A Randomized, Double-blind, Placebo-controlled, Parallel-group, Phase 3, Multicenter Trial Investigating the Efficacy and Safety of C21 as add-on to Standard of Care in Adult Subjects With COVID-19
Phase: PHASE3
Conditions: COVID-19
Sponsor: Vicore Pharma AB

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Clinical Trial Protocol 
 
 
Protocol Number: 
VP-C21-008 
Title: 
A randomized, double-blind, placebo-controlled, parallel 
group, phase 3, multicenter trial investigating the efficacy and safety 
of C21 as add on to standard of care in adult subjects with COVID-19. 
Brief Title: 
A trial to investigate recovery from COVID-19 with C21 in adult 
subjects 
Acronym: 
ATTRACT-3 
Trial Phase: 
3 
Compound: 
C21 (Compound 21) 
Version: 
5.0 
Sponsor: 
Vicore Pharma AB 
Kronhusgatan 11 
SE-411 05 Gothenburg, Sweden 
EudraCT No. 
2021-000264-29 
 
 
 
 
This document is the property of sponsor. No unpublished information contained herein may be 
disclosed without prior written approval from sponsor. 
 
 

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Medical Monitor Coverage Contact Information 
 
The Principal Investigators (PIs) are responsible for ensuring that procedures and expertise are 
available to handle any potential medical emergencies occurring during the trial. A medical 
emergency usually constitutes a serious adverse event (SAE) and is to be reported as such. 
Detailed SAE reporting procedures are described in Section 8.5. 
The Sponsor CRO provides a 24-hour, 7-days a week (24/7) phone service for all active sites, 
their PIs and site support staff for urgent cases. 24/7 medical monitoring service is available for 
any medical or safety issues related to subjects included in the trial or subjects screening for 
participation in the trial.  
Medical Monitoring support center contact information: 
Region 
Phone  
Fax 
E-mail 
North America 
and South 
America 
+1 866 326 5053 (toll-free) 
+1 434 951 4082 (direct) 
+1 800 280 7035 (toll-free) 
+1 913 307 5751 (direct) 
C21008-MA@prahs.com 
 
Europe, Asia-
Pacific and 
Africa 
+ 49 621 878 2850 
+ 44 203 365 6752 
 

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Table of Contents 
1. 
Protocol Summary ..........................................................................................................6 
1.1. 
Synopsis ............................................................................................................................6 
1.2. 
Schema ..............................................................................................................................9 
1.3. 
Schedule of Activities (SoA) ..........................................................................................10 
2. 
Introduction ...................................................................................................................11 
2.1. 
Trial Rationale ................................................................................................................11 
2.2. 
Background .....................................................................................................................11 
2.3. 
Benefit/Risk Assessment ................................................................................................13 
2.3.1. 
Risk Assessment .............................................................................................................14 
2.3.2. 
Benefit Assessment .........................................................................................................15 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................15 
3. 
Objectives, Endpoints, and Estimands .......................................................................16 
4. 
Trial Design ...................................................................................................................19 
4.1. 
Overall Design ................................................................................................................19 
4.2. 
Scientific Rationale for Trial Design ..............................................................................19 
4.3. 
Justification for Dose ......................................................................................................20 
4.4. 
End of Trial Definition ...................................................................................................21 
5. 
Trial Population ............................................................................................................22 
5.1. 
Inclusion Criteria ............................................................................................................22 
5.2. 
Exclusion Criteria ...........................................................................................................23 
5.3. 
Lifestyle Considerations .................................................................................................24 
5.4. 
Screen Failures ................................................................................................................24 
6. 
Investigational Medicinal Product and Concomitant Therapy ................................25 
6.1. 
Investigational Medicinal Product Administered ...........................................................25 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................25 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................26 
6.4. 
Investigational Medicinal Product Compliance ..............................................................26 
6.5. 
Dose Modification ..........................................................................................................27 
6.6. 
Continued Access to the Investigational Medicinal Product after 
End of Trial .....................................................................................................................27 
6.7. 
Treatment of Overdose ...................................................................................................27 
6.8. 
Prior and Concomitant Therapy ......................................................................................27 
7. 
Discontinuation of Investigational Medicinal Product and 
Subject Discontinuation/Withdrawal ..........................................................................29 
7.1. 
Discontinuation of Investigational Medicinal Product ...................................................29 
7.1.1. 
Temporary Discontinuation ............................................................................................29 
7.2. 
Subject Discontinuation/Withdrawal from the Trial ......................................................29 
7.3. 
Lost to Follow up ............................................................................................................30 
8. 
Trial Assessments and Procedures ..............................................................................31 
8.1. 
Screening Assessments ...................................................................................................31 
8.1.1. 
Demographics .................................................................................................................31 
8.1.2. 
Medical History ..............................................................................................................31 

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8.2. 
Efficacy Assessments .....................................................................................................32 
8.2.1. 
8-point Ordinal Scale ......................................................................................................32 
8.2.2. 
Supplemental Oxygen .....................................................................................................32 
8.2.3. 
Oxygen Saturation ..........................................................................................................33 
8.3. 
Survival and Hospitalization ...........................................................................................33 
8.4. 
Safety Assessments .........................................................................................................33 
8.4.1. 
Physical Examinations ....................................................................................................33 
8.4.2. 
Vital Signs .......................................................................................................................33 
8.4.3. 
Electrocardiograms .........................................................................................................34 
8.4.4. 
Clinical Safety Laboratory Tests ....................................................................................34 
8.4.5. 
Hepatic Impairment ........................................................................................................35 
8.4.6. 
Pregnancy Testing ...........................................................................................................36 
8.4.7. 
SARS-CoV-2 Variant .....................................................................................................37 
8.4.8. 
New Infections ................................................................................................................37 
8.5. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ........................................................................................................................37 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................37 
8.5.2. 
Method of Detecting AEs and SAEs ..............................................................................37 
8.5.3. 
Follow-up of Aes and SAEs ...........................................................................................38 
8.5.4. 
Regulatory Reporting Requirements for SAEs ...............................................................38 
8.5.5. 
Pregnancy ........................................................................................................................38 
8.6. 
Pharmacokinetics ............................................................................................................39 
8.7. 
Genetics ..........................................................................................................................39 
8.8. 
Biomarkers ......................................................................................................................39 
8.9. 
Immunogenicity Assessments.........................................................................................40 
8.10. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................40 
9. 
Statistical Considerations .............................................................................................41 
9.1. 
Statistical Hypotheses .....................................................................................................41 
9.1.1. 
Multiplicity Adjustment ..................................................................................................41 
9.2. 
Analysis Sets ...................................................................................................................41 
9.3. 
Statistical Analyses .........................................................................................................42 
9.3.1. 
General Considerations ...................................................................................................42 
9.3.2. 
Primary Endpoint/Estimand Analysis .............................................................................42 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................43 
9.3.4. 
Exploratory Endpoint Analysis .......................................................................................44 
9.3.5. 
Safety Analyses ...............................................................................................................45 
9.3.6. 
Other Analyses ................................................................................................................45 
9.4. 
Interim Analysis ..............................................................................................................46 
9.5. 
Sample Size Determination ............................................................................................46 
10. 
Supporting Documentation and Operational Considerations ..................................47 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations ................................................................................................................47 
10.1.1. Regulatory and Ethical Considerations ...........................................................................47 
10.1.2. Financial Disclosure........................................................................................................47 

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10.1.3. Informed Consent Process ..............................................................................................47 
10.1.4. Data Protection................................................................................................................48 
10.1.5. Committees Structure......................................................................................................48 
10.1.6. Dissemination of Clinical Trial Data ..............................................................................48 
10.1.7. Data Quality Assurance ..................................................................................................49 
10.1.8. Source Documents ..........................................................................................................49 
10.1.9. Trial and Site Start and Closure ......................................................................................50 
10.1.10. Publication Policy ...........................................................................................................51 
10.2. 
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................52 
10.2.1. Definition of AE .............................................................................................................52 
10.2.2. Definition of SAE ...........................................................................................................53 
10.2.3. Recording and Follow-Up of AE and/or SAE ................................................................54 
10.2.4. Reporting of SAEs ..........................................................................................................56 
10.3. 
Appendix 3: Contraceptive and Barrier Guidance ..........................................................58 
10.3.1. Requirements ..................................................................................................................58 
10.3.2. Definitions.......................................................................................................................59 
10.3.3. Contraception Guidance..................................................................................................60 
10.4. 
Appendix 4 Standard of Care for COVID-19 .................................................................61 
10.5. 
Appendix 5: Country-specific Requirements .................................................................62 
10.5.1. India ................................................................................................................................62 
10.6. 
Appendix 6: Abbreviations .............................................................................................63 
11. 
Protocol Amendment History ......................................................................................66 
12. 
References ......................................................................................................................74 
13. 
Sponsor and Coordinating Investigator Signatures ..................................................77 
 

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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A randomized, double-blind, placebo-controlled, parallel group, phase 3, 
multicenter trial investigating the efficacy and safety of C21 as add on to standard of 
care in adult subjects with COVID-19. 
Brief Title: A trial to investigate recovery from COVID-19 with C21 in adult subjects. 
Rationale: The corona virus disease 2019 (COVID-19) is an ongoing pandemic caused by 
severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). Although several therapeutic 
agents have been evaluated for the treatment of COVID-19, the morbidity and mortality are still 
significant. The need for safe, effective, and convenient COVID-19 drugs is likely to remain 
even after the launch of vaccine programs. The safety and efficacy of C21 in subjects with 
COVID-19 have been investigated in a phase 2 trial. The results show that C21, as add on to 
standard of care (SoC), reduced the need for extended oxygen supplementation and had a 
favorable benefit/risk profile. The rationale for conducting this phase 3 trial is to confirm the 
efficacy of C21 in subjects with COVID-19. 
Objectives, Endpoints and Estimands: 
 
Objectives 
Endpoints 
Primary 
 
• Evaluate the efficacy of C21 versus 
placebo as add on to SoC on recovery 
in subjects with COVID-19. 
•  All-cause mortality up to Day 60. 
Key secondary  
 
 
• Time to sustained hospital discharge 
up to Day 60. 
• Supplemental oxygen free days up to 
Day 29. 
• Proportion of subjects free of 
respiratory failure, defined as an 8-
point ordinal scale score ≤5, at Day 
15. 
• Proportion of subjects discharged 
from hospital and free of supplemental 
oxygen at Day 15. 
Secondary 
 

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• Evaluate the safety profile of C21 
versus placebo as add on to SoC in 
subjects with COVID-19. 
• Adverse events (AE)s. 
• Serious AEs (SAE)s. 
• Changes in safety laboratory 
assessments. 
• Withdrawals due to AEs. 
• Characterize the PK profile of C21 in 
subjects with COVID-19. 
• PK parameters. 
• Evaluate the efficacy profile of C21 
versus placebo as add on to SoC in 
subjects with COVID-19. 
• Proportion of subjects discharged 
from hospital and free of supplemental 
oxygen at Days 8, 22 and 29. 
• Proportion of hospitalized subjects on 
non-invasive, invasive mechanical 
ventilation, extra corporeal membrane 
oxygenation (ECMO) or supplemental 
oxygen use at Days 8, 15, 22, 29 and 
60. 
• Proportion of subjects in each 
category of the 8-point ordinal scale at 
Days 8, 15, 22, 29 and 60. 
• Duration of hospitalization, including 
re-hospitalization, up to Day 60. 
• Proportion of subjects needing 
intensive care unit stay at Days 8, 15, 
22, 29 and 60. 
• Duration of intensive care unit stay, 
including re-admission, up to Day 60. 
• Proportion of subjects on invasive 
mechanical ventilation or ECMO at 
Days 8, 15, 22, 29 and 60, and 
duration of use up to Day 60.  
• Proportion of subjects free of 
respiratory failure at Days 8, 22, 29 
and 60, and respiratory failure free 
days up to Day 60. 
• All-cause mortality up to Days 8, 15, 
22 and 29. 
• Change from baseline in peripheral 
capillary oxygen saturation (SpO2) / 

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fraction of inspired oxygen (FiO2) at 
Day 15. 
 
Exploratory 
 
• To explore the effect of C21 versus 
placebo as add on to SoC on 
inflammation. 
• Change from baseline in CRP at Day 
15. 
• To explore the effect of C21 versus 
placebo as add on to SoC on lung 
injury. 
• Change from baseline in lactate 
dehydrogenase (LDH) at Day 15. 
 
Primary Estimand:  
All-cause mortality up to Day 60 defined as the time to day of death from any cause assessed for 
the intention-to-treat population with treatment as randomized, independent of treatment 
withdrawal or major protocol deviations according to the treatment policy, with subjects with no 
confirmed death before or at Day 60 being censored at day of withdrawal/Day 60 follow-up. The 
stratified log-rank test will be used to compare the treatments. The treatment difference will be 
expressed as a hazard ratio with 95% confidence intervals. 
Overall Design: 
This trial is a randomized, double-blind, placebo-controlled, parallel-group, 2-arm, multicenter 
trial to evaluate the efficacy and safety of C21 versus placebo as add on to SoC in adult subjects 
with COVID-19. 
The trial will enroll a total of maximum 300 subjects, 150 per arm (oral C21 100 mg twice a day 
(b.i.d.) or placebo for 14 days) according to the 1:1 randomization. 
Randomization will be stratified by: 
• Disease severity (8-point ordinal scale score at Day 1, score 5 or 6). 
• Region (North America, South and Central America, Europe, Africa, or Asia). 
Approximately 350 subjects will be screened to achieve maximum 300 enrolled and randomly 
assigned subjects to investigational medicinal product (IMP) treatment. 
An independent data monitoring committee (DMC) will review unblinded safety data from the 
trial after data collection for at least 15 days on the first 150 randomized subjects. In addition, the 
DMC members may call for an ad hoc safety review meeting at any time during the trial. 
The trial consists of 3 consecutive periods: a screening period of up to 48 hours, a 2-week IMP 
treatment period and a follow-up period of up to 7 weeks after last IMP intake. Daily visits are 
required until discharge. Discharged subjects will return to the clinic for the Day 15 visit. Days 
8, 22, 29 and 60 visits will be conducted as phone or video visits for discharged subjects. 
All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety 
laboratory tests and samples for future exploratory analysis will be obtained at the screening 

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visit, Day 1 (prior to treatment) and Days 3, 5, 8, 11 and 15. Laboratory samples will not be 
collected at Days 3, 5, 8 and 11 if the subject is discharged from the hospital prior to the visit. 
The trial duration for an individual subject will not exceed 9 weeks. End of trial is defined as last 
subject’s last follow-up visit. 
The primary endpoint in the trial is all-cause mortality up to Day 60. 
The key secondary endpoints are time to sustained hospital discharge up to Day 60, supplemental 
oxygen free days up to Day 29, the proportion of subjects free of respiratory failure and 
proportion of subjects discharged from hospital and free of supplemental oxygen at Day 15. 
Type 1 errors will be controlled using a fixed sequential testing hierarchy. 
1.2. 
Schema 

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1.3. 
Schedule of Activities (SoA) 
 
Screening 
IMP Treatment Period 
 
In-patient  
Stay1)  
Follow-up Period2) 
Unsche-
duled3) 
Visit 
V1 
V2 
V3-151) 4) 
V164) EWD5) 
V17-29 
V30 
V31 
V32 
UV 
Day (Visit window) 
Up to 48h 
prior to V2 Day 1 
Days  
2-14 
Day 15 
(+1 day) 
 
Days  
16-28  
Day 22 
(±1 days) 
Day 29 
(±1 days) 
Day 60 
(±3 days) 
 
Eligibility/General 
Informed consent  
X 
 
  
 
 
 
Eligibility criteria  
X 
x6) 
 
 
 
 
Demographics  
X 
  
 
 
 
 
Medical history  
X 
  
  
 
 
 
 
IMP and Concomitant Therapy 
Randomization  
  
x 
  
  
 
  
  
 
 
 
IMP administration7)  
  
x 
x 
 
 
  
  
 
 
(x) 
Check of fasting criteria  
  
x 
x 
 
 
  
  
 
 
(x) 
IMP accountability  
  
  
x8) 
x 
x 
  
  
 
 
 
Previous and 
concomitant therapy  
X 
x 
x 
x 
x 
x 
x 
x 
 
(x) 
Trial Assessments and Procedures  
8-point ordinal scale  
X 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
Supplemental O2 
X 
x 
x 
x 
x 
x 
x 
x 
 
(x) 
Oxygen saturation  
X 
x 
x 
x 
x 
x 
 
 
 
(x) 
Hospitalization 
X 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
Physical examination 
X 
 
 
x 
x 
 
  
 
 
(x) 
Body weight and height 
X 
  
  
  
 
  
  
 
 
 
Vital signs  
X 
x 
x 
x 
x 
x 
  
 
 
(x) 
12-lead ECG9)  
X 
  
 
  
 
  
  
 
 
(x) 
Adverse events  
X 
x 
x 
x 
x 
x 
x 
x 
x10) 
x 
Biochemistry11) 
X 
x12) 
Days 3, 5, 8, 11 
(all ± 1 day) 
x 
x 
 
  
 
 
(x) 
Haematology11) 
X 
x12) 
Days 3, 5, 8, 11 
(all ± 1 day) 
x 
x 
 
  
 
 
(x) 
Urinanalysis11) 
X 
x12) 
 
x 
x 
 
  
 
 
(x) 
Pregnancy testing 13) 
X 
  
  
x 
x 
  
  
 
 
(x) 
Oropharyngeal swab 
 
x 
 
 
 
 
 
 
 
 
Pharmacokinetics14) 
 
x 
 
 
 
 
 
 
 
 
Blood sample for future 
exploratory analysis 
  
x12) 
  
x 
x 
  
  
 
 
 
 
1. 
Daily visits until discharge. Visits will be re-initiated in case of a COVID-19 related hospital re-admission. 
2. 
Follow-up visits by phone or video. 
3. 
Assessments marked with () will be performed per investigator judgment at e.g., COVID-19 related hospital re-admission after Day 
29. 
4. 
Days 8 and 15 visits must be performed for all subjects. If a subject is discharged before Day 8, the Day 8 visit will be done by phone 
or video. Site assessments e.g., oxygen saturation, vital signs and blood sampling will not be performed. 
5. 
An early withdrawal (EWD) visit should be performed for subjects withdrawn from the trial prior to Day 15 (Visit 16). 
6. 
Re-evaluation of eligibility including evaluation of electrocardiogram (ECG) and laboratory results from screening. 
7. 
IMP is administered b.i.d. from Days 1 to 14. 
8. 
IMP accountability will be performed at hospital discharge. 
9. 
A historical 12-lead ECG is acceptable. The ECG should be ≤2 days old at the time of screening (Visit 1). 
10. SAEs only.   
11. Blood samples taken at screening will be analyzed locally. Samples taken at Days 1 to 15, or at the EWD visit will be analyzed at a 
central laboratory (if needed due to special circumstances e.g. delays in turn-around time due to COVID-19, blood samples may be 
analyzed locally after sponsor approval). Days 3, 5, 8 and 11 samples will only be collected if the subject is hospitalized. 
12. Blood sampling and urinalysis must be performed prior to IMP dosing. 
13. Applicable in women of childbearing potential. If positive, the urine dipstick will be followed up by a blood test. 
14. Pharmacokinetic (PK) samples will be collected in a subgroup of approximately 10 subjects.  

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2. 
Introduction 
C21 is a first-in-class, low molecular weight, orally available, potent, and selective angiotensin II 
type 2 receptor (AT2R) agonist being developed for treatment of COVID-19 and fibrotic lung 
diseases such as idiopathic pulmonary fibrosis. 
2.1. 
Trial Rationale 
Although several therapeutic agents have been evaluated for the treatment of COVID-19, the 
morbidity and mortality are still significant, and the need for safe, effective, and convenient 
COVID-19 drugs is likely to remain even after the launch of vaccine programs. 
The recently completed phase 2 trial in hospitalized patients with COVID-19 (VP-C21-006) 
showed that C21 on top of standard of care significantly reduced the need for extended oxygen 
supplementation and had a favorable benefit/risk profile. The rationale for conducting this phase 
3 trial is to confirm the efficacy and safety of C21 in a larger group of COVID-19 patients. 
2.2. 
Background 
COVID-19  
In January 2020, SARS-CoV-2 was identified as the causative agent of an outbreak of the new 
viral pneumonia disease, COVID-19, with the first cases reported in December 2019 (Lu et al., 
2020; Wu et al., 2020; Zhou et al., 2020). The disease expanded rapidly, and by March 12, 2020, 
COVID-19 was classified as a pandemic by the World Health Organization (WHO). As of 
January 31, 2021, the WHO has reported more that 100 million confirmed cases of COVID-19 
and 2.2 million deaths globally (WHO, 2020a). 
While most COVID-19 cases result in only mild disease, a substantial proportion of patients 
develop severe respiratory illness resulting in impaired gas exchange, hypoxia, need of 
supplementary oxygen and, in the most severe cases, mechanical ventilation (Chen et al., 2020; 
Ruan et al., 2020; Zhou et al., 2020). 
Remdesivir and dexamethasone, have shown some impact on disease remission in large 
controlled trials in hospitalized COVID-19 patients and are now part of current standard of care 
(Beigel et al., 2020; Group et al., 2020) in many countries. Despite the benefits of these drugs, 
the morbidity and mortality in COVID-19 are still significant, particularly in moderately severe 
disease where it could be argued that no therapies have shown a consistent meaningful benefit. 
The need for safe, effective, and convenient COVID-19 drugs is likely to remain even after the 
launch of vaccine programs. 
IMP treatment C21  
C21 is a first-in-class, low molecular weight, orally available potent and selective AT2R agonist 
being developed for oral treatment of COVID-19 and fibrotic lung diseases such as idiopathic 
pulmonary fibrosis. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of C21 is provided in 
the Investigator’s Brochure (IB). 

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C21 has been evaluated in 3 completed phase 1 trials (C21-001-16, C21-002-16 and C21-003) 
and in 1 recently completed phase 2 trial in subjects with COVID-19 (VP-C21-006). In total, 134 
subjects have been exposed to at least 1 dose of C21. Overall, C21 was well tolerated at doses up 
to 100 mg b.i.d. administered for up to 8 days. 
The SARS-CoV-2 virus is known to bind to and enter target cells through angiotensin converting 
enzyme (ACE) 2, an integral component of the renin-angiotensin system (RAS) (Zhang et al., 
2020). Within the RAS, the Angiotensin II type 1 receptor (AT1R) normally mediates the 
classical actions of Angiotensin II, including constriction of blood vessels, sodium retention and 
cell growth, while abnormal AT1R activation contributes to the pathogenesis of certain 
cardiovascular, renal and pulmonary diseases (de Man et al., 2012; Savoia & Schiffrin, 2006; 
Sumners et al., 2019). Conversely, activation of the AT2R causes dilatation of blood vessels and 
inhibition of inflammation and fibrosis, and is considered to be counter-regulatory to the 
negative effects of AT1R activation (Matavelli et al., 2015; Sumners et al., 2019). 
While the AT2R is only expressed at low levels in most tissues in healthy adults (De Gasparo, 
2002; Steckelings et al., 2005), it is highly expressed in alveolar type 2 progenitor cells in the 
adult human lung and can be upregulated during repair and regeneration (Akishita et al., 1999; 
Protein-Atlas). This, coupled with the belief that the RAS may play a key role in the 
development of COVID-19 led us to the view that C21 may have a role in the treatment of the 
disease by directly activating AT2R downstream of ACE2, thus by-passing any inherent negative 
effects in the infected state. 
The safety and efficacy of C21 in subjects with COVID-19 were investigated in a randomized, 
double-blind, placebo-controlled, phase 2 trial (VP-C21-006). The trial included 106 adult 
subjects hospitalized with COVID-19, having a CRP between 50-150 mg/L and not in need of 
mechanical ventilation. The subjects were randomized to receive oral treatment with C21 (100 
mg b.i.d., n=51) or placebo (n=56) for 7 days on top of standard of care. All subjects were 
followed up for 7 to 10 days after receiving the last investigational medicinal product (IMP) 
dose. 
The treatment groups were well balanced regarding age (mean 52.6 years) and gender (75.5% 
males). Most patients had one or more coexisting medical conditions. Hypertension and 
overweight/obesity were more common in the C21 group compared with the placebo group, but 
there was no difference in the presence of diabetes mellitus. Supplementary oxygen supply at 
baseline was needed in 57.5% of the patients with no major difference between the treatment 
groups. Concomitant medication according to local standard of care was permitted in the trial. A 
vast majority of the patients received glucocorticoids, and most patients received antibacterial 
and antiviral compounds (remdesivir in 67.0%), with no major differences between the treatment 
groups. 
Extended need for oxygen therapy was more frequent in the placebo group than in the C21 
group. At Day 14, only one patient in the C21 group, compared to 11 patients in the placebo 
group, needed supplementary oxygen (p=0.003). This difference was already apparent at the end 
of the 7-day treatment period, when 27.5% of patients in the C21 group and 45.5% in the placebo 
group were in need of supplemental oxygen (p=0.055). The reduced need for extended oxygen 
supplementation indicates that treatment with C21 improves gas exchange at the alveolar level. 
Considering that the alveolar type 2 progenitor cells appear to be the only cells in the lungs that 
express the AT2R (Protein-Atlas) and are suggested to be the primary site for viral replication in 

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the distal airways (Szekely et al., 2020), C21 may restore respiratory function by acting directly 
on these cells. 
There were 4 deaths in the trial, one in the C21 group and 3 in the placebo group. All deaths 
occurred in patients with progressive respiratory insufficiency and need for mechanical 
ventilation. One more patient in the placebo group deteriorated and developed need for 
mechanical ventilation. 
CRP was initially selected as the primary endpoint because CRP has been reported to predict 
severe disease (Tan et al., 2020; Wang, 2020) and mortality (Ruan et al., 2020) in COVID-19. 
However, there was a rapid and profound decrease in CRP in both the C21 and the placebo 
group, most likely because the patients were treated with glucocorticoids which became part of 
standard of care at the time of trial initiation likely leading to no statistical difference in the 
primary endpoint CRP. Nevertheless, in the patients with more pronounced respiratory distress 
with need of supplementary oxygen at baseline, there was a small but significantly greater 
reduction of CRP in the C21 than in the placebo group. 
There were 64 treatment-emergent AEs reported by 60.8% of the patients in the C21 group and 
90 events reported by 67.3% of the patients in the placebo group. Most events were mild, and no 
event in either group was classified as related to trial treatment by the investigators. The most 
frequent AE was hyperglycemia, which occurred more frequently in the C21 group than in the 
placebo group. The level of hyperglycemia was predominantly mild and not reported as related 
to C21 by investigators. 
Taken together, C21 on top of standard of care, including glucocorticoids and remdesivir, 
significantly improved respiratory function reflected by a reduced need for supplemental oxygen 
in hospitalized COVID-19 patients. 
2.3. 
Benefit/Risk Assessment 
COVID-19 can be a fatal disease, and the respiratory system is usually the worst affected bodily 
system. In general, hypoxemia is an accepted indication for intubation in COVID-19 patients 
(Voshaar et al., 2021). The results of the phase 2 trial in patients with COVID-19 (VP-C21-006) 
suggest a clinically relevant beneficial effect on the need for oxygen supplementation at a dose 
of 100 mg b.i.d. Overall, the safety profile of C21, as available from pre-clinical and phase 1 and 
2 clinical trial data, is interpreted as favorable for the treatment of COVID-19. 
More detailed information about the known and expected benefits and risks, and reasonably 
expected AEs of C21 may be found in the IB. 
 
 
 
 

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2.3.1. 
Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale 
for Risk  
Mitigation Strategy 
IMP - C21 
Alopecia 
 
Reversible alopecia was 
observed in subjects who 
received 200 mg b.i.d. for 8 
days in a phase 1 trial, C21-
003. Alopecia was not 
observed in the VP-C21-006 
trial (51 subject treated with 
100 mg b.i.d. for 7 days). 
Further information can be 
found in the IB. 
No mitigation strategy 
implemented due to the severity 
of the COVID-19 disease in the 
trial population and the low risk 
of developing alopecia at the 
selected dose and treatment 
duration (100 mg b.i.d. for 14 
days). 
Drug-drug interactions 
C21 is metabolized primarily 
by CYP3A4. 
 
Exclusion of subjects treated with 
strong CYP3A4 inducers and/or 
with Warfarin. 
In vitro data show that a 
clinically relevant interaction 
with CYP enzymes (e.g., 
CYP2C9, CYP3A4 and 
CYP1A2) and efflux 
transporters (multi-drug 
resistance gene (MDR1) and 
breast cancer resistance protein 
(BCRP)) cannot be excluded. 
The medical monitor and the 
DMC will monitor the extent of 
co-administration with CYP1A2, 
CYP3A4 and CYP2C9 substrates 
with a narrow therapeutic index 
and will inform the investigator if 
sub-optimal combinations occur. 
Exclusion of subjects treated with 
P-gp substrates with narrow 
therapeutic index, high dose 
BCRP sensitive substrates, and 
sulphasalazine or rosuvastatin. 
Drug-food interactions 
Exposure of C21 was 
substantially decreased under 
fed conditions as compared to 
fasted conditions indicating an 
interaction with food (VP-C21-
003). 
IMP will be administered in 
fasting conditions (see Section 
5.3). 
Correct administration of IMP in 
relation to food intake will be 
monitored during the trial. 

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2.3.2. 
Benefit Assessment 
Up to 20% of symptomatic individuals with COVID-19 will develop severe disease including 
acute respiratory distress syndrome and death. There is no cure, and interventions administered 
early in the course of the illness could prevent disease progression. Hypoxemia has been 
independently associated with in-hospital mortality, and medicines that improve respiratory 
insufficiency coupled with an effective vaccine, would have significant implications for the 
ability to end this pandemic (Xie et al., 2020). 
Subjects randomized to active treatment in this trial may recover earlier or have a reduced risk of 
developing severe complications related to the COVID-19 disease. The option for out-patient 
treatment (following hospitalization) could reduce the strain on vital costly hospital resources. 
All subjects will receive regular medical evaluations associated with their participation in the 
trial and will contribute to the development of new therapies in a disease area with a high unmet 
need. 
2.3.3. 
Overall Benefit Risk Conclusion 
Considering the measures taken to minimize risk to subjects participating in this trial, the 
potential risks identified in association with C21 are justified by the anticipated benefits that may 
be afforded to subjects with COVID-19. 
 

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3. 
Objectives, Endpoints, and Estimands 
 
 
Objectives 
Endpoints 
Primary 
 
• Evaluate the efficacy of C21 versus 
placebo as add on to SoC on recovery 
in subjects with COVID-19. 
• All-cause mortality up to Day 60 
Key secondary  
 
 
• Time to sustained hospital discharge 
up to Day 60. 
• Supplemental oxygen free days up to 
Day 29. 
• Proportion of subjects free of 
respiratory failure, defined as an 8-
point ordinal scale score ≤5, at Day 
15. 
• Proportion of subjects discharged 
from hospital and free of supplemental 
oxygen at Day 15. 
Secondary 
 
• Evaluate the safety profile of C21 
versus placebo as add on to SoC in 
subjects with COVID-19. 
• AEs. 
• SAEs. 
• Changes in safety laboratory 
assessments. 
• Withdrawals due to AEs. 
• Characterize the PK profile of C21 in 
subjects with COVID-19. 
• PK parameters. 
• Evaluate the efficacy profile of C21 
versus placebo as add on to SoC in 
subjects with COVID-19. 
• Proportion of subjects discharged 
from hospital and free of supplemental 
oxygen at Days 8, 22 and 29. 
• Proportion of hospitalized subjects on 
non-invasive, invasive mechanical 
ventilation, ECMO or supplemental 
oxygen use at Days 8, 15, 22, 29 and 
60. 

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• Proportion of subjects in each 
category of the 8-point ordinal scale at 
Days 8, 15, 22, 29 and 60. 
• Duration of hospitalization, including 
re-hospitalization, up to Day 60. 
• Proportion of subjects needing 
intensive care unit stay at Days 8, 15, 
22, 29 and 60. 
• Duration of intensive care unit stay, 
including re-admission, up to Day 60. 
• Proportion of subjects on invasive 
mechanical ventilation or ECMO at 
Days 8, 15, 22, 29 and 60, and 
duration of use up to Day 60.  
• Proportion of subjects free of 
respiratory failure at Days 8, 22, 29 
and 60, and respiratory failure free 
days up to Day 60. 
• All-cause mortality up to Days 8, 15, 
22 and 29. 
• Change from baseline in SpO2/FiO2 at 
Day 15. 
Exploratory 
 
• To explore the effect of C21 versus 
placebo as add on to SoC on 
inflammation. 
• Change from baseline in CRP at Day 
15. 
• To explore the effect of C21 versus 
placebo as add on to SoC on lung 
injury. 
• Change from baseline in lactate 
dehydrogenase (LDH) at Day 15. 
Primary estimand 
All-cause mortality up to Day 60 defined as the time to day of death from any cause assessed for 
the intention-to-treat population with treatment as randomized, independent of treatment 
withdrawal or major protocol deviations according to the treatment policy, with subjects with no 
confirmed death before or at Day 60 being censored at day of withdrawal/Day 60 follow-up. The 
stratified log-rank test will be used to compare the treatments. The treatment difference will be 
expressed as a hazard ratio with 95% confidence intervals. 
. 
 

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Key Secondary estimands 
Time to sustained hospital discharge up to Day 60; The first occurrence of a score ≤ 2 whereafter 
the score stays ≤2 for the remainder of the 60 days trial period, assessed for the intention-to-treat 
population with treatment as randomized, independent of treatment withdrawal or major protocol 
deviations according to the treatment policy, with subjects who die prior to Day 60 being 
censored at Day 60 and subjects withdrawing due to other causes than death and not fulfilling the 
event being censored at the withdrawal day. The Kaplan-Meier difference in median time to 
sustained hospital discharge with 95% confidence intervals will be estimated. 
Supplemental oxygen free days up to Day 29; For each subject the number of days between Day 
1 and Day 29 with a score of ≤4 on the 8-point ordinal scale and with no documented use of 
COVID-19 related supplemental oxygen, assessed for the intention-to-treat population with 
treatment as randomized, independent of treatment withdrawal or major protocol deviations 
according to the treatment policy, with subjects who die prior to Day 29 being given the value –1 
day and trial withdrawals prior to Day 29 due to other causes than death and not possible to 
follow-up being imputed using multiple imputation including assessments from day 1 to day 29. 
The Hodge-Lehmann median estimated of the difference in days between treatments with 95% 
confidence intervals will be estimated. 
Proportion of subjects free of respiratory failure at Day 15; The proportion of subjects with a 
score of ≤5 on the 8-point ordinal scale at Day 15, assessed for the intention-to-treat population 
with treatment as randomized, independent of treatment withdrawal or major protocol deviations 
according to the treatment policy, with subjects who die prior to Day 15 considered as 
respiratory failure and trial withdrawals prior to Day 15 due to other causes than death and not 
possible to follow-up being imputed using multiple imputation including their baseline 
characteristics and last known status. The difference in proportions between treatments with 95% 
confidence intervals will be estimated. 
Proportion of subjects discharged from hospital and free of supplemental oxygen at Day 15; The 
proportion of subjects with a score of ≤2 on the 8-point ordinal scale and free of COVID-19 
related supplemental oxygen use at Day 15, assessed for the intention-to-treat population with 
treatment as randomized, independent of treatment withdrawal or major protocol deviations 
according to the treatment policy, with subjects who die prior to Day 15 considered not 
discharged and trial withdrawals prior to Day 15 due to other causes than death and not possible 
to follow-up being imputed using multiple imputation including baseline characteristics and their 
last known status. The difference in proportions between treatments with 95% confidence 
intervals will be estimated. 
. 

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4. 
Trial Design 
4.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, parallel-group, 2-arm, multicenter trial. 
• Subjects hospitalized due to ongoing COVID-19 will be enrolled. 
• The trial consists of 3 consecutive periods: a screening period of up to 48 hours, a 2-week 
IMP treatment period and a follow-up period of up to 7 weeks. Daily visits are required 
until discharge. Discharged subjects should return to the clinic for the Day 15 visit. Days 
8, 22, 29 and 60 visits will be conducted as phone or video visits for all discharged 
subjects. 
• The trial duration for an individual subject will not exceed 9 weeks. 
• The trial will enroll a total of maximum 300 randomized subjects, 150 per arm (C21 100 
mg b.i.d. or placebo for 14 days) according to a 1:1 randomization. 
• Blinding will be performed with a matching placebo. 
• Randomization occurs at visit 2 and will be stratified by: 
o Disease severity (based on the ordinal scale score at Day 1). 
o Region. 
• An independent DMC will actively monitor data from the trial.  
4.2. 
Scientific Rationale for Trial Design 
The proposed clinical trial design is based on the guidance provided in the WHO COVID-19 
therapeutic trial synopsis (WHO, 2020b), the FDA Guidance for Industry to support clinical 
development of drugs for the treatment and prevention of COVID-19 (FDA, 2020a), investigator 
and authority guidance. 
The trial will enroll hospitalized subjects with a confirmed SARS-CoV-2 infection and on 
supplemental oxygen but not requiring mechanical invasive ventilation. There is a high unmet 
need for an efficacious treatment of COVID-19 in this population to halt respiratory failure and 
ultimately reduce mortality. 
The primary endpoint is all-cause mortality up to Day 60. This endpoint is considered clinically 
relevant in the population studied and the timepoint of evaluation will ensure capturing the 
majority of events to assess a treatment response.  
The primary endpoint is supported by data from the completed Phase 2 trial (VP-C21-006), in 
which C21 was associated with a numerical reduction in the mortality rate (one and three deaths 
in the C21 and placebo group, respectively). All deaths occurred in patients with progressive 
respiratory insufficiency and need for mechanical ventilation. One more patient in the placebo 
group deteriorated and developed need for mechanical ventilation.  
The 8-point ordinal scale together with an assessment of supplemental oxygen use will be used 
for assessment of the key secondary endpoints. The ordinal scale is considered responsive to the 
selected COVID-19 population with respect to the treatment and course of the illness and such 

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scales have been used in the majority of phase 2 and 3 COVID-19 trials to date (Dodd et al., 
2020). The 8-point ordinal scale is a composite measure of clinical improvement and/or survival 
assessed up to 60 days post randomization.  
It has been demonstrated that there is a strong association between days on oxygen during the 
acute phase of COVID-19 and long-term recovery (Shah et al., 2021). In the Phase 2 trial, 
patients on C21 had a significantly lower use of supplementary oxygen therapy at end of 
treatment, only 1 out of 51 subjects in the C21 group was using supplemental oxygen at Day 14.  
The WHO COVID-19 therapeutic trial synopsis recommends that subjects will be treated with 
IMP on top of SoC in (WHO, 2020b). Guidance on SoC is provided in Appendix 4 (see Section 
10.4). 
The placebo group and the blinding in the trial was implemented to minimize bias. The 
randomization will be stratified to ensure an equal distribution of active and placebo subjects by 
region and disease severity. 
4.3. 
Justification for Dose 
Subjects will be treated with oral 100 mg C21 or placebo b.i.d. for 14 days. 
The results of the completed phase 2 trial in COVID-19 subjects (VP-C21-006) and of the phase 
1 trial in healthy subjects (VP-C21-003) indicate an acceptable safety and tolerability profile for 
the 100 mg b.i.d. dose. The risks of C21 in adults are considered primarily related to reversible 
alopecia seen at the higher dose of 200 mg b.i.d. In the phase 2 trial in COVID-19 subjects (VP-
C21-006) and the phase 1 trial (VP-C21-003), the 100 mg b.i.d. dose did not cause any hair loss 
(Further details can be found in the IB).  Alopecia is therefore not considered to present any 
significant safety risk to subjects in this trial. 
In the phase 1 trial (VP-C21-003), 100 mg b.i.d. dosing prolonged the duration of the plasma 
concentration at therapeutic relevant levels. After oral administration, C21 was rapidly absorbed. 
On Day 8, median tmax was 0.33 hours after each dose post-dose, and C21 was measurable in 
plasma until 4-6 hours after the first and second dose. Lower doses than 100 mg b.i.d. may not 
provide maximal efficacy benefit. 
In the completed phase 2 trial (VP-C21-006) in COVID-19 subjects, treatment with 100 mg b.i.d. 
for 7 days, reduced the need for extended oxygen supplementation. 
The recently completed phase 2 trial (VP-C21-006) indicates that C21 can prevent hypoxic 
critical illness and based on the course of the disease, there is a strong rational to extend the 
treatment duration from 7 to 14 days. Furthermore, 27% of subjects within the C21 arm were still 
in need of oxygen (vs 45% on placebo) at the end of the 7 days treatment, highlighting an 
opportunity to treat for a longer period to gain additional benefit, with the aim of returning 
patients to normoxia. 
There is not enough evidence to treat beyond 14 days at this stage.  
Based on the above, C21 will be administered at an oral dose of 100 mg b.i.d. for 14 days in the 
present trial. 
 
 

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4.4. 
End of Trial Definition 
End of trial is defined as the date of the last visit of the last subject in the trial. 
A subject is considered to have completed the trial if he/she has completed all periods of the trial 
including the Day 60 visit. 
 

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5. 
Trial Population 
The trial will enroll adult subjects hospitalized due to SARS-CoV-2 infection. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Subjects are eligible to be included in the trial only if the following criteria are fulfilled: 
Age 
1. Age ≥18 years or the legal age of consent in the jurisdiction in which the trial is taking 
place at the time of signing the informed consent. (Specific for India; Age ≥18 at the time 
of signing the informed consent to ≤65 years.) 
Type of Subject and Disease Characteristics 
2. Hospitalized due to SARS-CoV-2 infection confirmed by a hospital-approved polymerase 
chain reaction (PCR) test, documented by either of the following: 
a. PCR positive in sample collected <72 hours prior to randomization (Visit 2); OR 
b. PCR positive in sample collected ≥72 hours and ≤7 days prior to randomization, 
documented inability to obtain a repeat sample AND progressive disease 
suggestive of ongoing SARS-CoV-2 infection. 
3. A score of 5 or 6 on the 8-point ordinal scale: 
a. Score 5: Hospitalized, requiring supplemental oxygen. 
b. Score 6: Hospitalized, on non-invasive ventilation or high-flow oxygen device. 
Sex and Contraceptive/Barrier Requirements 
4. Contraceptive use by men and women of childbearing potential consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies and according to Appendix 3 (see Section 10.3). 
Informed Consent 
5. Written informed consent, consistent with International Council for Harmonization (ICH 
Good Clinical Practice (GCP) R2 and local laws, obtained before the initiation of any trial-
related procedure. 
6. Capable of giving signed informed consent as described in Appendix 1 (see Section 10.1.3) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
Country specific  
7. Specific for India: For subjects with an ordinal scale score of 5, moderate to severe 
COVID-19 disease confirmed by at an SpO2 ≤ 93 % or a respiratory rate ≥ 24/min on room 
air. Note: If a subject is on supplemental oxygen with SpO2 >93% and respiratory rate 
<24/min, but desaturation to ≤ 93 % or increase of respiratory rate to ≥ 24/min on lower 
supplemental oxygen or room air is documented during screening, the inclusion criterion is 
considered to be met. 

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5.2. 
Exclusion Criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
Medical Conditions 
1. Concurrent serious medical condition which in the opinion of the investigator constitutes a 
risk or a contraindication for the participation in the trial or that could interfere with the 
trial objectives, conduct or evaluation. 
2. Known, active tuberculosis, active hepatitis B, C, or human immunodeficiency virus (HIV) 
infection (i.e., HIV with a CD4 count <500 cells/mm³). 
3. Moderate or severe impairment of hepatic function (e.g., Child-Pugh class B or C where 
alterations in the score components are not due to another underlying disease (see Section 
8.4.5)). 
4. Severe renal impairment (i.e., estimated glomerular filtration rate (eGFR) ≤30 
ml/min/1.73 m2). 
5. COVID-19 symptom onset >21 days prior to screening (Visit 1). 
6. Hospitalized due to COVID-19 for >72 hours at screening (Visit 1). 
7. Invasive mechanical ventilation or ECMO within 72 hours of screening (Visit 1). 
8. Expected need for invasive mechanical ventilation or ECMO in <48 hours in the opinion 
of the investigator. 
9. Moderate to severe ARDS (e.g., same-day PaO2/FiO2 ≤200 mmHg; or SpO2/FiO2 ≤232 if 
arterial blood gas test is not available), if on non-invasive mechanical ventilation or high-
flow oxygen. 
10. Pregnant or breast-feeding female subjects.  
Prior/Concomitant Therapy 
11. Any previous and concurrent experimental treatment for COVID-19 that is not considered 
local SoC. 
12. Treatment with the medications listed below within 1 week prior to screening (Visit 1) or 
anticipated need for such medication during the participation in this trial: 
a. Strong Cytochrome P450 (CYP) 3A4 inducers. 
b. P-glycoprotein (P-gp) substrates with narrow therapeutic index.  
c. High dose BCRP sensitive substrates. 
d. Warfarin. 
e. Sulphasalazine or rosuvastatin. 
Prior/Concurrent Clinical Trial Experience 
13. Current or previous participation in any other clinical trial where the subject has received 
a dose of IMP within 1 month or 5 half-lives of the IMP, whichever is longest, prior to 
screening (Visit 1). 
Diagnostic Assessments 
14. Positive pregnancy test (see Section 0). 
15. Abnormal laboratory value at screening (Visit 1) indicating a potential risk for the subject 
if enrolled in the trial as evaluated by the investigator. 
 
 

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5.3. 
Lifestyle Considerations 
In relation to IMP administration, subjects should adhere to meals and dietary restrictions 
regarding food intake:  
• No food intake for 2 hours prior to taking the IMP. 
• No food intake for 1 hour after taking the IMP. 
5.4. 
Screen Failures 
A screen failure occurs when a subject who consents to participate in the clinical trial is not 
subsequently randomly assigned to IMP. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. Individuals who do not meet the criteria for participation in this trial (screen failure) must 
not be rescreened. 

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6. 
Investigational Medicinal Product and Concomitant Therapy 
The IMP is the active (C21) or placebo treatment intended to be administered to a trial subject 
according to the trial protocol. 
6.1. 
Investigational Medicinal Product Administered 
Each subject will be randomized to receive treatment with the IMP (C21 or placebo). The IMP 
will be administered as a capsule for oral administration. Each subject will receive 4 capsules per 
day, divided in 2 doses given twice a day. 
IMP will be administered in fasting conditions (see Section 5.3). C21 is an AT2R agonist. The 
drug substance is 3-[4-(1H-imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophene-2-[(N-
butyloxylcarbamate)-sulphonamide] sodium salt supplied as a free form equivalent (eq.) 50 mg 
C21 oral capsule. 
Table 1. Investigational Medicinal Product Administered 
IMP Name 
Active / C21 
Placebo 
Dose Formulation 
Capsule 
Capsule 
Unit Dose Strength(s) 
52.3 mg pr capsule 
Placebo 
Dosage Level(s) 
2 capsules, b.i.d. 
2 capsules, b.i.d. 
Excipients 
Mannitol, Anhydrous colloidal 
silica, Magnesium stearate 
Mannitol, Anhydrous colloidal 
silica, Magnesium stearate 
Capsule  
Vcaps® plus 
Vcaps® plus 
Route of 
Administration 
Oral 
Oral 
Dosage description  
Subjects will receive 100 mg C21 
b.i.d. on Day 1 to Day 14. 
Subjects will receive Placebo b.i.d. 
on Day 1 to Day 14. 
Sourcing 
Provided centrally by the sponsor  
Provided centrally by the sponsor  
Packaging and 
Labeling 
IMP will be provided in a 
container. Each container will be 
labeled as required per country 
requirement. 
IMP will be provided in a 
container. Each container will be 
labeled as required per country 
requirement. 
6.2. 
Preparation, Handling, Storage, and Accountability 
• The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IMP received, and any discrepancies are reported and 
resolved before use of the IMP. 
• Only subjects enrolled in the trial may receive IMP, and only authorized site staff may 
supply or administer IMP during hospitalization. Prior to dispensing, all IMP must be 
stored at 15 to 25 °C (59-77°F) in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff. 

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• If a subject is discharged from the hospital prior to Day 15, IMP accountability will be 
performed, and the subject will be instructed to self-administer the remaining IMP at 
home. The subject must be instructed to store IMP at room temperature (15-25°C, 59-
77°F). The IMP should be kept in the plastic container until intake, out of reach from 
children. 
• In subjects where oral intake becomes a significant challenge e.g., during invasive 
mechanical ventilation or ECMO treatment, IMP will be administered as a dispersion, 
either orally or via a nasogastric or nasoenteral feeding tube. It may also include 
situations in which nasogastric or nasoenteral tube feeding may become required, such as 
non-invasive mechanical ventilation, high flow oxygen therapy and gastric/oesophagal 
discomfort. Route of administration will be collected in the eCRF.  
• The subject should return all used and unused IMP at Visit 16 (Day 15) or at the EWD 
visit for subject withdrawing prior to Visit 16. 
• The investigator and the pharmacy (if applicable) are responsible for IMP accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition 
records). 
Further guidance and information on preparation, handling, storage, and accountability are 
provided in the IMP handling manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a double-blind trial in which subjects, care providers, investigators, outcomes assessors, 
sponsor and CRO/vendor staff are blinded to IMP allocation i.e., intervention assignment. The 
interactive web response system will be programmed with blind-breaking instructions.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subjects’ intervention assignment is warranted. Subject safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to unblinding a 
subject’s intervention assignment unless this could delay emergency treatment for the subject. If 
a subject’s intervention assignment is unblinded, the sponsor must be notified within 24 hours of 
this occurrence. The date and reason for the unblinding must be recorded. 
Sponsor pharmacovigilance staff or the pharmacovigilance vendor appointed by the sponsor may 
unblind the intervention assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s intervention assignment, may be sent to investigators in accordance with 
local regulations and/or sponsor policy. A blinding plan will describe any unblinded sponsor, or 
CRO/vendor staff during the conduct of the trial.  
6.4. 
Investigational Medicinal Product Compliance 
When subjects are randomized at the site, they will receive the IMP doses directly from the 
investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents. The IMP container number and trial 

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subject identification will be confirmed at the time of dosing by a member of the trial site staff 
other than the person dispensing the IMP. 
During the hospitalization, the investigator or designee should investigate and document if the 
fasting criteria for the IMP (see Section 5.3) has been fulfilled. 
If a subject is discharged from the hospital prior to Day 15 and self-administer the remaining 
IMP at home, IMP compliance and compliance with fasting criteria will be assessed at Visit 16 
(Day 15) and documented in the source documents and the eCRF relevant form. Deviation(s) 
from the prescribed dosage regimen and fasting criteria should be recorded. 
A record of the quantity of IMP dispensed to and administered by each subject must be 
maintained and reconciled with IMP and compliance records. Intervention start and stop dates, 
including dates for intervention delays and/or dose reductions will also be recorded. 
6.5. 
Dose Modification 
Dose modifications during the 14-day IMP treatment period are not allowed. 
6.6. 
Continued Access to the Investigational Medicinal Product after End 
of Trial 
There will not be continued access to the IMP after end of treatment (Day 15). 
6.7. 
Treatment of Overdose 
In this trial, any dose of C21 exceeding a total daily dose of 200 mg (i.e., 4 capsules of IMP) is 
considered an overdose. 
Sponsor does not recommend any specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
• Evaluate the subject to determine, in consultation with the medical monitor, whether IMP 
treatment should be interrupted. 
• Closely monitor the subject for any AE/SAE and laboratory abnormalities. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
Overdoses should be reported as an AE. 
6.8. 
Prior and Concomitant Therapy 
Concomitant therapy is defined as any medication or vaccine (including over-the-counter, 
prescription medicines, recreational drugs, vitamins, and/or herbal supplements) or other specific 
categories of interest that the subject is receiving at the time of enrollment or receives during the 
trial. 
SoC for COVID-19 as described in Appendix 4 should be applied during the trial. 
All concomitant therapy and prior therapy taken up to 4 weeks prior screening (Visit 1) should 
be recorded. The investigator must obtain information on medications and therapies for the 
COVID-19 related infections for each subject. 

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Other relevant prior therapy as judged by the investigator will be collected and recorded. 
Concomitant therapy and prior therapy must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
COVID-19 vaccination is allowed prior to screening (Visit 1) and after the end of the IMP 
treatment period (Day 15). Vaccination for COVID-19 during the IMP treatment period is 
prohibited. COVID-19 vaccinations should be recorded in the eCRF. Treatment with the 
following prohibited medication is not allowed from 1 week prior to screening (Visit 1) and until 
Day 15 (Visit 16): 
a. Strong Cytochrome P450 (CYP) 3A4 inducers 
b. P-glycoprotein (P-gp) substrates with narrow therapeutic index  
c. High dose BCRP sensitive substrates 
d. Warfarin 
e. Sulphasalazine or rosuvastatin 
Strong Cytochrome P450 (CYP) 3A4 inducers, P-glycoprotein (P-gp) substrates with narrow 
therapeutic index and high dose BCRP sensitive substrates considered prohibited medication 
include drugs listed in the FDA tables of substrates, inhibitors and inducers for drug 
development and drug interactions (FDA, 2020b). 
 
 
 

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7. 
Discontinuation of Investigational Medicinal Product and Subject 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the trial are detailed in Appendix 1 (see Section 10.1). 
7.1. 
Discontinuation of Investigational Medicinal Product 
A subject should be withdrawn from the IMP treatment if it in the opinion of the investigator is 
medically necessary or if it is the wish of the subject. 
If IMP treatment is discontinued, the date of last IMP administration and the date and reason for 
treatment withdrawal should be reported in the eCRF. If a subject is removed from treatment 
because of an AE, the reason for treatment withdrawal should always be stated as ‘adverse event’ 
irrespective of whether this was the investigator’s or the subject’s decision. 
If IMP treatment is discontinued, the investigator should make all efforts to ensure that the 
subject will remain in the trial and ensure that the subject attends the remaining visits in the trial. 
IMP treatment should be discontinued in case of drug induced liver injury according to criteria 
specified in FDA guidance (FDA, 2009), moderate or severe impairment of hepatic function 
(e.g., Child-Pugh class B or C where alterations in the score components are not due to another 
underlying disease (see Section 8.4.5)), or severe renal impairment (i.e., estimated glomerular 
filtration rate (eGFR) ≤30 ml/min/1.73 m2). 
7.1.1. 
Temporary Discontinuation 
There are no specific criteria for temporary discontinuation of IMP treatment. If temporary 
discontinuation of IMP is required according to investigator’s judgement, the date and reason for 
a temporary discontinuation should be reported in the eCRF. If the subject is still within the 
treatment period of the trial when a temporary discontinuation is no longer required, IMP 
treatment can be restarted. 
7.2. 
Subject Discontinuation/Withdrawal from the Trial 
• A subject may withdraw from the trial at any time at his/her own request i.e., withdrawal 
of consent.  
• At the time of discontinuing from the trial, if possible, an EWD visit should be 
conducted, as described in the SoA. 
• The subject will be permanently discontinued from the IMP at the time of withdrawal 
from the trial. 
• If the subject withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a subject withdraws from the trial, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site trial records. 
 
 

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7.3. 
Lost to Follow up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site. 
The following actions must be taken if a subject fails to return to the clinic for a required trial 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether the subject wishes to and/or should continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls, and if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the trial. 

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8. 
Trial Assessments and Procedures 
• Trial procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor or designee immediately 
upon occurrence or awareness to determine if the subject should continue or discontinue 
IMP. 
• Adherence to the trial design requirements, including those specified in the SoA, is 
essential and required for trial conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management (e.g., PCR 
tests for SARS-CoV-2 collected less than 3 days prior to Visit 2 (or less than 7 days prior 
to Visit 2 in case of documented inability to obtain a repeat sample and progressive 
disease suggestive of ongoing SARS-CoV-2 infection)) and obtained before signing of 
the ICF may be utilized for screening or baseline purposes provided the procedures met 
the protocol-specified criteria and were performed within the timeframe defined in the 
SoA. 
The maximum amount of blood collected from each subject over the duration of the trial, 
including any extra assessments that may be required, will not exceed 130 mL. 
8.1. 
Screening Assessments 
Planned timepoints for all screening assessments are provided in the SoA. Screening procedures 
may be done over 1 to 2 calendar days.  
8.1.1. 
Demographics 
Demographic and baseline characteristics will be obtained. This following information will be 
collected:  
• Age at screening 
• Race and ethnicity 
• Sex 
• Height 
• Body weight 
 
8.1.2. 
Medical History  
All current medical conditions and relevant previous medical conditions according to 
investigator judgement should be recorded. 
The medical history should include the following information:  

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• Date of onset of COVID-19 signs and symptoms. 
• Date of COVID-19 diagnosis (defined as sample date for positive COVID-19 PCR test). 
• History of chronic medical conditions including chronic supplemental oxygen 
requirement prior to onset of COVID-19 signs and symptoms. 
• History of previous COVID-19 diagnosis and serology results (if relevant and known). 
8.2. 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA. 
8.2.1. 
8-point Ordinal Scale  
The clinical status of COVID-19 is scored at each visit according to the 8-point ordinal scale 
(Beigel et al., 2020), which is an investigator evaluation of the clinical status at the first 
assessment of a given trial day. The clinical status of COVID-19 according to the 8-point ordinal 
scale must further be scored at the time of hospital discharge. For subjects hospitalized between 
Day 29 (Visit 31) and Day 60 (Visit 32), the clinical status of COVID-19 should be scored each 
time a change in clinical COVID-19 status is seen and until hospital discharge.  
The 8-point ordinal scale is as follows: 
1. 
Not hospitalized, no limitations on activities 
2. 
Not hospitalized, limitation on activities and/or requiring home oxygen 
3. 
Hospitalized, not requiring supplemental oxygen - no longer requires 
ongoing medical care 
4. 
Hospitalized, not requiring supplemental oxygen - requiring ongoing 
medical care (COVID-19-related or otherwise) 
5. 
Hospitalized, requiring supplemental oxygen 
6. 
Hospitalized, on non-invasive ventilation or high flow oxygen devices 
7. 
Hospitalized, on invasive mechanical ventilation or ECMO 
8. 
Death 
A subject re-admitted to the hospital for a non-COVID-19 related reason should be considered 
not hospitalized when scoring the clinical status of COVID-19 on the 8-point ordinal scale.   
8.2.2. 
Supplemental Oxygen 
Any daily need for supplemental oxygen will be recorded at each visit from screening (Visit 1) to 
Day 29. This will include use of supplemental oxygen during hospitalization and at home.  

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8.2.3. 
Oxygen Saturation 
• Resting peripheral capillary oxygen saturation (SpO2) will be performed as outlined in 
the SoA. 
• SpO2 recording should be preceded by at least 5 minutes of rest for the subject in a quiet 
setting. 
• SpO2 will be recorded up to 2 times with a 5-minute interval between the measurements.  
• Supplemental oxygen flow rate (L/min), oxygen delivery device, FiO2, airway pressure, 
if applicable, must be assessed at the time of measuring SpO2. 
8.3. 
Survival and Hospitalization 
Data on survival, hospital discharge and hospital re-admissions will be collected at each visit 
from Day 2 (Visit 3) to Day 60 (end-of-trial). Information on the hospital setting, including 
intensive care unit (ICU), high flow oxygen device use, ventilator use (Non-invasive, Invasive or 
ECMO) will be collected. 
8.4. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (see Section 1.3). 
8.4.1. 
Physical Examinations 
• Physical examinations will be performed as outlined in the SoA (see Section 1.3). 
• The physical examination will include assessments of the respiratory and cardiovascular 
systems. Other systems will be assessed per investigator judgment.  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Each body system will be reported as “normal” or “abnormal”. Any clinically significant 
abnormalities prior to initiation of IMP should be specified and recorded as medical 
history. New clinically significant abnormalities occurring after initiation of IMP should 
be reported as AEs. 
8.4.2. 
Vital Signs 
• Body temperature, pulse rate, respiratory rate and blood pressure will be measured as 
outlined in the SOA (see Section 1.3). 
• Blood pressure, respiratory rate and pulse measurements should be preceded by at least 5 
minutes of rest for the subject in a quiet setting without distractions (e.g., television, cell 
phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
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• Any clinically significant abnormalities prior to initiation of IMP should be specified and 
recorded as medical history. New clinically significant abnormalities occurring after 
initiation of IMP should be reported as AEs. 
8.4.3. 
Electrocardiograms 
• 12-lead electrocardiograms (ECGs) will be obtained as outlined in the SoA (see 
Section 1.3) using local ECG equipment that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals. 
• Historical 12-lead ECGs are acceptable if ≤2 days old at the time of screening (Visit 1). 
• The ECG assessment will be reported as “normal” or “abnormal”. Any clinically 
significant abnormalities should be specified and recorded as medical history. 
8.4.4. 
Clinical Safety Laboratory Tests 
• Blood and urine samples for clinical safety laboratory tests will be collected as outlined 
in the SoA (see Section 1.3). Samples collected at screening (Visit 1) will be analyzed 
using local laboratories and used to confirm eligibility for participation in the trial.  
• Day 1 (Visit 2), samples will be collected before IMP administration. 
• Samples collected at all other visits will be analyzed by the central laboratory. 
• If needed due to special circumstances e.g., delays in turn-around time due to COVID-19, 
blood samples may be analyzed locally after sponsor approval. 
• The tests detailed in Table 2 will be performed. 
 
 

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Table 2. Protocol-required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
Hematology 
Platelet count (thrombocytic 
particle concentration) 
Hemoglobin 
Hematocrit (erythrocyte volume 
fraction) 
Mean corpuscular volume (MCV) 
 
White blood cell (WBC) count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
chemistry 
Blood urea nitrogen (BUN) 
Glucose, fasting 
Potassium 
Sodium 
Calcium 
Ferritin 
Prothrombin time (PT) 
International Normalized Ratio 
(INR) 
activated partial thromboplastin 
time (aPTT) 
AST 
Alanine transferase (ALT) 
Alkaline phosphatase (ALP) 
Albumin 
Total and direct bilirubin 
Serum creatinine 
eGFR 
CRP 
LDH  
Routine 
urinalysis 
• pH, glucose, protein, ketones, bilirubin, urobilinogen, and specific 
gravity by dipstick 
• Microscopic examination (per investigator judgment) 
Pregnancy 
testing 
• Highly sensitive urine or serum human chorionic gonadotropin 
pregnancy test (as needed for women of childbearing potential) 
• Investigators must review of each laboratory safety report. Any clinically significant 
abnormalities at screening (Visit 1) or Day 1 (Visit 2) will be reported as medical history. 
New clinically significant abnormalities after Day 1 (Visit 2) should be reported as AEs. 
8.4.5. 
Hepatic Impairment  
In subjects with hepatic impairment, the grade of impairment will be assessed by the investigator 
prior to randomization and as needed during the trial using the Child-Pugh system (FDA, 2003). 
For subjects assessed using the Child-Pugh system, it is important that impaired hepatic function, 
not another underlying disease, is the cause of alterations in the Child-Pugh components 
(bilirubin, albumin, prothrombin time, encephalopathy, and ascites). Scoring will be performed 
according to Table 3 and the classification will be based on the total score; 
• Class A (mild): 5 or 6 points 

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• Class B (moderate): 7 to 9 points 
• Class C (severe): 10 to 15 points  
 
Table 3. Child-Pugh System 
 
Points scored for observed findings 
1 
2 
3 
Encephalopathy grade1) 
None  
1 or 2 
3 or 4 
Ascites 
Absent 
Slight 
Moderate 
Total bilirubin2) 
<2 mg/dL 
 
(<34.2 µmol/L) 
2 to 3 mg/dL 
 
(34.2 to 51.3 µmol/L) 
>3 mg/dL 
 
(>51.3 µmol/L) 
Serum albumin2) 
>3.5 g/dL 
 
(>35 g/L) 
2.8 to 3.5 g/dL 
 
(28 to 35 g/L) 
<2.8 g/dL 
 
(<28 g/L) 
Prothrombin time, sec 
prolonged (or INR as 
below) 
 
INR 
<4 
 
 
 
<1.7 
4 to 6 
 
 
 
1.7 to 2.3 
>6 
 
 
 
>2.3 
1) Grade 0: normal consciousness, personality, neurological examination, electroencephalogram  
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves  
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves  
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves  
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity 
2) If using results from the central laboratory for calculating the scores, the alternative units may have to be 
considered 
8.4.6. 
Pregnancy Testing 
Women of childbearing potential will undergo pregnancy tests (urine dip-sticks or serum if 
required by local regulations) at the screening and Day 15 visits or at the EWD visit if the subject 
is withdrawn prematurely. The outcome of the test will be reported as “positive” or “negative” in 
the eCRF. If the urine pregnancy test is positive, a blood pregnancy test will be performed to 
confirm positive pregnancy.  
Women of non-childbearing potential are defined as pre-menopausal females who are sterilised 
(tubal ligation or permanent bilateral occlusion of fallopian tubes); or post-menopausal defined as 
12 months of amenorrhea) (see Section 10.3). 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject’s participation in the trial. 

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8.4.7. 
SARS-CoV-2 Variant 
Oropharyngeal swabs will be collected as outlined in the SoA (see Section 1.3). A central 
laboratory will determine the SARS-CoV-2 variant.   
8.4.8. 
New Infections 
Information on new infections (viral and non-viral) should be reported as AEs. Information should 
preferably include the site of infection and source of culture. 
8.5. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 2 (see Section 10.2). 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs OR AEs that are serious, considered related to the IMP or trial procedures, or that 
caused the subject to discontinue the IMP or trial (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2 (see Section 
10.2). 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from signing of the ICF until Day 29 at the timepoints specified in the 
SoA (see Section 1.3). SAEs will further be collected until Day 60. All AEs are followed until 
they have reached a final outcome (see Section 10.2) or the subject’s participation in the trial 
ends, whichever comes first.  
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours after SAE awareness, as indicated in Appendix 2 (see 
Section 10.2). The investigator will submit any updated SAE data to the sponsor within 24 hours 
of it being available. 
Information on SAEs must be entered in the eCRF. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the trial participation. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the trial, and he/she considers the event to be 
reasonably related to the IMP or trial participation, the investigator must promptly notify the 
sponsor regardless of the time that has elapsed (post-trial events). 
8.5.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 

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8.5.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (see Section 7.3). Further information on 
follow-up procedures is provided in Appendix 2 (see Section 10.2). 
8.5.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification – within 24 hours of SAE awareness - by the investigator to the 
sponsor of an SAE is essential so that legal obligations and ethical responsibilities 
towards the safety of subjects and the safety of the IMP under clinical investigation are 
met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of the IMP under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review board (IRB)s/ independent 
ethics committee (IEC)s, and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it in the investigator site file and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.5.5. 
Pregnancy 
• Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of IMP and until the end of trial visit. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the female 
subject or female partner of male subject (after obtaining the necessary signed informed 
consent from the female partner) pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The subject/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the subject/pregnant 
female partner and the neonate, and the information will be forwarded to the sponsor. 
• Any posttrial pregnancy-related SAE considered reasonably related to the IMP by the 
investigator will be reported to the sponsor (see Section 8.5.4). While the investigator is 
not obligated to actively seek this information in former trial subjects/pregnant female 
partner, he or she may learn of an SAE through spontaneous reporting. 

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8.6. 
Pharmacokinetics 
• PK data will be collected at a pre-selected number of trial sites in a subgroup of 
approximately 10 subjects. 
• Blood samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of C21 as specified in the SoA (see Section 1.3). At Day 1 (Visit 2), blood 
samples will be collected before the first IMP administration and 30 minutes, 1, 2, 3, 4 
and 6 hours after the IMP administration. 
• Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample as well as the date 
and time of the IMP administration will be recorded. 
• PK data will not be reported to the trial sites, sponsor or blinded CRO/vendor staff until 
the trial has been unblinded. 
• The individual plasma concentration data, and the actual time for IMP administration and 
blood sampling will be used throughout the analyses.  
• All C21 plasma concentration data collected in this trial can be included in population PK 
and population PK/PD analyses with the objective of exploring the impact of covariates 
(e.g., body weight and age) on the PK of C21, or the relationship between the C21 
exposure and selected efficacy and safety endpoints. Any population PK and population 
PK/PD analyses will be reported separately. 
• From the plasma C21 concentration data analysis, the following PK variables will be 
derived using non-compartmental analysis: 
• Cmax - Observed maximum plasma concentration of C21. 
• tmax - Time to reach Cmax following IMP administration. 
• AUC(0-6) - Area under the plasma concentration curve from time zero to 6 hours.  
• AUClast - Area under the plasma concentration-time curve from time zero to the last 
quantifiable concentration. 
• AUC(0-inf) - Area under the plasma concentration-time curve from time zero 
extrapolated to infinity. 
• t½ - Apparent terminal half-life. 
• C6 - Actual plasma concentration of C21 at 6 hours after IMP administration. 
8.7. 
Genetics 
Genetics are not evaluated in this trial. 
8.8. 
Biomarkers 
• Plasma samples will be collected to investigate a range of laboratory parameters as 
potential biomarkers of inflammation, fibrosis, and viral activity including serology. 

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Samples will be collected according to the schedule described in the SoA and as detailed 
in laboratory manual provided separately to sites.  
• Sponsor may store and analyze samples for up to 2 years after the end of the trial to 
achieve trial objectives. 
• Biomarker results will be reported separately from the clinical trial report. 
8.9. 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this trial. 
8.10. 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Medical resource utilization and health economics parameters will be evaluated in terms of days 
hospitalized and days at intensive care unit. Additional analyses may be conducted outside of the 
clinical trial report. 

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9. 
Statistical Considerations 
The statistical analysis plan will be finalized prior to unblinding, and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses 
The aim of this trial is to show superiority of C21 over placebo regarding selected efficacy 
measures. The null hypothesis to be tested for each endpoint will be that there is no difference 
between C21 and placebo, against the alternative hypothesis that C21 is better than placebo. All 
tests will be done using 2-sided alternatives. 
9.1.1. 
Multiplicity Adjustment 
The statistical comparisons for the primary efficacy endpoint and the key secondary endpoint 
will be carried out in following hierarchical order; all-cause mortality up to Day 60, time to 
sustained hospital discharge up to Day 60, supplemental oxygen free days up to Day 29, 
proportion of subjects free of respiratory failure at Day 15, and proportion of subjects discharged 
from hospital and free of supplemental oxygen at Day 15. This means that statistically significant 
results for the comparison in the higher rank are required to initiate the testing of the next 
comparison in the lower rank. Since a step-down procedure is used, each comparison will be 
tested at a significance level of 0.05 and an overall alpha level of 0.05 will be preserved.  
9.2. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
 
Subject Analysis Set 
Description 
Intention to treat (ITT) 
analysis set 
All randomized subjects. Subjects will be included in the analyses 
according to the intervention they were randomized to. 
Per protocol (PP) analysis 
set 
All subjects in the ITT set without major protocol deviations deemed 
to have an impact on efficacy readouts. In addition, subjects who 
prematurely discontinued IMP during the treatment period but 
continued with data collection in the trial will also be excluded from 
the PP. Subjects withdrawn from the trial unrelated to trial 
participation due to extraordinary circumstances (for example 
subjects lost-to follow up due to unstable geopolitical situation) may 
also be excluded from the PP set (further specified in the SAP). 
Subjects will be included in the analyses according to the intervention 
they were randomized to. 
Safety analysis set 
All randomized subjects who are exposed to IMP. Subjects will be 
analyzed according to the actual intervention received. 

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Subject Analysis Set 
Description 
PK analysis set 
All subjects randomized to C21, exposed to IMP and with at least one 
post-IMP blood sample with quantifiable C21 concentration 
collected. Participants may be excluded from the PK analysis 
population if they have important protocol deviations that are judged 
to significantly impact the PK analyses. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
All tests will be 2-sided at a 5% significance level. 
Baseline will be defined as the last non-missing assessment obtained prior to first IMP 
administration. 
Stratification will be done based on baseline disease severity, that is the score on the ordinal 
scale at baseline (5 or 6), and region (North America, South and Central America, Europe, 
Africa, or Asia). The actual stratification will be used as factors in the statistical analysis, 
subjects included in wrong stratum at randomization will be moved to their correct strata 
belonging in the analyses. Due to small strata, the regions may be merged; details of this will be 
given in the SAP. 
Continuous variables will be summarized using (arithmetic) means, standard deviation (SD), 
median, minimum, and maximum value, categorical variables will be summarized using numbers 
and percentages. For variables with an expected skew distribution, geometric means, and 
coefficient of variation (CV) will be used instead of arithmetic means and SD. 
The ITT analysis set is used to analyze endpoints related to the efficacy objectives, the PP 
analysis set will be used for sensitivity analyses related to efficacy objectives and the safety 
analysis set is used to analyze the endpoints and assessments related to safety. PK data will be 
presented using the PK analysis set. 
All data regarding subject characteristics, efficacy and safety will be listed. 
9.3.2. 
Primary Endpoint/Estimand Analysis 
The primary endpoint, all-cause mortality up to Day 60, will be defined as the time to day of 
death from any cause within Day 1 to Day 60 follow-up. Subjects without event will be censored 
at Day 60 follow-up. Withdrawn subjects without event will be censored at day of 
discontinuation. Treatment groups will be compared using a stratified log-rank test adjusting for 
treatment, baseline disease severity (score on ordinal scale at baseline) and region. The size of 
the treatment effect will be given as a hazard ratio with 95% confidence intervals. Analysis will 
be illustrated using a Kaplan-Meier plot.  
As a sensitivity analysis, the proportion of subjects with death up to Day 60 will be compared 
between treatment groups using a logistic regression model adjusting for treatment, baseline 
disease severity and region. The estimated difference between treatment groups will be 
expressed as a difference in proportions based on the fitted logistic regression model. The delta 

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method will be used to calculate the standard error for the difference and the associated 95% 
confidence interval (Ge et al., 2011). In addition, the raw proportions per treatment group will be 
given. 
The ITT analysis set will be used for primary analysis and sensitivity analysis will be performed 
using the PP analysis set, subjects will be included as randomized. All collected data post-
treatment will be used to assess the status of the subjects. Impact of subjects not properly being 
followed-up regarding status at Day 60 follow-up will be investigated. 
9.3.3. 
Secondary Endpoints Analysis 
The ITT analysis set will be used for primary analysis and the PP analysis set will be used for 
sensitivity analysis of key secondary endpoint. Subjects will be included in analyses as 
randomized. The key secondary endpoints will be time to sustained hospital discharge up to Day 
60, supplemental oxygen free days up to Day 29, the proportion of subjects free of respiratory 
failure at Day 15 and proportion of subjects discharged from hospital and free of supplemental 
oxygen at Day 15. 
The key secondary endpoints will be tested in a pre-specified hierarchical order following the 
test of the primary endpoint. Other secondary endpoints will be tested independently without 
adjustment for multiple tests. 
The first key secondary endpoint, time to sustained hospital discharge, will be defined as the first 
occurrence of a score of ≤2 on the ordinal score within Day 1 to Day 60, after which the score 
must stay ≤2 for the remainder of the trial (no re-hospitalization related to COVID-19). 
Treatment groups will be compared using a stratified log-rank test adjusting for treatment, 
baseline disease severity and region. The size of the treatment effect will be given as a hazard 
ratio with 95% confidence intervals. Analysis will be illustrated using a Kaplan-Meier plot and, 
if a sufficient number meets the endpoint, the median time to hospital discharge will be estimated 
with 95% confidence intervals for each treatment group. Subjects who die prior to Day 60 will 
be censored at Day 60 and trial withdrawals prior to Day 60 due to other causes than death 
without fulfilling the event will be censored at day of withdrawal. Subjects still in trial but not 
discharged from hospital at Day 60 will be censored at Day 60. 
The second key secondary endpoint, oxygen supplemental free days up to Day 29, will be 
defined as the number days for each subject with a score of ≤4 and no use of COVID-19 related 
supplemental oxygen. Treatment groups will be compared using the Wilcoxon rank-sum test and 
the treatment difference will be expressed as the Hodge-Lehmann difference in median number 
of days with 95% confidence intervals. All collected data post-treatment will be used. Subjects 
who die prior to Day 29 will be given the value of –1 day in the analysis and trial withdrawals 
prior to Day 29 due to other causes of death will be imputed (for each day) using multiple 
imputation including status for all of days 1 - 29. The cumulative distribution functions will be 
plotted to visualize the differences between treatment groups.  
The third key secondary endpoint, subjects free of respiratory failure, will be defined as subjects 
with an ordinal scale score of ≤5 at Day 15. Treatment groups will be compared using a logistic 
regression model adjusting for treatment, baseline disease severity and region. All collected data 
post-treatment will be used to assess the scores. Subjects who die prior to Day 15 will be 
considered in respiratory failure and trial withdrawals prior to Day 15 due to other causes than 
death and not possible to follow-up will be imputed using multiple imputation taking subjects 

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baseline characteristics and last known status into account. The adjusted proportions as 
calculated from (Ge et al., 2011) and the statistics (treatment difference, SE and CI) following 
multiple imputation will also be presented. The ITT will be used for the analysis. The number of 
responders/non-responders will also be presented (these will be the non-imputed values).   
The fourth key secondary endpoint, proportion of subjects discharged from hospital and free of 
supplemental oxygen at Day 15, will be defined as subjects with a score of ≤2 on the ordinal 
scale and free of COVID-19 related supplemental oxygen use at Day 15. Treatment groups will 
be compared using a logistic regression model adjusting for treatment, baseline disease severity 
and region. All collected data post-treatment will be used to assess the scores. Subjects who die 
prior to Day 15 will be considered not discharged and trial withdrawals prior to Day 15 due to 
other causes than death and not possible to follow-up will be imputed using multiple imputation 
taking subjects baseline characteristics and last known status into account. The adjusted 
proportions as calculated from (Ge et al., 2011) and the statistics (treatment difference, SE and 
CI) following multiple imputation will also be presented. The ITT will be used for the analysis. 
The number of responders/non-responders will also be presented (these will be the non-imputed 
values). 
Other endpoints assessing proportion of subjects will be compared using similar logistic 
regression models as for the primary endpoint with the treatment effect expressed as a difference 
in proportions. Death prior to endpoint readout will be handled as worst case, that is subject will 
be assumed to be in mechanical ventilator need or to be in oxygen need or not to have fulfilled 
an improvement of 1 or 2 units. Subjects in ventilator need at readout will be considered in 
oxygen need. 
Other endpoints assessing time to event will be compared using the stratified log-rank test 
similar to time to sustained discharge with similar imputations for missing data. 
Endpoints assessing duration of event will be compared between treatments using the Wilcoxon 
rank sum test, with similar imputations for missing data. All days up during which the subject is 
hospitalized for COVID-19 will be used for computation with imputation of days as being in 
event for subjects in ventilator care and for subjects with death as outcome. For duration of ICU 
stay, subjects with no ICU stay will be given the value 0 days in the analysis and subjects with 
death as outcome will be considered in ICU from time of death until end of observational period. 
The change from baseline to Day 15 in SpO2/FiO2 will be compared between treatment groups 
using an analysis of covariance (ANCOVA) model with treatment, baseline disease severity and 
region as factors and the baseline SpO2/FiO2 as covariate. The adjusted mean difference 
between treatments will be given together with 95% confidence intervals and associated 2-sided 
p-value. 
9.3.4. 
Exploratory Endpoint Analysis 
The change in CRP and LDH from baseline up to Day 15 will be compared between treatment 
groups with ANCOVA models adjusting for treatment, baseline disease severity and region as 
factors and baseline as a covariate. Model for CRP and LDH will be multiplicative, that is data 
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9.3.5. 
Safety Analyses 
Safety analysis will be based on the safety set. 
AEs will be analyzed using quantitative and qualitative measures. Treatment-emergent AEs 
(TEAEs) will be summarized by treatment group for all AEs, related AEs, SAEs, deaths, AEs 
leading to discontinuation of blinded IMP treatment or to withdrawal from trial, AEs of different 
severity and AEs of different chronicity. AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by system organ class and preferred term for 
each treatment group. 
Laboratory data will be summarized by each visit including change from baseline. The number 
of high, low, and normal values for each continuous parameter, and the normal and abnormal 
values for each categorical parameter, will be summarized for change over time using shift 
tables. 
Vital signs (body temperature, pulse rate, respiratory rate, and blood pressure) will be 
summarized by each visit including change from baseline. Abnormalities find at physical 
examination will be summarized by visit. Outcome of pregnancy tests will be listed. 
9.3.6. 
Other Analyses 
The subject flow including total number of screened subjects, number of randomized subjects, 
completers, withdrawn subjects (including reason for withdrawal) and subjects included in each 
of the analysis sets will be summarized by treatment group and for the total. 
The number of subjects with major protocol deviations will be summarized by category of 
violation and by treatment group including subset of major protocol deviations leading to 
exclusion from the per-protocol analysis set. 
Demographic and baseline characteristics will be summarized using descriptive statistics for 
each treatment group and for the total number of randomized subjects. Medical history will be 
coded using MedDRA and summarized by system organ class and preferred term for each 
treatment group. Prior medications will denote medications used prior to first dose of IMP 
independent of if stopped at randomization or not. Concomitant therapy will denote medications 
started prior to but continuing after randomization or medications with a start date at or after the 
randomization date. Prior and concomitant therapy will be summarized separately by Anatomical 
Therapeutic Chemical levels 2 and 4. 
Several sensitivity analyses will be performed on the primary and key secondary endpoints 
regarding choice of population (PP population) and choice of imputation for missing data. 
Specifically tipping point analyses will be performed on key secondary endpoints based on the 
ordinal scale.  
Subgroup analyses of the primary and key secondary endpoints will be made to assess 
consistency of the intervention effect across at least the following subgroups: 
• Age group: <65 vs ≥65 years 
• Sex: female vs male 
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• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White or Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Region (North America, South and Central America, Europe, Africa, or Asia) 
• Presence of risk factors for severe COVID-19 (Yes, No)  
 
If the number of subjects is too small (less than 10%) within a subgroup, then the subgroup 
categories may be redefined prior to unblinding the trial. Further details on the statistical analysis 
will be provided in the SAP. 
9.4. 
Interim Analysis 
No formal interim analysis will be performed. The DMC will review the safety results after the 
first 150 randomized subjects have completed trial up to Day 15. 
9.5. 
Sample Size Determination 
The sample size is based on the all-cause mortality up to Day 60. For the placebo (SOC) group, 
the proportion of subjects dead at Day 60 is estimated to 10% (Marconi et al., 2021).   
With 150 evaluable subjects per trial group, there will be an 80% power to detect a difference 
between C21 and placebo if the proportion of subjects dead at Day 60 in the C21 group is 2.5% 
(corresponding to a HR of 0.24). In this calculation, a 5% withdrawal rate has been assumed. For 
the actual detection limit (corresponding to 50% power), if 15 subjects die in the placebo group, 
significance will be seen if at most 6 subjects die in the C21 group. 
This assumes using a 2-sided test at a 5% significance level. Analysis will be by intention-to-
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines. 
o Applicable ICH GCP guidelines. 
o Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, IB and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the trial is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes except for changes necessary to eliminate an immediate hazard to trial subjects. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to trial subjects. 
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the trial to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
o Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies, and all other applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the trial and for 1 year after 
completion of the trial. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the trial, including the 
risks and benefits, to the subject and answer all questions regarding the trial. 

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• Subjects must be informed that their participation is voluntary. Subjects will be required 
to sign a statement of informed consent that meets the requirements of 21 CFR 50 (US 
only), local regulations, ICH guidelines, privacy, and data protection requirements, where 
applicable, and the IRB/IEC or trial center. 
• The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the trial and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Subjects must be reconsented, as applicable, to the most current version of the ICF(s) 
during their participation in the trial. 
• A copy of the ICF(s) must be provided to the subject.  
10.1.4. 
Data Protection 
• Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
• The subject must be informed that his/her personal trial-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject who will be required to give consent for their data to be used as 
described in the informed consent. 
• The subject must be informed that his/her medical records may be directly examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
10.1.5.1. Data Monitoring Committee 
An independent DMC will be established. The functions and responsibilities of the DMC will be 
described in a DMC charter.  
Throughout the duration of the trial, the DMC will evaluate all SUSARs on an ongoing basis. 
The DMC is scheduled to meet twice during trial conduct, to review unblinded safety data from 
the trial after data collection for 15 days on the first 25% of randomized subjects, and to review 
safety and efficacy data after data collection for 15 days on the first 50% of randomized subjects. 
In addition, the DMC members may call for an ad hoc safety review meeting at any time during 
the trial. This may include a review of unblinded safety data after data collection for 15 days on 
the first 75% of randomized subjects. The DMC will provide appropriate written 
recommendations to the sponsor regarding trial continuation, protocol modifications or trial 
suspension. The DMC will operate unblinded and independent from all sites, CRO, vendor and 
sponsor staff involved in the conduct of the trial. 
10.1.6. 
Dissemination of Clinical Trial Data 
Information about the clinical trial and tabular trial results will be posted on the US National 
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Regulating Authorities Clinical Trials Database (EudraCT) prior to first subject first visit and 
after trial completions. Information about the clinical trial may also be posted on other 
governmental webpages according to local regulations. 
10.1.7. 
Data Quality Assurance 
• All subject data relating to the trial will be entered into electronic CRFs unless 
transmitted to the sponsor or designee electronically (Central laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in CRF completion guideline provided 
separately to sites. 
• The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be predefined in the sponsor risk management plan 
to identify systematic issues that can impact subject safety and/or reliability of trial 
results. These predefined QTLs will be monitored during the trial, and important 
deviations from the QTLs and remedial actions taken will be summarized in the clinical 
trial report. 
• Monitoring details describing strategy, including definition of trial critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
• The sponsor or designee is responsible for the data management of this trial, including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this trial 
must be retained by the investigator for 25 years after trial completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
10.1.8. 
Source Documents 
• Source documents containing source data provide evidence for the existence of the 
subject and substantiate the integrity of the data collected. Source documents are filed at 
the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
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explained. The investigator may need to request previous medical records or transfer 
records, depending on the trial. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in the monitoring 
manual. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
trial is being conducted in accordance with the currently approved protocol and any other 
trial agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9. 
Trial and Site Start and Closure 
First Act of Recruitment 
The trial start date is the date on which the clinical trial will be open for recruitment of subjects. 
The first act of recruitment is the first site open and will be the trial start date. 
Trial/Site Termination 
The sponsor or designee reserves the right to close the trial site or terminate the trial at any time 
for any reason at the sole discretion of the sponsor. Trial sites will be closed upon trial 
completion. A trial site is considered closed when all required documents and trial supplies have 
been collected and a trial-site closure visit has been performed. 
The investigator may initiate trial-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the sponsor or investigator may include but are not 
limited to: 
For trial termination: 
• Discontinuation of further IMP development. 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by 
the investigator. 
• Total number of subjects included earlier than expected. 
If the trial is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the trial of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the subject and should assure 
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10.1.10. 
Publication Policy 
• The primary publication should be published by the sponsor prior to any other 
investigator-initiated publications, manuscripts, abstracts, or presentations. 
• The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• The sponsor will comply with the requirements for publication of trial results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 

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10.2. 
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.2.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical trial subject, temporally 
associated with the use of IMP, whether or not considered related to the IMP. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of IMP. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New condition detected or diagnosed after IMP administration even though it may 
have been present before the start of the trial. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either IMP or a 
concomitant therapy. Overdose to be reported as an AE/SAE.  
• Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT Meeting the AE Definition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the trial that do not worsen. 

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10.2.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the subject has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions or 
development of intervention dependency or intervention abuse. 

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10.2.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• AEs will be collected from signing the ICF. AEs occurring after first IMP intake will be 
considered treatment-emergent adverse events (TEAEs) in the statistical analysis. 
• A pre-existing medical condition should be reported as an adverse event if the condition 
increases in severity (e.g. from mild to moderate).  
• At each visit the subject should be asked about AEs in an objective manner, e.g.: “Have 
you experienced any problems since the last visit?”. 
• Only medically qualified personnel (investigators) must assess AEs. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the sponsor or designee in lieu of completion of the SAE form. 
• There may be instances when copies of medical records for certain cases are requested 
by the sponsor or designee. In this case, all subject identifiers, with the exception of the 
subject number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
• All AEs should be followed until they have reached a final outcome 
(Recovered/resolved, recovering/ resolving, recovered/resolved with sequelae) or the 
subject’s participation in the trial ends, whichever comes first.  
• SAEs and non-serious AEs considered related to IMP treatment should be followed on 
a regular basis according to the investigator’s clinical judgment until a final outcome 
has been established.  
• The outcome “recovering” can be used as the final outcome for events that are 
stabilized (in essence no further worsening is expected) and expected by the 
investigator to resolve over time.  
The outcome “not resolved” can be used as the final outcome for events that are not 
expected to resolve over time (e.g. cancer). 
 
 
 
 

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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the trial and assign it to one of the following categories: 
• Mild: Awareness of symptoms, sign, illness, or event that is easily tolerated. 
• Moderate: Discomfort sufficient to interfere with usual activities. 
• Severe: Incapacitating with inability to work or undertake further normal activities. 
Note the distinction between seriousness and severity: The term severe is used to describe the 
intensity of the event and a severe event is not necessarily serious. A severe headache would 
probably not constitute a SAE whilst a mild myocardial infarction likely would constitute a 
SAE. The seriousness criteria serve as a guide for defining regulatory reporting obligations. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between IMP and each 
occurrence of each AE/SAE. The investigator will use clinical judgment to determine 
the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated. 
• The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always makes an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee. 
• The investigator may change his/her opinion of causality when new follow-up 
information is available and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
• The relationship will be characterized using the following causality ratings: 
o Related: There is a reasonable possibility that the AE was caused by the IMP 
treatment. There is a reasonable time relationship to IMP treatment intake. The 
AE cannot be explained by disease or other drugs. There may or may not be 
information about de-challenge or re-challenge. Disappearance of the AE upon 
de-challenge supports this category. Reappearance upon re-challenge is 
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o Not related: There is no reasonable possibility that the event was caused by the 
IMP. The temporal relationship to drug administration makes a causal 
relationship improbable or other drugs or underlying disease or conditions 
provide plausible explanations. 
o Not applicable: This assessment can be used e.g., in cases where the subject did 
not receive any treatment with IMP 
Outcome 
The Investigator is obliged to record the most appropriate outcome using the following categories: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved/ongoing 
• Recovered/resolved with sequelae 
• Fatal 
• Unknown 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• The investigator will submit any updated SAE data to sponsor or designee within 24 
hours of receipt of the information. 
10.2.4. 
Reporting of SAEs 
SAE Reporting to the sponsor or designee via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the sponsor or designee will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the trial is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a trial subject or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken 

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offline, then the site can report this information on a paper SAE form or to the sponsor 
or designee by telephone. 
• Contacts for SAE reporting can be found in the Safety Management Plan provided to 
the sites. 
 
 

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10.3. 
Appendix 3: Contraceptive and Barrier Guidance 
10.3.1. 
Requirements 
Contraceptive use by men and women must be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies and be according to the 
following gender specific requirements: 
1. Male subjects are eligible to participate if they agree to the following during the IMP 
treatment period and for at least 2 weeks after the last dose of IMP: 
i. Refrain from donating fresh unwashed semen 
AND 
ii. Must agree to use contraception/barrier as detailed below 
iii. Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom 
may break or leak when having sexual intercourse with a woman) of 
childbearing potential (WOCBP) who is not currently pregnant 
iv. Agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person 
 
2. Female subjects are eligible to participate if she is not pregnant or breastfeeding, and the 
following conditions applies: 
i. Is a woman of nonchildbearing potential (WONCBP) as defined in section 
10.3.2. Contraception and Barrier Guidance. 
ii. Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency. 
Contraception and Barrier Guidance during the IMP treatment period and for 
at least 2 weeks after the last dose of IMP and agrees not to donate eggs (ova, 
oocytes) for the purpose of reproduction during this period. The investigator 
should evaluate the potential for contraceptive method failure (e.g., 
noncompliance, recently initiated) in relationship to the first dose of IMP. 
iii. A WOCBP must have a negative highly sensitive pregnancy test (urine or 
serum) as required by local regulations) before the first dose of IMP (see 
Section 0). 
iv. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the subject must be excluded 
from participation if the serum pregnancy result is positive. 
v. Additional requirements for pregnancy testing during and after IMP treatment 
(see Section 8.5.5). 
vi. The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy. 

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10.3.2. 
Definitions 
Women in the following categories are considered WOCBP (fertile): 
• Following menarche 
• From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below) 
• Permanent sterilization methods (for the purpose of this trial) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
o For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining trial entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
• If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of IMP treatment, additional evaluation should be 
considered. 
Women in the following categories are considered WONCBP: 
• Premenopausal female with permanent infertility due to one of the following: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
d. For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining trial 
eligibility. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
i. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
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Females on HRT and whose menopausal status is in doubt should not be 
considered to be in a postmenopausal state. 
10.3.3. 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male subject can come from the site personnel’s review of the 
subject’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
o 
oral 
o 
intravaginal 
o 
transdermal 
o 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
oral 
o 
injectable 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.  
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for 
this trial. Male condom and female condom should not be used together (due to risk of failure from friction). 
 
 
 
 

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10.4. 
Appendix 4 Standard of Care for COVID-19 
 
All subjects receiving IMP will also receive SoC for COVID-19, which may include:  
• Oxygen administration to maintain oxygen saturation of 90 % to 96 %, including 
supplemental oxygen (low flow or high flow), non-invasive or invasive mechanical 
ventilation or ECMO 
• Frequent clinical assessments of neurological, pulmonary, cardiac, gastrointestinal, and 
urinary status as required depending on clinical status 
• At least daily monitoring of vital signs (heart rate, blood pressure, body temperature, 
respiratory rate and oxygen saturation (SpO2))  
• Telemetry monitoring to evaluate hearth rhythm and rate  
• Diet as tolerated to satisfy nutritional needs 
• Mobilization of the subject and rotation to prone positioning of ventilated subjects 
• Treatment for COVID-19 symptoms including antibiotics, cough suppressant / 
expectorants, anti-coagulants, analgesics, antipyretics, antiemetics and/or 
bronchodilators; refer also to section 6.8 regarding permitted prior or concurrent therapy 
• Treatments for COVID-19 which are: Administered in accordance with approved 
conditions by the national health authority (Specific for India; Indian Council for 
Medical Research (ICMR) guidelines for management of COVID-19 patients (ICMR, 
2021)), including emergency use authorizations, conditional approvals, or article 5(3) 
reviews,  
 
AND  
 
• Approved under such conditions in the US or EU, and/or recommended in international 
consensus guidelines (e.g., remdesivir, dexamethasone, tocilizumab, convalescent 
plasma, and certain monoclonal antibodies). See section 6.8 regarding permitted prior or 
concurrent therapy. 
 

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10.5. 
Appendix 5: Country-specific Requirements 
 
10.5.1. 
India  
The trial will be a phase 2/3 trial. 80 subjects will be enrolled from India in the phase 2 part of 
the trial.   
Protocol title: A randomized, double-blind, placebo-controlled, parallel group, phase 2/3, 
multicenter trial investigating the efficacy and safety of C21 as add on to standard of 
care in adult subjects with COVID-19. 
Inclusion criterion 1: Age ≥18 at the time of signing the informed consent, to ≤65 years. 
 
Inclusion criterion 7: Specific for India: For subjects with an ordinal scale score of 5, moderate to 
severe COVID-19 disease confirmed by at an SpO2 ≤ 93 % or a respiratory rate ≥ 24/min on 
room air. Note: If a subject is on supplemental oxygen with SpO2 >93% and respiratory rate 
<24/min, but desaturation to ≤ 93 % or increase of respiratory rate to ≥ 24/min on lower 
supplemental oxygen or room air is documented during screening, the inclusion criterion is 
considered to be met. 
 
Standard of Care for COVID-19 includes the ICMR guidelines for management of COVID-19 
patients (ICMR, 2021) (ICMR, 2021).  
 
 
 
 
 

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10.6. 
Appendix 6: Abbreviations 
ACE 
Angiotensin Converting Enzyme 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
ALT 
Alanine Transferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase  
AT1R 
Angiotensin II type 1 Receptor 
AT2R 
Angiotensin II type 2 Receptor 
BCRP 
Breast Cancer Resistance Protein 
b.i.d. 
bis in die (i.e. twice a day) 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulation 
COVID-19 
Corona Virus Disease 2019 
CYP 
Cytochrome P450 
CYP1A2 
Cytochrome P450 Family 1 Subfamily A Member 2 
CYP2C9 
Cytochrome P450 Family 2 Subfamily C Member 9 
CYP3A4 
Cytochrome P450 Family 3 Subfamily A Member 4 
DMC 
Data Monitoring Committee 
ECMO 
Extra Corporeal Membrane Oxygenation 
ECG 
Electrocardiogram 
eGFR 
estimated Glomerular Filtration Rate 
EWD 
Early Withdrawal 
FiO2 
Fraction of inspired Oxygen 
GCP 
Good Clinical Practice 

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HIV  
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form  
ICH 
International Council for Harmonization 
ICMR 
Indian Council for Medical Research 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IMP 
Investigational Medicinal Product 
LDH 
Lactate Dehydrogenase 
MCV 
Mean Corpuscular Volume 
MDR1 
MedDRA 
Multi Drug Resistance 1 
Medical Dictionary for Regulatory Activities 
PCR 
Polymerase Chain Reaction 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PR 
Retrograde P waves 
QTc 
QT corrected 
QTcF 
QT corrected by Fridericia 
QTL 
Quality Tolerance Limits 
RAS 
Renin Angiotensin System 
SAE 
Serious Adverse Event 
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2  
SpO2 
Peripheral Capillary Oxygen Saturation 
SoA 
Schedule of Activities 
SoC 
Standard of Care 

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WOCBP 
Woman of Childbearing Potential 
WONCBP 
Woman of non-childbearing Potential 

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11. 
Protocol Amendment History  
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Description of Change 
Rationale for changes 
Final protocol, 
version 1.0, 
dated 14-Apr-
2021 
First version  
 
Amendment 1 to 
the protocol. 
Non-substantial.  
Final protocol, 
version 2.0, 
dated 06-May-
2021. 
Section 2.2. Background 
Statistical conclusion on 
the primary endpoint in the 
phase 2 trial added. 
Sentence added to provide more 
clarity. 
 
Section 5.2 Exclusion 
Criteria 
Exclusion criterion: 
Impaired hepatic function 
(i.e., Child-Pugh class A or 
B) changed to Impaired 
hepatic function (i.e., 
Child-Pugh class B or C). 
Correction of error in the exclusion 
criterion. 
 
Section 9.3.3 Secondary 
Endpoint Analysis 
Removal of text describing 
the change from baseline 
ordinal scale score 
analysis. 
Correction of error in the protocol. 
Amendment 2 to 
the protocol. 
Substantial.  
Final protocol, 
version 3.0, 
dated 02-Jul-
2021. 
Section 1.1. Synopsis 
Endpoint, change in LDH 
added. 
Interim analysis and DMC 
process clarified. Ad hoc 
safety review meeting 
added. 
Endpoint added to include a lung 
injury biomarker. 
 
Per. authority request. and alignment 
with interim analysis plan.   
Section 3 Objectives, 
Endpoints, and Estimands 
Endpoint added to include a lung 
injury biomarker. 

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Endpoint, change in LDH 
added. 
 
 
Section 4.2. Scientific 
rationale for Trial Design 
Description of individual 
change in ordinal scale 
scores reflected in the 
primary endpoint added.  
Additional clarification of the 
primary endpoint.  
 
Section 5.1 Inclusion 
Criteria 
Indian specific; Age limits 
and SpO2 criteria added to 
inclusion criteria 1 and 7, 
respectively.  
Per. authority request.  
 
Section 5.2 Exclusion 
Criteria 
 
 
Active tuberculosis added 
to exclusion criterion 2. 
Per. authority request.  
 
SpO2 / FiO2 ratio added to 
exclusion criterion 9. 
Added if a blood gas test is not 
available. 
 
Section 6.2 Preparation, 
Handling, Storage and 
Accountability 
Oral dispersion and 
nasoenteral feeding tube 
added as alternative 
administration forms. 
To align with common drug 
administration practices at hospitals 
treating COVID-19 patients. 
 
Section 6.8 Prior and 
Concomitant Therapy 
List with Prohibited 
medication added. 
Per. authority request. 

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Section 7.1 
Discontinuation of 
Investigational Medicinal 
Product 
IMP discontinuation 
criteria added for acute 
kidney and hepatic injury. 
Per. authority request. 
 
Section 7.1.1. Temporary 
discontinuation  
Text updated to specify 
that there are no specific 
criteria for temporary 
discontinuation of IMP in 
the protocol. 
Wording updated for clarification. 
 
Section 8.2.1 8-point 
ordinal Scale 
Additional 8-point ordinal 
scale assessment added at 
time of hospital discharge 
and in patients hospitalized 
between Day 29 and 60.  
Improve data collection.  
 
8.3 Survival and 
Hospitalization 
Section updated to collect 
data on all types of hospital 
re-admissions. 
Per. authority request. 
 
8.4.4. Clinical Safety 
Laboratory Tests  
Albumin and LDH added 
to lab parameters. 
Albumin added to assess hepatic 
impairment using the Child-Pugh 
system. LDH added as a biomarker 
for lung injury.  
 
8.4.5 Hepatic Impairment  
Serum albumin added to 
Child-Pugh System table. 
Correction of error in the protocol. 

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9.3.3. Secondary Endpoint 
Analysis 
Added that the cumulative 
distribution functions will 
be plotted for the oxygen 
supplemental free days up 
to Day 29 endpoint. 
 
 
To aid the interpretation of the 
results. 
 
 
 
 
Plots of cumulative 
distribution functions 
added.  
Per. authority request. 
9.3.4 Exploratory Endpoint 
Analysis  
LDH added.  
LDH added as laboratory 
assessment. 
9.3.6 Other analysis  
Added text on additional 
sensitivity analyses.  
Per. authority request. 
9.4 Interim Analysis 
Additional details on the 
interim analysis provided 
including a cap of 450 
subjects per. treatment arm. 
Additional clarifications on the 
interim analysis. 
10.1.5.1. Data monitoring 
committee  
Option for a third DMC 
meeting added. 
Per authority request.  
 
 
 
 
 
 
 
10.3 Appendix 3: 
Contraceptive and Barrier 
Guidance  
Abstinence removed. 
Per authority request. 
10.3.2 Definitions 
Procedure for 
discontinuation of HRT to 
check menopausal status 
removed. 
Per authority request. 

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10.4 Appendix 4 Standard 
of Care for COVID-19 
Section added. 
Per authority request. 
Section 10.5 Appendix 5: 
Country-specific 
Requirements for India 
added. 
Per authority request. 
 
 
Amendment 3 to 
the protocol. 
Substantial. 
Added section including 
contact details for 24/7 
medical coverage 
In accordance with the information 
already distributed to the sites. 
Final protocol, 
Version 4.0, 
dated 07-Dec-
2021. 
Section 1.3 Schedule of 
Activities  
Added possibility to use local lab for 
analysis of safety samples in special 
circumstances. 
 
Section 5.1 Inclusion 
criteria  
Added “hospital-approved 
diagnostic” PCR test to 
inclusion criterion 2. 
Per authority request.  
 
 
 
 
Section 5.2 Exclusion 
criteria  
Exclusion criterion 3 
rephrased to clarify that the 
alterations in the Child-
Pugh score are caused by 
altered hepatic function, 
not another underlying 
disease. 
Clarification of the severity 
assessment of hepatic impairment. 
 
Section 5.2 Exclusion 
criteria 
Exclusion criterion 5 
changed to a COVID-19 
symptom onset >21 days 
prior to screening (Visit 1). 
 
To align with new evidence 
suggesting that subjects infected 
with SARS-CoV-2 after vaccination 
have a longer duration of illness 
(Antonelli et al., 2021).  

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Section 6.2 Preparation, 
Handling, Storage and 
Accountability 
Oral dispersion added as 
option for patients with 
gastric discomfort  
Specified that route of 
administration is captured 
in eCRF. 
To align with common practice at 
hospital treating patients with gastric 
discomfort.  
 
 
Data collection further specified. 
 
 
Section 7.1 
Discontinuation of 
Investigational Medical 
Product  
Clarify the assessment of 
severity of hepatic 
impairment.  
Clarification and alignment with 
Exclusion criterion 3. 
 
Section 8.4.4. Clinical 
Safety Laboratory Tests 
Added option of local 
laboratory analysis of 
safety samples in special 
circumstances 
To ensure subjects safety and 
sufficient medical oversight of 
enrolled subjects e.g. in case of 
prolonged turnaround time for 
analysis of lab samples at central 
lab. 
 
 
Section 8.4.5 Hepatic 
Impairment  
Clarification of grading of 
Hepatic Impairment 
Update of Table 3 
To ensure that impaired hepatic 
function, not another underlying 
disease, is the cause of alterations in 
the Child Pugh components.  
To include central lab units to ease 
the process for sites. 
 
Section 9.3.5 Safety 
analysis 
Clarify the type of shift 
tables to be produced. 
Alignment with SAP. 
 
Section 9.3.6 Other 
analyses. Sub-group 
analysis including presence 
of risk factors for severe 
COVID-19 added 
Alignment with SAP. 

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Section 9.4 Interim 
analysis 
Clarified that no 
adjustment for alpha will 
be required.  
Per authority request.  
Amendment 4 to 
protocol.  
Substantial.  
Final protocol, 
Version 5.0, 
dated 13-Apr-
2022. 
Overall changes (all 
changes were implemented 
without access to 
unblinded data from the 
ongoing trial):  
The   primary endpoint has 
been changed from 
proportion of subjects 
discharged from hospital 
and free of supplemental 
oxygen at Day 15 to all-
cause mortality up to Day 
60. The previous primary 
endpoint is now considered 
a key secondary endpoint. 
Major changes throughout 
the document to reflect the 
new primary endpoint for 
the trial Sections 1.1, 3.0, 
4.2, 9.1.1, 9.3.2 and 9.3.3 
have been updated to 
reflect these changes. 
 
Since trial planning, the assumptions 
for the primary endpoint have 
changed and the current primary 
endpoint is not likely to reflect the 
presumed benefit of C21. The new 
primary endpoint will ensure 
capturing the majority of clinical 
events to assess a treatment response 
and thus evaluate the complete 
treatment effect over time.  
 
 
 
 
 
 
 
 
 
 
 
 

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Sample Size has been 
reduced from 600 to 
maximum 300 patients. 
Section 1.1, 1.2, 4.1, 9.3.1 
and 9.5 have been updated 
to reflect the reduced 
sample size. Power 
calculations have been 
updated to incorporate the 
new primary endpoint. 
 
 
 
 
Due to the current instable 
geopolitical situation and to ensure 
patient safety and data integrity in 
the trial, the Sponsor has closed all 
clinical sites in the Ukraine and 
Russia. This impacts enrolment, and 
a significant challenge in completing 
the recruitment is foreseen. Current 
estimates indicate that the target 600 
patients will not be reached in a 
foreseeable future and is contingent 
on the occurrence of new COVID-19 
waves with virus variants of a more 
severe phenotype. The Sponsor has 
decided to complete the trial when a 
maximum of 300 patients have been 
enrolled. 
 
 
Removal of Interim 
Analysis revised in section 
9.4  
 
Due to decreased sample size. 
 
Decrease of PK sample 
size revised in section 1.3 
and 8.6 
 
Due to decreased sample size. 
 
 
 
Section 9.2 Analysis sets 
 
In alignment with SAP. 
 
 
Section 9.3.6 Other 
analyses 
Added race and ethnicity 
Per Authority request. 
 
 

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13. 
Sponsor and Coordinating Investigator Signatures  
 
Vicore Pharma 
 
 
Chief Medical Officer  
Rohit Batta, MBBS, MRCGP, FFPM 
 
 
 
 
 
 
 
Signature 
 
Date 
VP, Clinical Development 
Elin Rosendahl, M.Sc. 
 
 
 
 
 
 
 
Signature 
 
 
Date 
Statistical Expert 
Thomas Bengtsson, M.Sc.   
Statmind AB 
 
 
 
 
 
 
Signature 
 
Date 
 
 
Coordinating investigator 
Prof. Maureen Horton, M.D. 
Johns Hopkins University School of 
Medicine, Baltimore, USA 
 
 
 
 
 
 
Signature 
 
Date