR: 
INMUNOVA S.A. 
25 de Mayo 1021 (ZC 1650), 
San Martín, Buenos Aires, Argentina. 
 
DATE OF ORIGINAL 
PROTOCOL: 
05-Jul-2020 
 
VERSION NUMBER: 
1.1 ADMINISTRATIVE AMENDMENT 
VERSION DATE: 
28SEP2020 
 
This study will be carried out in accordance with the protocol, the ICH GCP and the 
applicable 
regulatory 
requirements. 
The information contained in this document is the property of INMUNOVA S.A. and its 
copying, disclosure or distribution by an external authority to other persons without the 
prior written permission of INMUNOVA is prohibited.  

 
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CLINICAL PROTOCOL APPROVAL FORM 
Protocol title: A phase II/III, adaptive, randomised, controlled, double-blind study to 
investigate the pharmacokinetics, efficacy and safety of the hyperimmune equine serum 
INM005 in adult patients with moderate to severe confirmed SARS-CoV-2 disease. 
 
Study No.: CT-INM005-01 
Date of original protocol: 5-Jul-2020 
 
Protocol version No.: 1.1 ADMINISTRATIVE AMENDMENT 
Protocol version date.:  28SEP2020 
 
This study protocol has been critically reviewed and approved by the sponsor's Protocol Review 
Committee. The information contained in this protocol is consistent with: 
● The current benefit-risk assessment of the investigational medicinal product (IMP) (i.e., 
INM005). 
● The moral, ethical and scientific principles that govern clinical research as established in the 
Declaration of Helsinki, the principles of Good Clinical Practice (GCP) and the applicable local 
requirements. 
The investigator will be informed of any new or significant findings, including adverse events (AE), 
related to the treatment with INM005. 
Name and title 
Contact information 
Signature 
Date 
Santiago 
Sanguineti,  
PhD in Biological 
Sciences 
Project Manager   
INMUNOVA S.A. 
Tel: (5411) 2033 1455 - Ext. 6059 
Mobile: (54911) 4564 3625 
25 de mayo 1021 -B1650HMP 
San Martin - Buenos Aires, Argentina 
ssanguineti@inmunova.com 
 
  
  

 
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Mariana Colonna 
Biochemist 
Clinical 
Research 
Manager 
INMUNOVA S.A. 
Tel: (+5411) 20331455 - Ext. 6184 
Mobile: (+54911) 61718697 
25 de mayo 1021 -B1650HMP 
San Martin - Buenos Aires, Argentina 
mcolonna@inmunova.com 
 
  
  
Pedro Cahn, MD 
Scientific Director  
 
 
Fundación Huésped                      
Tel: (+5411) 49817777, Ext. 153     
 
 
Carlos Gianantonio 3932, CABA, 
C1202ABB                                      
pedro.cahn@huesped.org.ar 
 
  
 
Omar Sued, MD 
Director of Clinical 
Research  
Fundación Huésped                           
Tel: (+5411) 49817777, Ext. 153     
 
 
Carlos Gianantonio 3932, CABA, 
C1202ABB                                      
omar.sued@huesped.org.ar 
 
  
 
 
 

 
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INVESTIGATOR 
STATEMENT 
OF 
CONFIDENTIALITY 
AND 
COMMITMENT 
A PHASE 2/3, ADAPTIVE, RANDOMISED, CONTROLLED, DOUBLE-BLIND STUDY 
TO INVESTIGATE THE PHARMACOKINETICS, EFFICACY AND SAFETY OF THE 
HYPERIMMUNE EQUINE SERUM INM005 IN ADULT PATIENTS WITH MODERATE 
TO SEVERE CONFIRMED SARS-COV-2 DISEASE. 
The information contained in this protocol and all other relevant information in relation to 
INM005 constitutes confidential information owned by INMUNOVA S.A., and may not be 
disclosed to third parties without prior written authorisation from INMUNOVA SA, unless 
required by local, state or federal laws or regulations. 
I agree to provide all study staff under my supervision with copies of the protocol and its 
amendments, as well as access to all the information provided by INMUNOVA or the persons 
designated to that end. I will also review this material with the staff members to ensure they 
are fully informed about INMUNOVA and this study. 
By signing below, I confirm that I have read this protocol and consider that it contains all the 
information necessary to carry out the study. I confirm that I will carry out the study in 
accordance with the provisions of current local regulations on the matter and the guidelines 
of the International Council on Harmonisation of Technical Requirements for the 
Registration of Pharmaceutical Products for Human Use that have their origin in the 
Declaration of Helsinki, and in accordance with the procedures described in this protocol. 
 
 
Name of the Principal Investigator 
(printed) 
 Signature 
 
 
Date 
 Site number 
 
 

 
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CHANGES IN THE AMENDMENT CT-INM005-01 
Below is the summary of the changes included in this administrative amendment to the 
Protocol: 
 
Section 5.2 and 11.7 
The cut-off value of the interim analysis is modified: it will be carried out when the follow-
up of approximately 145 patients (60% recruitment) is completed instead of 192 patients 
(80% recruitment). 
 
The changes notified in due time in the ERRATUM v1.0_7ago2020 are also incorporated: 
 
• 
MANAGEMENT OF THE STUDY DRUG 
 
By mistake, on page 97, it was stated, "Each vial contains 25 mg of protein/ml", but it should 
read, "Each ml contains 30 mg of protein," as stated in Table 8.1, on page 96. 
 
By mistake, on page 97, it was stated, “Each vial contains 25 mg of protein/ml, therefore 
each subject should receive 0.16 ml/kg”. The statement should read, "Each vial contains 30 
mg of protein/ml, therefore each subject must receive 0.13 ml/kg," as established in the 
INVESTIGATIONAL PRODUCT HANDLING MANUAL: INM005 (v1.0 of 15Jul2020). 
 
By mistake, on page, 97 it was stated, "Two doses of IMP will be administered as an infusion 
at a rate of 2.0 ml/min over a 50 min period with a 24 h interval between doses." It should 
read, “Two doses of IMP will be administered as an infusion at a rate of 2.0 ml/min over a 
50-minute period with a 48-hour interval between doses” as stated in section 1.4. 
 
• 
PHARMACOKINETICS 
 
In the study schedule, on page 73, an “X” appears on day 5 for the item “Extraction of PK 
samples (pharmacokinetics)”, but it should appear on day 7 as established in section 1.4.6, 
and in the footer of the schedule (item 24). 
 
The changes notified in due time in the CLARIFICATION LETTER v1.0_19ago2020 are 
also incorporated: 
 
• 
SECTION 1.1.1.3 Stratification by Risk - DEFINITION OF MODERATE 
CASE OF COVID-19 
 
It is hereby clarified that the definition used in the reference protocol is that cited by the US 
National Institute of Health (NIH) according to what is mentioned on protocol page 32 (quote 
36): 
https://www.covid19treatmentguidelines.nih.gov/overview/management-of-covid-19/: 

 
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Moderate disease: Individuals who have evidence of lower respiratory disease, as assessed 
by clinical evaluation or imaging and an oxygen saturation (SpO2) ≥ 94% in ambient air. 
 
By mistake, a preliminary definition was left in the protocol that does not coincide with quote 
36: (Patients with fever, respiratory symptoms and radiological findings of pneumonia) 
 
 
• 
SECTION 7.1 Efficacy Assessments - WHO ORDINAL SCALE 
 
Patient classification according to the WHO scale is based on the quote “WHO R&D 
Blueprint Novel Coronavirus,” as stated in the protocol, on page 88 (quote 78): 
https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf  
 
By mistake, the inclusion for scale 4 that the requirement for oxygen can be by means of a 
mask or nasal tube, was omitted  
0- No evidence of infection 
1- Outpatient, with no limitation to activities 
2- Outpatient, with limitation to activities 
3- Hospitalised with no oxygen therapy requirement 
4- Oxygen therapy employing either a mask or a nasal tube 
5- Non-invasive ventilation or high-flow oxygen 
6- Intubation and mechanical ventilation 
7- Mechanical ventilation and organ support (vasopressors, ECMO [extracorporeal 
membrane oxygenation], RRT [renal replacement therapy]) 
8- Death 
 
• 
5.3 Inclusion/Exclusion Criteria - EXAMPLES OF PRIOR USE OF EQUINE 
SERUM IN HISTORY 
 
In relation to the examples proposed for the assessment of the exclusion criterion 4: 4. History 
of anaphylaxis, previous administration of equine serum (e.g. anti-tetanus serum or antivenin 
serum, or arachnid antitoxin serum), or an allergic reaction by contact or exposure to horses”, 
it is clarified that the production of equine anti-tetanus serum stopped in 1970, and therefore 
a patient to whom the anti-serum was administered after that date may be a candidate for the 
study, for the serum is of human origin. 
 
• 
10.2 NOTIFICATION OF SERIOUS ADVERSE EVENTS (SAEs) 
 
It is clarified that, for the reference study, the events that the investigator considers to be 
related to COVID-19 progression are part of the primary and secondary data set used for the 
study efficacy analyses, and therefore will not be considered as an AE, will not be registered 

 
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as a SAE in the clinical study safety database, and will not be notified to regulatory authorities 
under expedited modality. 
 
Regarding death events, in all cases they should be reported as an SAE as described in Section 
10.1 of the protocol. 
 
 
 
 
 
 
 

 
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STUDY SUMMARY 
Title: 
A phase 2/3, adaptive, randomised, controlled, double-blind study to investigate the 
pharmacokinetics, efficacy and safety of the hyperimmune equine serum INM005 
in adult patients with moderate to severe confirmed SARS-CoV-2 disease. 
Clinical Phase: 
2/3 
Rationale: 
The pandemic caused by the novel coronavirus has generated an unprecedented 
situation in recent history, with several million infected and hundreds of thousands 
of deaths. This disease is easily transmissible by air. Although a high percentage of 
patients have a mild clinical presentation, approximately 15% of them present a 
moderate to severe disease, and 5% require intensive care with mechanical 
ventilation and face a high risk of mortality. No effective therapies for the 
treatment or prevention of SARS-CoV-2 have been identified so far. Preliminary 
evidence indicates that passive immunotherapy with convalescent plasma could 
favourably alter the clinical course of this infection. This strategy, even if confirmed 
as successful, requires voluntary donation by patients who have recovered, not all 
of whom are eligible as donors, since the antibody response magnitude varies 
among different patients. This study aims at studying the efficacy and safety of 
passive immunotherapy by administering hyperimmune serum INM005 generated 
by the antigenic stimulation of equines. INM005 is a product that is biologically 
equivalent to the anti-Shiga toxin serum that neutralises the interaction of SARS-
CoV-2 with its cellular receptor, thus preventing virus multiplication. The safety 
information for the anti-Shiga toxin serum indicates that it is well tolerated and 
that no serious adverse events or suspensions of treatment have been reported. The 
objective of this adaptive  Phase 2/3 study is to demonstrate the safety and efficacy 
of INM005 to improve the clinical course of COVID-19 28 days after the start of 
treatment with the investigational product, in individuals with moderate to severe 
disease requiring hospitalisation. 
Target 
Population: 
Patients with moderate or severe COVID-19 as defined by NIH, requiring 
hospitalisation, excluding patients with either mechanical ventilation or admission 
to ICU. 
Number of 
Participants: 
242 patients / approximately 10 sites 

 
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Objectives and 
Endpoints: 
  
Primary objective 
To demonstrate the efficacy and safety of INM005 in COVID-19 in terms of clinical 
improvement 28 days after the start of treatment with the investigational product.  
Primary efficacy endpoint: 
The proportion of patients that showed improvement 28 days after the 
administration of the first dose will be determined. A responder subject is defined 
as a subject with an improvement in at least 2 categories in the 8-point WHO 
clinical status ordinal scale, or with hospital discharge. 
Safety endpoints: 
Incidence of related adverse events and of adverse events of special interest during 
the study period 
Secondary objectives 
1) Assessment of the pharmacokinetics of INM005 
2) Assessment of efficacy in terms of time to disease progression 
3) Assessment of efficacy in terms of disease progression 
4) Assessment of efficacy in terms of change in viral load 
Secondary endpoints: 
1) Concentration of product INM005 in serum at different times after 
administration of treatment 
2) Time to improvement in at least 2 categories in the 8-point WHO clinical status 
ordinal scale 
Time to discharge (days) 
Time to discharge from ICU (days) 
3) Proportion of patients who show an improvement in at least 2 categories in the 
8-point WHO clinical status ordinal scale 7 and 14 days after the start of the 
treatment 
Proportion of patients with hospital discharge at 28 days 
Proportion of patients who required admission to ICU 
Proportion of patients who required MV 

 
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Proportion of patients who died 
 
4) Changes in viral load from baseline to 7 days and 21 days after the start of 
treatment 
Exploratory objectives: 
1) Assessment of anti-SARS-CoV-2 antibodies levels 
2) Assessment of changes in laboratory variable predictors of disease progression 
3) Assessment of immunogenicity at 28 days 
Exploratory endpoints: 
1) Measurement of anti- SARS-CoV-2 antibody titres: IgG (0, 21 days) 
2) Measurable laboratory variables at baseline, 7 and 21 days: troponin T, D-
dimer, ferritin, LDH, C-reactive protein 
3) Measurement of anti-INM005 product antibodies: baseline and 21 days 
Study Design: 
  
  
 
Randomised, double-blind, parallel group study with adaptive design. The interim 
analysis will be performed in a "blinded" manner and, based on the rate of events 
in the control group, the futility of the treatment, the feasibility of the study, or the 
sample size will be adapted. 
Randomisation: 
1:1 (INM005: placebo) 
A staggered enrolment of the first 12 subjects will be performed in 6:6 blocks. 
Randomisation will be carried out maintaining a 1:1 ratio in each sub-cohort: 
•           active treatment regime [2 4-mg/kg doses of INM005] 
•           placebo 
 
 
 

 
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Study Visits: 
Visit 1 - Screening Day 0 
After confirmation of COVID-19 diagnosis by PCR, the following procedures will 
be conducted 
– Explanation and signature of the informed consent 
 
- Demographics: 
•        Age 
•        Sex 
•        Ethnicity 
 
- Clinical History: 
• Relevant Medical History 
• Underlying Diseases: 
o any cardiovascular disease 
o any chronic pulmonary disease 
o kidney disease 
o diabetes 
o liver disease 
o immunodeficiencies 
o neurological disability 
o others 
• Allergies to medications and/or horses 
• Any medical condition that after signing the informed consent should be 
informed as an adverse event (AE) 
 
 

 
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- History of the Disease: 
• date of the first symptom 
• source of infection 
• symptoms according to the definition of case by the Ministry of Health of 
Argentina 
- Patient classification according to the 8-point WHO scale 
- Physical Exam 
- Vital Signs 
• Heart rate 
• Respiratory rate 
• Oxygen saturation percentage/FiO2 saturation 
• Blood pressure 
• Temperature 
- Laboratory tests and imaging 
• Haematology 
• Full chemical panel (including LDH) 
• Chest X-ray 
- Inclusion/Exclusion criteria 
 
Visit 2 - Baseline - Day 1 (within 24 hours after screening visit) 
- Physical exam and laboratory tests, if more than 24 hours have elapsed 
- Assessment of COVID-19 symptoms 
- Patient classification according to the WHO Scale 
- Confirmation of eligibility 
- Randomisation 

 
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- Preparation of the infusion by the unblinded staff 
- Vital signs 15 minutes prior to infusion 
- For PK sub-study: pre-infusion blood sample for the pharmacokinetics study 
- Blood samples for viral load (central laboratory) 
- Blood samples for anti-SARS-CoV-2 antibodies, biomarkers and immunogenicity 
(central laboratory) 
- Administration of double-blind treatment: 100 ml infusion over 50 minutes 
Post-treatment administration procedure: 
- For PK sub-study: Sample tests for pharmacokinetics (5 minutes after the end of 
infusion) 
- Assessment of hypersensitivity reactions within 15 minutes post-infusion 
- Assessment of adverse events and concomitant medication 
- Vital signs within 15 minutes post-infusion 
 
Visit 2 - Day 2 (1st. dose follow-up) 
- Safety laboratory tests 24 h post-infusion 
• Haematology 
              • Full chemical panel 
– Vital signs 
- Patient classification according to the WHO scale 
- Assessment of hypersensitivity reactions 
- Assessment of adverse events and concomitant medication 
- Assessment of COVID-19 disease and complications 
 
Visit 3 - Day 3 (second dose of treatment) 
- Preparation of the infusion by the unblinded staff 

 
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- Assessment of adverse events and concomitant medication 
- Patient classification according to the WHO scale 
- Assessment of COVID-19 disease and complications 
- Vital signs 15 min prior to infusion 
- For PK sub-study: Pre-infusion blood sample for the pharmacokinetics 
- Administration of double-blind treatment: 100 ml infusion over 50 minutes 
Post-treatment administration procedure: 
- For PK sub-study: Samples for pharmacokinetics (5 minutes after the end of 
infusion) 
- Assessment of hypersensitivity reactions within 15 minutes post-infusion 
- Assessment of adverse events and concomitant medication 
- Vital signs within 15 minutes post-infusion 
 
Visit 3 - Day 4 (2nd. dose follow-up) 
- For PK sub-study: Samples for pharmacokinetics (24 h post second infusion) 
- Safety laboratory tests, 24 h post-infusion 
• Haematology 
• Full chemical panel 
- Vital signs 
- Patient classification according to the WHO scale 
- Assessment of hypersensitivity reactions 
- Assessment of adverse events and concomitant medication 
- Assessment of COVID-19 disease and complications 
– Hospital discharge if the patient is clinically stable and with medical criteria for 
discharge 
Visit 4- Day 5 (follow-up) 
- Vital signs 

 
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- Patient classification according to the WHO scale 
- Assessment of COVID-19 disease and complications 
- Assessment of hypersensitivity reactions 
- Assessment of adverse events and concomitant medication 
 
Visit 5- Day 7 (follow-up) 
- Vital signs 
- Patient classification according to the WHO scale 
- Assessment of COVID-19 disease and complications 
- Assessment of hypersensitivity reactions 
- Assessment of adverse events and concomitant medication 
- Obtention of samples for viral load 
- Obtention of blood samples for anti-SARS-CoV-2 antibodies and laboratory 
markers 
- Only for PK sub-study: Obtention of blood sample for the pharmacokinetics study 
 
Visit 6- Day 14 (follow-up) 
- Vital signs 
- Patient classification according to the WHO scale 
- Assessment of COVID-19 disease and complications 
- Assessment of hypersensitivity reactions 
- Assessment of adverse events and concomitant medication 
 
Visit 7- Day 21 (follow-up) 
- Vital signs 

 
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- Patient classification according to the WHO scale 
- Assessment of COVID-19 disease and complications 
- Assessment of hypersensitivity reactions 
- Assessment of adverse events and concomitant medication 
- Samples for viral load 
- Blood samples for anti-SARS-CoV-2 antibodies and laboratory markers, 
immunogenicity 
– Safety laboratory tests 
• Haematology 
• Full chemical panel 
 
Visit 8- Day 28 (End of study) 
- Vital signs 
- Patient classification according to the WHO scale 
- Assessment of COVID-19 disease and complications 
- Assessment of hypersensitivity reactions 
- Assessment of adverse events and concomitant medication 
- Assessment of adverse events and concomitant medication 
Eligibility 
criteria: 
  
Inclusion criteria 
Subjects must meet all the inclusion criteria at Screening: 
1. Both sexes, aged 18 to 79 years of age 
2. SARS-CoV-2 infection confirmed by PCR 
3. Moderate or severe disease according to NIH definition, requiring 
hospitalisation 
4. Acceptance of participation in the study by signature of informed consent 
(by subject or relative, if applicable) 

 
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5. To be within 10 days of the onset of symptoms at the time of the Screening 
visit, according to a case definition from the National Ministry of Health 
6. Female patients at child-bearing age with negative pregnancy test 
Exclusion criteria 
Subjects must not meet any of the following exclusion criteria at the time of 
Screening: 
1. Patients who have received treatment with plasma from COVID-19 
convalescents 
2. Patients who are participating in other therapeutic clinical trials 
3. Patients who require mechanical ventilation or who are hospitalised in the 
ICU at the screening visit 
4. History of anaphylaxis, prior administration of equine serum (for 
example, anti-tetanus serum or anti-ophidic serum or anti-arachnid toxin 
serum) or allergic reaction due to contact or exposure to horses 
5. Pregnant or breastfeeding women 
6. Patients who, at the doctor's judgement, within the next 30 days due to a 
concomitant disease other than the study disease 
7. Patients who are expected to be referred to another institution within 72 
hours of enrolment, which prevents adequate follow-up of that patient 
Study drug: 
  
  
The INM005 treatment scheme is based on a history of INM004 (hyperimmune 
equine anti-Shiga toxin serum). The maximum dose tested in Phase I of INM004 
was 4 mg/kg and up to 3 doses spaced 24 apart. 
Each dose is administered as an intravenous infusion (i.v.) over a period of 50 min 
with an interval of 48 h (± 2 h) with each other. 
The proposed treatment scheme is as follows: 
·       2 doses of INM005, 4 mg/kg, or 
·       2 doses of placebo 
Safety 
evaluations 
Vital signs 
Laboratory evaluations 
AE and serious adverse events (SAEs) 
AESI: 
o Injection site reaction 

 
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o Hypersensitivity reactions (i.e. allergic reaction, anaphylaxis and serum sickness) 
Data monitoring 
committee 
A DMC will be formed to evaluate the Safety of the study periodically when the 
first 12, 24, 48, 96 and 192 patients have been recruited. A data review will be done 
during the interim analysis when approximately 145 patients have been recruited. 
  
A staggered recruitment of the first 12 subjects will be performed in 6:6 blocks. 
Randomisation will be carried out maintaining a 1:1 ratio in each sub-cohort: 
•           Active treatment regime [two 4-mg/kg doses of INM005] 
•           Placebo 
Intensive monitoring will be done during this stage. 
After the first 6 subjects have been recruited and 24hours post treatment have 
passed after the second dose, the Sponsor’s Medical Monitor will review the safety 
data for this acute phase and report the safety findings. 
This evaluation will be repeated for the 2 blocks of 6 subjects each. 
Any safety findings will be notified immediately to the Sponsor, DMC and 
Regulatory Agency, as established in current regulations. 
The monitoring details will be specified in the Study Pharmacovigilance Plan, 
which will be finalised before the recruitment of the first patient into the study 
begins. 
When the recruitment of the first 12 patients is complete, the DMC will review the 
safety data and inform whether the staggered recruitment should continue. 
All DMC reports will be duly notified to the ANMAT. 
Pharmacokinetic 
assessments 
A PK sub-study will be carried out on 20 subjects.  A blood sample will be drawn 
for Pharmacokinetic tests immediately before the 1st. administration of the study 
drug, at the end of the 1st. administration of the study drug, immediately before 
the 2nd administration of the study drug, at the end of the 2nd study drug 
administration, 24h after 2nd study drug administration and 7 days after 1st. study 
drug administration. 
Discontinuation 
criteria 
The study medication will not be discontinued due to progression of disease. 
Discontinuation from the study drug must be done in case of an allergic reaction > 
= grade 3 and/or anaphylaxis 

 
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Standard 
of 
care/ medication 
 
 
 
 
 
 
 
 
 
Statistical 
procedures 
Standard of care: 
•           Hospital 
•           Guidelines from the Ministry of Health of Argentina: 
  
Treatment: 
There is no specific treatment recommended for COVID-19 infection. Patients 
infected with COVID-19 must receive care to alleviate  symptoms. For severe cases, 
treatment must include support of vital functions. In accordance with the 
recommendation of the Ministry of Health, the use of treatment that does not have 
scientific evidence should be used in the context of research studies. 
     
Prohibited medication: medication that is being administered in the context of a 
clinical trial. 
All treatment with a therapeutic objective against SARS-CoV-2 must be reported 
to the medical monitor. 
Sample size 
Assuming 
a 
70% 
“standard 
of 
care” 
event 
rate 
(Wang 
2020, 
https://doi.org/10.1016/S0140-6736(20)31023-0) and an absolute effect size of 15 
percentage points, for a power of 80% and an error α = 0.025 (for a one-tailed 
comparison), 121 subjects will be required in each treatment group, totalling 242 
participating subjects. 
Interim analysis 
An interim analysis will be carried out after 60% of recruitment has been reached; 
that is, approximately after the end of the follow-up of the first 145 subjects. The 
Data Monitoring Committee will analyse the event rate in the group under the 
“standard of care” and may recommend: (1) modifying the sample size, based on 
the observed event rate, or (2) stopping the study if: (2.a) it’s considered that it is 
not feasible because it requires an excessively large sample size or (2.b) it’s 
considered futile because of an event rate ≥ 95%. 
The re-estimation of the sample size will allow the sample to be increased by up to 
72 subjects, to reach 314 subjects. The requirement of a greater number of subjects 
would be considered "Not Feasible" and will cause the study to be stopped. 
Analysis set 
The Full Analysis Set (FAS) will be made up by all the subjects randomised to 
INM005. 

 
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The modified intent-to-treat group will be made up of all subjects who have been 
randomised to receive INM005 and who have received the full treatment regime of 
INM005. This will be the primary population for all efficacy analysis. 
The Per Protocol population will be made up by all the subjects in the mITT who 
have no major protocol deviations. Major protocol deviations will be reviewed and 
subjected to determination prior to closing the database and breaking the blind. 
The PP population will be used for the endorsement sensitivity analysis. 
The Safety Population will be made up of all subjects who have received at least 1 
dose of INM005. This population will be used for all summaries of accounting data, 
baseline and demographic characteristics of subjects, and safety information, 
including incidence of adverse events. 
Statistical analysis 
Differences between patients in both treatment groups in the proportions of the 
primary and secondary efficacy endpoints will be analysed using the Chi-square 
test. The differences between these groups in the endpoints that involve the time to 
the occurrence of the events will be analysed using the non-parametric Mann-
Whitney test. Antibody levels will be compared using a Levine’s fit T test, if 
necessary. The main analyses will be carried out in the mITT population and the 
sensitivity analyses in the PP population. 
For the exploratory analysis of the change in laboratory variables predictors of 
disease progression, a multivariate logistic regression analysis will be used. 

 
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TABLE OF CONTENTS 
1 
INTRODUCTION AND RATIONALE ................................................................. 33 
1.1 
Context .................................................................................................................. 33 
1.1.1 
DISEASE ........................................................................................................ 33 
1.1.1.1 
Clinical Presentation ............................................................................... 34 
1.1.1.2 
Risk factors ............................................................................................... 35 
1.1.1.3 
Stratification by risk ................................................................................ 36 
1.1.1.4 
Situation in Argentina ............................................................................. 37 
1.1.2 
Treatment approaches .................................................................................. 37 
1.1.2.1 
Symptomatic therapy .............................................................................. 37 
1.1.2.2 
Specific treatments .................................................................................. 37 
1.1.2.3 
Support treatment ................................................................................... 40 
1.1.3 
Investigational medicinal product ................................................................ 40 
1.1.4 
Rationale for the use of placebo ................................................................... 43 
1.2 
Study rationale ..................................................................................................... 44 
1.3 
Preclinical safety and clinical support data ...................................................... 45 
1.3.1 
F(ab’)2 fraction of equine immunoglobulins .............................................. 45 
1.3.2 
F(ab’)2 fraction of equine immunoglobulins - similar products ............... 48 
1.3.3 
F(ab’)2 fraction of equine immunoglobulins - Safety information of 
similar products ............................................................................................. 48 
1.3.4 
F(ab’)2 fraction of equine immunoglobulins - Phase 1 results with 
INM004 ........................................................................................................... 51 
1.3.4.1 
General considerations related to the safety of CT-INM004-01 ......... 54 
1.3.5 
F(ab’)2 fraction of equine immunoglobulins - Phase 2/3 results with 
INM004 ........................................................................................................... 55 
1.3.6 
Clinical development plan .............................................................................. 5 
1.4 
Dose selection ......................................................................................................... 5 
1.4.1 
Dosage rationale ............................................................................................... 5 
1.4.2 
Assumptions ..................................................................................................... 6 
1.4.3 
Preclinical data ................................................................................................ 7 
1.4.4 
Phase 1 study .................................................................................................... 8 
1.4.5 
Extrapolation of kinetic data at planned doses for INM005 ..................... 11 
1.4.6 
Future pharmacokinetics measurements .................................................... 15 
2 
STUDY OBJETIVE ................................................................................................. 16 
2.1 
Primary ................................................................................................................. 16 
2.2 
Secondary ............................................................................................................. 16 
2.3 
Exploratory .......................................................................................................... 16 
3 
STUDY ENDPOINTS .............................................................................................. 17 
3.1 
Primary ................................................................................................................. 17 
3.2 
Secondary ............................................................................................................. 17 
3.3 
Exploratory .......................................................................................................... 18 
4 
STUDY PLAN........................................................................................................... 19 

 
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4.1 
Study design ......................................................................................................... 19 
4.2 
Schematic representation of the study ............................................................... 19 
4.3 
Study design scheme ............................................................................................ 20 
4.4 
Schedule of assessments ...................................................................................... 21 
5 
POPULATION ......................................................................................................... 30 
5.1 
Target population ................................................................................................ 30 
5.2 
Number of subjects .............................................................................................. 30 
5.3 
Inclusion and Exclusion criteria ......................................................................... 30 
5.4 
Patient selection ................................................................................................... 31 
5.5 
Deviations from the Inclusion and Exclusion criteria ...................................... 31 
6 
CONDUCT OF THE STUDY ................................................................................. 32 
6.1 
Study procedures ................................................................................................. 32 
6.2 
Study procedures by time-point ......................................................................... 32 
6.2.1 
Visit 1 - Screening .......................................................................................... 32 
6.2.2 
Visit 2. Baseline .............................................................................................. 36 
6.2.2.1 
Day 1 - First dose of treatment ..................................................................... 36 
Must be done within 24 h of the screening visit. ........................................................... 36 
6.2.2.2 
Day 2 - 1st. dose follow-up ............................................................................ 37 
6.2.3 
Visit 3 .............................................................................................................. 37 
6.2.3.1 
Day 3 Second dose of treatment ................................................................... 37 
6.2.3.2 
Day 4 2nd dose follow-up .............................................................................. 38 
6.2.4 
Visit 4- Day 5 follow-up ................................................................................. 38 
6.2.5 
Visit 5- Day 7 follow-up ................................................................................. 39 
6.2.6 
Visit 6 - Day 14 follow-up .............................................................................. 39 
6.2.7 
Visit 7 - Day 21 follow-up .............................................................................. 39 
6.2.8 
Visit 8- Day 28 - End of study ....................................................................... 40 
6.3 
Early termination ................................................................................................ 40 
7 
DESCRIPTION OF THE STUDY PROCEDURES ............................................. 42 
7.1 
Efficacy evaluations ............................................................................................. 42 
7.2 
Safety evaluations ................................................................................................ 42 
7.2.1 
Electrocardiogram ......................................................................................... 42 
7.2.2 
Vital signs ....................................................................................................... 42 
7.2.3 
Clinical laboratory analysis .......................................................................... 43 
7.2.4 
Adverse events ............................................................................................... 43 
7.2.5 
Adverse event of special interest .................................................................. 43 
7.2.5.1 
Injection site reaction .............................................................................. 44 
7.2.5.2 
Hypersensitivity reaction ........................................................................ 44 
7.2.5.2.1 
Allergic reaction ................................................................................. 44 
7.2.5.2.2 
Anaphylaxis: ...................................................................................... 45 
7.2.5.2.3 
Serum sickness: .................................................................................. 45 
7.3 
Other assessments ................................................................................................ 45 
7.3.1 
General survival ............................................................................................. 45 
7.3.2 
Complications of COVID infection .............................................................. 46 

 
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7.3.3 
Other secondary endpoints: .......................................................................... 46 
7.3.4 
Exploratory endpoints ................................................................................... 46 
7.3.4.1.1 
Duration of hospitalisation ............................................................... 46 
7.3.4.1.2 
Mortality predictors .......................................................................... 46 
7.4 
Sample for immunogenicity testing and future analysis .................................. 47 
7.4.1 
Immunogenicity assessments ........................................................................ 47 
7.4.2 
Biological properties of INM005 .................................................................. 48 
7.4.3 
Immunogenicity reactions - Phase I ............................................................. 48 
7.4.4 
Sample for immunogenicity testing and future analysis ............................ 49 
7.5 
Pharmacokinetics ................................................................................................ 49 
7.6 
Protocol deviations .............................................................................................. 49 
8 
MANAGEMENT OF THE STUDY DRUG .......................................................... 51 
8.1 
Description ........................................................................................................... 51 
8.1.1 
Dosage Form .................................................................................................. 51 
8.1.2 
Storage conditions ......................................................................................... 51 
8.2 
Conditioning and transport ................................................................................ 52 
8.3 
Dosage and administration ................................................................................. 52 
8.4 
Accountability ...................................................................................................... 53 
8.5 
Concomitant medication ..................................................................................... 53 
8.5.1 
Allowed concomitant medication ................................................................. 53 
8.5.2 
Prohibited concomitant medication ............................................................. 54 
8.6 
Compliance with the treatment regime ............................................................. 54 
8.7 
Study drug discontinuation criteria ................................................................... 54 
9 
ADVERSE EVENTS ................................................................................................ 55 
9.1 
Documentation of adverse events ....................................................................... 56 
9.2 
Assessment of intensity ........................................................................................ 57 
9.3 
Assessment of causality ....................................................................................... 57 
9.4 
Action taken in relation to the study drug ........................................................ 58 
9.5 
Other action taken in relation to the event........................................................ 58 
9.6 
Result of the adverse event ................................................................................. 59 
9.7 
Changes in the parameters of the clinical laboratory ...................................... 59 
9.8 
Overdose ............................................................................................................... 60 
9.9 
Adverse events of special interest ....................................................................... 60 
9.10 
Follow-up of adverse events ................................................................................ 60 
10 SERIOUS ADVERSE EVENTS ............................................................................. 61 
10.1 
Definition of serious adverse events ................................................................... 61 
10.2 
Notification of serious adverse events ................................................................ 62 
11 STATISTICS ............................................................................................................ 65 
11.1 
General procedures ............................................................................................. 65 
11.2 
Analysis set ........................................................................................................... 65 
11.3 
Determination of the sample size ....................................................................... 65 
11.4 
Randomisation ..................................................................................................... 66 
11.5 
Statistical methods ............................................................................................... 66 

 
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11.5.1 
Efficacy analysis ............................................................................................. 66 
11.5.1.1 
Primary and secondary analysis ............................................................ 66 
11.5.1.2 
Exploratory analysis ................................................................................ 66 
11.5.2 
Safety analysis ................................................................................................ 67 
11.5.2.1 
Adverse events ......................................................................................... 67 
11.5.2.2 
Laboratory data ....................................................................................... 67 
11.5.2.3 
Vital signs ................................................................................................. 67 
11.5.3 
Demographics and baseline .......................................................................... 68 
11.6 
Blinded safety data review .................................................................................. 68 
11.7 
Interim analysis ................................................................................................... 68 
11.7.1 
Data monitoring committee .......................................................................... 68 
11.7.2 
Futility in the interim analysis ...................................................................... 70 
12 ETHICAL CONSIDERATIONS AND RESPONSIBILITIES ............................ 71 
12.1 
Good Clinical Practice ........................................................................................ 71 
12.2 
Data monitoring committee ................................................................................ 71 
12.2.1 
Members of the Data Monitoring Committee ............................................. 72 
12.2.2 
Generation of the Data Monitoring Committee Charter ........................... 72 
12.2.3 
Data Monitoring Committee Meetings ........................................................ 73 
12.2.4 
Role of the Data Monitoring Committee in adaptive designs .................... 73 
12.3 
Steering Committee ............................................................................................. 74 
12.4 
Institutional Review Board/Ethics Committee ................................................. 74 
12.5 
Informed consent ................................................................................................. 74 
12.6 
Records management .......................................................................................... 75 
12.7 
Source documents ................................................................................................ 75 
12.8 
Study records and record retention ................................................................... 75 
13 AUDITS AND MONITORING ............................................................................... 76 
14 AMENDMENTS ....................................................................................................... 77 
15 STUDY REPORT AND PUBLISHING ................................................................. 78 
16 INTERRUPTION OF THE STUDY ...................................................................... 79 
17 CONFIDENTIALITY .............................................................................................. 80 
18 BIBLIOGRAPHY ..................................................................................................... 81 
19 86 
 
 
 

 
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LIST OF TABLES 
Table 1.1 
Products similar to INM005 approved by the Food and Drug Administration 
(FDA) and European Union 
Tabla 1.3 
Adverse events occurring in clinical trials with Anascorp 
 
Table 1.4 
CT-INM004-01 - Adverse events reported in each treatment arm, 
regardless of causality l 
 
Tabla 1.5 
CT-INM004-01 - Adverse events reported with a possible or probable 
causal relation to the investigational medicinal product  
 
Tabla 1.6 
CT-INM005-01 - Adverse events reported by System Organ Class 
(SOC) 
 
Tabla 1.7  
CT-INM004-02 Listado de RAMSI 
 
Tabla 1.8 
 CT-INM004-02 LISTA DE EVENTOS ADVERSOS 
Tabla 1.9          Parámetros de simulación 
 
 
[NB1] 
 
 
 

 
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LIST OF FIGURES 
Figure 1.1 Tridimensional model of the Spike protein, in green is the receptor-binding 
domain (RBD) of the Spike glycoprotein 
Figure 1.2 Schematic representation of an immunoglobulin with the F(ab')2 fragments 
linked by disulphide bridge 
Figure 1.3 Administration regime proposed for INM005* 
Figure 1.4 As an example, the seroneutralisation analysis carried out at the Centre de 
Recerca en Sanitat Animal (CReSA) is shown as Log10 of the dilution of the sample 
vs. % of neutralisation. 
Figure 1.5 Concentration of INM004 over time in 6 volunteers of the Phase 1 study (3 
volunteers received 2 mg/kg, 3 volunteers received 4 mg/kg) 
Figure 1.6 Concentration of INM004 over time (logarithmic scale) 
Figure 1.7 Bicompartmental population pharmacokinetics model scheme.  
Figure 1.8 Simulations of INM005 concentrations over time (3 administrations) 
Figure 1.9 Simulation of INM005 concentration over time (2 administrations) 
Figure 4.2 Schematic representation of the study 
Figure 4.3 Study design scheme 
 
 
 
 

 
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ABBREVIATIONS 
Abbreviation 
Definition 
ACE 
angiotensin converting enzyme II 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
AF/CF 
Assent form/ consent form 
ALT 
alanine aminotransferase 
ANMAT 
Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (National 
Administration of Drugs, Food and Medical Technology) 
ARDS  
Acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
AUC0-inf 
area under the curve of concentration over time extrapolated to infinity 
BMI 
body mass index 
Btk 
Bruton tyrosine kinase  
C 
Centigrade 
cGAS 
MP-AMP synthetase  
Cmax 
maximum concentration observed 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 

 
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COVID-19 
Coronavirus disease  
CreatS 
serum creatinine 
CRF 
Case Report Form 
CRP 
polymerase chain reaction 
CSR 
Clinical Study Report 
CT  
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data monitoring committee 
EC 
Ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOS 
End of study 
ESR 
erythrocyte sedimentation rate 
ET 
Early termination 
EU 
European Union 
FDA 
Food and Drug Administration 

 
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FiO2  
Fraction of inspired oxygen 
g 
grams 
GCP 
Good Clinical Practices 
h 
hour(s) 
Hb 
haemoglobin 
Hct 
haematocrit 
HGF 
hepatocyte growth factor  
HIV 
Human immunodeficiency virus 
i.v. 
Intravenous 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for the Registration 
of Pharmaceuticals for Human Use 
 ICU 
 Intensive care unit 
IFN-a/b 
type I interferons 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IRF3 
interferon regulator factor  
Jak1 
Janus kinase 1  

 
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kg 
kilogram 
l 
litres 
LDH 
lactate dehydrogenase 
MCSF 
monocyte colony stimulating factor  
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV  
Middle East respiratory syndrome-related coronavirus 
mg 
milligram 
min 
minute 
mITT 
modified intent-to-treat 
MRA 
Mechanical ventilation 
Na 
sodium 
NCA 
non-compartmental analysis 
NF-KB  
nuclear transcription factors KB  
NIH 
 National Institute of Health 
NIPPV  
non-invasive positive pressure ventilation  
PaCO2 
partial pressure of carbon dioxide 
PaO2 
partial pressure of oxygen 
PK 
pharmacokinetics 
PP 
Per Protocol 

 
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PT 
preferred term 
RBC 
red blood cells 
RBD  
Receptor binding dominion  
RIG-I 
retinoic acid inducible gene-like RNA receptor  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2  Severe acute respiratory syndrome coronavirus 2 
SatO2  
Oxygen saturation 
SBP 
supine blood pressure 
SoC 
Standard of care 
SOFA  
Sequential organ failure assessment 
TEAE 
treatment emergent adverse event 
TLR 
Toll-like receptors  
tmax 
time until maximum concentration 
Tyk2 
 tyrosine kinase 2 
ULN 
upper limit of normal 
US 
United States 
V 
visit 

 
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Vd 
volume of distribution 
w 
week(s) 
WBC 
white blood cells 
WHO 
World Health Organisation 

 
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1 INTRODUCTION AND RATIONALE 
1.1 
Context 
1.1.1 DISEASE 
Etiology and epidemiology 
The pandemic caused by the novel coronavirus has generated an unprecedented situation in 
recent history, with several million infected and hundreds of thousands of deaths. Although 
there have been reports of respiratory infections due to COVID-19 as from December 2019, 
the WHO declared the infection caused by coronavirus called COVID-19 a pandemic in 
March of this year (1-3). 
Coronavirus disease (COVID-19) is caused by SARS-CoV-2, a zoonotic, positive-sense, 
single-stranded RNA betacoronavirus that has a protein envelope structurally related to 
SARS-CoV (the coronavirus that causes a severe and acute respiratory syndrome) and 
MERS-CoV (Middle East respiratory syndrome-related coronavirus) (4). SARS-CoV-2 and 
SARS-CoV bind to the angiotensin-converting enzyme II (ACE2) receptor to enter lung and 
intestinal epithelial cells; after binding to the receptor, they fuse with the cell membrane and 
release viral RNA (5-7). 
Once released, the RNA is recognised by Toll-like receptors (TLR); it forms complexes with 
the retinoic acid-inducible gene-like RNA receptor (RIG-I), the cytolosic receptor for 
melanoma  differentiation-associated protein 5 (MDA5) and cyclic GMP-AMP 
nucleotidyltransferase synthetase (cGAS) in the cytoplasm and stimulate signalling cascades 
that activate nuclear transcription factors like factor-B (NF-B) and interferon regulatory 
factor (IRF3) with the production of type I interferons (IFN-a/b) and pro-inflammatory 
cytokines (8, 9). Both infected pneumocytes and macrophages produce IL-6, IL-8, MCP-1, 
TGF-β1 and other cytokines and inflammatory mediators responsible for the immune 
response and the limitation of infection; however, this pathway may also be responsible for 
the pulmonary damage in the context of the cytokine storm (8-11). 
The production and release of pulmonary and systemic cytokines, stimulated in part by the 
IL-6 pathway or the JAK/STAT signalling pathway, is related to the infiltration of activated 
neutrophils into the alveolar space, followed by a phase with interstitial fibrosis that can take 
a long time to resolve. In severe cases, this time can be important not only due to the 
availability of resources but also due to the complications that individuals requiring ICU 
hospitalisation and mechanical ventilation may have (10-15). 

 
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The virus has a highly contagious capacity and can be transmitted by human-human contact 
with reproduction rates of around 2.2, meaning that its growth can be exponential in the 
community. The basic reproduction number (R 0) defined as the average number of 
secondary cases that a primary case can generate in the susceptible population according 
ranges from 1.4 and 2.5; although its value varies in reports due in part to the different 
methods used, geographic areas, and sample sizes, it suggests that SARS-CoV-2 has a high 
propagation capacity (16-20). The control strategies implemented related to avoid close 
contacts between people have had different degrees of compliance and in some countries, 
they have managed to avoid the peak of cases, and the collapse of the health system. Over 
8,900,000 cases and 466,500 deaths have been reported worldwide (22.06.2020) and the 
numbers continue to grow (21). This scenario has raised challenges not only in the Health 
system but also at governmental level since the measures taken will impact not only on Health 
but also on socioeconomic aspects. 
1.1.1.1 
Clinical Presentation 
 
The incubation period varies between 3 and 7 days, although periods of more than 14 days 
have been observed; while the average time between the onset of symptoms and the diagnosis 
is 4 to 6 days and may coincide with the time to the first consultation (2-9 days). The main 
transmission route is from person to person and occurs in a similar way to influenza. An 
infected person who coughs, sneezes or speaks, eliminates viral particles that travel inside 
respiratory secretion droplets (in general for no more than 2 meters) which then come into 
direct contact with the mucosa of another individual, transmitting the disease; it can also 
occur if a person touches an infected surface and then the eyes, nose, or mouth (22). 
The most common symptoms are fever, cough, dyspnoea, headache, odynophagia; 
gastrointestinal disorders such as diarrhoea, nausea, vomiting or asthenia, dysgeusia and 
anosmia have also been described (23-25). 
Pneumonia is the most common severe manifestation of the infection, characterised by fever, 
cough, dyspnoea, and bilateral infiltrates on chest imaging; in the most severe cases, they can 
mainly evolve in the second week from the onset of symptoms to respiratory failure with 
different degrees of severity, including the need for mechanical ventilation in the intensive 
care unit (ICU) (22-25). 
Severe conditions can also affect the liver, kidney, heart, oesophagus, bladder, ileum, 
pancreas and progress to septicaemia, coagulopathy, septic shock and multi-organ failure 
with a high mortality rate depending on age and comorbidities amongst other factors. The 
acute respiratory and other organs damage is associated with the "cytokine storm" as seen in 
patients with SARS-CoV and MERS-CoV pneumonia, in which levels of IL-6 and other pro-

 
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inflammatory cytokines correlate with the clinical and radiographic severity picture of the 
clinical picture (26, 27).  
In most patients, COVID-19 presents itself with either mild or asymptomatic condition; it is 
estimated that 15.7% of patients undergo a severe form of the disease and mortality in critical 
cases that progress with the need for ICU is 37-50% according to different series (26, 27). 
The cytokine storm triggered in COVID-19 and the patient´s clinical condition could be 
responsible for the damage to the lung and other organs. In patients with severe pneumonia, 
conditions include lymphopenia, elevated CRP with normal levels of procalcitonin, elevated 
LDH with decreased albumin, as well as elevated levels of IL-6 and other mediators such as 
IL-1, IL-2, IL-4, IL-7, IL-10, IL-12, IL-13, IL-17, GCSF, monocyte colony stimulating factor 
(MCSF), IP-10, MCP-1, MIP-1α, hepatocyte growth factor (HGF), IFN-γ and TNF-α (28-
31). 
The laboratory findings that have been frequently detected in patients diagnosed with 
COVID-19 (especially in severe forms) are hypoalbumin (75%), increased C-reactive protein 
(58.3%), increased lactate dehydrogenase (LDH, 57%) , lymphopenia (43.1%), and increased 
globular sedimentation rate (GSR, 41.8%) (26). 
The majority of patients with pneumonia present bilateral infiltrates (72.9%) with ground 
glass opacities, particularly on chest computed axial tomography (CT). The distribution of 
infiltrates with areas of consolidation can be located in the sub-pleural as well as the 
pulmonary lobe areas and then progress to diffuse bilateral opacities in severe cases (32).  
Determination of RT-PCR in nasopharyngeal/oropharyngeal swabs, sputum and other 
respiratory secretions, blood and faeces is one of the main techniques to detect the SARS-
CoV-2. Despite its good sensitivity and specificity, false negative reactions may occur, which 
is why it is sometimes necessary to take samples on more than one occasion. Techniques are 
currently being developed with the aim of solving this problem, reducing costs, and reducing 
times to obtain the test results (33).  
1.1.1.2 
Risk factors 
Older people with high blood pressure, asthma, diabetes, and other underlying diseases have 
a significantly higher risk of infection. A 36.8% of patients with SARS-CoV-2 infection have 
underlying non-communicable diseases, the most frequent of which are high blood pressure 
(18.6%), cardiovascular diseases (14.4%) and diabetes (11.9%) (26). It has also been 
observed that people with blood group A have a higher risk of infection as compared to those 
with blood group non-A, while blood group O has a significantly lower susceptibility to 
infection as compared to non-O blood groups. 

 
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Older age (particularly over 60 years) and underlying diseases (diabetes, high blood pressure, 
heart disease, obesity, chronic lung disease, cerebrovascular disease, chronic kidney disease, 
immunosuppression, and cancer) increase the likelihood of severe illness and death. In a 
meta-analysis that included 77,932 patients, male sex was associated with morbidity (OR = 
1.12; 95% CI: 1.01–1.25), severity (OR = 1.63; 95% CI: 1.28–2.06) and mortality (OR = 
1.71; 95% CI: 1.51–1.93) (26, 34). 
Recently, information has been published that relates the presence of the HLA-B*46:01 allele 
to a greater severity of the clinical picture, probably linked to the lower capacity to present 
the SARS-CoV-2 epitopes (35).  
 
1.1.1.3 
Stratification by risk 
The clinical classification (NIH) according to the severity level of the COVID-19 condition 
is divided into (36): 
1. Mild cases 
-Clinical symptoms are mild and imaging show no sign of pneumonia. 
2. Moderate cases 
-Patients who have evidence of lower respiratory disease by clinical 
evaluation or imaging and an oxygen saturation (SpO2) ≥ 94% in ambient air. 
3. Severe cases 
- Patients who meet any of the following criteria: 
-Respiratory failure (≧ 30 breaths/min) 
-Oxygen saturation ≤ 93% at rest 
-Partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen 
(FiO2) ≦ 300 mmHg (l mmHg = 0.133kPa) 
-Images of the chest that show progression > 50% in 24-48 hours 
3. Critical cases 
Patients who meet any of the following criteria: 

 
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-Respiratory failure with need for mechanical assisted respiration 
- Shock 
-Other organ failure that requires care at the ICU 
1.1.1.4 
Situation in Argentina 
According to the Ministry of Health, in Argentina 23 provinces are affected, more than 
59,000 cases were diagnosed, most in CABA (i.e. the Buenos Aires metropolitan area) and 
the province of Buenos Aires; and more than 1,000 deaths, of which the majority are over 60 
years old. The array of measures adopted at government level has managed to avoid the 
excessive growth in the number cases and has allowed the health system to respond to the 
growing demand. Despite these measures, both in the public and private sub-sectors, the 
number of admissions to ICU beds is still high, increasing diagnoses and consultations, so 
the measures adopted are susceptible to change according to the evolution of the situation 
(37). 
1.1.2 Treatment approaches 
 
No effective therapies for the treatment or prevention of SARS-CoV2 have been identified 
yet. Preliminary evidence indicates that passive immunotherapy with convalescent plasma 
could alter the clinical course of this infection in a favourable manner. This strategy, even if 
confirmed as successful, requires voluntary donation by patients who have recovered, not all 
of whom are eligible as donors, since the antibody response varies in magnitude in different 
patients (38-44). 
1.1.2.1 
Symptomatic therapy 
 
Clinical management of hospitalised COVID-19 patients includes supportive treatment: 
supplemental oxygen therapy, antipyretics, empirical antimicrobials, neuraminidase 
inhibitors for the treatment of influenza when there is local circulation, and intensive care as 
needed. In patients with a mild condition, isolation, antipyretics and evolutionary control are 
mainly indicated, while in those patients who must be hospitalised, the use of additional 
measures such as those previously mentioned is considered. 
1.1.2.2 
Specific treatments 
Currently there is no specific antiviral treatment and no vaccine available; all  molecules are 
under evaluation, some of them in more advanced stages. Therapeutic targets include virus 
binding, inhibition of specific enzymes involved in replication, transcription, helicases and 

 
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proteases, siRNA, antisense RNA and ribozyme or neutralising antibodies or even 
monoclonal antibodies directed at the host receptor or interfering with S1, amongst others 
(38).  
Remdesivir demonstrated in the preliminary results of a double-blind, randomised, placebo-
controlled trial (n = 1063) greater efficacy in mean recovery time, 11 days (95% CI: 9-12), 
compared to 15 days (CI 95%: 13-19) of those who received placebo (recovery rate index, 
1.32; 95% CI, 1.12-1.55; p <0.001). On the other hand, in mortality at 14 days, the difference 
between the two arms was smaller, 7.1% with remdesivir and 11.9% with placebo (HR: 0.70; 
95% CI, 0.47 to 1.04). The results of studies in which remdisivir is used as part of a 
combination therapy are currently awaited (39).  
Lopinavir/ritonavir is a protease inhibitor drug approved for the treatment of HIV infection; 
in a 2-arm, randomised, controlled, open-label study it was compared with standard 
management for patients hospitalised for severe Covid-19 disease (n = 199). In the study, no 
differences were observed in the time for clinical improvement (1.31; 95% CI: 0.95-1.80, 
p = 0.09), nor were differences in mortality at day 28 (19.2% vs. 25.0%; risk difference: −5.8; 
95% CI: −17.3 to 5.7). However, when considering the sub-group of patients who started 
treatment early in a post-Hoc analysis the lopinavir/ritonavir group tended to be better than 
standard treatment although it was not statistically significant in the end. As the sample size 
was not calculated taking into account the multiplicity of hypotheses, the authors speculate 
that the study did not have enough power to demonstrate differences in this sub-group. The 
results of other studies such as Solidaridad that incorporated lopinavir ritonavir into one of 
its branches are currently awaited (40). 
The combination of lopinavir/ritonavir and interferon-1β is being evaluated as it 
demonstrated anti-MERS-CoV activity in vitro and in an in vivo study carried out in common 
marmosets they had better results than untreated animals. Favourable responses have also 
been found with the combination lopinavir/ritonavir-ribavirin, we will probably have more 
information on these combinations in a short time (38). 
Interferon alpha-1 activates the phosphorylation of Janus kinase 1 (Jak1) and tyrosine kinase 
2 (Tyk2) initiating the expression of immunomodulators and the expression of antiviral 
proteins; some publications have shown antiviral activity of IFN-α and IFN- β and IFN-α / 
β, IFN-β 1a and IFN-γ combinations against SARS-CoV. These combinations could also be 
effective against SARS-CoV-2 and are under assessment (38).  
Oseltamivir is a neuraminidase inhibitor that has been used as an empirical drug for COVID-
19, although there is no evidence of its efficacy in clinical trials yet; it is also included within 
the therapeutic strategy for the treatment of influenza (38). 

 
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Chloroquine is an antimalarial drug that can inhibit both virus-host cell interaction and pH-
dependent virus replication. Studies have been published that include branches of treatment 
with chloroquine and hydroxychloroquine with or without azithromycin, but which have the 
difficulty of having included the same few individuals; additionally, in a meta-analysis it was 
observed that the individuals who received these drugs had a higher risk of serious adverse 
events, particularly cardiological, although this information is under review (41).  
The use of convalescent plasma is a passive immunotherapy method, which was used for 
SARS in 2003 and for MERS in 2012, and has been proposed as a treatment for COVID-19. 
In the case of SARS-CoV in 2003, the antibodies of individuals who were cured could persist 
in high concentrations for long periods of time and could be a treatment option in SARS-
CoV-2 2020 (42-44).  
There is evidence in a small number of patients that this strategy could be effective in 
individuals with pneumonia or severe conditions. However, this depends on maintaining a 
sufficiently high antibody titre in donors and on developing production and supply strategies, 
as well as validating these findings with clinical trials with the appropriate design on a larger 
scale (38, 42-44). 
Although SARS-CoV-2 is an emerging pathogen, it has high homology with SARS-CoV and 
MERS-CoV, so research and development of novel coronavirus vaccines can be based on the 
methods used in SARS and MERS. Studies have begun for mRNA vaccines, recombinant 
proteins, viral vectors, DNA, among others, and some of them have continued to testing 
phase in humans; however, it remains to be determined whether the production of specific 
antibodies is related to the rapid elimination of SARS-CoV-2 and what is its impact on the 
community in terms of blocking the infection and the immune response of the individual 
(44). 
Monoclonal antibodies have shown activity against SARS, for example, the CR3022 
molecule binds effectively to the receptor-binding domain (RBD) of SARS-CoV-2 and 
prevents interaction with receptor proteins of human cells such as ACE2. Other fusion 
proteins with high affinity to the extracellular domain of human ACE2 with activity against 
SARS-CoV and SARS-CoV-2 are being evaluated. This therapeutic target is under 
development. It will be very important to consider the adverse events of this group related to 
the immune response (38, 44).  
Different molecules that act trying to avoid the damage caused by the release of cytokines, 
such as IL 6 inhibitors (tocilizumab, sarilimumab amongst others), IL2 inhibitors, JACK 
inhibitors (e.g. Ruxolitinib) or Bruton's tyrosine kinase (Btk) inhibitors such as acalabrutinib 
are under evaluation (38, 44).   

 
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The preliminary results of the Recovery study, a randomised, controlled, open-label, adaptive 
platform clinical study with 5 arms, demonstrated the benefit of the dexamethasone 6 mg 
oral or intravenous arm for 10 days (n=2104) compared with those receiving standard 
treatment (n=4321). The study observed lower mortality (RR 0.76; 95% CI: 0.6-0.96; 
p=0.021) in those patients with pneumonia who required oxygen (RR 0.8; 95% CI: 0.7-0.92; 
p <0.002) or were on mechanical ventilation (RR 0.65; 95% CI: 0.51-0.82; p <0.001) who 
received dexamethasone (45).  
1.1.2.3 
Support treatment 
 
In patients with COVID-19 pneumonia, dyspnoea is variable and does not always correlate 
with oxygen levels in the blood, so oxygen therapy must be guided by other parameters. A 
recent randomised trial compared patients receiving oxygen therapy; a branch whose oxygen 
saturation objective was ≥ 96% and another conservative branch whose saturation objective 
was 88-92% had to be stopped prematurely due to the poor benefit of the conservative 
branch. In patients with oxygen requirements, the indication for nasal cannulas and masks 
with different inspired oxygen fractions is defined based on the oxygen levels in the blood 
measured through oxygen saturation or blood gases. There is evidence that the high flow of 
oxygen and the change to prone position of the patient while receiving oxygen therapy are 
alternatives in these strategies that could be useful and are being evaluated (46, 47). 
Non-invasive positive pressure ventilation (NIPPV) is an option that does not require 
endotracheal intubation in patients who can remain awake. Although this strategy has the 
advantage of not being invasive, in a retrospective case series from Wuhan, 72% of patients 
with NIPPV died. The benefit of this technique is unclear so its usefulness is limited, in 
addition to the risk associated with aerosolisation, which is difficult to quantify (46, 48).  
Whether to start mechanical ventilation early or later is debated, some prefer to wait based 
on the mortality rate of intubated patients, while others argue that early ventilation would 
prevent further lung damage. It is recommended that the mechanical ventilation modality be 
the same as for patients with acute respiratory distress syndrome (ARDS) of other causes; 
fundamentally with low pressures in the airway and low lung volumes (46).   
  
1.1.3 Investigational medicinal product 
INM005 is an animal-source haemoderivate. The active ingredient is the F(ab’)2 purified 
from total equine immunoglobulins. These immunoglobulins were obtained from a pool of 
sera from horses previously immunised with the glycoprotein S (Spike Protein) RBD 
(Receptor Binding Domain) of SARS-CoV-2 , as illustrated in Figure 1, obtained by genetic 

 
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engineering techniques. The RBD is obtained in the laboratory through biotechnology 
techniques and is responsible for the binding of the virus to the Angiotensin-converting 
enzyme 2 (ACE2) receptor through which the virus is internalised in the cell (49-50). 
 
Figure 1. Tridimensional model of the Spike protein, in green is the 
receptor-binding domain (RBD) of the Spike glycoprotein 
Adapted from Wrapp D. et al, 2020 (65). 
The F(ab')2 fragments are obtained from the digestion of the total equine immunoglobulin 
fraction with the enzyme pepsin. The process includes a subsequent removal of the 
immunoglobulin constant region, keeping the hinge region intact (Figure 2). F(ab')2 
fragments have two F(ab) binding domains connected by a disulphide bridge and are 
therefore divalent, with a molecular weight of approximately 110 kiloDaltons. 
 

 
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Figure 1.2 
Schematic representation of an immunoglobulin with the F(ab')2 
fragments linked by disulphide bridge 
 
 
 
In vitro assays using Vero E6 cells have shown that INM005 has a very high titre of 
neutralising anti-SARS-CoV-2 INM005 F(ab’)2 antibodies (1:10240) (51). The proposed 
mechanism of action for the investigational medicinal product (IMP) is the blockade of the 
virus entry by means of binding the IMP to the viral S protein RBD, in this way the virus 
cannot be internalised and the cytopathic effect is avoided. 
The IMP would be administered within the first days after the onset of symptoms and after 
the diagnosis of the disease is confirmed. The efficacy of an equine serum in humans lies in 
its capacity to neutralise the virus in the bloodstream of infected individuals. 
The use of this type of antibody would constitute a fast and effective therapeutic strategy 
since it has the advantage of recognising a wide variety of epitopes on the antigen - thus 
limiting the risk of mutations that lead to a possible viral evasion. Besides, they tend to 
develop higher avidity relative to monoclonal antibodies for a given antigen. Although the 
use of equine sera has been associated with disease risk in the past, the new generation of 
F(ab')2 fragments have been shown to be safe and well tolerated in humans. The F(ab´)2 are 
easy to produce, allowing the scaling up for rapid product availability (55, 65). 
In this context, at present, the use of convalescent plasma is the only possible immunotherapy 
for hospitalised patients with COVID-19 (66-68). However, there are some limitations on the 
availability of these plasmas. On the one hand, specific antibodies against the virus with 
neutralising potential generally appear 2 to 3 weeks after the onset of symptoms in patients. 
On the other hand, its extraction depends on the donation of plasma from patients already 
recovered without viral load. Furthermore, various studies show great variability in the 
response of neutralising titres between individuals and even the efficacy in critical patients 
in the ICU has not been fully demonstrated (66, 70). In contrast, the use of F(ab')2 fragments 
 

 
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developed using RBD as antigen, rather than the whole Spike protein or the whole virus, 
avoids the injection of other antibodies against other Spike domains that can lead to unwanted 
adverse events, such as enhancing the infection through what is known as antibody dependent 
enhancement (ADE) (71). The results of the in vitro seroneutralisation tests have shown that 
INM005 is around 50 times more potent than the average observed with convalescent 
plasmas, which allows the use of a smaller amount of product with neutralising capacity (51). 
INM005 is very similar to other antitoxins such as those used for diphtheria and tetanus, 
which have been successfully used since 1890. Recently, the United States Food and Drug 
Administration (FDA) has approved a product based on an equine hyperimmune antibody 
fragment that specifically neutralises toxins produced by Clostridium botulinum; the trade 
name of this product is BAT®, and its approved indication is the treatment of symptomatic 
botulism (72). We believe that a therapeutic approach similar to this one can be used to 
prevent the progression of COVID-19 disease. 
1.1.4 Rationale for the use of placebo 
The development process for the proposed protocol included consideration of the need for a 
placebo group combined with standards of care as a concurrent control in a fully blinded 
study. It should be noted that the body of literature related to this indication, as well as the 
serious nature of this disease, provide a potential clinical justification for choosing a study 
design that includes a placebo control, under the presumption that there are no other available 
means of active drug therapy. 
In the first place, the inclusion of a placebo group in this indication, combined with the 
standard of care (SoC), is not considered a decision contrary to the interests of the patient 
from the clinical perspective, since there is currently no preventive or acute treatment for the 
treatment of COVID-19. All subjects randomised to the treatment groups within this study 
will receive the best options from the current standard of care of the institution where they 
are hospitalised. 
Finally, there is no active treatment (of proven efficacy) to estimate placebo event rates 
consistently. Furthermore, the experimental intervention (INM005) for this study does not 
have previous data on efficacy or safety in a population with COVID-19. 
As a result, a concurrent placebo control group combined with the best standard of care 
options will be included in the proposed study, and a clinical break-even point is maintained 
between the treatment groups. 

 
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1.2 
Study rationale 
Treatment of COVID-19 is basically symptomatic. There is no specific treatment capable of 
preventing or controlling the damage caused by SARS-CoV-2. 
The pandemic caused by the novel coronavirus has generated an unprecedented situation in 
recent history, with several million infected and hundreds of thousands of deaths. This 
disease is easily transmissible by air. Although a high percentage of patients have a mild 
clinical presentation, approximately 15% of them present moderate to severe cases and 5% 
require intensive care with mechanical ventilation and face a high risk of mortality. No 
effective therapies for the treatment or prevention of SARS-CoV-2 have been identified so 
far. Preliminary evidence indicates that passive immunotherapy with convalescent plasma 
could favourably alter the clinical course of this infection. This strategy, even if confirmed 
as successful, requires voluntary donation by patients who have recovered, not all of whom 
are eligible as donors, since the antibody response magnitude varies amongst different 
patients.  
This study aims at studying the efficacy and safety of passive immunotherapy by 
administering hyperimmune serum INM005 generated by the antigenic stimulation of 
equines. INM005 is a product that is biologically equivalent to the anti-Shiga toxin serum 
INM004 that neutralises the interaction of SARS-CoV-2 with its cellular receptor, thus 
preventing virus multiplication. The safety information for the anti-Shiga toxin serum 
INM004 indicates that it is well tolerated and that no serious adverse events or suspensions 
of treatment have been detected. 
INM005 is being developed for the treatment of COVID-19 infection. It is anticipated that 
INM005 treatment should be initiated for a SARS-CoV-2 infection diagnosed on the basis of 
laboratory results early in the onset of the disease. This is likely to be the recommended 
paradigm after conducting clinical studies, as these patients are most likely to benefit from 
the use of neutralising anti-SARS-CoV-2 antibody fragments. Therefore, this product could 
be used in patients with a clinical manifestation of moderate to severe disease of COVID-19. 
An early interruption of the cascade mediated by virus entry into cells is expected to prevent 
the development of disease progression and reduce the severity of the condition, the rate of 
complications, and the incidence/duration of hospitalisations. Therefore, the proposed 
research will evaluate patients who are in the early stages of this disease, that is, patients who 
attend a medical consultation as a result of a SARS-Cov-2 infection prior to the development 
of a highly advanced condition of the illness.  
INMUNOVA hypothesised that patients between 18-79 years of age with SARS-CoV-2 
infection would be the ones most likely to benefit from INM005 treatment administered to 
improve the symptoms of COVID-19. The proposed INM005 administration regimen is only 

 
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after PCR confirmation of the presence of SARS-CoV-2 in the patient's clinical sample 
(Figure 1.3).  
 
Figure 1.3 
Administration regime proposed for INM005* 
 
 
The objective of this adaptive Stage II/III study is to demonstrate the efficacy and safety of 
INM005 in terms of improving the clinical course of COVID-19, at 28 days after the start of 
treatment with the investigational product in individuals with moderate to severe disease 
requiring hospitalisation. 
1.3 
Preclinical safety and clinical support data 
Observations supporting the exposure of an adult population to INM005 within the 
framework of the proposed investigation include preclinical and clinical evaluations of 
INM004 and related compounds. 
1.3.1 F(ab’)2 fraction of equine immunoglobulins 
Passive immunotherapy is one of the most promising therapeutic strategies to reduce the 
lethality and morbidity of the pandemic. Anti-venoms and antitoxins in the form of equine 

 
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F(ab')2 fragments have been used for more than 30 years. Therefore, the safety profile of 
products of similar structure but with different specificity is well known in adults and 
children, and is generally considered manageable, as they have been used without the 
occurence of significant adverse events. 
The product INM005 is made with the same technological platform with which the Shiga 
antitoxin has been made, and fractions of F(ab’)2 of viper venom neutralising equine 
immunoglobulins have been made for more than 30 years. The difference for each product 
lies in the initial antigen (venom/toxin) with which the horses are immunised, and therefore 
in the main specificity of the antiserum. 
The products having different specificity cannot be structurally distinguished by performing 
complex physicochemical analytical techniques (electrophoresis, chromatography) and a 
challenge against the antigen used in immunisation is required for their recognition. 
For the reasons explained, this type of biological product differs widely from synthetic 
chemical products and from biological products obtained by recombinant DNA technology 
(biotechnological) in which homogeneous protein preparations are mostly obtained with a 
low percentage of variations at the level of molecular modifications. 
Particularly in Argentina, the Instituto Biológico Argentino S.A.I.C. - BIOL (manufacturer 
of the investigational product), has produced this type of preparations derived from equine 
plasma since 1908 and since 1984 it has used the same procedure to elaborate the fraction 
F(ab´)2 purified from horse plasma that is injected to over 1000 patients every year for the 
treatment of snake poisoning. 
It is important to note that the product is not innovative in its structure, but rather in its 
specificity of recognition towards SARS-CoV-2. As for the anti-Shiga toxin product 
(INM004), the anti-SARS-CoV-2 serum will be formulated at a lower concentration of the 
equine active ingredient F(ab´)2 than the current BIOL formula for antivenin (2.5% versus 
6%) and consequently there will be a lower degree of exposure to the product and its possible 
adverse reactions. 
Although the product is not strictly an anti-venom, it is produced as such and it is proposed 
to be used in a similar way, that is, to neutralise the interaction of SARS-CoV-2 with its 
cellular receptor, preventing the multiplication of the virus and therefore, the COVID-19 
disease. This is why, both for the production and for the control and regulation for INM005, 
we rely on the World Health Organisation guide for the production, control and regulation of 
anti-venom immunoglobulins. The current version is the 2016 edition (52). Chapter 18, 
devoted to the clinical evaluation of anti-venoms, begins by explaining how unusual anti-
venoms are compared to other pharmaceutical agents. Then, it explains the standard pathway 

 
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for the clinical evaluation of new therapeutic products and suggests that the relevance of this 
pathway for anti-venoms depends on a number of factors, mainly, whether an anti-venom is 
new or has previously been used in human patients, the ethical basis for the study, the 
feasibility of conducting such studies, as well as ethical and national regulatory 
considerations. Section 18.1.2 Phase I studies states “Conventional clinical studies using 
healthy volunteers are not appropriate in the case of anti-venoms due to the risk of 
anaphylactic and other reactions (e.g. pyrogenic or serum diseases, and rarely 
hypersensitivity reactions to equine/sheep plasma proteins) and the risk of generating 
sensitisation to equine/sheep plasma proteins in healthy volunteers”. Phase I studies, 
designed mainly to detect unanticipated adverse reactions, would not apply in this case due 
to previous experience with INM004 (manufactured with the same technological platform) 
and other anti-venoms and antitoxins. 
Therefore, in the case of INM005, as it is the biologically equivalent product to anti-Shiga 
toxin serum, it would be coherent to follow these guidelines for its regulatory development. 
Also using the results obtained in the clinical development for the latter. During this 
development program, INMUNOVA has carried out several preclinical tests, in accordance 
with the guidelines established by ICH S6, which included 10 toxicology studies with more 
than 500 animals. A standard tissue cross-reactivity (TCR) test was performed with 34 frozen 
tissues. In the case of Shiga toxin, no safety concerns were reported in any of these preclinical 
studies. Then in 2017, a first trial in humans was conducted with 14 healthy adult volunteers 
(clincaltrias.gov identifier: NCT03388216) that showed an excellent safety profile, in which 
there was no hypersensitivity event reported in the 30-day safety follow-up period for the 
subjects of the single and repeat dose stages. Additionally, in the samples of the evaluated 
subjects there is no evidence of a change in the reactivity towards the product (reactivity 
against Equine Ig) in serum samples taken 30 days after the administration of both single and 
repeated doses. 
Taking into account these antecedents with INM004, and added to the results of the study 
with convalescent plasma in 5000 patients in the US, where it was demonstrated that the 
incidence of serious adverse events after infusion was less than 1% (7), it is assumed that 
there is no cross-reactivity of anti RBD (human convalescent plasma) antibodies and human 
tissues.  
Since October 2019, INMUNOVA has been conducting a phase II/III clinical trial to evaluate 
the safety and efficacy of INM004 in paediatric patients with Shiga toxin-positive bloody 
diarrhoea for the prevention of haemolytic uremic syndrome (clincaltrias.gov identifier: 
NCT041323 75). Recruitment to date has been 11 children and no safety findings have been 
reported (currently the enrolment of this trial is suspended due to the pandemic, see section 
1.3.5- semi-annual safety report).  

 
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1.3.2 F(ab’)2 fraction of equine immunoglobulins - similar 
products 
As mentioned above, antivenins and antitoxins in the form of equine F(ab')2 fragments have 
been used for more than 30 years as anti-tetanus and antivenin sera. The safety profile of 
similar products is well characterised. Currently, the products listed in Table 1.1, which are 
similar to INM005, are approved by the FDA and also in the European Union (EU):  
Table 1.1 
Products similar to INM005 approved by the Food and Drug 
Administration (FDA) and European Union 
Product 
Company 
Application 
Type 
Approval by 
the EU/FDA 
FAVIRAB
® 
Sanofi 
Pasteur S.A. 
Post-exposure prophylaxis to 
Favirab 
in 
subjects 
with 
suspected exposure to the 
Favirab virus, particularly in 
the case of severe exposure 
F(ab')2 of equine 
immunoglobulin 
(antirabies) 
EU 
Anascorp®  
RDTX Inc. 
Centruroides (scorpion) sting 
F(ab')2 of equine 
immunoglobulin 
FDA 2011 
BAT®  
Emergent 
Biosolutions 
Heptavalent 
botulinus 
antitoxin (A, B, C, d, E, F, G)  
F(ab')2 of equine 
immunoglobulin 
FDA 2013 
Anavip™  
RDTX Inc. 
Crotalid bite 
F(ab')2 of equine 
immunoglobulin 
FDA 2015 
 
 
1.3.3 
F(ab’)2 fraction of equine immunoglobulins - Safety information of 
similar products 
Purification methods were introduced in order to reduce the frequency of reactions to 
antivenin, through the elimination of the Fc fragment of IgG, which prevents complement 
activation and could perhaps reduce the intensity of complex formation responsible for the 
appearance of late reactions to antivenin (serum sickness). The F(ab')2 fragments of 
immunoglobulins have been widely used for 60-70 years. However, it was the aggregation 
of antivenin proteins, and not the activation of complement mediated by the FC fragment, 
that was increasingly identified as the main cause of antivenin reactions. Therefore, regarding 
the safety of antivenins, a critical issue is probably the physicochemical characteristics of the 

 
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antivenins and not exclusively the type of neutralising molecules that constitute the active 
ingredient. It is also important to ensure that currently available methodologies for antivenin 
production provide a sufficient margin of safety with regard to the potential risk of zoonosis 
transmission (53). 
In 2013, a series of clinical studies carried out in a significant population of patients was 
published as part of the development of Anascorp (an antivenin indicated for the treatment 
of scorpion sting poisoning). These consisted of five prospective clinical studies and one 
historical-controlled case study that together included a total of 1,534 patients with a wide 
range of ages (from less than 1 month of age to 90 years of age) (54). The patient population 
included 802 men and 732 women; 307 people > 18 years of age and 1,118 patients between 
0 and 18 years of age.  
Monitoring of vital signs and adverse reactions, including acute hypersensitivity reactions 
and serum sickness, was performed in all patients. Follow-up telephone interviews were 
conducted at 24 hours, and 7 and 14 days after the administration of the treatment to obtain 
data on symptoms that could suggest the existence of a poison effect, the presence of serum 
sickness, or any other adverse reaction. In the patients studied, the most commonly observed 
AEs were vomiting, pyrexia, rash, nausea, and pruritus. The incidence of these AEs was 
greater than 2% but less than 5%. 
Table 1.3 shows the AEs that occurred in patients in all clinical studies conducted on 
Anascorp. 27% (421/1534) of patients receiving Anascorp had at least 1 adverse reaction. 
Table 1.3 
Adverse events occurring in clinical trials with Anascorp 
Adverse event 
Number of patients who had AE [N=1534] 
n (%) 
Vomiting 
72 (4.7) 
Pyrexia 
63 (4.1) 
Rash 
41 (2.7) 
Nausea 
32 (2.1) 
Itching 
31 (2.0) 
Headache 
29 (1.9) 
Rhinorrhoea 
28 (1.8) 
Myalgia 
25 (1.6) 
Fatigue 
24 (1.6) 

 
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Cough 
22 (1.4) 
Diarrheal 
20 (1.3) 
Lethargy 
17 (1.1) 
No patient died or discontinued participation in the study due to severe adverse reactions. 
Eight patients (0.5%) were considered affected by a condition of serum sickness (type III 
hypersensitivity); in no patient was a complete syndrome of serum sickness reported. Three 
patients were treated with systemic corticosteroids and another five received no treatment or 
received symptomatic treatment. There were 34 patients with a total of 39 severe adverse 
reactions such as respiratory distress, aspiration, hypoxia, ataxia, pneumonia, and eye 
swelling. It is unclear whether these adverse reactions were related to Anascorp, poisoning, 
or a combination of both factors (55-56). 
Appendices hereto also include the Anascorp, BAT and Anavip package inserts, since they 
provide safety reference information on the Fab'2 fractions of equine immunoglobulins (57-
61): 
● Anavip: The most frequent adverse reactions (>2%) in clinical studies were: pruritus, 
nausea, rash, arthralgia, peripheral oedema, myalgia, headache, pain in extremities, 
vomiting and erythema. 24% (21/86) of the patients studied in clinical studies were 16 
years of age or younger (6 patients were between 2 and 5 years of age, and 15 patients 
were between 5 and 16 years of age). None of the paediatric patients in the phase 3 study 
had a recurrent coagulopathic effect. None of the adverse reactions in paediatric patients 
were serious. The most common adverse reactions amongst paediatric patients were 
nausea and vomiting, itching, and fever. Therefore, safety and efficacy in the paediatric 
population did not differ from that observed in adults. 
● BAT: The most common adverse reactions observed in ≥ 5% of healthy volunteers in 
clinical studies were headache, nausea, pruritus, and urticaria. The most common adverse 
reactions reported in ≥ 1% of patients in the context of a clinical study were pyrexia, rash, 
chills, nausea, and oedema. 
● Post-marketing experience: the following hypersensitivity/allergic reactions have been 
reported in patients treated with BAT: anaphylactic shock; angioedema; urticaria. 
● Post-marketing experience with Anascorp: chest tightness, palpitations, rash and 
pruritus. 
● FabenFlu: In the phase 1 study, this F(ab')2 was well tolerated, and there were no deaths 
or serious adverse events (SAEs). Three patients had mild AE (1 each with 
blepharospasm, sinusitis, and pyrexia). The pyrexia event (38°C) was considered 

 
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probably related to the infusion and resolved after 37 min. Laboratory evaluations of 
blood and urine samples and physical examinations of heart rate, electrocardiographic 
readings, and body weight did not reveal any clinically significant safety concerns. 
● An evaluation of the use of fixed-dose monovalent immunoglobulin G (equine) antivenin 
from vipera palaestinae was carried out for the treatment of the most venomous snakebite 
in Israel, in cases that occurred from March 2008 to March 2014 and cared for in two 
paediatric emergency departments. 57 patients between 1 and 17 years of age were 
evaluated. The antivenin was administered to 25 (42%) children who presented local and 
systemic reactions of moderate to severe intensity to the snakebite. None of these patients 
developed adverse reactions, serum sickness, or any other side effect to the antivenin. 
1.3.4 F(ab’)2 fraction of equine immunoglobulins - Phase 1 
results with INM004 
The safety data obtained from the phase 1 study (CT-INM0004-01) indicate that INM004 
was well-tolerated. Table 1.4 presents complete information on AEs that occurred during 
human exposure to IMP. The AE considered possibly or probably related to the IMP by the 
investigator are presented in Table 1.5. 
Table 1.4 
CT-INM004-01 - Adverse events reported in each treatment arm, 
regardless of causality 
Adverse event 
Active 
treatment 
arm 
(n = 11) 
Placebo 
arm 
(n = 3) 
Headache 
5 (45 %)1 
0 
Constipation 
1 (9 %) 
0 
Pain in the site of extraction 
1 (9 %) 
0 
Flushing 
1 (9 %) 
0 
Worsening of plantar fascitis 
1 (9 %) 
0 
Bruising in the site of extraction 
2 (18 %) 
0 
Diarrhea 
0 
1 (33 %) 
Anal irritation 
0 
1 (33 %) 
Rhinitis 
1 (9 %) 
1 (33 %) 
Earache 
1 (9 %) 
0 
1 Three (3) AE correspond to the same subject. 
 

 
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Table 1.5 
CT-INM004-01 - Adverse events reported with a possible or 
probable causal relation to the investigational medicinal product 
Subject 
code 
Treatment 
arm 
assigned 
Dose 
Body 
weight 
(kg) 
Total 
dose 
(mg) 
Sex 
Age 
Ethnicity 
Adverse 
events 
Relationshi
p/causality 
3231-16 INM004 
3 repeat 
doses 
4 mg/kg 
69.9 
838.8 
Female 
23 
Hispanic 
Flushing 
Possibly 
related 
Headache Possibly 
related 
3231-18 INM004 
3 repeat 
doses 
4 mg/kg 
57.2 
686.4 
Female 
50 
Hispanic 
Headache 
(mainly 
frontal) 
Probably 
related 
Frontal 
headache 
Probably 
related 
3231-23 INM004 
3 repeat 
doses 
4 mg/kg 
67.1 
805.2 
Female 
23 
Hispanic 
Rhinitis 
Possibly 
related 
Two subjects had headache; this AE was assessed as possibly or probably related to the study 
drug in both cases. The occurrence of the headache event was not associated with the infusion 
or any other activity carried out during the study.  
One subject developed mild flushing lasting 1 minute at the beginning of the 1st. infusion. 
The reaction stopped spontaneously and required no treatment. This reaction was rated as 
possibly related to the study drug.  
One subject presented moderate rhinitis with full recovery (restoration of the original state). 
This case is included within the adverse reactions at the investigator´s judgement, and was 
classified as an event possibly related to the investigational product; for INMUNOVA, it was 
not possible to determine the existence of a causal relationship with the study drug. 
Analysis of the distribution of AE amongst the subjects indicated that 2 AE (mild headache 
and flushing events) occurred in 1 subject; the headache event occurred twice in another 
subject, and rhinitis was a single event that occurred in a 3rd subject.  
There were no serious and unforeseen adverse drug reactions upon application of the product 
in humans, and no SAEs have been reported. Adverse reactions are listed in Table 1.6, 
ordered by System Organ Class (SOC). All the reported events were non-serious, as were the 
adverse events that are presented in Table 1.4. 

 
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Table 1.6 
CT-INM004-01 - Adverse events reported by System Organ Class 
(SOC) 
 
System Organ Class (SOC) 
Adverse event 
Number 
of 
subjects 
Serious 
(yes/no) 
Number 
of 
events 
General disorders and 
administration site conditions 
Flushing 
1 
No 
1 
Injuries and poisoning 
0 
0 
0 
0 
Nervous system disorders 
Headache 
2 
No 
3 
Skin and subcutaneous tissue 
disorders 
0 
0 
0 
0 
Gastrointestinal disorders 
0 
0 
0 
0 
Musculoskeletal and 
connective tissue disorders 
0 
0 
0 
0 
Infections 
0 
0 
0 
0 
Respiratory, thoracic and 
mediastinal disorders 
Rhinitis 
1 
No 
1 
Immune system disorders 
0 
0 
0 
0 
Vascular disorders 
0 
0 
0 
0 
Psychiatric disorders 
0 
0 
0 
0 
Eye disorders 
0 
0 
0 
0 
Haematological and 
lymphatic disorders 
0 
0 
0 
0 
Hepatobiliary disorders 
0 
0 
0 
0 
Renal and urinary disorders 
0 
0 
0 
0 
Cardiac disorders 
0 
0 
0 
0 
Pregnancy, postpartum and 
perinatal disorders 
0 
0 
0 
0 
Ear and labyrinth disorders 
0 
0 
0 
0 
Metabolism and nutrition 
disorders 
0 
0 
0 
0 

 
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Social circumstances 
0 
0 
0 
0 
Benign, malignant and 
unspecified neoplasms 
(including cysts and polyps) 
0 
0 
0 
0 
Reproductive system 
disorders 
0 
0 
0 
0 
Endocrine disorders 
0 
0 
0 
0 
Medical and surgical 
procedures 
0 
0 
0 
0 
Birth defects and genetic 
disorders 
0 
0 
0 
0 
Others 
0 
0 
0 
0 
● Table 1.4 shows the AE that occurred in the treated group versus the group that received 
placebo, with their incidence %. The AE listed do not necessarily have a causal relation 
with the IMP. The latter are presented in Table 1.5 A subject may have presented more 
than one event, or the same event on more than one occasion. 
1.3.4.1 
General considerations related to the safety of CT-INM004-01 
● There were 14 non-serious AE (Table 1.4), mild to moderate intensity, none severe. 
Those possibly or probably related to the medication are headache, predominantly 
frontal, and flushing (Table 1.5). Headache occurred in 3 of 11 subjects in the active 
treatment arm and in 0 of 3 subjects in the placebo arm, all of them in stage II; this 
represents a prevalence of 27%, a value that is not definite and that could be modified 
during phase 2.  
● Changes in laboratory and physical examination parameters are not considered clinically 
significant. There were no cardiovascular or haematological events. 
● IMP was well tolerated. 
● There were no adverse events of special interest (AESI), such as hypersensitivity or 
immunogenicity reactions. These reactions are frequently observed in response to 
infusion of biological products and were therefore considered “of special interest”. 
It was concluded that the presence of headache is an AE that could be related to the 
investigational product. It could be an adverse event of the class, in accordance with the 
events that have occurred for other similar F(ab’)2 drugs. The presence of other 
observations of safety events has not been detected at any time during the study. 

 
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1.3.5 F(ab’)2 fraction of equine immunoglobulins - Phase 2/3 
results with INM004 
At the end of the evaluation period in May 2020 of the study CT-INM004-02 (Double-blind, 
placebo-controlled, adaptive, Phase 2/3 study, to evaluate the pharmacokinetics, safety and 
efficacy of INM004 in paediatric patients with diarrhoea Bloody Shiga toxin positive for the 
prevention of Haemolytic Uremic Syndrome) a total of 11 patients had been randomised. Of 
these, two patients received only the first dose of the investigational product due to 
withdrawal of consent (patient AR01-001) and due to non-compliance with study entry 
criteria (patient AR08-004), while seven patients received full treatment of the study 
(blinded).  
25 non-serious AE were reported out of a total of ten patients Table 1.7. Only three of them 
(mild "headache" [patient AR05-001] and two reports of mild "rhinitis" [patients AR08-001 
and AR08-003] were listed (expected) AE. The investigator considered the following AE as 
possibly related to the administration of the investigational product: "morbiliform allergic 
rash" (AESI, patient AR01-001), "neutropenia" (SAE, patient AR08-002), "mild afebrile 
rhinitis" and "rhinorrhoea" (non-serious AE, patient AR08-003). Furthermore, the AE 
"vomiting" (non-serious AE, patient AR06-001) was considered related to the underlying 
disease of the study.  
One AE occurred within 24 h after the administration of the 1st. dose of the investigational 
product (“rhinorrhoea” [patient AR08-003] and three AE occurred on the same day as the 
2nd infusion of the investigational product (“fever” [patient AR05-003], “increased LDH” 
[patient AR08-003] and “neutropenia” [patient AR08-002]). 
Two cases of neutropenia were reported, one of them was evaluated as serious AE (patient 
AR08-002, described above) and possibly related to the administration of the investigational 
product (Table XX) and the other referred to a non-serious neutropenia (patient AR08-001) 
evaluated as not related to the investigational product, but related to recent exposure to 
routine vaccination (Sabin + pentavalent + chickenpox vaccines). No therapy was performed 
for these AE and the subjects made a full recovery. 
Results of physical examination, laboratory data, vital signs, and ECG evaluations revealed 
no safety-relevant findings. No unblinding was performed due to emergency/therapeutic 
reasons. At the time of this report, no patient developed haemolytic uremic syndrome. 
The benefit risk profile remains favourable for the investigational product. 
 

 
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Table 1.7- CT-INM004-02 List of SUSARs 
Subject ID 
AE 
term 
(according to the 
investigator) 
Seriousness criteria 
System Organ 
Classification 
(MedDRA SOC) 
Preferred 
term 
(MedDRA 
PT) 
Start date 
Country of 
occurrence 
Medical assessment 
AR08-002 
Neutropenia 
Others 
(medically 
important 
event 
due to sudden drop 
in neutrophil count)
Blood 
and 
lymphatic system 
disorders 
Neutropenia 
16/01/2020 
Argentina 
Female patient who developed a decrease in neutrophil count 
from baseline (-27% in 24-h, nadir: -71% in approximately 48
h) after infusion of the 1st. dose of the investigational product. 
The patient had no fever or other complications associated 
with neutropenia and had a rapid improvement in neutrophil 
count. 
As possible confounding factors, although an association 
between the underlying positive STEC infection and 
decreased neutrophil count is unlikely, this cannot be ruled 
out. In addition, the patient had received midazolam 
(intranasal) and chloral hydrate a few minutes before the start 
of the infusion of the investigational product (blinded) and due 
to the patient's concern. Although the search in the scientific 
literature did not show evidence of an association between the 
use of midazolam and/or chloral hydrate and the development 
of haematological adverse reactions, a causal relationship 
cannot be ruled out at this time. However, an association of 
the event with these drugs is considered unlikely. 
A class effect cannot be established, as no safety data were 
found on haematological involvement with respect to the use 
of similar F(ab')2 drugs (e.g. equine sera such as tetanus toxin, 
antivenin, or arachnid serum). 
From the assessment of the principal investigator and the 
consulted external haematologist, at this point it is not possible 
to establish a clear causal relationship. 
The patient did not develop haemolytic uremic syndrome. 
The risk-benefit profile continues to be favourable for the 
investigational product. 
 

 
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Table 1.8- CT-INM004-02 LIST OF ADVERSE EVENTS 
Subject 
number 
Randomisation 
date 
Name of adverse event 
Start date 
End date 
Serious AESI 
Outcome 
Action 
taken with 
the study 
medicatio
n 
Other 
measure 
taken 
Causal relation with the 
investigational 
product 
(investigator) 
Relation with the 
other treatment 
Severity 
AR01-001 
2020-01-29 
MORBILIFORM 
ALLERGIC RASH 
01/02/2020 
01/02/2020 No 
Yes 
Recovered Not 
applicable 
Medication 
needed 
Possibly related 
Other 
medical 
condition 
Mild 
AR05-001 
2019-10-22 
VULVITIS 
UNK/11/201
9 
21/11/2019 No 
No 
Recovered Not 
applicable No 
Not related 
No 
Mild 
AR05-001 
2019-10-22 
PARASITOSIS 
18/12/2019 
 
No 
No 
Not 
recovered 
Not 
applicable Other 
Not related 
No 
Mild 
AR05-001 
2019-10-22 
HEADACHE 
22/12/2019 
22/12/2019 No 
No 
Recovered Not 
applicable 
Medication 
needed 
Not related 
No 
Mild 
AR05-002 
2020-01-15 
LARYNGITIS 
13/02/2020 
16/02/2020 No 
No 
Recovered Not 
applicable 
Medication 
needed 
Not related 
No 
Mild 
AR05-002 
2020-01-15 
BRONCHOSPASM 
29/02/2020 
06/03/2020 No 
No 
Recovered Not 
applicable 
Medication 
needed 
Not related 
Other 
medical 
condition 
Mild 
AR05-003 
2020-01-21 
FEVER 
22/01/2020 
22/01/2020 No 
No 
Recovered Dose 
not 
modified 
Medication 
needed 
Not related 
No 
Mild 

 
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Subject 
number 
Randomisation 
date 
Name of adverse event 
Start date 
End date 
Serious AESI 
Outcome 
Action 
taken with 
the study 
medicatio
n 
Other 
measure 
taken 
Causal relation with the 
investigational 
product 
(investigator) 
Relation with the 
other treatment 
Severity 
AR05-003 
2020-01-21 
CUT ON THE CHIN 
27/01/2020 
05/02/2020 No 
No 
Recovered Not 
applicable Other 
Not related 
No 
Mild 
AR06-001 
2019-10-24 
VOMITING 
26/10/2019 
26/10/2019 No 
No 
Recovered Not 
applicable No 
Not related 
Study disease 
Mild 
AR06-001 
2019-10-24 
TONSILITIS 
14/11/2019 
22/11/2019 No 
No 
Recovered Not 
applicable 
Medication 
needed 
Not related 
No 
Moderate 
AR08-001 
2019-12-30 
NEUTROPENIA 
27/01/2020 
29/01/2020 No 
No 
Recovered Not 
applicable No 
Not related 
No 
Moderate 
AR08-001 
2019-12-30 
COMMON COLD 
UNK/01/202
0 
UNK/01/202
0 
No 
No 
Recovered Not 
applicable No 
Not related 
No 
Mild 
AR08-001 
2019-12-30 
LARYNGITIS 
19/02/2020 
UNK/UNK/
2020 
No 
No 
Recoverin
g 
Not 
applicable 
Medication 
needed 
Not related 
No 
Moderate 
AR08-002 
2020-01-15 
NEUTROPENIA 
16/01/2020 
20/01/2020 Yes 
No 
Recovered Dose 
not 
modified No 
Possibly related 
No 
Severe 
AR08-002 
2020-01-15 
FEVER 
01/02/2020 
01/02/2020 No 
No 
Recovered Not 
applicable 
Medication 
needed 
Not related 
No 
Mild 
AR08-002 
2020-01-15 
UPPER 
RESPIRATORY 
TRACT COLD 
01/02/2020 
01/02/2020 No 
No 
Recovered Not 
applicable 
Medication 
needed 
Not related 
No 
Mild 

 
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Subject 
number 
Randomisation 
date 
Name of adverse event 
Start date 
End date 
Serious AESI 
Outcome 
Action 
taken with 
the study 
medicatio
n 
Other 
measure 
taken 
Causal relation with the 
investigational 
product 
(investigator) 
Relation with the 
other treatment 
Severity 
AR08-003 
2020-01-31 
LDH INCREASED 
02/02/2020 
28/02/2020 No 
No 
Recovered Dose 
not 
modified No 
Not related 
No 
Mild 
Subject 
number 
Randomisation 
date 
Name of adverse event 
Start date 
End date 
Serious AESI 
Resolution 
Action 
taken with 
the study 
drug 
Other 
measure 
taken 
Causal relation with the 
investigational 
product 
(investigator) 
Relation with the 
other treatment 
Severity 
AR08-003 
2020-01-31 
RHINORRHOEA 
01/02/2020 
01/02/2020 No 
No 
Recovered Dose 
not 
modified No 
Possibly related 
No 
Mild 
AR08-003 
2020-01-31 
MILD 
AFEBRILE 
RHINITIS 
06/02/2020 
09/02/2020 No 
No 
Recovered Not 
applicable No 
Possibly related 
No 
Mild 

 
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1.3.6 Clinical development plan 
INMUNOVA plans to bring COVID-19 treatment directly into phase II/III trials, bypassing 
phase I and preclinical trials due to previous experience and safety data that have been 
obtained from Shiga antitoxin (INM004), as well as other similar F(ab) for other indications 
like botulism, snake and scorpion poisoning as explained above. COVID-19 infection is a 
serious and life-threatening condition that has become a pandemic, for which there is no drug 
for prevention or treatment. The proposed drug INM005 represents a potentially important 
advance, so we believe that it is desirable that there are no unnecessary delays to the start of 
the phase II/III study in the target population. 
1.4 
Dose selection 
The dosage regime of INM005 planned for use in this clinical study are 2 doses of 4 mg/kg, 
administered 2 times approximately 48 h (± 2 h) apart. The selection of the exposure level is 
based on preclinical in vitro data related to the seroneutralisation assay performed with 
SARS-CoV-2, clinical data on the levels of neutralising antibodies supplied in convalescent 
plasma, as well as PK of INM004 obtained from the phase 1 study (CT-INM004-01) in 
healthy adult volunteers. 
 
1.4.1 Dosage rationale 
In the phase 1 clinical study (CT-INM004-01), carried out in Argentina with 14 healthy adult 
volunteers (of both sexes), the safety, tolerance and PK of INM004 were evaluated. This 
study was divided into 2 stages; in stage I, patients in cohort I received a single dose of 
INM005 of 2 mg/kg and patients in cohort II received a single dose of INM005 of 4 mg/kg. 
After an interim analysis, stage II involved three doses of INM004 of 4 mg/kg administered 
every 24 hours (i.e., at t=0 h, 24 h, and 48 h). INM004 plasma concentrations for PK analysis 
were obtained at predefined time points over 7 days (plus a final sample obtained at 30 days) 
from the 1st. dose of INM004.  
The product INM005 is manufactured using the same technological platform and the same 
manufacturing plant used to obtain Shiga anti-toxin (INM004) throughout its development. 
Both molecules correspond to the fraction F(ab')2 of hyperimmune equine immunoglobulin, 
in one case anti-Shiga toxin and in the other anti-SARS-CoV-2, so they are indistinguishable 

 
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from a physicochemical point of view. Added to this, within a hyperimmune serum, no more 
than 10% of the immunoglobulins correspond to those specific against the antigen of interest, 
so no variation is expected in the PK of both products. All the same, a PK study is planned 
to be carried out in this protocol to corroborate these assumptions. Therefore, priority was 
given to define a dosage that ensures an administration of a quantity of neutralising antibodies 
for SARS-CoV-2 greater than the convalescent plasma and that at the same time are present 
in the body for at least 8 days. 
1.4.2 Assumptions 
● The i.v. (mg/kg) and peak serum concentrations (ng/ml) of INM005 after administration 
of a single dose are proportional. In other words, immediately after i.v. injection, the total 
amount of INM005 is diluted in the patient's blood and reaches the maximum 
concentration, within the dose range of INM005 studied; higher doses lead to larger peaks 
whose increase is roughly proportional.  
● There is a very high probability that moderate to severe illness will develop within 7 days 
after symptoms begin. It is very difficult to accurately estimate the amount of virus 
present in the body as this depends on many factors such as inoculum size and type of 
host. 
●  It is intended to maintain the concentrations of the product for at least 8 days to control 
the entry of the virus into the cells and prevent its spread. 
● Comparison between the neutralising power of convalescent plasma vs the chosen dose 
of INM005 
A Neutralising Unit (NU) is defined as the inverse of the neutralising titre in a validated 
serum neutralisation assay. 
Convalescent plasma 
Average titre 1:200 equals 200 NU/ml 
Average transfusion volume 200 ml 
The dose is around 40,000 NU per patient, regardless of the patient's weight. 
 INM005 

 
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Average titre 1:10,000 equals 10,000 NU/ml 
Two doses of 4 mg/kg spaced by 48 h 
For an individual weighing 80 kg, two doses of 10.67 ml would be injected, total 
21.33 ml 
The dose is 213,333 NU for a patient of this weight, being more than 5 times higher 
than the neutralising power of average plasma. 
● The planned dosage of INM005 is intended to obtain, at the maximum concentration 
peak, concentration levels of INM005 that would have the ability to neutralise the virus, 
with a higher potency than convalescent plasma as demonstrated in the seroneutralisation 
tests in vitro. 
1.4.3 Preclinical data 
The potency of INM005, that is, the neutralising capacity of INM005 for infection with 
SARS-CoV-2, was tested in independent laboratories (Respiratory Diseases Service of 
INEI-ANLIS Malbrán; Instituto de Virología "Dr J. M. Vanella"; Laboratorio COVID-
19 Facultad de Ciencias Médicas, National University of Córdoba, and Centre for 
Research in Animal Health (CReSA) - IRTA- Campus of the Autonomous University of 
Barcelona. Briefly, in this assay, serial dilutions of INM005 were made and SARS-CoV-
2 is used to infect a monolayer of the VERO cell line and the titre is determined by means 
of the reduction of plaque-forming units (PFU), TCID50 (Median Tissue Culture 
Infectious Dose). In all cases, the neutralising antibody titre was higher than 1:10,000, 
while convalescent plasma   [AIM2]. 
Figure 1.4 As an example, the seroneutralisation analysis carried out at the Centre 
de Recerca en Sanitat Animal (CReSA) is shown as Log10 of the dilution of the 
sample vs. % of neutralisation. 

 
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1.4.4 Phase 1 study 
A phase 1 study with INM004 has been completed in Argentina (Protocol No. CT-INM004-
01). A total of 14 volunteers enrolled; 3 volunteers received 2 mg/kg of INM004, 3 volunteers 
received 4 mg/kg of INM004, 5 volunteers received 3 doses of 4 mg/kg 24h apart, and 3 
volunteers received placebo. 
The PK data obtained from the 8 healthy volunteers in a single dose cohort can be 
summarised as follows: 
● A total of 19 samples were obtained for each volunteer for antitoxin PK 
measurements, after the completion of the 50 min infusion of INM004. (Sample 
collection times: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 3, 3.5, 4, 4.5, 5, 
6; 8, 12, 24, 48 and 72 h). INM004 concentrations were quantified using the ELISA 
method. 
● 
 Terminal half-lives of INM004 (lambda z) after a single dose were relatively long, 
with a median of 41.24 h (range 33.19-52.92 h). 
● 
 The peak concentrations of INM004 (maximum observed concentrations, Cmax) had 
a median value of 45.14 mg/L (range: 41.76-48.11 mg/L) for the volunteers who were 
administered the dose of 2 mg/kg and 77.70 mg/L (range 64.8-88.4 mg/L) for those 
to whom the 4 mg/kg dose was administered. 
● The area under the concentration versus time curve extrapolated to infinity (AUC0-
inf) had a median of 1557.82 mg * h/L for the volunteers who received 2 mg/kg and 
3496.34 mg*h/L for those who received 4 mg/kg. The increase in AUC0-inf was 

 
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basically proportional to the dose of INM004 administered. The dose-normalised 
AUC0-inf had a median value of 11.84 mg*h/L for each mg of INM004 administered 
(range: 7.29-14.84 g*h/L/mg). 
● The Volume of distribution (Vd) of the terminal phase had a median value of 4.73 L 
(range: 4.22-8.81 L). The median Vd corrected for body weight was 77 ml/kg (range: 
52-89 ml/kg), which suggests a predominantly intravascular distribution of the 
product. 
● The clearance (clearance, Cl) observed had a median value of 84 ml/h (1.41 ml/min) 
and a range between 67 and 137 ml/h (1.12-2.29 ml/min). 
● There is a biphasic elimination profile compatible with a two-compartment model. 
This is summarised in Figure 1.5 
Figure 1.5 
Concentration of INM004 over time in 6 volunteers of the Phase 1 study 
(3 volunteers received 2 mg/kg, 3 volunteers received 4 mg/kg) - Logarithmic scale 
 
Abbreviations: h, hours 
The non-compartmental analysis (NCA) of INM004 concentrations for the repeated dose 
cohort (N=5) yielded the following results (see Figure 1.6), which was consistent with the 
results obtained for the administration of single doses of INM004: 

 
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● The estimated terminal half-lives after the third dose of INM004, using at least 3 
plasma concentrations of INM004, (lambda z) were relatively long, with a median 
value of 68.6 h (range of 55.3-137 h). These observed half-lives were longer than 
those observed after a single dose of INM004, in the 1st. cohort of the phase 1 study. 
These differences could be due to some degree of saturation of the mechanisms of 
elimination of INM004 after the administration of repeated doses. However, these 
changes appear of relatively limited relevance in the context of the few doses of 
INM004 that are required (i.e. 1 or 2 doses of INM004), as proposed for the treatment 
regimen. On the other hand, in the event that a larger quantity of INM004 doses 
should be administered, it seems likely that it is possible to expect an accumulation 
of INM004, at levels higher than those suggested by the estimated half-lives after 
administration of INM004 in single doses. 
● The Cmax at the end of the third infusion of INM004 had a median of 175.7 mg/L 
(range 143.5-200.9 mg/L).  
● The Cmax observed after the first infusion had a median value of 85.7 mg/L (range: 
77.8-98.6 mg/l, similar to that observed previously in volunteers who received only 
a dose of 4 INM004 mg/ kg (median Cmax of 77.7 mg/l for INM004 single dose study 
above); the Cmax observed after the second infusion of INM004 had a median value 
of 130.1 mg/l (range 125.5-155 mg/l).  
● The median area under the concentration versus time curve, extrapolated to infinity, 
(AUCinf) for the total amount administered of 3 doses of INM004 (total cumulative 
dose of INM004: 12 mg/kg divided into 3 doses of INM004, 4 mg/kg each, spaced 
by a period of 24 h, t=0 h, 24 h and 48 h) was 14,121.98 mg*h/L (range 12426.61-
20198.89).  
● The dose-normalised AUCinf had a median value of 18.73 mg*h/L for each mg of 
INM004 (range 15.62-25.09 mg*h/L/mg for each mg of INM004). Median dose-
normalised AUCinf was 58% higher than in the previous INM004 single dose study 
(dose-normalised median AUCinf in INM004 single dose study: 11.84 mg*h/L for 
each mg of INM004, range 7.29-14.84), supporting the suggested possibility that the 
clearance rate of INM004 is reduced after the administration of multiple doses. 
● The median volume of distribution (Vd) was 5.26 L (range 4.27-7.88 L), similar to 
the value previously observed after a single dose of INM004. The median Vd 
corrected 
for 
body 
weight 
was 
84 
ml/kg 
(range  
61-117 ml/kg), consistent with a predominantly intravascular INM004 distribution. 
● The median clearance (Cl) was 53 ml/h (0.88 ml/min), with a range between 40 and 
64 ml/h (0.66-1.06 ml/min). The median CL with correction for body weight was 0.85 
ml/h/kg (range: 0.59-0.96 ml/h/kg). 
 

 
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Figure 1.6  Concentration of INM004 over time (logarithmic scale) 
 
Abbreviations: hs = hours 
The pharmacokinetics of INM004 after 3 doses spaced 24 h apart did not differ significantly 
from what had already been observed in the single dose study of INM004. However, a 
moderate accumulation of INM004 was observed, beyond that expected based on the PK 
observed in the INM004 single dose study. This accumulation (resulting from the lower 
clearance observed after administration of repeated doses) is not expected to significantly 
affect the anticipated exposure in view of the administration regimen proposed to date (i.e., 
single dose or 2 doses of INM004). On the other hand, if a larger number of doses is used, 
the potential for disproportionate accumulation of dose (due to reduced clearance with the 
administration of multiple doses) should be considered when making a decision regarding 
the dosages dose of INM004 to be administered. 
The INM004 levels observed after the 2nd dose (median Cmax of 130.1 mg/L) were close to 
the levels that, as predicted, would be recorded after the administration of 2 doses (predicted 
based on the behaviour of PK in the single dose study). 
1.4.5 Extrapolation of kinetic data at planned doses for INM005 
From a population pharmacokinetics model (63-64) using as a basis the PK data obtained 
from the phase 1 trial for INM004 (CT-INM004-01), different dosage schedules and PK for 

 
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INM005 were simulated. This type of model works very well since the study population and 
the product are similar to that of phase 1. 
The simulations were done assuming doses of 4 mg/kg in patients of 70 kg. The curves 
represent the population median concentration, with the 90% confidence interval. Five 
hundred simulations of the entire population of 11 volunteers obtained from the CT-INM004-
01 trial were performed. The pharmacokinetics model is made in Monolix (62), 2019R2, and 
the simulations and graphs in R, with the Simulx package. This is a bi-compartmental 
population pharmacokinetics model, and the parameters are V1 (central volume of 
distribution), Cl (elimination constant, indicates excretion from the central compartment to 
the "outside", V2 (peripheral volume, e.g. tissues, extravascular water, lymph, etc.), and Q 
(clearance to and from the peripheral volume). The model assumes that it is eliminated from 
the central compartment, that is, there is no elimination from V2 and therefore what goes 
from V1 to V2 at some point returns to V1. The infusion enters compartment 1, which has 
volume of distribution V1, it is distributed to compartment 2, which has volume of 
distribution V2. The passage from compartment 1 to 2 (and vice-versa) has a "speed" Q. 
Finally, the drug is eliminated from compartment 1 with a "speed" Cl (see figure). The 
population distribution gives a statistical variability to the parameters, with a distribution 
(logNormal). The statistical model (residual error l) takes into account a combined error 
(proportional + fixed residual error), the residual error being low. The V2 is influenced by 
weight.  
 
Figure 1.7 Bicompartmental population pharmacokinetics model scheme.  
 

 
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Table 1.9 Simulation parameters 
CI pop 
0.071976554800018 
V1 pop 
0.447770889301066 
Q pop 
6.03570568981478 
V2 pop 
0.849574567795506 
Beta V2 WT 
0.0214472765523809 
Omega Cl 
0.252701314813687 
Omega V2 
0.0306518348168635 
Fixed error (a) 
0.143635819360993 
Proportional error (b) 
0.173797848707843 
Different dosage schedules were simulated taking into account 2 and 3 administrations of 4 
mg/kg. 
For 3 administrations the following times were simulated: 
·         t=0h; t= 24h and t=72h 
·         t=0h; t= 48h and t=96h 
·         t=0h; t= 24h and t=96h 
·         t=0h; t= 24h and t=48h 

 
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 Figure 1.8  Simulations 
of 
INM005 
concentrations 
over 
time 
(3 
administrations) 
 
For two administrations the following were simulated: 
          t=0h and t=48h 
  
 
 

 
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Figure 1.9 Simulation of INM005 concentration over time (2 administrations) 
 
Taking into account the results obtained in the simulations, the scheme of two administrations 
spaced by an interval of 48 h was chosen as it minimizes the number of infusions, and a 
permanence of the investigational product is obtained at concentrations compatible with the 
neutralisation of the virus up to 9 days on average. 
 
1.4.6 Future pharmacokinetics measurements 
The PK profile of INM005 in the study population will be evaluated in a sub-study with 20 
subjects. A blood sample will be drawn from subjects for PK tests immediately before the 
1st. administration of the study drug, at the end of the 1st. administration of the study drug, 
24 h after the 1st. administration of the study drug, immediately before the 2nd 
administration of the study drug, at the end of the 2nd administration of the study drug, 24h 
after 2nd study drug administration and 7 days after 1st. study drug administration. 
Whenever possible, an opportunistic sampling approach will be implemented (that is, 
samples will be obtained from the remnant of blood obtained for routine clinical evaluation 
of the patient, which will avoid additional venipuncture and minimize exposure of the health 
staff). 

 
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2 STUDY OBJETIVE 
2.1 
Primary 
The primary objective of the study is: 
Demonstrate the efficacy and safety of INM005 in COVID-19 in terms of clinical 
improvement 28 days after the start of treatment with the investigational product.  
 
2.2 
Secondary 
The secondary objectives of the study are: 
1) Assessment of the pharmacokinetics of INM005 
2) Assessment of efficacy in terms of time to disease progression 
3) Assessment of efficacy in terms of disease progression 
4) Assessment of efficacy in terms of change in viral load 
 
2.3 
Exploratory 
The exploratory objectives of the study are: 
1)  Assessment of anti-SARS-CoV-2 antibodies levels 
2)  Evaluation of the change in laboratory variables and other markers related to the 
immune response and inflammation that can be identified as possible factors of 
progression of COVID 
3)  Assessment of immunogenicity at 28 days 
  
 

 
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3 STUDY ENDPOINTS  
3.1 
Primary 
Primary efficacy endpoint: 
The proportion of patients that showed improvement 28 days after the administration of the 
first dose will be determined. A responder subject is defined as a subject with an 
improvement in at least 2 categories in the 8-point WHO clinical status ordinal scale (Section 
7.1) or with hospital discharge. 
Safety endpoints: 
The incidence of related adverse events and of adverse events of special interest during the 
study period 
 
3.2 
Secondary 
1) Concentration of product INM005 in serum at different times after administration of 
treatment 
2) Time to improvement in at least 2 categories in the 8-point WHO clinical status ordinal 
scale 
Time to discharge (days) 
Time to discharge from ICU (days) 
3) Proportion of patients who show an improvement in at least 2 categories in the 8-point 
WHO clinical status ordinal scale 7 and 14 days after the start of the treatment 
Proportion of patients with hospital discharge at 28 days 
Proportion of patients who required admission into ICU up to Day 28 
Proportion of patients who required MRA up to Day 28 
Proportion of patients who died up to Day 28 

 
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4) Changes in viral load from baseline to 7 days and 21 days after starting treatment 
 
3.3 
Exploratory 
The following exploratory endpoints will be evaluated in all subjects: 
·  To be carried out by a central laboratory 
1. Measurement of anti- SARS-CoV-2  antibody titres: IgG (0, 21 days) 
2. Evaluable laboratory variables at baseline, 7 and 21 days: Troponin T, D-dimer, 
ferritin, LDH, C-reactive protein or other clinically relevant markers related to 
immune response and inflammation that can be identified as possible factors of 
progression of COVID 
3. 
 Measurement of anti- product INM005 antibodies: baseline and 21 days 
 
 

 
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4 STUDY PLAN 
4.1 
Study design 
Phase II/III, randomised, double-blind, parallel group study, with an adaptive study design. 
The interim analysis will be performed in a "blinded" manner and, based on the rate of events 
in the control group, the futility of the treatment, the feasibility of the study, or the sample 
size will be adapted (73). 
4.2 
Schematic representation of the study 
 
 
 
 
 
 

 
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4.3 
Study design scheme 
 
 
 
A staggered recruitment of the first 12 subjects will be performed in 6:6 blocks. 
Randomisation will be carried out maintaining a 1:1 ratio in each sub-cohort: 
•           active treatment regime [two 4 mg/kg doses of INM005] 
•           placebo 
Intensive monitoring will be done during this stage. 
After the first 6 subjects have been recruited and 24 h post treatment have passed after the 
second dose, the Sponsor’s Medical Monitor will review the safety data for this acute phase 
and report the safety findings. 
This assessment will be repeated for the 2 blocks of 6 subjects each. 
Any safety findings will be notified immediately to the Sponsor, DMC and Regulatory 
Agency, as established in current regulations. 

 
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The monitoring details will be specified in the Study Pharmacovigilance Plan, which will be 
finalised before the recruitment of the first patient into the study begins. 
When the recruitment of the first 12 patients is complete, the DMC will review the safety 
data and inform whether the staggered recruitment should continue. 
All DMC reports will be duly notified to the ANMAT. 
 
 
4.4 
Schedule of assessments 
The procedures that will be carried out throughout the study are detailed in the Evaluation 
Schedule provided below. A detailed description of each assessment is provided in Section 
6.2.  

 
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Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Time from the 1st. 
dose of study drug 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 525 
Day 725 
Day 1425 
Day 2125 
Day 2825 
Study 
procedures 
Screening 
visit1 
Treatment phase 
Follow-up visitFollow-up visit 
Follow-up visit 
Follow-up visit 
Follow-up visit 
End of study visit 
Baseline 
visit 
Dose 12 
Dose 22 
Location of visit 
Hospital3 
Hospital/outpatient 
Window 
 
≤ 24 h 
from V1 
24 h ± 2 h 
from first 
dose 
≤ 24 h ± 2 h 
from Day 2 
24 h ± 2 h 
from last 
dose 
± 1 day 
± 1 day 
±2 days 
±2 days 
± 2 days 
Review 
of 
results 
PCR 
diagnosis 
X5 
 
 
 
 
 
 
 
 
 
IA/CF 
X5 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical 
history/underlyi
ng diseases4 
X 
 
 
 
 
 
 
 
 
 

 
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Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Inclusion 
/Exclusion 
criteria 
X 
X6 
 
 
 
 
 
 
 
 
COVID history 
and symptoms18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam7 
X 
X17 
 
 
 
 
 
 
 
 
Height7 
X 
 
 
 
 
 
 
 
 
 
Body weight7 
X7 
X17 
 
 
 
 
 
 
 
 
Vital signs8 
X9 
X10 
X10 
X 
X 
X 
X 
X 
X 
X 
Oxygen 
saturation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Haematology11 
X12 
 
X9 
 
X9 
 
 
 
X 
 
Serum 
biochemistry13 
X12 
 
X9 
 
X9 
 
 
 
X 
 
Pregnancy test 
X14 
 
 
 
 
 
 
 
 
 
X-rays or chest 
CAT26 
X 
 
 
 
 
 
 
 
 
 

 
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Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Classification by 
WHO scale15 
X 
X17 
X 
X 
X 
X 
X 
X 
X 
X 
Randomisation16 
 
X 
 
 
 
 
 
 
 
 
Blood 
samples 
for viral load19 
 
X 
 
 
 
 
X 
 
X 
 
Blood 
samples 
for 
biomarkers 
and 
future 
analysis20 
 
X 
 
 
 
 
X 
 
X 
 
Blood 
samples 
for 
immunogenicity 
and anti-SARS-
CoV-2 
antibodies20 
 
X 
 
 
 
 
 
 
X 
 
Administration 
of study drug 
 
X 
 
X 
 
 
 
 
 
 
Evaluation 
of 
hypersensitivity 
reactions 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hospital 
discharge 
 
 
 
 
X 
X 
X 
X 
X 
X 

 
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Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Assessment 
of 
COVID 
complications   
22 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomita
nt medication23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
samples 
for PK, only for 
participating in 
the sub-study24 
 
X 
X 
X 
X 
 
X 
 
 
 
 
1 
At the time of the diagnosis of infection by COVID-19 
2 
Description of the drug, dose.. Medication must be prepared by designated unblinded staff.; it will be 
administered in 100 ml i.v. infusion over 50 min. During the infusion, the medical staff in charge will be 
present for safety evaluation. 
3 
On day 4, discharge from the hospital could be granted if the patient is clinically stable 
4 
Medical history/history of underlying diseases includes referenced by the patient: 
o Cardiovascular disease: coronary artery disease/ischemic cardiomyopathy documented by non-invasive 
studies such as ergometry, ECHO, nuclear magnetic resonance (i.e. alterations in myocardial 
perfusion), single photon emission computer tomography (SPECT) and positron emission 
tomography (PET) showing ischemic myocardium. History of revascularisation surgery, stenting, 
acute myocardial infarction, or angina. By invasive methods such as angiography. High blodd 
pressure defined as a record of SBP > 140 mmHg, DBP > 90 mmHg, or both, or SBP > 135 mmHg, 
DBP > 85 mmHg in the 24-hour outpatient blood pressure monitoring. 

 
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o Chronic obstructive pulmonary disease/asthma: defined in spirometry as obstruction with some degree 
of reversibility in spirometric test but the FEV1/FVC ratio will never completely normalize in the 
case of COPD and as a history of diagnosis of Asthma with or without abnormal spirometry. History 
of tuberculosis. 
o Kidney disease according to the glomerular filtration rate (< 90 ml/min/1.73 m2 is considered renal 
damage) calculated by the Cockcroft-Gault formula; GFR, glomerular filtration rate estimated by the 
abbreviated formula of the MDRD study (Modification of Diet in Renal Disease). 
o 
Blood glucose > 200 mg/dl at any time of the day or fasting > 126 mg/dl (7 mmol/l) or more in two 
individual A1C tests of 6.5% or more in two individual tests. 
o Liver disease alteration in the laboratory parameters of the hepatogram and/or compatible images 
 
History of transplantation-related treatment with immunosuppressants/immunomodulators, HIV 
infection. 
o 
Neurological disability or any neurological disease that affects the strength of the rib cage such as 
amyotrophic lateral sclerosis, neuromuscular (Eaton-Lambert, myasthenia), myopathies (dystrophies, 
metabolic, polymyositis/dermatomyositis, congenital and progressive) Guillain-Barré. Other 
clinically relevant diseases. 
 
5 
The SARS-CoV-2 PCR test result must be positive before the IA/CF can be obtained for the study. The 
source document with this result must be attached to the patient's medical record. 
6 
Confirm eligibility criteria before administration of study drug 
7     Physical exam: height in cm (may be referred); body weight in kilograms; general appearance; skin and 
mucous; membranes; head, ears, eyes, nose, throat; neck; adenopathies; respiratory system; cardiovascular 
system; abdomen; musculoskeletal system; central nervous and peripheral system; other 
     The BMI (height (cm)/weight (kg)2) must be calculated. The weight measurement that was made in the 
initial screening assessment will be used for the calculation of the dose. 
8. Vital signs measurements (i.e. SBP, body temperature, pulse, and respiratory rate) are recommended after 
the subject has been in the supine position for at least 3 min. 
9. 24 h +/- 2 h after the end of study drug administration 
10. They must be obtained immediately prior to study drug administration (approximately within 15 min) and 
within 15 min after completion of study drug administration. 
11. Haematology: platelet count, erythrocyte count, haemoglobin, haematocrit, white blood cell count, 
neutrophils, lymphocytes, eosinophils (relative formula). 

 
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12. Laboratory results must be obtained within 24 h of the 1st. administration of study drug. Results should 
be available and reviewed prior to randomisation. If there is any change in clinical presentation within 24 
h of the 1st. administration of study drug, laboratory evaluations should be repeated, and the results of 
such tests should be reviewed prior to administration of study drug. The results will be acceptable if they 
were obtained within the last 24 h of V2, as long as they were carried out in the local laboratory of the 
institution participating in the clinical trial. 
13. Serum biochemistry tests will include the following: urea, creatinine, glycaemia, potassium, sodium, 
AST/ALT, alkaline phosphatase, total and direct bilirubin, total protein, albumin, LDH DH 
14. In women of childbearing age (urine or blood according to the usual practice of the site) 
15. 8-point WHO scale: 0 = no evidence of infection, 1 = outpatient, with no activities limitation; 2 = 
outpatient, with activities limitation; 3 = hospitalised with no oxygen therapy required; 4 = oxygen therapy 
employing a mask; 5 = non-invasive ventilation or high flow oxygen; 6 = Mechanical ventilation; 7 = 
mechanical ventilation and organ support (vasopressors, ECMO, RRT); 8 = Death  
16. It should be done by the unblinded study staff through a randomisation sealed envelope system. The first 
12 subjects will be randomised through a centralised system. An appropriate instruction manual will be 
provided to the site. 
17. Should only be carried out in V2 if > 24 h have elapsed since the initial screening assessment 
18. COVID-19 history and symptoms assessment: 
-   Symptoms according to the definition of case by the Ministry of Health of Argentina: fever (37.5 °C or 
more), cough, odynophagia, shortness of breath, new onset anosmia/dysgeusia, others (nausea, vomiting, 
abdominal pain, diarrhoea, asthenia, headache, myalgia, nasal congestion, others). The start date, severity 
and follow-up must be verified to evaluate resolution/worsening during the 28 days that the study lasts. 
       -  
History of the disease: date of first symptom 
       - Category of the disease according to NIH classification: mild, moderate, severe, critical. 
19. Blood samples immediately prior to 1st. administration of study drug, on day 7 and on day 21 for viral load 
detection. These samples will be sent to a central laboratory. More information will be provided in the study 
laboratory manual. 
20. Blood sample immediately before 1st. administration of the study drug, on day 7 and on day 21 for 
biomarkers (troponin T, D-dimer, ferritin, and C-reactive protein), anti-SARS-CoV-2 antibodies, 
immunogenicity test and future analysis. These samples will be sent to a central laboratory. More information 
will be provided in the study laboratory manual. 

 
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21 To be obtained within approximately 15 min after completion of each study drug administration and prior 
to hospital discharge (V3-Day 4).  
Injection site reaction (definition: a disorder characterised by a severe adverse reaction - usually immune - 
at the site where an injection is given). Classified by CTCAE criteria  
1 = Pain at palpation with or without associated symptoms (e.g. warmth, erythema, itching). 
2 = Pain; lipodystrophy; oedema; phlebitis. 
3 = Ulceration or necrosis; severe tissue damage; surgical intervention indicated. 
4 = Life threatening consequences; emergency intervention indicated. 
5 = Death 
Hypersensitivity reactions 
To be obtained within approximately 15 min after completion of each study drug administration and prior 
to hospital discharge (V5) and at each subsequent visit until V8. 
Allergic reaction: (definition: disorder characterised by local or generalised adverse response to exposure 
to an allergen): 
1 = Transient symptoms of hot flashes or rash, drug fever < 38 °C; intervention not indicated. 
2 = Intervention or interruption of the indicated infusion; responds quickly to symptomatic 
treatment (e.g. antihistamines, nonsteroidal anti-inflammatory drugs, narcotics). 
3= Prolonged (e.g. does not respond rapidly to symptomatic medication and/ or brief interruption 
of infusion); recurrence of symptoms after initial improvement; hospitalisation indicated for 
clinical sequelae (e.g. renal impairment, pulmonary infiltrates). 
4 = Life threatening consequences; emergency intervention indicated. 
5 = Death 
Anaphylaxis:(definition: a disorder characterised by an acute inflammatory reaction resulting from the 
release of histamine and histamine-like substances from mast cells, generating a hypersensitivity 
immune response; clinically, it presents with shortness of breath, dizziness, hypotension, cyanosis, and 
loss of consciousness, and can lead to death). Categorised by CTCAE criteria:  
1 = Not applicable 
2 = Not applicable 
3 = Symptomatic bronchospasm, with or without urticaria, parenteral intervention indicated; 
oedema/angioedema of allergic origin; hypotension 
4 = Life threatening consequences; emergency intervention indicated. 
5 = Death 

 
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Serum sickness disease: (definition: a disorder characterised by a delayed hypersensitivity reaction to 
foreign proteins derived from animal serum. It occurs approximately 6 to 21 days after administration 
of the foreign antigen. Symptoms include fever, arthralgia, myalgia, rashes, lymphadenopathy, marked 
chest discomfort, and dyspnoea). Categorised by CTCAE criteria: 
1 = Asymptomatic; clinical or diagnostic observations only; intervention not indicated. 
2 = Moderate arthralgia; fever, rash, hives; indicated antihistamines 
3 = Arthritis or severe arthralgia; generalised rash; steroids or i.v. fluids indicated. 
4 = Life threatening consequences; vasopressors or mechanical ventilation support indicated. 
5 = Death 
22. Assessment of MV requirement, transfer to ICU and death. 
23 Concomitant medication description, dose, dosage and start date within the last 7 days of V1. 
24 Blood sample for PK assessments from subjects participating in the PK sub-study immediately before the 
1st. administration of the study drug, at the end of the 1st. administration of the study drug, 24 h after the 
1st. administration of the study drug, immediately before the 2nd. administration of the study drug, at the 
end of the 2nd. administration of the study drug, 24 h after 2nd. study drug administration, and 7 days after 
1st. study drug administration. The PK study will be carried out only in pre-selected institutions and a 
separate consent will be provided. 
25. As from Day 5, if the patient is under outpatient follow-up, Visits on day 5, 7, 14, and 28 will be on the 
telephone. In those cases, invasive procedures will not be performed. 
26 The imaging taken as part of the evaluation of the the patient's institution SoC, will be accepted for 
confirmation of pneumonia, despite the fact that it is prior to Day 0. 
 

 
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5 POPULATION 
5.1 
Target population 
Patients with moderate or severe COVID-19 as defined by NIH (74), which requires 
hospitalisation, excluding patients with assisted ventilation or admission in the ICU. 
5.2 
Number of subjects 
The recruitment of 242 patients in approximately 10 sites is planned. After approximately 
145 subjects complete their follow-up (60% of the original sample), an interim analysis will 
be carried out to define whether it is necessary to adjust the sample size to the event rate; an 
increase of up to 72 individuals will be allowed (n = 314). 
5.3 
Inclusion and Exclusion criteria 
Subjects must meet all the inclusion criteria at Screening: 
1. 
Patients of both sexes aged 18 to 79 years of age 
2. 
SARS-CoV-2 infection confirmed by PCR 
3. 
Patients with moderate or severe disease by NIH definition, requiring 
hospitalisation. 
4. 
Acceptance to participate in the study by the signature of the informed consent 
by a subject or their relative, if applicable 
5. 
Be within 10 days of the onset of symptoms at the time of the Screening visit 
according to a case definition from the National Ministry of Health 
6. 
Female patients of child-bearing age with negative pregnancy test 
 

 
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Subjects must not meet any of the following exclusion criteria at the time of screening 
1. Patients who have received treatment with plasma from COVID-19 convalescents 
2. Patients who are participating in other therapeutic clinical trials 
3. Patients who require mechanical ventilation or who are hospitalised in the ICU at 
the screening visit 
4. History of anaphylaxis, prior administration of equine serum (e.g. anti-tetanus 
serum or anti-ophidic serum or anti-arachnid toxin serum) or allergic reaction due to 
contact or exposure to horses 
Note: the production of anti-tetanus serum of equine origin stopped in 1970, and 
therefore a patient who used it after that date could be a candidate for the study since 
the serum is of human origin. 
5. Pregnant or breastfeeding women 
6. Patients who, at the doctor's judgement, are likely to die within the next 30 days 
due to a concomitant disease other than the study disease 
7. Patients who are expected to be referred to another institution within 72 hours of 
recruitment, which prevents adequate follow-up of that patient 
 
5.4 
Patient selection 
The subject or the subject's legal guardian, if applicable, must sign an AF/CF before any of 
the procedures related to the study can be carried out. 
5.5 
Deviations from the Inclusion and Exclusion criteria 
No deviation from what is established in the inclusion and exclusion criteria will be allowed. 
The investigator may contact the Medical Monitor to discuss the eligibility of a particular 
subject.  
 

 
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6 CONDUCT OF THE STUDY 
6.1 
Study procedures 
Those patients who are hospitalised with a diagnosis of moderate to severe COVID in the 
participating centres will have the study explained and informed consent will be provided. 
Once the consent process is concluded, if the patient agrees and signs the IA/CF, they will 
undergo a screening process to ensure their eligibility for the study. 
6.2 
Study procedures by time-point 
6.2.1 Visit 1 - Screening 
The subject or the subject's legal guardian and/or, if applicable, must provide their 
assent/consent so that the subject can undergo the screening process necessary for 
participation in the study, through the signature of an IA/CF.  
The screening visit (V1) must take place within 10 days of the onset of coronavirus symptoms 
after obtaining the result of the diagnostic tests for SARS COV 2. After the confirmation of 
positive results in the test by PCR, performed according to the site’s SoC, the study staff will 
perform the following: 
● Informed consent process and signature of the informed consent. 
The particular situation related to the extreme transmission and virulence of COVID-19, 
raises new challenges related to the documentation of the informed consent process (75-76). 
In that order, when the usual mechanisms are not possible, it is necessary to consider 
alternative forms. For example, contacting patients by video calls, developing a record of 
consents by audiovisual means or digital images, obtaining oral consents supplemented with 
confirmation by email and entry in the Medical Record with the signature of one or more 
health professionals.  
Taking into account that the “paper” consent signed by the patient is a source of potential 
transmission of COVID-19, an alternative signature process is proposed: 
The investigator signs and dates 2 copies of the consent, after the process described above 
has occurred, and before entering the patient's room. Then, if the patient agrees to participate, 
they will be asked to sign and date the same document. The patient will be asked to obtain a 
photo of the signature page and send it to the investigation team in order to have a safeguard 

 
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that the process was carried out. The patient retains one of the forms and the other CF will 
be protected in a transparent plastic sheet, which when leaving the room will be placed in a 
secondary envelope for a period of 72 hours. After this time, it is removed from the secondary 
envelope, the plastic sheet is cleaned with alcohol and the copy is filed in the regulatory 
folder of the study or in the patient's medical record.  
 
● Demographics: 
Age: in years 
 Sex: male/female 
 Ethnicity: White, Blanc, mixed Asian, Indigenous or other 
● Clinical history: 
Relevant medical history (description and date of diagnosis) 
History of comorbidities: 
● Cardiovascular disease 
● Any chronic pulmonary disease 
● Kidney disease 
● Diabetes 
● Liver disease 
● Immunocompromised 
● Neurological disability 
● Others 
Allergies to medications and/or horses 
Concomitant medication description, dose, dosage and start date within the last 7 days. 
Any medical condition that after signing the informed consent should be informed as an 
adverse event (AE). 
●  History of the disease: 
- 
Date of the first symptom 

 
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- 
Symptoms according to the definition of case by the Ministry of Health of 
Argentina (77): Fever (37.5°C or higher), Cough, Odynophagia, Shortness of breath, 
New-onset anosmia/dysgeusia, others 
● Patient classification according to the 8-point WHO scale (78) 
0- No evidence of infection 
1- Outpatient, with no limitation to activities 
2- Outpatient, with limitation to activities 
3- Hospitalised with no oxygen needed  
4- Use of oxygen with mask 
5- Non-invasive ventilation or high-flow oxygen 
6- Mechanical ventilation 
7- Mechanical ventilation and organ support (vasopressors, ECMO, RRT) 
8- Death  
● Vital signs 
• Heart rate 
• Respiratory rate 
• Oxygen saturation: obtained from the measurement of arterial gases or 
using the pulse oximeter. In addition, the inspired fraction of oxygen the 
patient receives will be documented as follows: 
- 
Ambient air FiO2: 0.21 
- 
Nasal tube to FiO2 0.24 (1 l/min); 0.28 (2 l/min); 0.32 (3 l/min) or 
0.36 (4 l/min) 
- 
Face mask with nasal tube: 0.24 (3 l/min); 0.28 (4 l/min); 0.31 
(6 l/min); 0.35 (8 l/min); 0.4 (10 l/min); 0.45 (12 l/min), and 0.5 
(15 l/min) 
- 
Mask with reservoir 0.9-1 (10-15 l/min)  
• Supine blood pressure 

 
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• Temperature 
●  Full physical exam: 
            Height in cm, body weight in kilograms, BMI 
         General appearance 
Skin and mucous membranes 
Head, Ears, Eyes, Nose, Throat 
Neck 
Adenopathies 
Respiratory system 
Cardiovascular system 
Abdomen 
Musculoskeletal system 
Central nervous and peripheral system 
Other 
 
● Laboratory tests 
- 
Haematology Platelet count, erythrocyte count, haemoglobin, haematocrit, 
neutrophils, lymphocytes, eosinophils. 
- 
Full chemical panel Urea, Creatinine, Glycaemia, Potassium, Sodium, AST/ALT, 
Alkaline Phosphatase, Total and Direct Bilirubin, Total Protein, Albumin, LDH. 
- 
Pregnancy test, if applicable. 
● 12-lead ECG 
● Imaging 
- 
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- 
Chest TC; description of the type of infiltrate, affected areas.    
● Eligibility criteria 
- 
Inclusion criteria confirm all inclusion criteria are met 
- 
Exclusion criteria confirm that no exclusion criteria are met 
 
Note on laboratory samples: laboratory results prior to V1 will be accepted if they have 
been obtained during the admission of the patient evaluated for COVID-19 according to 
SoC of each institution. The results will be acceptable if they were obtained within the last 
24 h of V1, as long as they have been performed in the local laboratory of the institution 
participating in the clinical trial. 
The administration of the study drug should be done as soon as possible after obtaining the 
results of the Screening visit (V1)  
6.2.2 Visit 2. Baseline 
6.2.2.1Day 1 - First dose of treatment 
    Must be done within 24 h of the screening visit. 
● Physical exam and laboratory tests if more than 24 h have elapsed. 
● Assessment of COVID symptoms if more than 24 h have elapsed. 
● Patient classification according to the WHO scale if more than 24 h have elapsed. 
● Confirm eligibility 
● Randomisation to treatment assignment by unblinded staff 
Prior to the start of administration of study drug: 
● Notify the pharmacy to prepare the study drug for its administration.  
● Preparation of the infusion by the unblinded staff 
● Prepare the subject for i.v. infusion per standard operating procedure.  
● Vital signs 15 min prior to infusion 
● For PK sub-study: pre-infusion blood sample for the pharmacokinetics  
● Samples for viral load  
● Blood 
samples 
for 
anti-SARS-CoV-2 
antibodies, biomarkers and 
immunogenicity 

 
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● Administration of double-blind treatment: i.v. infusion of 100 ml over 50 min per 
standard operating procedures (Section 8.3) 
Post-treatment administration procedure: 
● For PK sub-study: Study samples for pharmacokinetics (5 min after the end 
of infusion) 
● Vital signs within 15 min post-infusion. 
● Assessment of hypersensitivity reactions within 15 min post-infusion. 
● Assessment of adverse events (Sections 9 and 10) and concomitant 
medication 
6.2.2.2 Day 2 - 1st. dose follow-up 
●  Assessment of COVID-19 disease and complications 
● Safety laboratory 24 h post-infusion 
Haematology Platelet count, erythrocyte count, haemoglobin, haematocrit, neutrophils, 
lymphocytes, eosinophils.  
Full chemical panel Urea, Creatinine, Glycaemia, Potassium, Sodium, AST/ALT, Alkaline 
Phosphatase, Total and Direct Bilirubin, Total Protein, Albumin, LDH. 
● Vital signs 
● Patient classification according to the WHO scale 
● Assessment of hypersensitivity reactions 
● Assessment of adverse events and concomitant medication 
6.2.3 Visit 3 
6.2.3.1 
Day 3 Second dose of treatment 
● Assessment of COVID-19 disease and complications 
● Assessment of adverse events (Sections 9 and 10) and concomitant medication 
● Patient classification according to the WHO scale 
● Assessment of adverse events and concomitant medication 
● Assessment of hypersensitivity reactions  
Prior to the start of administration of study drug: 
○ Preparation of the infusion by the unblinded staff 

 
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○ Vital signs within 15 min prior to the infusion (SBP, body temperature, pulse 
and respiratory rate). 
○ For PK sub-study: pre-infusion blood sample for the pharmacokinetics 
● Administration of double-blind treatment: 100 ml infusion over 50 min 
Post-treatment administration procedure: 
● For PK sub-study: Study samples for pharmacokinetics (5 min after the end of 
infusion) 
● Vital signs within 15 min post-infusion. 
● Assessment of hypersensitivity reactions within 15 min post-infusion  
● Assessment of adverse events and concomitant medication 
6.2.3.2  Day 4 2nd dose follow-up 
● Assessment of COVID-19 disease and complications 
● For PK sub-study: Study samples for pharmacokinetics (24 h post second infusion) 
● Safety laboratory 24 h post-infusion 
Haematology Platelet count, erythrocyte count, haemoglobin, haematocrit, neutrophils, 
lymphocytes, eosinophils. 
Full chemical panel Urea, Creatinine, Glycaemia, Potassium, Sodium, AST/ALT, Alkaline 
Phosphatase, Total and Direct Bilirubin, Total Protein, LDH. 
● Vital signs 
● Patient classification according to the WHO scale 
● Assessment of hypersensitivity reactions 
● Assessment of adverse events (Sections 9 and 10) and concomitant medication 
The subject will be discharged if he/she is clinically stable and per medical judgement. 
6.2.4 Visit 4- Day 5 follow-up 
● Vital signs (SBP, body temperature, pulse and respiratory rate). 

 
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● Patient classification according to the WHO scale 
● Assessment of COVID-19 disease and complications 
● Assessment of hypersensitivity reactions 
● Assessment of adverse events (Sections 9 and 10) and concomitant medication 
6.2.5 Visit 5- Day 7 follow-up 
● Vital signs (SBP, body temperature, pulse and respiratory rate). 
● Patient classification according to the WHO scale 
● Assessment of COVID-19 disease and complications 
● Assessment of hypersensitivity reactions (Section 7.2.5) 
● Assessment of adverse events (Sections 9 and 10) and concomitant medication 
● Samples for viral load 
● Blood samples for anti-SARS-CoV-2 antibodies and biomarkers 
● For PK sub-study only: pre-infusion blood sample for the pharmacokinetics 
Schedule a visit to the clinic to be conducted on Day 14. 
6.2.6 Visit 6 - Day 14 follow-up 
The subject should be examined in the clinic 14 days (± 1 day) after the 1st. administration 
of the study drug. This visit may be carried out at the subject's home, if necessary. At this 
visit, the study staff undertake the following: 
● Vital signs (SBP, body temperature, pulse and respiratory rate). 
● Patient classification according to the WHO scale 
● Assessment of COVID-19 disease and complications 
● Assessment of hypersensitivity reactions (Section 7.2.5) 
● Assessment of adverse events (Sections 9 and 10) and concomitant medication 
Schedule a visit to the clinic to be conducted at Week 3 (± 2 days) after the 1st. 
administration of the study drug. 
6.2.7 Visit 7 - Day 21 follow-up 
● Vital signs (SBP, body temperature, pulse and respiratory rate). 

 
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● Patient classification according to the WHO scale 
● Assessment of COVID-19 disease and complications 
● Assessment of hypersensitivity reactions (Section 7.2.5) 
● Assessment of adverse events (Sections 9 and 10) and concomitant medication 
● Samples for viral load 
● Blood samples for anti-SARS-CoV-2 antibodies, immunogenicity and laboratory 
markers 
● Safety laboratory tests: 
a. Haematology 
b. Serum chemistry 
6.2.8 Visit 8- Day 28 - End of study 
The subject should be examined in the clinic 28 days (± 2 days) after the 1st. administration 
of the study drug. This visit should also be carried out if the subject prematurely discontinues 
participation in the study. This visit is considered the End of Study (EOS) visit for all 
subjects.  
● Vital signs (SBP, body temperature, pulse and respiratory rate) 
● Patient classification according to the WHO scale 
● Assessment of COVID-19 disease and complications 
● Assessment of hypersensitivity reactions (Section 7.2.5) 
● Assessment of adverse events (Sections 9 and 10) and concomitant medication 
6.3 
Early termination 
If the subject's participation in the study is prematurely interrupted for any reason, the reason 
for such Early Termination (ET) must be documented, and the V8 (EOS) procedures must be 
performed as indicated in Section 6.2.8. 
The electronic CRF (eCRF) Case Report Form Termination page must be completed for each 
subject to whom the study drug has been administered, regardless of whether the subject has 
completed the study or not. In this form the reason for the ET must be indicated; as much 
information as possible should be provided. The primary reason for the early termination of 
the subject’s participation should be selected from the following standard ET categories: 
● Adverse event: There have been clinical or laboratory events that, based on the 
investigator's medical judgment, make the termination of the subject's participation to be 

 
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in the best interest of the subject. This includes serious and non-serious AEs, regardless 
of their relationship to IMP. 
● Death: The subject died. 
● Withdrawal of consent: The subjects or their caregivers decided not to continue 
participating in the study, without there being a medical need determined by the 
investigator for such withdrawal. If the subject stated the reason for the withdrawal, such 
reason must be recorded in the CRF. 
● Failure to meet the randomisation requirements: Subject does not meet eligibility criteria 
during reassessment at Visit 2 (Dose 1), prior to randomisation. 
● Protocol violation: The findings or the subject's behaviour did not meet the criteria for 
entry to the protocol or did not meet the requirements of the protocol (e.g. non-
compliance with the drug regimen, non-compliance with the stipulated number of visits). 
This violation required premature discontinuation of participation in the study. 
● Lost to follow-up: Subject stopped attending visits and could not be contacted by study 
staff. 
● Non-compliance: Subject did not comply with study visits or procedures.  
● Others: Study participation was interrupted for any reason that is not amongst the 
aforementioned, such as the case that the study is definitively interrupted by 
INMUNOVA or at the discretion of the investigator. 
 

 
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7 DESCRIPTION OF THE STUDY PROCEDURES 
7.1 
Efficacy evaluations 
The investigator will document whether the subject has an improvement within 28 days of 
the administration of the first dose. A responder subject is defined as a subject with an 
improvement in at least 2 categories in the 8-point WHO clinical status ordinal scale or 
hospital discharge. 
Patient classification according to the WHO scale (78) 
0- No evidence of infection 
1- Outpatient, with no limitation to activities 
2- Outpatient, with limitation to activities 
3- Hospitalised with no oxygen needed  
4- Use of oxygen with mask or nasal tube 
5- Non-invasive ventilation or high-flow oxygen 
6- Mechanical ventilation  
7- Mechanical ventilation and organ support (vasopressors, ECMO, RRT) 
8- Death  
 
7.2 
Safety evaluations 
7.2.1 Electrocardiogram 
12-lead ECGs will be performed on hospital/clinic electrocardiographs at Screening (V1). 
ECG results will be documented in eCRF. 
7.2.2 Vital signs 
Vital signs to be measured are: SBP, body temperature, pulse and respiratory rate. Vital signs 
will be obtained at Screening (V1), immediately prior to study drug administration (within 
15 min), within 15 min after study drug administration is completed, and at follow-up visits. 

 
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7.2.3 Clinical laboratory analysis 
Blood samples will be obtained in Screening (V1), V2, V3 and V7, and in other visits if the 
clinical presentation of the subject warrants it, for the following:  
● Haematology: Hb, Hct, RBC count, WBC count (with differential con [lymphocytes, 
neutrophils, eosinophils]) and platelet count.  
● Biochemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin (TBIL), direct bilirubin, urea, creatinine, alkaline phosphatase (ALP), LDH, Na, 
potassium, albumin, and glucose.  
Laboratory samples will be analysed in the local/hospital laboratory. Normal laboratory 
ranges will be collected from each laboratory used to process the samples. The investigator 
should read the clinical laboratory results in a timely manner to assess the clinical 
significance of any abnormalities that may be present. In the event of an unexplained 
clinically significant abnormal laboratory value, the test in question should be repeated and 
followed until the parameter has returned to the normal range and/or an adequate explanation 
for the abnormality has been found. 
7.2.4 Adverse events 
All AE that occur within the period from the moment the subject or the subject's guardian 
signs the AF/CF until the last study procedure is carried out will be recorded. All AEs that 
occurred prior to the start of the study drug administration session (i.e., prior to administration 
of study drug in V2) will be recorded as medical history. All AE that are in progress at the 
time of V8 (EOS/ET) will be followed up until their resolution or until they are no longer 
clinically significant at the discretion of the investigator.  
See Sections 9 and 10 to for additional information. 
7.2.5 Adverse event of special interest 
The Common Terminology Criteria for Adverse Events (CTCAE) will be used to assess 
injection site reactions and hypersensitivity reactions during the study. These will be assessed 
any time they occur during the course of the study, but specifically within 15 min after each 
administration of the study drug is completed.  

 
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7.2.5.1 
Injection site reaction 
A disorder characterised by a severe adverse reaction (usually immune) that occurs at the site 
where an injection is given. Categorised by CTCAE criteria:  
1 = Pain on palpation with or without associated symptoms (e.g. warmth, erythema, 
itching).  
2 = Pain; lipodystrophy; oedema; phlebitis. 
3 = Ulceration or necrosis; severe tissue damage; surgical intervention indicated. 
4 = Life threatening consequences; emergency intervention indicated. 
5 = Death 
7.2.5.2 
Hypersensitivity reaction 
A hypersensitivity reaction comprises various levels of allergic reaction, both acute and 
delayed. Allergic reaction events, anaphylaxis, and serum sickness will all be evaluated using 
CTCAE criteria. The management of anaphylactic reactions should be carried out following 
the guidelines established in Appendix 2.  
7.2.5.2.1 
Allergic reaction 
An allergic reaction is disorder characterised by a local or generalised adverse response to 
exposure to an allergen. Categorised by CTCAE criteria:  
1 = Transient symptoms of hot flashes or rash, drug fever < 38 °C; intervention not 
indicated. 
2 = Intervention or interruption of the indicated infusion; responds quickly to 
symptomatic treatment (e.g. antihistamines, nonsteroidal anti-inflammatory drugs, 
narcotics). 
3= Prolonged (e.g. does not respond rapidly to symptomatic medication and/ or brief 
interruption of infusion); recurrence of symptoms after initial improvement; 
hospitalisation indicated for clinical sequelae (e.g. renal impairment, pulmonary 
infiltrates). 
4 = Life threatening consequences; emergency intervention indicated. 
5 = Death 

 
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7.2.5.2.2 
Anaphylaxis: 
Anaphylaxis is a disorder characterised by an acute inflammatory reaction resulting from the 
release of histamine and histamine-like substances from mast cells, which generates a 
hypersensitive immune response. Clinically, it presents with shortness of breath, dizziness, 
hypotension, cyanosis, and loss of consciousness, and can lead to death. Categorised by 
CTCAE criteria:  
1 = Not applicable 
2 = Not applicable 
3 = Symptomatic bronchospasm, with or without urticaria, parenteral intervention 
indicated; oedema/angioedema of allergic origin; hypotension 
4 = Life threatening consequences; emergency intervention indicated. 
5 = Death 
7.2.5.2.3 
Serum sickness: 
Serum sickness is a disorder characterised by a delayed hypersensitivity reaction to foreign 
proteins derived from animal serum. It occurs approximately 6 to 21 days after administration 
of the foreign antigen. Symptoms include fever, arthralgia, myalgia, rash, lymphadenopathy, 
marked chest discomfort, and dyspnoea. Categorised by CTCAE criteria: 
1 = Asymptomatic; clinical or diagnostic observations only; intervention not indicated. 
2 = Moderate arthralgia; fever, rash, hives; indicated antihistamines 
3 = Arthritis or severe arthralgia; generalised rash; steroids or i.v. fluids indicated. 
4 = Life threatening consequences; vasopressors or mechanical ventilation support 
indicated. 
5 = Death 
7.3 
Other assessments 
7.3.1 General survival 
Assessment of survival (i.e., the number of days elapsed between 1st. administration of the 
study drug until death, if applicable) in all visits 

 
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7.3.2 Complications of COVID infection 
The investigator will document if the subject requires: ICU admission, MRA, or dies, 
classifying it as absent/present until day 28. 
7.3.3 Other secondary endpoints: 
 
Pharmacokinetic parameters of INM005 
Evolution of the disease 
Time to response to treatment 
Viral load levels of SARS CoV-2 
 
7.3.4 Exploratory endpoints 
 
Anti-SARS-CoV 2 antibodies levels 
Measurement of Troponin T, D-dimer, ferritin, LDH, C-reactive protein at baseline, 
days 7 and 21. 
Level of anti INM005 antibodies 
7.3.4.1.1 
Duration of hospitalisation 
The length of stay in the hospital institution will be calculated taking into consideration the 
period between the date of admission and the date of hospital discharge for all subjects, taking 
into account that a minimum of 4 days of hospitalisation is required for all subjects enrolled 
given the drug administration schedule established by the protocol.  
7.3.4.1.2 
Mortality predictors 
The following predictors of mortality will be evaluated at the time of hospital admission: 
Age 
Comorbidities: diabetes, chronic obstructive disease, high blood pressure and coronary 
disease 

 
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Respiratory Rate > 24 breaths/min 
SOFA score 
White blood cell count 
Lymphocyte count 
AST level > 40 U/l 
Creatinine 
LDH 
CPK 
D-dimer 
Prothrombin time 
Serum ferritin 
IL-6 
 
7.4 
Sample for immunogenicity testing and future analysis 
7.4.1 Immunogenicity assessments 
Screening tests for antidrug antibodies (ADAs) are of fundamentally important in 
determining safety when biologics are being used. Immunogenic responses can lead to 
anaphylaxis, cytokine release syndrome, cross-reactivity to endogenous proteins, or 
neutralising antibodies that can affect the efficacy of the therapeutic product. Regulatory 
guidelines state that a method for the detection of drug-specific antibodies must be 
developed, as well as a method for determining whether any of the anti-drug antibodies are 
neutralising antibodies or are simply binding antibodies. In addition, clear thresholds should 
be established for "positive" and "negative" screening test results for ADAs. The frequency 
of testing for ADAs may be determined in part by non-clinical results (79). 

 
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Specific patient attributes can also influence immunogenicity. Such attributes may be the 
patient's immune status, prior sensitisation to the product under study, and the dose, route, 
and frequency of administration. As noted in the aforementioned guidelines, the intradermal, 
subcutaneous, and inhalable routes of administration are associated with increased 
immunogenicity compared to the intramuscular and intravenous routes, with the intravenous 
route generally being considered the least immunogenic. Increased product administration 
such as that of the multiple dose paradigm can lead to Ig class change and increased affinity 
antibody responses. Since the maximum number of administrations of INM005 in the 
proposed study is limited to 2 i.v. administrations by within a 48-hour period, the probability 
of higher magnitude affinity responses is considered nil. 
7.4.2 Biological properties of INM005 
INM005 is an antibody fragment of equine origin, and as such has the ability to induce an 
immune response. To reduce its potential immunogenic properties, the Fc region has been 
removed. This feature, combined with the fact that INM005 is administered intravenously as 
a single dose (or as two doses), it further reduces its potential to cause unwanted immune 
reactions. However, there is a variable incidence of type III hypersensitivity reactions (serum 
sickness) amongst products that are similar to this one, which are triggered by the formation 
of immune complexes in which ADAs participate (Section 1.3), which will be evaluated in 
this clinical study. 
Finally, a method has been developed to detect drug-specific antibodies, and thresholds have 
been established for the categories of “positive” and “negative” results of the ADA detection 
tests during the development of the Phase I study. The frequency determined for ADA testing 
is before the administration and 28 days after administration. 
7.4.3 Immunogenicity reactions - Phase I 
No AE compatible with immunogenicity reactions were observed in a phase 1 study in 
healthy adult volunteers that has already been completed with INM004. An immunogenicity 
assessment for the product INM004 was carried out with the samples from the 11 subjects 
enrolled in Stage I and Stage II (Section 1.3.4). It was concluded that, for serum samples 
obtained 30 days after administration, there was no change in reactivity to the immobilised 
product. There were no clinical observations that could indicate the presence of 
immunogenicity reactions, and no antidrug antibodies were detected in any of the samples 
tested. 

 
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With the understanding that the clinical assessment will ultimately determine the diagnosis 
of hypersensitivity reactions, the study of the formation of antibodies as a consequence of 
the administration of the product will be based on the immunomolecular evaluation.  
7.4.4 Sample for immunogenicity testing and future analysis 
Blood/serum samples will be extracted for future analysis. Future analyses include 
evaluations of biomarkers related to COVID-19 disease or potential drug-induced side 
effects; these tests will under no circumstances include genetic testing. These analyses will 
contribute to establishing the safety and efficacy profile of INM005. The samples will be 
kept frozen at -20°C for a period of 5 years; once this period is over, they will be destroyed. 
All samples will be processed and transported as indicated in the Study Manual. The sponsor 
may send the samples to 1 or more laboratories for analysis, according to what is indicated 
in the Study Manual. Analyses made from these samples could lead to scientific publications. 
The data will be analysed in the context of this study, but may also be explored in 
combination with data from other studies. Access to these samples will be restricted to 
authorised staff, and the privacy and confidentiality of the subject will be preserved at all 
times, since all data will be anonymised for exploratory analysis. 
Blood/serum samples will also be obtained for immunogenicity tests as indicated in the 
previous paragraphs. The samples will be processed and transported as indicated in the Study 
Manual. The sponsor may send the samples to 1 or more laboratories for analysis, according 
to what is indicated in the Study Manual. 
7.5 
Pharmacokinetics 
A blood sample will be drawn from subjects in the PK sub-study (20 subjects) for PK tests 
immediately before the 1st. administration of the study drug, at the end of the 1st. 
administration of the study drug, 24 h after the 1st. administration of the study drug, 
immediately before the 2nd administration of the study drug, at the end of the 2nd 
administration of the study drug, 24h after 2nd study drug administration and 7 days after 
1st. study drug administration. 
7.6 
Protocol deviations 
All deviations from what is established by the protocol will be evaluated and documented 
individually for each case prior to closing the database, and those that, as considered, have 

 
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serious repercussions on the efficacy results will lead to the subject in question is excluded 
from the analysis. Major protocol deviations will be fully characterised in the SAP. 
Deviations from the protocol will be summarised by centre and grouped into different 
categories. The major deviations described below will result in the exclusion of the subject 
from the PP population, as indicated in section 11.2:   
● Subjects who entered the study despite not meeting the entry criteria. 
● Subjects who developed any of the criteria for withdrawal during the study, but were not 
withdrawn. 
● Subject who received 1 (or none) of the 2 doses established in the protocol 
● Subjects who received the wrong treatment or the wrong dose. 
● Subjects who received compassionate treatment with convalescent serum or antivirals or 
immunomodulators without having developed the primary event. 
● Subjects who, without having developed the primary event, did not complete the 28-day 
follow-up. 

 
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8 MANAGEMENT OF THE STUDY DRUG 
8.1 
Description 
8.1.1 Dosage Form 
The dosage form is described in Table 8.1. 
Table 8.1 
Data of the investigational medicinal products 
Active pharmaceutical ingredient: 
anti-SARS-CoV-2 
F(ab’)2 
fragments 
of 
equine 
immunoglobulins 
Concentration: 
Each ml of the medicinal product contains purified equine 
immunoglobulins (F(ab')2 fragments) with the capacity to 
neutralise the cytopathic effect of the SARS-CoV-2 exerted in 
vitro on the Vero cell line, in at least a 1:2000 dilution. 
 Each ml contains 30 mg of protein (equine immunoglobulins, 
F(ab')2 fragments). 
The product contains phenol in amounts less than  
2.5 mg/ml, which is used as a preservative during the 
manufacturing process. 
Presentation: 
INM005 is presented as a sterile solution for intravenous 
administration (5 ml vial). 
8.1.2 Storage conditions 
Refrigerated storage at 2-8°C (range 1.5 to 8.4°C) Under these conditions, INM005 can be 
stored for up to 36 months from the date of manufacture (stability studies are underway to 
confirm shelf life). Do not freeze. Once the vial has been perforated, the contents should be 
used to prepare the infusion bag and should be administered as soon as possible within a 
maximum period of 4 h. INM005 vials are intended for single use only and contain no 
preservatives. Any remainder must be discarded.  
In the event that a deviation in temperature occurs during storage, the investigator must 
contact the sponsor within 24 h of becoming aware of the deviation through the specific study 
form. The Sponsor will inform the investigator in writing whether the vials are suitable for 
use or not. The procedure is described in detail in the Study manual. 

 
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The investigator is responsible for taking all the necessary measures to keep adequate records 
and ensure the supply, handling, storage, distribution and use of these materials, in 
accordance with the protocol and the regulations and laws in force on the matter. 
8.2 
Conditioning and transport 
INM005 is presented in 10 ml glass vials, with a butyl rubber stopper and an aluminium seal, 
with a flip-top plastic cap, with a fill volume of 5 ml per vial. Each vial is packed in an 
individual cardboard box. 
8.3 
Dosage and administration 
For i.v. use only. The dose of the IMP must be administered as shown in Table 8.2. 
Table 8.2 
Data related to the administration of the investigational medicinal 
product 
Patient group 
Dose 
Rate 
of 
the 
infusion 
Duration 
of 
the infusion 
Volume 
of 
infusion 
Adult patients  
4 mg/kg of body 
weight 
2.0 ml/min 
50 min 
100 ml 
Abbreviations: kg, kilograms; mg, milligrams; min, minutes; ml, millilitres 
Preparation of the dose for the active treatment/placebo arm: 
The dose of the IMP is 4 mg of protein/kg of subject body weight. Each vial contains 30 mg 
of protein/ml. Therefore, each subject should receive 0.13 ml/kg. 
The IMP should be prepared as follows. According to the subject's body weight, the number 
of vials required to prepare the indicated dose should be calculated according to the following 
formula: 
V (ml/subject) = (P × 0.13 ml/kg), in which P is the body weight expressed in kg. 
The calculated IMP volume will be added to the 100 ml physiological saline infusion bag. 
Two doses of IMP will be administered as an infusion at a rate of 2.0 ml/min over a 50-
minute period with a 48-hour interval between doses. 

 
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8.4 
Accountability 
The investigator must keep an accurate accounting of the quantity of IMP units delivered to 
the centre, administered to subjects, and returned to INMUNOVA or its designee or affected 
to another destination (i.e., destroyed at the centre at the direction of INMUNOVA or its 
designee) during the course of the study and at the time of its completion. The IMP should 
be administered to subjects only by suitably qualified staff. The IMP must be used in 
accordance with the provisions of the protocol and by persons under the direct supervision 
of the investigator. Investigators must maintain records that adequately document the fact 
that subjects received the protocol-specified dose of IMP and that a reconciliation of all IMP 
received at the centre is made prior to final disposal. Upon completion of the study, or as 
indicated, all IMP, including unused, partially used or empty containers will be returned to 
INMUNOVA or its designee, or destroyed at the centre at the direction of INMUNOVA or 
its designee. 
8.5 
Concomitant medication 
All prescription or over-the-counter medications (e.g. over-the-counter medications and 
dietary supplements) that subjects refer as a medication they have taken within the 7 days 
prior to Screening (V1) will be evaluated and recorded on that visit. For each drug, the 
documentation must document the generic name or the name or brand name, the total daily 
dose, including the units (or the scheduled and actual dose, units and frequency of 
administration in the event that the medication is not administered on a daily basis), the route 
of administration and the reason for its use.  
Concomitant medication refers to all drugs and treatments used within the period between 
signing the IA/CF prior to screening and the end of participation in the study. 
Medication changes, additions, and discontinuations will be evaluated and recorded in the 
CRF during each study visit. All prescriptions given on demand (pro re nata) should be 
converted to reflect the actual number of tablets or doses received per day. 
8.5.1 Allowed concomitant medication 
The treatments considered necessary for the well-being of the subject may be indicated 
according to the criteria of the study clinician. If the permissibility of a certain drug/treatment 
is in doubt, INMUNOVA or its designee should be contacted to resolve the issue. 

 
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8.5.2 Prohibited concomitant medication 
The treatments considered necessary for the well-being of the subject may be indicated 
according to the criteria of the study clinician. If the permissibility of a certain drug/treatment 
is in doubt, INMUNOVA or its designee should be contacted to resolve the issue. All 
treatment with a therapeutic objective against SARS - CoV-2 must be reported to the medical 
monitor.           
8.6 
Compliance with the treatment regime 
Administration of the IMP will be supervised by study staff to ensure adherence to the 
treatment regimen. 
8.7 
Study drug discontinuation criteria 
1) The study medication must be discontinued if: 
● In the event of a severe hypersensitivity phenomenon (allergic reaction ≥ grade 3 
and/or anaphylaxis), the study drug will be immediately discontinued and standard 
support and treatment measures will be implemented.  The subject will continue with 
the visit schedule as established by the protocol. 
● In the event that a subject has received the first dose of study drug without having 
met the criteria for entering the protocol. The study medication should be 
discontinued, i.e., the next dose will not be administered.  The reason for 
discontinuation must be recorded in the medical record and in the CRF.  The subject 
will continue with the safety controls complying with the schedule of the follow-up 
visits and will carry out the V8 (ET) 4 weeks after the last dose as indicated in Section 
8.7. This subject will not perform procedures related to taking pharmacokinetic 
samples at these visits.  
● In the event that the subject/legal guardian of a subject who received the first dose of 
study drug refuses the administration of the second dose, the study medication should 
be discontinued, that is, the next dose will not be administered.  The reason for 
discontinuation must be recorded in the medical record and in the CRF. The subject 
will continue with the visit schedule as established by the protocol. 
2) The investigator will decide, per his/her medical criteria, if the study drug is 
discontinued in the following cases: 

 
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● In the event of a Grade 1 or Grade 2 allergic reaction (infusion-related reaction). The 
investigator will provide symptomatic treatment and decrease the infusion rate or 
interrupt the infusion. The investigator must document the decision taken and any 
change in the administration of the study drug in the patient's medical history 
accordingly. In the event the physician determines to discontinue the study 
medication, the next dose will not be administered.  The reason for discontinuation 
must be recorded in the medical record and in the CRF. The subject will continue 
with the visit schedule as established by the protocol. 
● In the event that clinical and/or laboratory events are detected in a subject that make 
the investigator, per his/her medical criteria, consider that the discontinuation of the 
medication is the most convenient for the subject.  The study drug should be 
discontinued, i.e., the next dose will not be administered. The reason for 
discontinuation must be recorded in the medical record and in the CRF. The subject 
will continue with the visit schedule as established by the protocol. 
9 ADVERSE EVENTS  
Throughout the entire study, all AEs will be monitored and recorded in an AE eCRF, 
including the AE description, start and end date, seriousness, severity, action taken and 
relationship to IMP. In the event of an AE, the priority will be the safety of the study subject.  
According to the ICH E2A guideline (80): An AE is any unforeseen and unwanted medical 
event that occurs in a patient or clinical research participant who has been administered a 
pharmaceutical product, which does not necessarily have to have a causal relationship with 
such treatment. Therefore, an AE can be any unfavourable and unwanted sign (such as an 
abnormal laboratory finding) or symptom, or disease, temporarily associated with the use of 
a medicinal product, regardless of whether it is considered related to the drug medicinal 
product. 
According to the National Administration of Medicines, Food and Medical Technology 
(ANMAT) (81): any adverse clinical event that occurs in a patient or a subject of a clinical 
research study to which a pharmaceutical product has been administered or has been 
performed a therapeutic procedure and that does not necessarily have to have a causal 
relationship with the treatment. Therefore, an AE can be any sign (including an abnormal 
laboratory finding) or symptom, unfavourable or unintentional, or disease, that has a temporal 
association with the use of the investigational medicinal product, regardless of whether or 
not it may be related to the same. 

 
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Medical interventions, such as surgeries, diagnostic procedures and therapeutic procedures 
are not AE, but they are the measure taken to treat the clinical condition. All of them must 
be registered as treatments for AE. 
9.1 
Documentation of adverse events 
All AE that occur within the period from the moment the subject or the subject's guardian 
signs the CF until the last study procedure is carried out will be recorded. All AEs that occur 
prior to the start of treatment (i.e. before the 1st. dose of the IMP) will be recorded as a 
medical history. Likewise, if the sign, symptom or disease was already present before the 
start of the treatment period, it will only be considered an AE in the event that it worsens 
after the start of the treatment period. Investigators must document all significant illnesses 
the subject has had within the 3 months prior to the Screening Visit. Additional pathologies 
that were present at the time of informed consent should be considered concomitant diseases. 
Pathologies that occur or are detected for the first time during the study, and/or concomitant 
conditions that worsen during the study, must be registered as AE in the eCRF. 
All clinical laboratory results, vital signs, and ECG results or findings should be evaluated 
by the investigator for their clinical significance. Isolated abnormal findings in clinical 
laboratory tests, vital signs or ECG (i.e., not part of an informed diagnosis) should be reported 
as AE if they are symptomatic, lead to discontinuation of the study drug or a dose reduction, 
require corrective treatment or constitute an AE as determined by the investigator based on 
clinical judgment. 
At each designated time point, the investigator will determine whether any AE has occurred 
by evaluating the subject. AEs can be observed directly, or they can be spontaneously 
reported by the subject or detected in the questioning of the subject at each time point. Open-
ended questions should be used to interrogate the subject, requesting information in a general 
way without specifically mentioning any particular symptoms. The investigator must 
evaluate all AEs for intensity, causality, and seriousness, according to the definitions given 
in Sections 9.2, 9.3 and 10.1, respectively. The investigator’s assessment must be clearly 
documented in the source documentation of the study centre, which must also include the 
signature of the investigator.  
The diagnosis in all cases should be reported using the term AE or SAE. In cases in which 
there is no diagnosis, the primary sign or symptom should be reported using the AE or SAE 
term along with additional data in the narrative report until it is available at the diagnosis. If 

 
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the signs and symptoms are independent and do not suggest a common diagnosis, they should 
be reported as individual AE or SAE reports. 
The investigator must report all AEs on the eCRF AE screen and source documents, 
regardless of seriousness, severity, and causality. Whenever possible, AE will be reported 
using a diagnostic term, (e.g. “common cold” or “upper respiratory infection” rather than 
“nasal congestion, cough, and low-grade fever”), and will be described with the attributes 
listed in Sections 9.2 and 9.3.  
9.2 
Assessment of intensity 
Each AE will be classified according to the following criteria: 
Mild: 
AE does not significantly interfere with the subject's normal performance 
level. 
Moderate: 
AE generates some deterioration in performance but does not imply a risk 
to the subject's health. 
Severe: 
AE generates a significant deterioration in performance or is disabling, and 
constitutes a clear risk to the subject's health. 
Severity vs. seriousness Severity is used to describe the intensity of a certain event, whereas 
the event itself may be of relatively minor medical significance (such as, for example, a 
severe headache). This is not the same as "seriousness", which is a concept that is based on 
the outcome of the event/subject at the time of the event. 
When changes in the intensity of an EA occur more than once in the course of the same day, 
the maximum intensity of the event must be recorded. If the intensity category changes over 
several days, these changes must be recorded separately (with separate start dates). 
9.3 
Assessment of causality 
Each AE will be ranked based on its relationship to the IMP, based on the criteria outlined 
below. Although the attribution of causality made by the investigator will be collected for 
the reported events, for analytical purposes the existence of a temporal association with the 
use of the IMP will be presumed sufficient for there to be at least one plausible association. 
Not related: 
There is no causal relationship between the IMP and the AE, and there is 
an obvious alternative cause, e.g. concomitant treatment or subject's 
underlying condition. 

 
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Possibly related: 
A relationship with the administration of the IMP seems unlikely, but 
cannot be ruled out with certainty. An AE may be considered possibly 
related if, or when, it meets 2 of the following criteria: (1) it follows a 
reasonable time sequence with respect to the administration of the IMP; 
(2) it is not a consequence that is to be expected in view of the subject's 
clinical condition or environmental or toxic factors or other forms of 
therapy administered to the subject; or (3) it follows a known pattern of 
response to PMI but does not reappear on repeat exposure or there is a 
cause that is more likely. 
Related: 
There is a reasonable/plausible chance that the AE may have been caused 
by the IMP. 
When evaluating the relationship with the IMP, the following criteria will be taken into 
consideration: 
● Known effect of the pharmacological class. 
● Biological plausibility. 
● Lack of an alternative explanation associated with a pathology or concomitant 
medication. 
Additionally, alternative causes of AE (not related to IMP) will be evaluated, such as: 
concomitant medication, study disease, study procedure or other medical conditions. 
9.4 
Action taken in relation to the study drug 
● Dose unchanged: No change was done to the dosage of the study drug. 
● Drug withdrawn: The study drug was interrupted definitively. 
● Drug interrupted: The study drug was temporarily suspended. 
● Not applicable: The subject died, study treatment had been completed prior to the 
reaction/event, or the reaction/event occurred before the start of the treatment. 
9.5 
Other action taken in relation to the event 
● None (this is, no treatment was necessary). 

 
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● Required medication (this is, over the counter and/or prescription drugs were needed to 
treat the AE). 
● Required hospitalisation or the prolongation of an existing hospitalisation (that is, the 
patient had to be admitted, or their hospitalisation had to be prolonged, as a consequence 
of the AE, regardless of whether or not medication was required). 
● Other 
9.6 
Result of the adverse event 
● Recovered/resolved (this is, subject fully recovered from AE with no residual effect 
observed). 
● On the mend/on the way to resolution (that is, the AE improved but has not been fully 
resolved). 
● Unrecovered/not resolved (that is, the EA itself is still present and manifest). 
● Recovered/resolved with sequelae (that is, residual effects of the AE continue to be 
present and manifest, including sequelae/residual effects). 
● Fatal (the event had a fatal outcome; this term should be used when death occurs as a 
direct result of AE). 
● Unknown 
9.7 
Changes in the parameters of the clinical laboratory 
Any abnormality in a laboratory value that occurs for the first time or that has worsened in 
terms of severity or frequency with respect to the baseline status and that meets 1 of the 
following criteria will be recorded in the AE pages of the eCRF: 
● Requires therapeutic intervention or diagnostic tests 
● Leads to IMP interruption 
● Occurs accompanied by, or induces, signs or symptoms 
● Is clinically significant at the discretion of the investigator 

 
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Combined elevations of aminotransferases and bilirubin, whether serious or not, and 
regardless of whether or not they are causally related, that meet the criteria for a potential 
case of Hy's Law (total bilirubin level ≥ 2 × ULN simultaneously accompanied by ALT or 
AST values ≥ 3 × ULN) should always be reported to the sponsor as soon as possible after 
performing the procedures detailed in Section 10.2 for the SAE report, and submitted along 
with the investigator's assessment of seriousness and causation and a detailed narrative 
report. 
9.8 
Overdose 
Any instance of overdose must be reported to INMUNOVA or its designee or a person 
specifically designated for that purpose within 24 hours, and must be fully documented as an 
AE or as an SAE in the event that it meets the SAE criteria. The details of the signs or 
symptoms and their management should be recorded, including details of the antidote(s) 
administered. 
9.9 
Adverse events of special interest 
An AESI is an AE (serious or non-serious) that raises concern from a medical or scientific 
point of view, that is specific to the study drug, and for which continuous monitoring and 
immediate notification by the investigator to INMUNOVA or its designated (see page) is 
required. These AE may require additional research to characterize and understand them.  
● Injection site reactions 
● Hypersensitivity reactions 
9.10 
Follow-up of adverse events 
All AE will be followed-up up to its resolution or stabilisation, and its result (outcome) must 
be documented in the eCRF. 
If the investigator detects an AE in a study subject after the last scheduled follow-up visit 
and considers that the event is possibly related or related to the study treatment received, the 
investigator should report this event to INMUNOVA or its designated representative. 

 
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10 SERIOUS ADVERSE EVENTS 
10.1 
Definition of serious adverse events 
A SAE is any event that meets any of the following criteria: 
● Results in death 
● Is life-threatening 
● Requires hospitalisation or prolongs existing hospitalisation 
● Results in significant or persistent incapacity/disability 
● It is a congenital anomaly or birth defect that develops in a child who has been 
fathered/conceived by a subject who received IMP. 
● Other: Major medical events that do not lead to death, are not life-threatening, or do not 
require hospitalisation may nevertheless be considered an SAE when, based on 
appropriate medical judgment, they may endanger the subject and may require medical 
or surgical intervention to avoid any of the outcomes mentioned in this definition. 
Examples of such events are the following: 
● Intensive treatment in the emergency room or at the subject's home for allergic 
bronchospasm 
● Blood dyscrasias or seizures that do not lead to the patient’s hospitalisation 
● Development of drug dependence or abuse 
Definition of terms 
Is life-threatening: an AE is life threatening if the subject was in imminent risk of death from 
the event as it occurred; that is, it does not include a reaction that, had it been more severe 
(serious), could have caused the death of the patient. For example, drug-induced hepatitis 
that resolved without evidence of liver failure would not be considered a life-threatening 
event, even though such an event could result in death. 
Hospitalisation: AEs that require hospitalisation should be considered SAE. Hospitalisation 
for elective surgery or routine clinical procedures that are not caused by an AE (e.g. elective 
surgery for a pre-existing condition that has not worsened) is not considered an AE or an 

 
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SAE. In any case, if the occurrence of an unforeseen and unwanted event is reported during 
the procedure, it must be reported as an AE, either "serious" or "not serious", according to 
the usual criteria. 
In general, hospitalisation means that the subject has been admitted (which usually involves 
at least one overnight stay) in the hospital institution or in the emergency room for 
observation and/or to receive treatment that could not be administered in the doctor's office 
nor on an outpatient basis. In the event that there is doubt as to whether what is considered a 
“hospitalisation” has occurred or whether it was necessary, the AE should be considered 
serious. 
Regarding death events, in all cases it should be reported as an SAE. 
Any unforeseen and unwanted event that is serious, that occurs after the reporting period, 
and that, in the investigator's discretion, is an event related to the study drug must also be 
reported and handled as an SAE. 
The investigator should follow up with subjects with AE until the event has resolved or the 
condition has stabilised. If there is no resolution of any of the AE, which includes significant 
clinical laboratory abnormalities detected in the EOS assessments, these events will be 
followed until they are resolved or until they are no longer clinically relevant.  
Disabling/incapacitating: An AE is incapacitating or disabling if it leads to a substantial 
and/or permanent impairment of the subject's ability to carry on her life normally. 
 
10.2 
Notification of serious adverse events 
Each AE will be evaluated to determine whether it complies with the seriousness criteria 
(Section 10.1). If the AE is considered serious, the investigator must notify such event to 
INMUNOVA or its designee and to the Institutional Review Board (IRB) or the Ethics 
Committee (EC) in accordance with their standard operating procedures. 
The events that at the investigator's discretion are considered progression of the COVID-19 
disease are part of the primary and secondary data set used for the study's efficacy analyses, 
and therefore will not be considered as an AE, will not be registered as a SAE in the clinical 
study safety database and will not be notified to regulatory authorities under expedited 
modality. 

 
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If the investigator detects a SAE in a study subject within 30 days of the last scheduled 
product application, and considers that the SAE is related or possibly related to the 
administration of the study IMP, the investigator should report such event to INMUNOVA 
or its designee. 
The investigator must report all SAEs to the sponsor using the SAE form within 24 h of 
becoming aware of the event, regardless of their relationship with the study drug. You should 
send it to the following email box: Farmacovigilancia@latresearch.com.   Additionally, 
he/she will document the SAE in the AE form in the eCRF of the corresponding subject. 
All information regarding the SAE will be collected and reported through the SAE form. The 
investigator must send the initial report within 24 h of becoming aware of the SAE. At a 
minimum, the initial report should include the following information: 
● Event 
● Study code  
● Subject code 
● Date of administration of the IMP 
● Name and contact information of the person reporting the event 
If the SAE has not been resolved by the time the investigator submits the initial SAE report, 
the investigator must provide a follow-up report as soon as the event is resolved (or when 
significant information is received in the event that the event is still is in progress). Additional 
follow-up information must be reported through the SAE form within 24 h after the 
investigator (or site staff) becomes aware of it. The investigator should not delay the SAE 
report to wait for additional information. Additional information, when it arises, must be 
reported in accordance with the aforementioned notification procedures. 
All SAEs should be followed up until they resolve, until the condition stabilizes, until the 
subject is lost, or until an alternative explanation for them is found. Once the SAE has been 
resolved, the centre staff must send an updated SAE form, as well as update the eCRF AE 
form corresponding to the subject. Likewise, in the event that there is a relevant laboratory 
report, the reports of consultation with other health professionals, discharge reports or other 
information that has been collected in relation to the event must be transmitted to the sponsor.  

 
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In the case of a “minimum report” (that is, a report that contains only the information 
mentioned in the previous bullets), a more detailed follow-up report should be sent as soon 
as more information emerges in this regard, always without exceeding a period of 7 calendar 
days from the date of the initial report. Each SAE must be followed up until its resolution or 
stabilisation, and in the case of reported deaths, the investigator must provide INMUNOVA 
or its designee and the IRB/EC with any additional information that they request (e.g. reports 
of autopsy and final medical reports). 
The sponsor or its representative will be responsible for determining and, in turn, reporting 
the SAE to regulatory authorities in accordance with the relevant regulatory requirements. 

 
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11 STATISTICS 
11.1 
General procedures 
Statistical analysis will be performed by INMUNOVA or its designee in collaboration with 
INMUNOVA. A detailed SAP will be finalised and signed prior to closing the database and 
prior to the opening of the study masking. All deviations that occur with respect to the 
analyses described below will be included in the SAP, which will be incorporated into the 
Clinical Study Report (CSR). The CSR will be written after all subjects have completed the 
28-day follow-up and the primary efficacy analysis and secondary efficacy analysis have also 
been completed. 
11.2 
Analysis set 
The Full Analysis Set (FAS) will be made up by all the randomised subjects to the IMP.  
The modified intent-to-treat group will be made up of all subjects who have been randomised 
to receive the IMP and who have received the full treatment regime of the IMP. This 
population will be the basis on which all efficacy analyses will be performed. 
The Per Protocol population will be made up by all the subjects in the mITT who have no 
major protocol deviations. Major protocol deviations will be reviewed and subjected to 
determination prior to closing the database and the unblinding. The PP population will be 
used for the endorsement sensitivity analysis. 
The Safety Population will be made up of all subjects who have received at least 1 dose of 
the IMP. This population will be used for all summaries of accounting data, baseline and 
demographic characteristics of subjects, and safety information, including incidence of AEs. 
11.3 
Determination of the sample size 
The purpose of the primary efficacy analysis is to demonstrate the superiority of INM005 
compared to placebo, based on an absolute reduction of 15% in the incidence of the event of 
primary interest, that is, a reduction of 2 orders on the severity scale. of illness or discharge 
in the treated cohort within 28 days (82). 
Assuming a 70% “standard of care” event rate (Wang 2020, https://doi.org/10.1016/S0140-
6736(20)31023-0) and an absolute effect size of 15 percentage points, for a power of 80% 

 
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and an error α = 0.025 (for a one-tailed comparison), 121 subjects will be required in each 
treatment group, totalling 242 participating subjects. 
 
11.4 
Randomisation 
Using a randomisation sealed envelope system, approximately 242 subjects will be assigned 
to treatment throughout the entire study span in a 1:1 ratio. Randomisation will be carried 
out in blocks of 4 and 6 subjects, stratified by participating site. 
 
11.5 
Statistical methods 
11.5.1 Efficacy analysis 
11.5.1.1 
Primary and secondary analysis 
The differences between patients in both treatment groups in the proportions of the primary 
and secondary efficacy endpoints will be analysed using the Chi-square test. The differences 
between these groups in the endpoints that involve the time to the occurrence of the events 
will be analysed using the non-parametric Mann-Whitney test (83). 
For the pharmacokinetic analysis, a non-compartmental model will be used. A population 
pharmacokinetic analysis will be performed using a non-linear mixed effects model (84). 
11.5.1.2 
Exploratory analysis 
Anti-SARS-CoV-2 antibody levels will be compared using a Levene's fit T test, if necessary. 
A descriptive analysis will be performed for the presence of anti-drug antibodies. 
The change in laboratory variables will be compared in those patients in whom disease 
progression is recorded or not by parametric or non-parametric tests, as appropriate. 
Variables with significant differences or those that are considered biologically relevant will 
be included in a multivariate logistic regression model. The presence of multicollinearity will 
be ruled out (83).  

 
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11.5.2 Safety analysis 
11.5.2.1 
Adverse events 
AEs will be coded by PT (Preferred Term) using the Medical Dictionary for Regulatory 
Activities (MedDRA) classification. All AEs reported with an onset or worsening after 
administration of study medication will be included in the analysis. The incidence of AE will 
be summarised by treatment group and by severity and relationship with the study drug. 
Serious AE and AE leading to withdrawal from the study will be tabulated. 
A treatment emergent adverse event (TEAE) is defined as an AE that starts simultaneously 
with or after the administration of the study drug dose, or a pre-existing condition that has 
worsened simultaneously with or after the administration of the dose of the study drug.  
The incidence of TEAEs and treatment-related AE will also be summarised by maximum 
severity and by the highest degree of relationship to IMP according to the main system organ 
class and MedDRA preferred term. This summary will include the total number and the 
percentage of subjects who report a certain event. In counting the number of reported events, 
an uninterrupted event, that is, one that is reported on more than one occasion and that did 
not cease, will be counted only once; AE that are not continuous and that are reported 
multiple times in relation to the same subject will be counted as multiple events. 
11.5.2.2 
Laboratory data 
Laboratory data (haematology parameters, blood chemistry and urinalysis) will be presented 
for each treatment group using descriptive statistics parameters, which include the mean and 
mean values of the change from baseline at each stipulated time point. on the schedule. 
Displacement tables will be generated in which the number of subjects with normal/abnormal 
values at baseline versus post-treatment will be presented. The frequency of laboratory 
abnormalities will be tabulated. In the data lists ordered by subject, laboratory values that are 
not within the normal reference ranges and markedly abnormal findings will be marked with 
an alert. 
11.5.2.3 
Vital signs 
Changes from baseline in vital signs, SBP (systolic and diastolic), body temperature, pulse, 
and respiratory rate will be summarised for each treatment group using descriptive statistics. 
The last measurement obtained prior to administration of the study drug will serve as the 
baseline level. The percentage of subjects with values outside the clinically important limits 

 
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will be summarised. A list of the values of body weight, height and BMI registered in the 
Screening (V1) will be provided.  
11.5.3 Demographics and baseline 
The treatment groups will be compared in terms of the demographic characteristics of the 
subjects, and the baseline characteristics will be summarised using descriptive statistics; tests 
will not be performed by formal statistical analysis. 
11.6 
Blinded safety data review 
The safety data (including demographic characteristics, disease characteristics, AE, AESI, 
vital signs, hematology, biochemistry) obtained from the Safety Cohorts (every 12, 24, 48, 
96, 192 enrolled patients) will be examined low masking by the DMC. The data will be 
presented using fictitious subject numbers in order to preserve masking. 
The Argentine Regulatory Agency (ANMAT) will be notified and the DMC reports will be 
presented accordingly. 
11.7 
Interim analysis 
An interim analysis will be carried out after 60% of recruitment has been reached; that is, 
approximately after the end of the follow-up of the first 145 subjects. The Data Monitoring 
Committee will analyse the event rate in the group under the SoC and may recommend: (1) 
modifying the sample size, based on the observed event rate, or (2) stopping the study if: 
(2.a) it’s considered that it is not feasible because it requires an excessively large sample size 
or (2.b) it’s considered futile because of an event rate ≥ 95%. 
The re-estimation of the sample size will allow the sample to be increased by up to 72 
subjects, to reach 314 subjects. The requirement of a greater number of subjects would be 
considered "Not Feasible" and will cause the study to be stopped. 
 
11.7.1 Data monitoring committee 
A DMC will periodically review and evaluate the accumulated study data regarding the safety 
of the subjects, the conduct and progress of the study, and, if relevant, the efficacy throughout 
both stages of the study. The DMC will issue recommendations regarding the continuation, 

 
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modification or interruption of the study in a process in which the highest priority will always 
be to guarantee the safety of the participants. The composition, the frequency of the review, 
the range of decisions allowed and the methods for the disclosure of the information are 
matters that will be addressed in a separate statute that will be in line with the guidelines that 
have been issued for other studies of continuous adaptive design (ASD).  
The DMC will determine if the study can be continued based on the safety findings (i.e., 
“there are no safety observations that warrant permanent cessation of subject recruitment” or 
“safety observations warrant permanent cessation of enrolment of subjects”). 
To maintain data integrity during interim analysis, use of a DMC will be used to make 
decisions regarding pre-specified study adaptations in relation to sample size estimation and 
premature study discontinuation for reasons of futility or overwhelming efficacy. Pre-
specified accommodations, as well as committee rules applicable to interpretation and 
decision-making regarding accommodations, will be defined in the DMC Charter. Next, the 
framework for the organisation of the DMC statute is provided, as well as biostatistical 
approaches to adaptations. 
The DMC Charter will define all the responsibilities, functions, composition, structure of 
meetings, communications, the Statistical Analysis Plan (SAP) of the DMC and the rules for 
decision-making. This document will be generated by the sponsor and will be presented for 
review after an organisational meeting, which will take place prior to the recruitment of the 
first subject. The organisational meeting will be attended by the members of the DMC, the 
director of the DMC, the study statistician, the unblinded statistician, the members of the 
pharmacovigilance team and a representative of the sponsor who will act as a link with the 
DMC. This meeting will be used to familiarize the DMC with the study protocol and to 
finalize the DMC Charter. Subsequently, the DMC will convene an open and closed data 
review session, as described in the Charter. The sponsor's representative may participate in 
open sessions to provide a report regarding the progress of the study, and to request advice 
and approval for amendments to the protocol, changes to the informed consent, or updates to 
the investigator's manual. The minutes of the open sessions generated by the Chairman of the 
DMC will be available to the sponsor's representative. The minutes of the closed sessions of 
the DMC will be kept within a confidentiality framework. The DMC Chairman will also have 
the prerogative to schedule ad hoc meetings for safety-related issues that may arise and 
warrant them. These meetings may be held without the sponsor's knowledge of their holding; 
however, in the event that they occur with the knowledge of the sponsor, the latter may not 

 
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have knowledge of the agenda of the day. Additional details about the communication 
process and data flow will be provided in the DMC Charter. 
This Charter will be organised in accordance with the directive documents for the 
organisation of the DMCs, and will be subject to regulatory review prior to the start of the 
clinical study. In accordance with regulatory guidelines regarding the role of DMC in 
adaptive designs, the DMC will not recommend or make changes to adaptive design once the 
DMC has access to data encoded by treatment or data that has been completely unblinded. 
11.7.2 Futility in the interim analysis 
Assuming that the safety data is permissive, the determination of futility in the interim 
analysis will be evaluated by the DMC. Futility is concluded when the rate of events in the 
standard therapy arm is greater than or equal to 95%. 
All analyses will be carried out by the DMC, and the charter of the DMC will be explicit 
regarding the composition of this committee, the methods for reviewing the data, and the 
possible decisions that might arise from such review. 

 
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12 ETHICAL CONSIDERATIONS AND RESPONSIBILITIES 
12.1 
Good Clinical Practice 
The study will be carried out in accordance with the provisions of this protocol, the ICH 
Good Clinical Practice (GCP) guidelines (85), the regulations relating to electronic records 
and electronic signature and the most recent versions of the guidelines of the Declaration of 
Helsinki (86) and the regulatory regulations applicable in Argentina (81). These guidelines 
are on file at INMUNOVA. 
12.2 
Data monitoring committee 
A DMC will periodically review and evaluate the accumulated study data regarding the safety 
of the subjects, the conduct and progress of the study, and, if relevant, the efficacy throughout 
both stages of the study. The DMC will issue recommendations regarding the continuation, 
modification or interruption of the study in a process in which the highest priority will always 
be to guarantee the safety of the subjects. The composition, the frequency of the review, the 
range of decisions allowed and the methods for the disclosure of the information are matters 
that will be addressed in a separate charter. The DMC will appoint a subcommittee that will 
be in charge of reviewing the safety data of the Safety Cohort.  
DMCs have traditionally been used to independently monitor studies for patient safety and 
to determine the risk-benefit ratio within studies. However, there is the possibility that the 
DMC may be asked to also issue pre-specified study adaptations, such as those envisaged in 
the proposed study in relation to dose selection, sample size estimation, and premature 
discontinuation of the study for reasons of futility or efficacy. The responsibilities of the 
DMC and the rules for decision-making will be defined in the DMC Charter (87-88). 
In the proposed study, the DMC will function as an independent review committee in that its 
members will be considered independent of the sponsor and of any provider contracted by 
the sponsor. Likewise, both INMUNOVA and the clinical study team will be limited in their 
access to the open parts of the DMC sessions, in which data such as recruitment, compliance 
with the treatment regimen, and study withdrawals, and study withdrawals, may be reviewed, 
cumulative AE rates, although not separately for each branch of the study. The DMC 
members must preserve the confidentiality of all study communications, including reports, 
data, review session discussions, conference calls, and session minutes, to ensure that no 
information is disclosed to the INMUNOVA clinical study team, INMUNOVA (with the 
exception of open reports), or third parties. An unblinded statistician, who will not be part of 

 
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the DMC, will act as a liaison between the sponsor and the DMC and will provide periodic 
presentations of efficacy and safety data for review by the DMC. The medical representative 
of INMUNOVA will be the one who receives the recommendations made by the DMC to 
INMUNOVA. The specific procedures to be used for interactions between DMC members 
and non-DMC individuals (i.e. the unblinded statistician, INMUNOVA, or any supplier 
contracted by the sponsor) will be defined in the DMC Charter. 
12.2.1 Members of the Data Monitoring Committee 
The DMC for this study will be made up of a minimum of 3 members, of whom one must 
have training in biostatistics. Members of the DMC will be appointed by INMUNOVA, and 
selected from the medical community based on their expertise in the area of interest and their 
expertise in biostatistics. All members of the DMC must also have experience in conducting 
clinical studies. Although formally he is not a member of the DMC, the non-blind 
biostatistician is essential in the communication of the study data to the DMC and, therefore, 
must be a person with experience in interim analysis of data from clinical studies. The 
members of the DMC will not be involved in the design of this study or its conduct, except 
through their role in the DMC, and may not have any significant financial or other relevant 
relationship with the sponsor. All members of the DMC must be present at the sessions for a 
quorum to be reached. Likewise, 1 member of the DMC will serve as the Chairman of such 
committee and will be responsible for presiding over the DMC sessions and preparing the 
minutes of the closed sessions, and will assume responsibility for all communications 
exchanged between the DMC and the sponsor. The roles and responsibilities of all members 
will be defined in the DMC Charter.  
12.2.2 Generation of the Data Monitoring Committee Charter 
The DMC Charter is a fundamental document that defines all the responsibilities, functions, 
composition, structure of meetings, communications, the Statistical Analysis Plan (SAP) of 
the DMC and the rules for decision-making. This document will be generated by the sponsor. 
Prior to the recruitment of the first patient, an organisational meeting will be held. The 
organisational meeting will be attended by the members of the DMC, the director of the 
DMC, the study statistician, the unblinded statistician, and the members of the 
pharmacovigilance team. This meeting will be used to familiarize the DMC with the study 
protocol and to finalize the DMC Charter.  

 
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12.2.3 Data Monitoring Committee Meetings 
The meetings will consist of open or closed sessions. In open sessions, only blind safety 
information will be dealt with, and the content of such sessions will be coordinated by the 
non-blind statistician. Only members of the DMC and the non-blind statistician may attend 
the closed sessions; in these sessions, the non-blind statistician will present the reports that 
are specifically programmed for the members of the DMC. These reports, which will be 
partially or totally blinded, will be grouped and presented by treatment group, but the names 
of the treatments in question will not be released. The non-blind statistician will not be 
present for the remainder of the DMC's deliberation, unless requested to do so by the DMC 
members. Likewise, ad hoc meetings may be held as required; the rules for such meetings 
will be defined in the DMC Charter.  
12.2.4 Role of the Data Monitoring Committee in adaptive designs 
The DMC considerations are highlighted in the US FDA guideline for adaptive design studies 
(53).  While most of the recommendations provided in such a guideline have been highlighted 
in the preceding paragraphs, key considerations regarding DMC and adaptive designs are 
outlined. As mentioned above, the DMC can be prospectively selected to implement 
decisions regarding pre-specified study adaptations, in addition to performing its role in 
relation to safety monitoring. This guideline states that “In those cases in which adaptations 
are based on interim analyses of unblinded results, robust, pre-specified and well-
documented procedures must be in place before the clinical study or data review can begin” 
(53). The content of this guideline underlines the importance of the DMC Charter in 
establishing the rules for adaptation within the framework of the study.  
In all studies involving a DMC in which the data is not protected by blinding, the integrity 
of the data is critical. Due to the nature of the analysis and the ability to influence the study 
based on interim data, this guideline emphasizes the critical nature of creating 
protection/safeguards mechanisms that allow the sponsor to remain unaware of unblinded 
data or any other influence that might arise from the interim data. Similarly, the guideline 
states that both researchers and study subjects should receive as limited information as 
possible regarding the extent of possible adaptive changes. Once again in this case, the DMC 
Charter plays a fundamental role in establishing the procedures by which the DMC will 
govern to evaluate the interim analysis and communicate adaptations.  
Finally, the FDA guideline on adaptive designs indicates that the DMC will not be able to 
recommend or make changes to the adaptive design after having had access to data encoded 

 
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by treatment or data that has been completely unblinded, since that such recommendations 
could lead to loss of data integrity.  
12.3 
Steering Committee 
No Steering Committee will be used for this study.  
12.4 
Institutional Review Board/Ethics Committee 
The study must be approved by a duly constituted IRB/EC. Such approval is required for the 
study protocol, protocol amendments, AF/CFs, subject information sheets, and publicity 
materials. The IMP will not be sent to the site until the Sponsor or its representative has 
received the written authorisation issued by the IRB/EC. 
12.5 
Informed consent 
For each study subject, a written AF/CF will be obtained prior to carrying out all activities 
related to the protocol. As part of this procedure, the investigator or a designated 
representative will deliver the AF/CF document to the subject, after which they must orally 
explain the nature, duration, and purpose of the study and the action of the IMP in such a 
way that the subject and the parent(s) or guardian are aware of the potential risks, annoyances 
or adverse events that could arise. Subjects should be informed of the possibility of 
withdrawing from the study at any time they wish. They will be provided with all the 
information required by local regulations and ICH guidelines. The Principal Investigator or 
a designated representative will provide the sponsor or his representative with a copy of the 
AF/CF approved by the IRB/EC/health authority prior to the start of the study. 
The informed consent form must contain, at a minimum, the elements of consent described 
in the ICH Good Clinical Practice (GCP) guideline. INMUNOVA or its designee will review 
a copy of the AF/CF intended for use to determine its acceptability; this document must be 
presented by the investigator or his/her designee, together with the protocol, to the 
corresponding IRB/EC for its due review and approval before the study begins at the research 
centre. The assent/consent forms must be written in such a way that they are fully 
comprehensible for the future subject. The investigator must provide the sponsor or his/her 
designee with a copy of the approval letter issued by the IRB/EC regarding the protocol and 
AF/CF before the study drug supplies can be dispatched and the study can begin. 

 
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The assent/consent forms should be modified in the event that new information emerges 
during the study that could be relevant to the subject. Any modification must be presented to 
the corresponding IRB/EC for its due review and approval before it can be implemented. 
A copy of the signed informed assent form and informed consent form must be given to the 
subject, and the original copies of these documents must be kept in the designated location 
within the study centre. 
Before starting any of the study procedures, it will be the responsibility of the investigator or 
his/her designee to obtain informed consent after an adequate explanation of the objectives, 
methods and anticipated benefits and potential risks of the study. The subject should be given 
sufficient time to make a decision regarding study participation, as well as the opportunity to 
ask questions about the particular issues in the study. The AF/CF approved by the IRB/EC 
must be signed and dated in handwriting by the subject and by the person in charge of 
carrying out the explanation of the informed consent. The investigator or appropriate centre 
staff should document the details of obtaining informed assent/consent in the subject's study 
documents. 
12.6 
Records management 
By signing this protocol, the investigator grants his/her permission for the sponsor's staff, 
their representatives and the corresponding regulatory authorities to carry out on-site 
monitoring of all the corresponding study documentation, on physical (paper) or electronic 
media, as well as on-site reviews of the procedures used to generate eCRFs, if clinically 
relevant. 
12.7 
Source documents 
Note that there will be various original documents, data, and records that will be considered 
source documents in this study. The eCRF itself cannot be used as a source document under 
any circumstances.  
12.8 
Study records and record retention 
The investigator must make arrangements for the retention of study records at the centre. The 
nature of the records and the length of the retention period must comply with the requirements 
of the relevant regulatory authority. The investigator must take steps to prevent accidental or 
premature destruction of such documents 
 

 
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13 AUDITS AND MONITORING 
This study will be subject to quality assurance monitoring at all stages of its development by 
the clinical research staff employed by the sponsor or its representative. This monitoring will 
include in-person visits, remote monitoring, and telephone communications designed to 
ensure that the investigation is being conducted in accordance with protocol, standard 
operating procedures, GCP guidelines, and relevant regulatory requirements. Quality control 
procedures will be applied to each stage of data management to ensure that all data is reliable 
and has been processed correctly. The on-site review of the eCRF will include a review of 
the forms in order to confirm that the information contained in them is clear and complete 
and agrees with what is contained in the existing source documents for each subject.  
There is the possibility that medical advisers or clinical monitors (clinical research associates, 
CRAs) or clinical trial assistants might request to witness the subject assessments that are 
performed as part of this protocol. The investigator and the corresponding staff will be 
requested periodically to attend the meetings/workshops organised by the sponsor, in order 
to ensure proper execution of the protocol. The study may be subject to audits by the sponsor 
or the regulatory authorities. If such an audit occurs, the investigator must provide access to 
the subject's records as necessary. By signing this protocol, the investigator grants his/her 
permission for the sponsor's staff, their representatives and the corresponding regulatory 
authorities to carry out on-site monitoring of all the corresponding study documentation, as 
well as on-site reviews of the procedures used to generate eCRFs, if clinically relevant. 

 
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14 AMENDMENTS 
Modifications to the protocol, with the exception of those intended to reduce an imminent 
risk to study subjects, may only be made by the sponsor. Any change in the protocol intended 
to avoid an obvious imminent risk to the subjects may be implemented immediately, subject 
to the condition that the IRB/EC is notified of this within a period of 5 days. 
Modifications to the protocol that are permanent in nature should be handled as an 
amendment to the protocol. The written amendment generated must be submitted to the 
IRB/EC, and the investigator must wait to receive the corresponding approval before 
implementing the changes. The sponsor will present the amendments to the protocol to the 
corresponding regulatory authorities for their corresponding approval. 
If the amendment to the protocol, at the discretion of the IRB/EC, the investigator and/or the 
Sponsor, substantially modifies the study design and/or increases the potential risk for the 
subject and/or has any repercussion on the subject's involvement as a subject. of the study, 
the AF/CF in writing in force will require a modification of the same content. In such cases, 
the informed consent of those subjects who are enrolled in the study must be renewed, before 
they can continue with their participation. 
 

 
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15 STUDY REPORT AND PUBLISHING 
The Sponsor is responsible for preparing and supplying the relevant regulatory authorities 
with the Clinical Study Reports (CSR) in accordance with the corresponding regulatory 
requirements. 
The sponsor's publication policy is discussed in the Clinical Research Agreement entered 
into with the investigator. 
 

 
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16 INTERRUPTION OF THE STUDY 
Both the sponsor and the Principal Investigator reserve the right to definitively interrupt the 
study at the investigator's centre at any time they deem it appropriate. If necessary, the 
sponsor or a specified designee will inform the corresponding regulatory authorities about 
the definitive discontinuation of the study and the reasons for such decision, and the Principal 
Investigator will inform the IRB/EC about it. In the event of a definitive interruption of the 
study, the sponsor and the Principal Investigator will guarantee due consideration of the 
safeguarding of the subjects' interests. 
 

 
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17 CONFIDENTIALITY 
All the information generated in the framework of this study is considered highly confidential 
and cannot be disclosed to any person or entity that is not directly involved with the study, 
unless there is prior written consent from the sponsor authorising such disclosure. 
Notwithstanding this, the officials of the authorised regulatory authorities, the staff of the 
IRB/EC, the sponsor and their authorised representatives have the right of full access to the 
records. 
The identification of the subjects and the eCRF will be carried out only by means of the 
screening and treatment numbers. If requested, the full name of the subject may be made 
known to an authorised regulatory entity/agency or other official or person in charge 
authorised for this purpose. 
 
 

 
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18 BIBLIOGRAPHY 
 
 
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APPENDICES 

 
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Apéndice 1. 
Names[NB3] of the members of the study staff 
The list of the team members is provided in a separate document.  
 
 

 
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Apéndice 2. 
Guidelines[NB4] 
for 
the 
management 
of 
an 
anaphylactic reaction 
Hypersensitivity reactions and severe hypersensitivity reactions, including anaphylaxis, have 
been described with other products based on F(ab')2 of equine origin, thus there is the 
possibility of such reactions occurring after administration of INM005. Patients who have 
received prior treatment with an antivenin/antitoxin derived from equines or who have a 
history of hypersensitivity to such animals are at increased risk of developing severe 
hypersensitivity reactions to the administration of INM005 (89). The existence of any of the 
aforementioned history will be an exclusion criterion for the recruitment of a subject in this 
phase 2/3 study. (89)      
An international anaphylaxis task force has recently recommended a new clinical working 
definition that should be useful to clinicians in making the diagnosis, and help lay people to 
recognize anaphylaxis (see adapted version in Box 1) (90) (90).      This definition will be 
provided as a guideline for investigators:  
 
Chart 1. Clinical criteria for the diagnosis of anaphylaxis 
Anaphylaxis is highly likely when any of the following three criteria is met: 
1.  Acute onset of a condition (minutes to several hours) involving skin, mucosa, or both 
(e.g. generalised hives, pruritus or flushes/blushing, swelling of the lips-tongue-bell). 
 
And at least one of the following: 
 
a. Respiratory compromise (e.g. dyspnoea, bronchospasm, stridor, hypoxia). 
 
b. Cardiovascular compromise (e.g. hypotension, collapse). 
2.  Two or more of the following, with rapid presentation after exposure to an element 
that constitutes a probable allergen for the patient (from minutes to several hours): 
 
a. Skin or mucosal involvement (e.g. generalised hives, itching, flushes/blushing, 
swelling). 
 
b. Respiratory compromise (e.g. dyspnoea, bronchospasm, stridor, hypoxia). 
 
c. Cardiovascular compromise (e.g. hypotension, collapse). 
 
d. Persistent gastrointestinal symptoms (e.g. abdominal cramps, vomiting). 

 
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3.  Hypotension after exposure to an allergen known to the patient (from minutes to 
several hours): 
 
Hypotension in children is defined as a systolic blood pressure value  
< 70 mmHg in children 1 month to 1 year of age [< 70 mmHg + (2 x age)] in children 1 
to 10 years, and ≤ 90 mmHg in children 11 to 17 years. 
Adapted from:  Sampson [5] (D) 
 
Source: Muraro (90)           
During this phase 2/3 clinical study, the subject will be hospitalised for a period of 48 h 
during the treatment period. Said hospitalisation will be monitored by a doctor and a member 
of the nursing staff. The administration of INM005 should be carried out in a context in which 
there is adequate equipment, medication, including epinephrine, and trained staff in the 
management of hypersensitivity, anaphylaxis and shock. Subjects will be monitored for signs 
and symptoms of an acute allergic reaction (e.g. urticaria, pruritus, erythema, angioedema, 
bronchospasm with wheezing or coughing, stridor, laryngeal oedema, hypotension, 
tachycardia) during infusion of INM005 and after this. In the event of an anaphylactic 
reaction, the administration of INM005 should be discontinued immediately and appropriate 
emergency medical care instituted, which will be in charge of the treating physician and will 
be carried out in accordance with the provisions of the emergency protocol of each institution. 
Subject will be cared for through appropriate life support and treatment. Medications for the 
emergency treatment of acute hypersensitivity reactions, such as epinephrine, should be 
readily available. Intramuscular epinephrine is recognised as the first-line therapy for 
anaphylaxis, both in hospital and out-of-hospital, and should be administered without delay 
after identification of the condition. Additional therapies, such as supportive volume 
replacement therapy, nebulised bronchodilators, antihistamines, or corticosteroids, are 
considered supplemental to adrenaline. If necessary, the subject will be transferred to the 
Intensive Care Unit. The patient will be withdrawn from the study and will be subjected to 
control and follow-up by the treating physician until the resolution of the event (89-101).      
Delayed allergic reactions (serum sickness, e.g. fever, urticarial or maculopapular rash, 
myalgia, arthralgia, and lymphadenopathy) have been reported with other equine F(ab')2-
based products, thus the possibility of these types of reactions also exists after administration 
of INM005, typically 10-21 days after infusion. Patients will be monitored for signs and 
symptoms of a delayed allergic reaction. In the event a delayed allergic reaction (serum 
sickness) is suspected, appropriate medical attention should be instituted.