Conditions: Covid19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
This double-blinded, randomized study is being conducted to see if the investigational new drug called FP-1201-lyo - intravenous Interferon beta-1a, hereafter IV IFN beta-1a, can help patients recover more quickly from COVID-19 and prevent worsening of the condition. To understand if IV IFN beta-1a can help treat patients with COVID-19, this study drug will be compared to dexamethasone.

Study subjects will be treated daily with IV IFN beta-1a 10 μg or IV dexamethasone for 6 consecutive days while hospitalized and will undergo daily assessments while in hospital for a maximum of 28 days. Study specific assessments will be collected at pre-dose Day 1 through Day 28 (PD and PIM assessments), in addition, clinical routine assessments will be utilized for safety and efficacy assessments.

Detailed description:

Arms:
arm 1: Patients receiving active drug: will receive two separate bolus injections one containing IFN-beta -1a and another injection containing Saline. arm 2: Patients receiving active comparator: will receive two separate bolus injections one containing saline and another injection containing Dexamethasone.

Interventions: intervention 1: IFN beta-1a intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Treated daily with IFN beta-1a 10 μg as an IV bolus for 6 days while hospitalised intervention 2: Treated daily with dexamethasone 6 mg as an IV bolus for 6 days while hospitalised

Protocol document:
Prot_000.pdf: 
Title: A Phase II Multi-Center, Double-Blind, Randomized and Controlled Study of the Safety and 
Efficacy of Intravenous Recombinant Human Interferon Beta-1a in Comparison to Dexamethasone 
for the Treatment of Hospitalized Patients with COVID-19 Infection  
 
NCT number: NCT04860518 
 
Document date: 27September2021 


 
 
  
 
 
 
A Phase II Multi-Center, Double-Blind, Randomized and 
Controlled Study of the Safety and Efficacy of Intravenous 
Recombinant Human Interferon Beta-1a in Comparison to 
Dexamethasone for the Treatment of Hospitalized Patients 
with COVID-19 Infection 
 
HIBISCUS Study Protocol 
 
Human intravenous Interferon Beta-Ia Safety and preliminary efficacy in 
hospitalized subjects with CoronavirUS 
 
 
 
Funding/Support: 
Sponsor: 
U.S. Department of Defense and Faron Pharmaceuticals Ltd. 
Faron Pharmaceuticals Ltd. 
Sponsor Study Number: 
FP1CLI017 
IND Number: 
149849 
NCT Number: 
04860518 
Study Drug Name: 
FP-1201-lyo 
Protocol Version: 
4.0 
Protocol date: 
27Sep2021 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the property of Faron 
Pharmaceuticals Ltd. No unpublished information contained herein may be disclosed  
without prior written approval of Faron Pharmaceuticals Ltd. 


Faron Pharmaceuticals Ltd. 
 
HIBISCUS Protocol v4.0
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(lyophilized human interferon beta-1a)  
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CONFIDENTIAL 
 
 
List of Study Personnel 
Sponsor 
 
Faron Pharmaceuticals Ltd 
Joukahaisenkatu 6 
20520 Turku 
Finland 
 
 
Global Co-ordinating 
Investigators 
  
Department of Anesthesia, Critical Care and Pain Medicine 
Beth Israel Deaconess Medical Center, Harvard Medical 
School, Boston, USA 
 
Department of Emergency Medicine, University of Colorado 
School of Medicine, Aurora, CO USA 
Contract Research 
Organisation 
Orion Clinical Services Limited, UK and USA 
Telephone, UK: +44 (0) 1753 578 080 
Telephone, US: +1 (0) 857 362 8782
Medical Monitor 
Orion Clinical Services Limited, UK 
Safety Reporting 
Orion Clinical Services Limited, UK  
Central Laboratory for 
Analysis of Neutralising 
Antibodies to IFN beta-1a, 
MxA and CD73 
Wieslab AB, a Svar Life Science company, Sweden 
Tel: +46 730659074 
Central Laboratory for 
Analysis of IFN beta-1a 
SYRINX Bioanalytics Oy, Turku, Finland 
Tel: +358 2 4667653 
Central Laboratory for 
Analysis of PIMs and genetic 
sample 
MediCity Research Laboratory, University of Turku, Finland 
Tel: +358 2 333 7001 
Central Laboratory for 
Analysis of interferon 
signalling markers 
Wake Forest University Medical School, Institute for 
Regenerative Medicine, Winston-Salem, NC 27101, USA 
Central Laboratory for 
SARS-CoV-19 virus analysis 
Q2 Solutions, Genomic Laboratories, 
Morrisville, NC, USA  
Drug Supply 
For contact details please refer to the Pharmacy Manual  
Study Statistics and 
Responsible Statistician  
4Pharma Ltd., Finland 
Tel: +358 2 2835700 
Interactive Web-Response 
System (IWRS) 
For contact details please refer to the IWRS User Manual in the 
Investigator Package 






Faron Pharmaceuticals Ltd. 
 
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CONFIDENTIAL 
 
 
SUMMARY OF CHANGES 
The following changes have been made to this protocol since the first approved protocol version. 
Changes in more detail can be seen in separate Summary of Changes document(s). 
Previous Protocol 
version and date 
Revised Protocol 
version and date 
Description of Change(s) 
v1.0, 17Dec2020 
v2.0, 05Feb2021 
Substantial changes 
Study treatment in accordance with standard treatment 
guidelines 
updated 
according 
to 
FDA 
recommendations and concomitant baricitinib usage 
with study IMP prohibited. Systemic baricitinib 
therapy have been added to the exclusion criteria and 
exclusion criteria have been further updated to better 
equate the clinical routine care. MxA, CD73, PIMs 
(D3), Interferon beta and SARS-CoV-2 sample 
collection timepoints and the list of PIMs have been 
updated. Analyses of PIMs and interferon signalling 
markers using the Nanostring technology has been 
added.  
 
Non-substantial changes 
Text about oxygen support and mechanical ventilation 
on Day 28 has been added to the exploratory outcome 
measures 
where 
incoherently 
described. 
Age 
stratification classes specified in the randomization 
criteria. Table 2 has been updated to be more readable 
and regarding the chapters 6.2  6.5 the chapter order 
has been rearranged, and text clarified. Also other 
non-substantial text clarifications and correction of 
typos have been made through the protocol.  
 
v2.0, 05Feb2021 
v3.0, 14Jun2021 
The comparator group is changed to dexamethasone
and the protocol is updated throughout to match this 
change. Eligibility criteria updated to exclude patients 
not requiring supplemental oxygen. Incidence of study 
treatment discontinuation and transition to an open 
label corticosteroid is added as exploratory efficacy 
endpoint. X-ray/CT scans performed as part of 
standard clinical care are used for COVID-19 
diagnostics accuracy, separate X-ray/CT scans are not 
performed for study purpose. A positive test for 
COVID-19 must be available for randomization, but 
now specified that it can be other than a PCR test. 
Nasal swab sampling and local analysis for viral load 
is exchanged to serum sampling and analysis at a
central laboratory (the maximum additional blood 
sampling equals 12.5 ml). The AE follow-up period
and pregnancy reporting period are further specified.


Faron Pharmaceuticals Ltd. 
 
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 (lyophilized human interferon beta-1a) 
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CONFIDENTIAL 
 
Statistical analyses section has been updated with the 
description of analysing also the use of unblinded 
corticosteroids as an intercurrent event. Global Co-
ordinating investigators is updated with Dr. Ginde, 
University of Colorado.  
Also other non-substantial text clarifications and 
correction of typos have been made throughout the 
protocol. 
v3.0, 14Jun2021 
v4.0, 27Sep2021 
A baseline nasopharyngeal swab is added for analysis 
of SARS-CoV-2 variants. All-cause mortality at Days 
28 and 90 are added to the secondary endpoints, and 
efficacy of study treatment based on viral variant and 
on vaccination status to the exploratory endpoints. The 
text in inclusion criteria 4 is harmonized with 
inclusion criteria 3 for better clarity by both referring 
to respiratory symptoms. Blood sampling for SARS-
CoV-2 viral burden is changed from Day 4 to Day 3
to harmonize with other blood sampling. Assessments 
on subjects that are discharged from the hospital but 
re-admitted due to COVID-19 have been specified. 
Description of the study design and risk-benefit 
assessment 
are 
adapted 
according 
recommendations. Specified that in addition to 
baricitinib, also concomitant tofacitinib (and other 
JAK-STAT signalling pathway inhibitors) usage with 
study IMP is prohibited. Updated that patients who 
have received at least one dose of study drug will not 
be replaced for any reasons.  
Also, other text clarifications and correction of typos 
have been made through the protocol. 


Faron Pharmaceuticals Ltd. 
 
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CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
1 
PROTOCOL SYNOPSIS .......................................................................................................................12 
2 
INTRODUCTION ...................................................................................................................................18 
2.1 
Background on COVID-19.........................................................................................................18 
2.2 
Scientific justification for IFN beta-1a for COVID-19 ..............................................................19 
2.2.1 
IFN beta and Severe Coronavirus disease ..................................................................................19 
2.3 
IV IFN beta-1a ............................................................................................................................19 
2.3.1 
Toxicological studies ..................................................................................................................20 
2.3.2 
Phase II dose finding study.........................................................................................................20 
2.3.3 
Phase III studies INTEREST and MR11A8-2............................................................................20 
2.3.4 
Clinical safety experience of IV IFN beta-1a .............................................................................21 
2.4 
Dexamethasone...........................................................................................................................21 
2.4.1 
Clinical safety experience of Dexamethasone ............................................................................21 
2.5 
Potential Interaction of glucocorticoids with IFN beta ..............................................................22 
2.6 
Risk/Benefit Assessment and Summary of Rationale ................................................................23 
3 
STUDY OBJECTIVES ...........................................................................................................................24 
3.1 
Primary Objective .......................................................................................................................24 
3.2 
Secondary Objectives .................................................................................................................24 
3.3 
Exploratory Objectives ...............................................................................................................25 
3.4 
Outcome Measures .....................................................................................................................25 
3.4.1 
Primary outcome measure ..........................................................................................................25 
3.4.2 
Secondary outcome measures.....................................................................................................25 
3.4.3 
Exploratory outcome measures ..................................................................................................26 
4 
OVERALL DESIGN AND PLAN OF THE STUDY ..........................................................................26 
4.1 
Overview ....................................................................................................................................26 
4.2 
Criteria for Evaluation of the Safety and Efficacy .....................................................................28 
4.2.1 
Criteria for Evaluation of Safety ................................................................................................28 
4.2.2 
Criteria for Evaluation of Efficacy .............................................................................................28 
4.2.3 
Criteria for Evaluation of Exploratory Endpoints ......................................................................28 
4.3 
Justification of the Study Design ................................................................................................29 
4.4 
Study Population ........................................................................................................................30 
4.5 
Inclusion Criteria ........................................................................................................................30 
4.6 
Exclusion Criteria .......................................................................................................................30 
4.7 
Confirmation of Patient Eligibility .............................................................................................30 
4.8 
Patient Withdrawal and Replacement ........................................................................................31 
4.8.1 
Discontinuation Criteria .............................................................................................................31 
4.8.2 
Replacement Policy ....................................................................................................................32 
4.9 
Planned Sample Size and Number of Study Centres..................................................................32 
4.10 
Subject Identification and Randomization .................................................................................32 


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4.10.1 
Subject Identification..................................................................................................................32 
4.10.2 
Randomisation Scheme ..............................................................................................................32 
4.10.3 
Randomisation of Subjects to Treatment ...................................................................................33 
4.11 
Minorities and Women ...............................................................................................................33 
5 
STUDY DRUG ........................................................................................................................................33 
5.1 
Identity ........................................................................................................................................33 
5.2 
Packaging, Labelling and Storage ..............................................................................................33 
5.3 
Administration ............................................................................................................................33 
5.4 
Blinding and Breaking the Blind ................................................................................................34 
5.5 
Drug Accountability ...................................................................................................................34 
5.6 
Compliance .................................................................................................................................35 
5.7 
Previous and Concomitant Medications .....................................................................................35 
6 
STUDY CONDUCT AND ASSESSMENTS.........................................................................................35 
6.1 
General Considerations ..............................................................................................................35 
6.2 
Study Baseline Assessments.......................................................................................................37 
6.2.1 
Screening ....................................................................................................................................37 
6.2.2 
Pre-dose D1 ................................................................................................................................38 
6.3 
Study Assessments During Hospital stay ...................................................................................38 
6.3.1 
Vital Signs ..................................................................................................................................39 
6.3.2 
Physical Examinations................................................................................................................39 
6.3.3 
Clinical status assessments .........................................................................................................39 
6.3.4 
Hospital Laboratory Assessments ..............................................................................................39 
6.3.5 
Central Laboratory Assessments ................................................................................................40 
6.3.6 
Lung X-ray/CT scan ...................................................................................................................42 
6.4 
Post-Discharge Assessments ......................................................................................................42 
6.5 
Withdrawal Prior to Day 28 .......................................................................................................42 
6.6 
Safety Variables..........................................................................................................................42 
6.6.1 
Adverse Events ...........................................................................................................................42 
6.7 
Pregnancy ...................................................................................................................................46 
7 
STATISTICAL METHODS ..................................................................................................................46 
7.1 
Study Patients .............................................................................................................................47 
7.1.1 
Disposition of Patients ................................................................................................................47 
7.1.2 
Protocol Deviations ....................................................................................................................47 
7.1.3 
Analysis Sets ..............................................................................................................................47 
7.2 
General Considerations ..............................................................................................................48 
7.2.1 
Analysis and Data Conventions..................................................................................................48 
7.3 
Demographics, Medical History, Baseline Characteristics and Concomitant Medications .......49 
7.4 
Determination of Sample Size ....................................................................................................49 
7.5 
Efficacy Analyses .......................................................................................................................49 
7.5.1 
Primary Efficacy Analysis ..........................................................................................................49 
7.5.2 
Secondary Efficacy Analyses .....................................................................................................50 
7.5.3 
Exploratory Efficacy Endpoints .................................................................................................50 
7.6 
Safety Analyses ..........................................................................................................................51 


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7.6.1 
Adverse Events ...........................................................................................................................51 
7.6.2 
Independent Data Monitoring Committee ..................................................................................51 
8 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ..............................................................51 
8.1 
Data Quality Assurance ..............................................................................................................51 
8.1.1 
Database Management and Quality Control...............................................................................51 
8.2 
Case Report Forms and Source Documentation .........................................................................52 
8.2.1 
Data Collection ...........................................................................................................................52 
8.3 
Access to Source Data ................................................................................................................52 
8.4 
Archiving Study Records ...........................................................................................................53 
8.5 
Good Clinical Practice ................................................................................................................53 
8.6 
Informed Consent .......................................................................................................................53 
8.6.1 
Consent Procedure ......................................................................................................................53 
8.6.2 
Retrospective Patient Informed Consent ....................................................................................54 
8.6.3 
Withdrawal of Consent ...............................................................................................................54 
8.7 
Protocol Approval and Amendment ...........................................................................................55 
8.8 
Independent Data Monitoring Committee ..................................................................................55 
8.9 
Steering Committee ....................................................................................................................55 
8.10 
Duration of the Study .................................................................................................................56 
8.11 
Premature Termination of the Study ..........................................................................................56 
8.12 
Confidentiality ............................................................................................................................56 
8.13 
Other Ethical and Regulatory Issues ..........................................................................................56 
8.14 
Publication Policy .......................................................................................................................56 
REFERENCE LIST .......................................................................................................................................58 
 
TABLE OF FIGURES 
 
FIGURE 1. STUDY DESIGN ................................................................................................................................27 
 
TABLE OF TABLES 
 
TABLE 1. SPECIFIC CONDITIONS NECESSITATING CORTICOSTEROID TREATMENT AND DISCONTINUATION OF 
THE IFN BETA-1A TREATMENT .................................................................................................................22 
TABLE 2. SCHEDULE OF PROCEDURES AND ASSESSMENTS ..............................................................................36 
TABLE 3. BIOCHEMISTRY AND HAEMATOLOGY VARIABLES ............................................................................40 


Faron Pharmaceuticals Ltd. 
 
HIBISCUS Protocol v4.0
FP-1201-lyo 
 
 (lyophilized human interferon beta-1a) 
page 10 (60)
 
 
CONFIDENTIAL 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
AEP 
Acute Eosinophilic Pneumonia 
AKI 
Acute Kidney Injury 
ALI 
Acute Lung Injury 
ARDS 
Acute Respiratory Distress Syndrome 
BIPAP 
Bilevel Positive Airway Pressure 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CD73 
Cluster of differentiation 73 
CI 
Confidence Interval 
CPAP 
Continuous Positive Airway Pressure 
CRA 
Clinical Research Associate (Monitor) 
CT 
Computerised Tomography 
D 
Day (as in treatment day) 
DNR  
 Do Not Resuscitate 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECMO 
Extracorporeal membrane oxygenation 
e-CRF 
Electronic Case Report Form 
FAS 
Full Analysis Set  
FU 
Follow-up 
HR 
Heart Rate 
HSP 
Hypersensitivity Pneumonitis 
ICD 
Informed Consent Document 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IRB 
IMP 
Institutional Review Board 
Investigational Medicinal Product 


Faron Pharmaceuticals Ltd. 
 
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(lyophilized human interferon beta-1a) 
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IV 
Intravenous 
IWRS 
Interactive Web-Response System  
JAK-STAT 
Janus kinase-signal transducer and activator of transcription 
MERS 
Middle East Respiratory Syndrome 
MIU 
Million International Units 
MOF 
Multiple Organ Failure 
MM 
Medical Monitor 
MxA 
Myxovirus resistance protein A 
NOAEL 
No Observed Adverse-Effect Level 
OSCI 
WHO ordinal scale for clinical improvement  
OTD 
Optimum Tolerated Dose 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PerLR 
Personal Legal Representative 
PD 
Pharmacodynamics 
PIM 
Potential Inflammatory Marker 
PPS 
Per-Protocol Set  
PrfLR 
Professional Legal Representative 
RRT 
Renal Replacement Therapy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
WBC 
White Blood Cells 


Faron Pharmaceuticals Ltd. 
 
HIBISCUS Protocol v4.0
FP-1201-lyo 
 
(lyophilized human interferon beta-1a) 
page 12 (60)
 
 
CONFIDENTIAL 
 
1 
PROTOCOL SYNOPSIS 
Title 
A Phase II Multi-Center, Double-Blind, Randomized and 
Controlled Study of the Safety and Efficacy of Intravenous 
Recombinant Human Interferon Beta-1a in Comparison to 
Dexamethasone for the Treatment of Hospitalized Patients with 
COVID-19 Infection 
Sponsor Study No. 
FP1CLI017 
Phase 
II 
Funding/Support 
Sponsor 
U.S. Department of Defense and Faron Pharmaceuticals Ltd. 
Faron Pharmaceuticals Ltd., Turku, Finland 
Co-ordinating 
Investigators 
Professor Daniel Talmor, Harvard Medical School 
Professor Adit Ginde, University of Colorado School of Medicine 
Study Centre(s) 
Approximately 5-15 investigational sites located in the USA and 
possibly also in other countries 
Objectives 
 
Primary Objectives 
- 
To demonstrate the safety and tolerability of early intravenous (IV) 
IFN beta-1a administration in hospitalized patients with COVID-
19 infection compared to dexamethasone 
- 
To investigate the efficacy of IV IFN beta-1a to improve clinical 
status in hospitalized patients with COVID-19 compared to 
dexamethasone 
Secondary Objectives  
- 
To assess the immunogenicity of IFN beta-1a 
- 
To investigate the efficacy of IV IFN beta-1a on clinical outcomes
in 
hospitalized 
patients 
with 
COVID-19 
compared 
to 
dexamethasone 
Exploratory 
Objectives 
- 
To investigate the efficacy of IV IFN beta-1a on additional clinical 
outcomes in hospitalized patients with COVID-19 compared to 
dexamethasone 
- 
To investigate study treatment discontinuation rate of IFN beta-1a 
compared to dexamethasone 
- 
To investigate the effect of IMPs on viral burden (quantitative) in 
blood during the disease course 
- 
To measure the pharmacodynamic (PD) effects of IFN beta-1a 
(Myxovirus Resistance Protein A (MxA) and cluster of 
differentiation 73 (CD73) 
- 
To measure IFN beta levels during the treatment 
- 
To evaluate potential inflammatory markers (PIMs) and interferon 
signalling markers at protein and RNA level in response to 
treatment 


Faron Pharmaceuticals Ltd. 
 
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(lyophilized human interferon beta-1a) 
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CONFIDENTIAL 
 
- 
To evaluate genetic susceptibility to IFN beta-1a treatment 
- 
To investigate the efficacy of study treatment based on SARS-
CoV-2 variant 
- 
To investigate the efficacy of study treatment based on the 
vaccination status 
Design 
This is a multi-center, double-blind, randomized and controlled trial of 
early IV administration of IFN beta-1a compared with dexamethasone 
in hospitalized patients with COVID-19 infection not requiring high-
flow (> 8L/min) oxygen therapy or mechanical ventilation. 
COVID-19 patients in the Emergency Department (ED) or early in 
hospitalization will undergo screening during which informed consent 
will be obtained and eligibility assessed by Inclusion and Exclusion 
criteria. No more than 48 hours may elapse between hospital arrival of 
the patient and administration of the first dose of the study drug. 
At randomization, subjects will be stratified by gender and age to be 
treated daily either with IV IFN beta-1a 10 µg or IV dexamethasone 6 
mg for 6 days while hospitalized and will undergo daily assessments 
while in hospital for a maximum of 28 days. Study specific 
assessments will be collected at pre-dose Day 1 through Day 28, in 
addition, clinical routine assessments will be utilized for safety and 
efficacy assessments. 
Due to preclinical and clinical data demonstrating that concomitant 
administration of systemic corticosteroids diminishes the effectiveness 
of IV IFN beta-1a, systemic open-label corticosteroids are not 
permitted during the 6-day acute intervention period. The requirement 
for systemic open-label corticosteroid treatment is an exclusion 
criterion in the study. However, if the Investigator/attending clinician 
determines that the subject requires open-label corticosteroids during 
the intervention period (Study Day 1 - Day 6), the investigational 
medicinal products (IMPs) will be discontinued, and the subject will 
continue to have the ongoing study assessments. From Day 7 onward 
corticosteroid treatment will be permitted if required according to the 
judgment of the treating attending clinician. Same principle should be 
applied for other co-medications with potential of interacting with IFN 
beta-1a, such as baricitinib, tofacitinib and other inhibitors of janus 
kinase-signal transducer and activator of transcription (JAK-STAT) 
signalling pathway. 
Specific medical conditions that require immediate corticosteroid 
treatment are specified in the protocol. Once diagnosed, treatment with 
IMP should be discontinued and the subjects will continue to have the 
ongoing study assessments. 
Standard treatment practice of COVID-19 should follow treatment 
guidelines, and should a study patient progress in disease severity 
requiring increasing amounts of supplemental oxygen, the study 
medication should be stopped and dexamethasone treatment should 


Faron Pharmaceuticals Ltd. 
 
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(lyophilized human interferon beta-1a) 
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CONFIDENTIAL 
 
begin 
according 
to 
guidelines 
(https://www.covid19treatmentguidelines.nih.gov/therapeutic-
management). Remdesivir does not impact study treatment. 
The main analysis and reporting will use Day 28 data after the last 
study subject has completed the Day 28 assessments.  
An Independent Data Monitoring Committee (IDMC) will be 
established to monitor safety on an ongoing basis.
Study treatments 
Investigational medicinal products (IMPs): 
- 
IFN beta-1a 10 µg (recombinant human IFN beta-1a) or 
Dexamethasone 6 mg will be administered once daily as an IV 
bolus injection for 6 days. 
- 
To maintain blinding at administration, every study subject will 
receive two separate bolus injections of IMP (either IFN-beta -
1a/saline, and another injection of Saline/Dexamethasone). Study 
IMPs will be prepared by an unblinded person according to the 
randomization code. 
Number of Study 
subjects 
140 subjects with COVID-19 infection will be randomized at 
approximately 5-15 investigational sites. 
Population 
The inclusion and exclusion criteria apply during screening and prior 
to administration of the first dose of study drug on Day 1. 
Inclusion Criteria 
1. Age 
 years 
2. Positive SARS-CoV-2 test by PCR (polymerase chain reaction) or 
other diagnostic method within the past 7 days 
3. Admission to hospital with respiratory symptoms of COVID-19 
requiring hospital care and oxygen supplementation (  8L/min) 
4. Respiratory symptom onset no more than 7 days prior to hospital 
arrival  
5. Informed consent from the subject or 
representative or a professional legal representative must be 
available 
Exclusion Criteria 
1. Unable to screen, randomize and administer study drug within 48
hours from arrival to hospital   
2. Systemic corticosteroid, baricitinib, tofacitinib or other JAK-
STAT signalling pathway inhibiting therapy within 7 days prior to
arrival to hospital or planned for the next days 
3. Known hypersensitivity or contraindication to natural or 
recombinant IFN-beta-1a or its excipients, or to dexamethasone or 
its excipients 
4. Currently receiving IFN-beta-1a therapy 
5. Home assisted ventilation (via tracheotomy or non-invasive) 
except for Continuous Positive Airway Pressure (CPAP) / Bilevel 


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Positive Airway Pressure (BIPAP) used only for sleep-disordered 
breathing 
6. Participation 
in 
another 
concurrent 
interventional 
pharmacotherapy trial during the study period 
7. Decision to withhold life-sustaining treatment; patient not 
committed to full support (except DNR after cardiac arrest only) 
8. Woman known to be pregnant, lactating or with a positive 
pregnancy test (urine or serum test)  
9. Subject is not expected to survive for 24 hours 
10. Subject has liver failure (Child Pugh grade C) 
11. Any clinical condition that in the opinion of the attending clinician 
or Investigator would present a risk for the subject to participate in 
the study 
Criteria for Evaluation 
of Safety 
- 
Adverse events, serious adverse events, and deaths  
- 
Physical 
examination, vital signs and laboratory results 
(biochemistry, haematology) collected as standard of care routine 
- 
Immunogenicity as measured by anti-IFN beta antibodies 
Criteria for Evaluation 
of Efficacy 
Primary Efficacy Endpoint: 
- 
Clinical status at Day 14 (first day of study drug is Day 1) as 
measured by WHO 9-point ordinal scale: 
0 - No detectable infection 
1 - Not hospitalized, no limitations on activities 
2 - Not hospitalized, limitation on activities 
3 - Hospitalized, not requiring supplemental oxygen  
4 - Hospitalized, requiring supplemental oxygen   
5 - Hospitalized, on non-invasive ventilation or high flow oxygen 
devices  
6 - Hospitalized, on invasive mechanical ventilation 
7 - Hospitalized, on mechanical ventilation plus additional organ 
support: renal replacement therapy (RRT), extracorporeal 
membrane oxygenation (ECMO)  
8 - Death 
Secondary Efficacy Endpoints:  
- 
Clinical status at Day 28 as measured by WHO 9-point ordinal scale
- 
In-hospital mortality at Day 28 and Day 90 
- 
Overall (all-cause) mortality at Day 28 and Day 90 
Criteria for Evaluation 
of Exploratory 
Endpoints 
Exploratory Efficacy Endpoints 
- 
Incidence of Acute Respiratory Distress Syndrome (ARDS)  
- 
Incidence of Acute Kidney Injury (AKI) 
- 
Incidence of new mechanical ventilation 


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- 
Days alive and free of renal support at Day 28 
- 
Days alive and free of ECMO at Day 28 
- 
Days alive and free of oxygen support at Day 28 
- 
ICU-days at Day 28 
- 
Days on mechanical ventilation on Day 28 
- 
Length of Hospital stay among survivors at Day 90 
- 
Incidence of study treatment discontinuation and transition to an 
open label corticosteroid 
- 
Association of the efficacy outcome measures of study treatment 
with vaccination status   
Exploratory Laboratory Efficacy Endpoints 
- 
Quantitative PCR for SARS-CoV-2 in blood on pre-dose Day 1 and
Day 4, Day 7, Day 10 and on Day 14 (only for hospitalized patients, 
if 
 discharge is before D14, the specimen is obtained also 
on the day of discharge)  
- 
CD73 in blood on pre-dose Days 1, 3, 5 and on Day 7 (only for
hospitalized patients) 
- 
INF beta levels in blood on Day 1 pre-dose, Day 1 (5 minutes after 
dosing), pre-dose on Day 3 and on Day 7 (only for hospitalized
patients) 
- 
Association of baseline IFN-beta level (possible deficiency in 
endogenous IFN-beta response to viral infection) with the disease 
outcome (WHO 9-point ordinal scale) 
- 
MxA levels in blood on pre-dose Days 1, 3, 5 and on Day 7 (only 
for hospitalized patients)  
- 
Changes in levels of potential inflammatory markers (PIMs) at 
protein and RNA level on pre-dose Days 1, 3, 5 and on Day 7 (only 
for hospitalized patients) 
- 
Correlation of pharmacogenetic markers with PD markers of IFN 
beta-1a activity, and disease outcome measures 
- 
Association of the efficacy outcome measures of study treatment 
with the variant of SARS-CoV-2 and vaccination status   
Statistical Methods 
 
Statistical power and 
sample size justification:  
140 patients will be randomised 1:1 for active: comparator. Conditional 
power re-assessment will be conducted at an interim analysis after circa 
70 patients have been enrolled and followed up for the primary efficacy 
endpoint variable. The primary variable is the clinical status at Day 14 
using a WHO 9-point scale (0=no detectable infection to 8=death). It 
will be analysed using ordinal logistic regression model comparing the 
odds of having better clinical status (smaller number in the 9-point 
scale) at day 14 between treatment groups. The sample size is based on 


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an assumption of odds ratio of 0.43 between groups leading to a power 
of 80% with 70 evaluable patients per group. In the interim analysis the 
conditional power will be calculated based on the observed result and 
the sample size will be increased in case the conditional power is in the 
predefined promising zone. Futility analysis is not included at interim. 
Dichotomous secondary efficacy variables will be analysed using 
logistic regression models and time-to-event variables using Cox 
proportional hazards models. Other secondary variables with non-
gaussian data (e.g., variables measuring number of days) will be 
analysed using general linear models or non-parametric methods 
Analysis Sets: 
 
The Full Analysis Set (FAS) will consist of all randomized patients 
who receive at least one dose of study medication. 
The Per-Protocol Set (PPS) will consist of those subjects in the FAS 
excluding subjects with major protocol violations. 
A list of major protocol violations relevant for excluding data from the 
PPS will be detailed in the Statistical Analysis Plan. The precise 
definition of the PPS at the subject level will be identified at the blinded 
data review meeting before the interim and final analysis. 
Statistical analyses for the primary and secondary endpoints will be 
performed on both the FAS and PPS. 
The safety set will consist of all subjects who receive at least one dose 
of the study IMPs. The safety and tolerability analyses will be based on 
this analysis set. A subject who receives the wrong treatment according 
to the randomization will be analysed for safety and tolerability in the 
treatment group corresponding to the treatment received. 
 
 
 


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2 
INTRODUCTION 
This is a Phase II clinical study to investigate the safety and efficacy of intravenous (IV) recombinant 
human interferon (IFN) beta-1a in hospitalized patients with COVID-19 infection not requiring high-
flow oxygen or mechanical ventilation. The study was initially planned to compare active drug to 
placebo, but compliance with treatment guidelines for patients with supplemental oxygen prompted 
a change in the comparator arm to dexamethasone instead of placebo. Recombinant human IFN beta-
1a is an approved treatment as an intramuscular (IM) or subcutaneous (SC) formulation for subjects 
with multiple sclerosis and its safety profile in these subjects is well characterised. IV IFN beta-1a 
has been administered previously to 314 critically ill patients in phase I-III clinical studies for the 
treatment and prevention of Multiple Organ Failure (MOF) and Acute Respiratory Distress 
Syndrome (ARDS) (The ARDS Definition Task Force 2012). Tolerability has been good in critically 
ill patients (Ranieri et. al. 2020), and in healthy volunteers (FP1CLI011 clinical study report). IFN 
beta-1a should not be administered with concomitant systemic corticosteroids, as corticosteroids may 
inhibit IFN beta signalling (Jalkanen et al. 2020) and may impair the up-regulation of CD73 (Kiss et. 
al. 2007) on vascular endothelium. Administering IFN beta-1a IV achieves broader exposure in the 
circulation, compared to SC or IM routes of administration (Buchwalder et. al. 2000). Therefore, IV 
administration is a desired administration method to achieve efficient CD73 upregulation and effect 
on vascular integrity, especially in pulmonary circulation and under critical illness conditions.  
2.1 Background on COVID-19 
Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious illness caused by severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Del Rio and Malani 2020 and Fauci et al. 
2020).  The COVID-19 infection represents the seventh coronavirus known to cause disease in 
humans. (Li et al. 2020).  Four of the coronaviruses are known to cause symptoms of the common 
cold in immunocompetent individuals while two others (SARS-CoV and MERS-CoV) have caused 
recent outbreaks of severe and sometimes fatal respiratory diseases (Cui et al. 2019). SARS-CoV-2 
appears to exploit the same cellular receptor as SARS-CoV and MERS-CoV, and thus the effects of 
IFN beta on SARS-CoV2 are likely to be very similar to these prior coronaviruses (Zhou et al. 2020). 
Although the epidemiology has not been fully elucidated, many adults with COVID-19 appear to 
experience fever, cough, and fatigue and then recover within 1-3 weeks.  However, approximate 20% 
of adults with COVID-19 develop severe illness, typically manifesting as pneumonia and acute 
hypoxemic respiratory failure, with continued progression to ARDS and death in some cases (Del 
Rio and Malani 2020, Fauci et al. 2020, Li et al. 2020). 
ARDS is a type of acute lung injury characterized by dysregulated inflammation, coagulopathy, and 
accumulation of immune cells, leading to injury of the endothelial barrier, increased permeability of 
the alveolar-capillary barrier, and non-cardiogenic pulmonary edema. Although mortality from 
ARDS appears to have decreased in the last couple of decades due to improvements in supportive 
care including lung protective ventilation and in the treatment of underlying conditions, it still 
remains up to 40% in moderate or severe ARDS. In addition, the impairment to quality of life among 
ARDS survivors is significant. At two years after a diagnosis of moderate to severe ARDS, 
approximately 35% of patients are still unable to return to work (Kamdar et al. 2018). There are 
currently no approved pharmacological therapies for ARDS. 


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2.2 Scientific justification for IFN beta-1a for COVID-19 
2.2.1 IFN beta and Severe Coronavirus disease 
IFN beta is a type I IFN, an endogenous signalling protein made and released by host cells in response 
to the presence of a viral infection. It is a natural defence mechanism released by virus infected cells 
to enhance the resistance of uninfected cells. Type I IFN deficiency has been associated with severe 
COVID-19 disease previously (Hadjadj et al. 2020, Zhang et al. 2020). 
Prior data indicates that treatment with IFN beta enhances viral clearance and improves clinical 
outcomes for Middle East Respiratory Syndrome (MERS) coronavirus in nonhuman primates (Chan 
2015). In addition, IFN alpha-2b combined with ribavirin reduced viral replication, moderates host 
response, and improves clinical outcomes in nonhuman primates with MERS coronavirus (Falzarano 
2013). In addition, a retrospective study of IFN alpha-2a combined with ribavirin was associated 
with lower mortality in MERS coronavirus (Omrani 2014). Recently, a clinical study by Arabi et al. 
(2020) showed that IFN beta significantly reduced mortality in MERS if given within 7 days of 
symptom onset. Concerning COVID-19, in vitro studies have shown that IFN beta inhibits replication 
of SARS-CoV-2 (Lokugamage et al. 2020) and has shown effect in treating hospitalized COVID-19 
patients both in IM (Hung et al. 2020) or inhaled form (Monk et al. 2020). 
The effect of IFN beta on COVID-19 was investigated in SOLIDARITY (WHO Solidarity Trial 
Consortium 2021) and ACTT-3 (NCT04492475) trials. In both trials overlapping use of 
corticosteroids with IFN beta-1a was permitted. In SOLIDARITY, approximately half the patients 
who were assigned to IFN beta (and half their controls) received concomitant glucocorticoids. Same 
information is not available for the ACTT-3 trial. Therefore, potential beneficial effects of IFN beta-
1a may have been mitigated by the concomitant use of corticosteroids in these trials. In these previous 
trials IFN beta-1a was almost entirely used in its subcutaneous form, which does not deliver the drug 
to the lung endothelium. 
2.3 IV IFN beta-1a 
IV IFN beta-1a has originally been developed for the prevention and treatment of cytokine release 
and capillary leak, based on CD73 induction. The first human studies have been conducted in acute 
lung injury (ALI) (Bellingan et al. 2014) and in ARDS (Ranieri et al. 2020). In serious life-
threatening situations, such as infection leading to sepsis or ARDS, an escalation of the systemic 
inflammatory response leads to ARDS and MOF. In the case of respiratory failure and ARDS, a key 
pathophysiological result is increased vascular leakage, which has been suggested to be related to a 
lack of adenosine, which acts to enhance endothelial barrier function. Therefore, any biological 
substances that act to increase adenosine levels should reduce vascular leakage and be of benefit in 
ARDS. Such a substance is cluster of differentiation 73 (CD73)  a cell surface enzyme. Interferons, 
such as IFN beta-1a, have been shown to up-regulate CD73 and therefore could be a potential 
treatment for ARDS. Preclinical studies have shown that CD73 expression on endothelial cells is up-
regulated by IFN beta-1a treatment in a time- and dose-dependent fashion. (Kiss et al. 2007) 
Furthermore, in a mouse multi-organ failure model, IFN beta was shown to be of benefit in protecting 
the alveolar structure from damage compared with controls (Kiss et al. 2007). In addition, IFN beta 
treatment has been shown to prevent leakage in animal models of ALI (Kiss et al. 2007). Enhanced 
adenosine production also controls leukocyte infiltration, thus reducing the escalation of 
inflammation in lungs. 


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2.3.1 Toxicological studies 
A 28-day safety study was conducted in cynomolgus monkeys at three IV dose levels 0.25, 1.0 and 
3.0 million international units (MIU)/kg/d, which were well tolerated. IFN beta-1a -treatment was 
associated with minor changes in haematological and clinical chemistry variables, including an 
expected increase in concentrations of MxA in the blood and increased neutralising antibody activity 
on completion of treatment, particularly at the highest dose. The no observed adverse-effect level 
(NOAEL) for IFN beta-1a was considered 3.0 MIU/kg/d for 28 days. In a 70 kg human this would 
translate to a dose of 210 MIU/d or a total dose of 1260 MIU over 6 days. The proposed daily dose 
for this clinical study is 2.7 MIU/d (10 µg/d), i.e., a total of 16.2 MIU (60 µg) over 6 days. The 
NOAEL is therefore 77.7 times the proposed 6-day exposure to IFN beta-1a. 
2.3.2 Phase II dose finding study 
Recombinant human IFN beta-1a (FP-1201; a liquid formulation / drug product) was assessed for the 
treatment of ALI and ARDS (1994 American-European Consensus Conference definition of 
ALI/ARDS (Bernard et al 1994)) in a Phase I/II study (FPCLI001, clinicaltrials.gov: NCT00789685) 
(Bellingan et al 2014). This open-label study included 37 subjects with ALI/ARDS and the optimum 
tolerated dose (OTD) for IFN beta-1a (FP-1201) was shown to be 10 µg daily for 6 days. The primary 
efficacy endpoint was the Day 28 mortality rate, which was 8.1% in the safety population. From the 
literature, Day 28 mortality rates for ALI/ARDS vary from 20% (ALI) to over 60% (ARDS), with a 
generally accepted figure of approximately 40%. (Phua et. al. 2009, Doyle et. al. 1995, Zilberberg et. 
al. 1998, Sloane et. al. 1992) The long-term efficacy endpoint of 6-month mortality also demonstrated 
a mortality rate well below that expected for this population of patients. Only four of the 37 subjects 
died before the 6-month time point. 
2.3.3 Phase III studies INTEREST and MR11A8-2 
A phase III clinical trial (FPCLI002, clinicaltrials.gov: NCT02622724) (Bellingan et. al. 2017) was 
recently completed. 
lyophilized IFN beta-1a (FP-1201-lyo) for six 
days was not associated with reduced mortality or ventilator use. D28 mortality in the FP-1201-lyo 
group was 26% and in the placebo group 23%. Post hoc analyses of the FPCLI002 study indicates 
that glucocorticoid use was significantly associated with an increased risk of mortality in this study 
population even when taking into account disease severity. Subjects receiving FP-1201-lyo without 
concomitant glucocorticoids had D28 mortality of 11% compared with 32% mortality in subjects 
receiving concomitant glucocorticoids. Additional in vitro and ex vivo analyses of human lung tissue 
demonstrated that glucocorticoids inhibit the effect of IFN beta-1a to up-regulate CD73 on lung 
capillary endothelium. In addition, a genetic polymorphism located in a regulatory motif of the IFN 
alpha/beta receptor beta chain gene (the polymorphic site is a binding site for glucocorticoid receptor) 
was found to be associated with lower mortality (D28 mortality 11 % regardless of glucocorticoids 
use). This indicates that without the interfering effect of glucocorticoids on CD73 induction, FP-
1201-lyo may reduce mortality. 
A Japanese phase III trial (MR11A8-2) was also recently completed. The trial closed recruitment 
early after an interim analysis triggered by the European Phase III results and Independent Data 
Monitoring Committee
a total of 87 subjects (45 subjects in 
FP-1201-lyo and 42 in placebo groups). D28 mortality in the FP-1201-lyo group was 40% and in the 
placebo group 21%. The use of corticosteroids was even higher being 77%, compared to that of the 
INTEREST trial. In post hoc analyses, subjects receiving FP-1201-lyo without overlapping 
glucocorticoids had D28 mortality of 23 % compared with 47 % mortality in subjects receiving 
overlapping glucocorticoids. 


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2.3.4 Clinical safety experience of IV IFN beta-1a 
In all of the above-mentioned trials, the use of IFN beta-1a has not been associated with significantly 
increased risks or adverse events in comparison to placebo. Fever was the most common adverse 
event in both phase III trials.  
In the INTEREST trial, 18 (12.5%) study subjects and 12 (7.9%) study subjects in the IFN beta-1a 
group and placebo groups, experienced fever as an AE. Anaemia was the second most common AE 
(16 [11.1%] study subjects and 11 [7.2%] study subjects in the IFN beta-1a group and placebo groups, 
respectively). 
In the Japanese phase III trial (MR11A8-2) fever was reported more frequently (34.7% and 6.8%) as 
an AE for IFN beta-1a and placebo groups, respectively. The second most commonly reported AE 
was decreased platelet count (6.1%) in the IFN beta-1a group and increased hepatic enzymes (6.8% 
in both groups). 
The incidence of serious adverse events (SAEs) in the INTEREST trial (fatal and non-fatal) was 
similar in the active (53.5%) and placebo (50.7%) groups. The overall incidence of AEs considered 
related to study drug was higher in the active group (28.5%) compared with the placebo group 
(21.7%).  
The incidence of SAEs in the MR11A8-2 trial (fatal and non-fatal) was similar in the active (53.1%) 
and placebo (47.7%) groups, but none of the events were strongly suspected of being causally related 
to the study drug. 
In healthy volunteers IV IFN beta-1a induced a decrease in circulating neutrophils below lower limit 
of normal approximately three days after the first dose. Blood neutrophils returned to normal range 
within a few days after the last administered dose. One possible explanatory mechanism is that IFN 
causes the transfer of neutrophiles from the blood to the tissue 
as a precaution to 
IFN signal and against the possibility of viral presence. In severely ill patients in clinical studies 
FPCLI002 and MR11A8-2 a similar phenomenon was not observed (Clinical study FP1CLI011, 
Faron data on file). 
2.4 Dexamethasone 
2.4.1 Clinical safety experience of Dexamethasone 
I.V dexamethasone is recommended therapy for hospitalized patients with hypoxemia who are 
receiving oxygen through a high-flow device, or non-invasive ventilation, or invasive ventilation. It 
is also recommended for patients receiving increasing amounts of supplemental oxygen therapy 
(https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/corticosteroids/). It 
has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or 
mitigate the deleterious systemic inflammatory effects in patients with severe form of COVID-19.  
The incidence of side effects associated with the use of dexamethasone generally correlates with 
dosage, timing of administration, and duration of treatment. The most commonly occurring side 
effects of dexamethasone have included a wide range of psychiatric reactions, psychotic reactions, 
behavioural disturbances, irritability, anxiety, sleep disturbances and cognitive dysfunction including 
confusion and amnesia, decreased blood eosinophils and lymphocytes, increased infection 
susceptibility, masking of infection signs, aggravated infection, and fungal infections of mucous 
membranes and the skin. In adults the frequency of severe reactions has been estimated to be 5-6%. 
In this study, 6 mg IV doses of dexamethasone will be administered for 6 days. Adverse reactions 
associated with the use of glucocorticoids are usually dependent on the dose and the duration of the 


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treatment. Treatment duration of 6 days is relatively short, and the occurrence of the above-mentioned 
reactions associated with long-term use is unlikely. 
2.5 Potential Interaction of glucocorticoids with IFN beta 
The results of the Phase I/II study (FPCLI001) and Phase III studies (FPCLI002 and MR11A8-2) 
provided evidence for the beneficial effect of intravenously administered IFN beta-1a in study 
subjects with ARDS and also potentially significant interaction caused by concomitantly used 
corticosteroids. Therefore, a new controlled Phase II study should not allow the overlapping use of 
glucocorticoids with IFN beta-1a treatment. 
The dose selected for this study (10 µg) is based on information from the previous studies, where the 
maximum tolerated dose was found to be 22 µg. A dose of 10 µg was shown to be the OTD based 
on information from dose-limiting toxicity and proven markers of IFN beta-1a biological activity. 
An expansion cohort of 22 subjects treated with the OTD (10 µg) demonstrated preliminary evidence 
for the efficacy and biological activity of IFN beta-1a using proven surrogate markers without major 
safety concerns and in the previous Phase III Study (INTEREST) 10 µg dose of IFN beta-1a was 
proven safe and indicative of efficacy if not used together with glucocorticoids. Banning the use of 
glucocorticoids during the use of IFN beta-1a is rational, since glucocorticoids have not shown any 
benefit in early or mild COVID-19. On the contrary, in early COVID-19 and viral induced ARDS 
(the treatment window for IFN beta-1a) glucocorticoids have instead shown more harm than good 
(Hough 2014, Zhang et al. 2015, The RECOVERY Collaborative Group 2020). The only possible 
beneficial effect of glucocorticoids has been shown in more severe COVID-19 patients that require 
supplemental oxygen or mechanical ventilation.  
In this study, standard treatment should follow treatment guidelines, and should a study patient 
progress in disease severity requiring increasing amounts of supplemental oxygen, the study 
medication should be stopped and dexamethasone treatment should begin according to guidelines 
(https://www.covid19treatmentguidelines.nih.gov/therapeutic-management). Remdesivir treatment 
should also be applied according to the treatment guidelines and standard of care for every subject  
without contraindication (remdesivir does not impact study treatment). 
Additionally, specific corticosteroid responsive conditions (Table 1) should be treated adequately, 
and if diagnosed during the administration of the study drug (IFN beta-1a/dexamethasone), proper 
treatment with corticosteroids should not be delayed, but the study drug should be immediately 
discontinued, for the safety interest of the study subjects. Such patients will be followed according 
to the protocol and included in the intent-to-treat analysis. Patients may receive open-label antivirals, 
or immunomodulators (other than glucocorticoids) and remain in the study without discontinuing 
study drug. Use of such interventions will be reported and analyzed. 
Table 1. Specific conditions necessitating corticosteroid treatment and discontinuation of the IFN 
beta-1a treatment  
Condition 
Acute eosinophilic pneumonia (AEP)  
Diffuse alveolar hemorrage from vasculitis 
Crytogenic organizing pneumonia 
Acute hypersensitivity pneumonitis (HSP) 
Pneumocystis jiroveci pneumonia complicating human immunodeficiency virus (HIV) 
Nonspecific interstitial pneumonitis and pneumonitis associated with connective tissue disease 


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2.6 Risk/Benefit Assessment and Summary of Rationale 
COVID-19 pandemic is a major health concern with insufficient effective treatment options. IFN 
beta represents a naturally occurring viral defence, but if deficient, associated with more severe 
disease outcome (Hadjadj et al. 2020, Zhang et al. 2020). ARDS is a severe condition with a high 
mortality rate, despite progress in ICU medicine. Currently there is no approved pharmacological 
therapy available for ARDS. Patients with ARDS are treated with intensive support, which includes 
various strategies for assisted ventilation. Therefore, IV IFN beta-1a is a plausible treatment option 
to be investigated for the treatment of hospitalized COVID-19 and prevention of the development of 
ARDS. This is what the current study aims to achieve.  
The previous results of the Phase I/II and Phase III studies in ARDS provided evidence for the 
beneficial effect of IFN beta-1a if not used together with corticosteroids. The safety profile of IFN 
beta-1a does not indicate serious adverse events based on one phase I study in healthy volunteers and 
two phase III studies in subjects with ARDS. Observed finding of neutrophils marginalization only 
in healthy volunteers (although not in severely ill ARDS patients), warrants investigation of complete 
blood count and leukocyte differential to monitor blood neutrophil levels in this study also. 
Non-clinical data from conventional studies of safety, pharmacology, repeated-dose toxicity and 
genotoxicity reveal no special hazard for humans treated with IFN beta-1a.  
Phase III clinical studies (INTEREST and MR11A8-2) and phase I clinical study (FP1CLI011) in 
healthy volunteers did not identify any major safety risks for FP-1201-lyo. A decrease in IL-6 IL-8 
and IFN-gamma values was observed in patients treated with FP-1201-lyo, a finding that was similar 
to those found in a placebo group (Ranieri et al. 2020). Fever was the most common AE in phase III 
studies, and all healthy volunteers in the study FP1CLI011 experienced fever as a response to the 
treatment. The pyrogenic effect is characteristic for IFN beta-1a as well as for other type I IFNs. In 
healthy volunteers, the body temperature characteristically reached 38 39°C (axillary) 1-2 hours 
after the FP-1201-lyo administration, and this elevation persisted for around 2 hours (all treated with 
antipyretic analgesics). The temperature elevations vary substantially among individuals. IFN beta-
1a induced fever responds to antipyretic analgesic drugs, which are recommended to decrease (or 
prevent) the flu-like symptoms associated with IFN beta-1a administration. Serious adverse reactions 
possibly related to IFN beta-1a reported more than once in phase III clinical trials, include two cases 
of increased transaminases, two cases of thrombocytopenia, three cases of hypertension, and two 
cases of rhabdomyolysis. The available information suggests that the present study
risk/benefit 
ratio is favourable. 
Investigating the effect of IFN beta-1a to prevent ARDS in viral pneumonia (and particularly SARS-
CoV-2) is especially intriguing because of the potential beneficial effects of IFN beta-1a in direct 
viral defense, association of type I IFN deficiency with worse outcomes in COVID-19 (Hadjadj et al 
2020, Zhang et al. 2020), and the induction of CD73-mediated preventive effects on endothelial 
barrier function and pulmonary capillary leak. The current study aims to detect the benefit of IFN 
beta-1a in clinical outcome measures (WHO 9-point ordinal scale), reduced need of mechanical 
ventilation, mortality and development of organ failure and ARDS versus the current standard of care 
for COVID-19. Dexamethasone was chosen as the comparator arm to align with treatment guidelines 
for hospitalized COVID-19 patients requiring supplemental oxygen. The rationale underlying the 
current design is provided below. Safety of both treatment arms will be assessed equally. 
Study subjects will be randomized in a 1:1 ratio of IFN beta-1a: dexamethasone. According to current 
NIH COVID-19 treatment guidelines, dexamethasone can be considered for all patients receiving 
increasing amounts of supplemental oxygen, but remdesivir without dexamethasone is a reasonable 


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treatment option for patients requiring  minimal levels of supplemental oxygen. Remdesivir does not 
impact study treatment. 
In the current study, the target population is mild COVID-19 subjects with a need for low levels of 
supplemental oxygen. Subjects randomised to IFN beta-1a treatment will not receive dexamethasone 
while on IFN beta-1a, but will receive it if deterioration occurs, at which point IFN beta-1a will be 
discontinued. However, not receiving dexamethasone should not subject the study participants to an 
increased risk for harm for the following reasons: 
In the RECOVERY trial (on which the NIH recommendations are largely based), increasing benefit 
from corticosteroids was associated with increased COVID-19 severity. The greatest benefit was 
seen in patients receiving invasive mechanical ventilation, somewhat less benefit in patients receiving 
supplemental oxygen (but not invasively ventilated), and no benefit  with a suggestion of harm - in 
patients not receiving supplemental oxygen (The RECOVERY Collaborative Group 2020). 
Unfortunately, the RECOVERY trial data were not sufficiently granular to identify the impact of the 
dose of oxygen in non-intubated patients, i.e., supplemental oxygen at low flows vs higher flow 
conventional oxygen vs high flow nasal oxygen vs non-invasive ventilation. Nonetheless, these data 
suggest a dose-
as determined by the application of supplemental oxygen. Given this dose-response, it is uncertain if 
subjects with low flow supplemental oxygen derive any benefit from dexamethasone. 
The rationale to randomise patients (IFN beta-1a or dexamethasone) with hospitalized COVID-19 
patients requiring lower flow oxygen supplementation is justified; IFN beta is an anti-viral that 
should be initiated relatively early for COVID-19 to enhance the dual mechanisms: natural anti-viral 
effect + protection of alveolar-capillary barrier function (see Sections 2.2.1 and 2.3). Corticosteroids 
are very effective immunosuppressants, but strong immune-suppression early in the disease course 
may be detrimental as evidenced by data suggesting worse outcomes with dexamethasone in COVID-
19 patients with mild disease, i.e., those hospitalized patients not receiving supplemental oxygen. 
Study subjects randomised to IFN beta-1a, will not receive dexamethasone at the earliest stage of the 
disease (while on low flow supplemental oxygen), but importantly, will receive it should their 
condition deteriorate as evidenced by the need for higher doses of supplemental oxygen (i.e., high 
flow oxygen at flow rates greater than 10 l/min, use of high flow nasal oxygen, non-invasive 
ventilation, or invasive ventilation).   
3 
STUDY OBJECTIVES 
3.1 Primary Objective 
 To demonstrate the safety and tolerability of early IV IFN beta-1a administration in 
hospitalized patients with COVID-19 infection compared to dexamethasone  
 To investigate the efficacy of IV IFN beta-1a to improve clinical status in hospitalized 
patients with COVID-19 compared to dexamethasone 
3.2 Secondary Objectives 
 To assess the immunogenicity of IFN beta-1a 
 To investigate the efficacy of IV IFN beta-1a on clinical outcomes in hospitalized patients 
with COVID-19 compared to dexamethasone 


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3.3 Exploratory Objectives 
 To investigate the efficacy of IV IFN beta-1a on clinical outcomes in hospitalized patients 
with COVID-19 compared to dexamethasone 
 To measure the pharmacodynamic (PD) effects of IFN beta-1a (MxA and CD73) 
 To measure IFN beta levels during the treatment  
 To evaluate potential inflammatory markers (PIMs) and interferon signalling markers at 
protein and RNA level in response to treatment 
 To evaluate genetic susceptibility to IFN beta-1a treatment 
 To investigate study treatment discontinuation rate of IFN beta-1a compared to 
dexamethasone 
 To investigate the effect of IMPs on viral burden (quantitative) in blood during the disease 
course 
 To investigate the efficacy of study treatment based on SARS-CoV-2 variant 
 To investigate the efficacy of study treatment based on the vaccination status 
3.4 Outcome Measures 
3.4.1 Primary outcome measure 
 Clinical status at Day 14 (where first day of study drug is Day 1) as measured by WHO 
9-point ordinal scale:  
0. No detectable infection;  
1. Not hospitalized, no limitations on activities;  
2. Not hospitalized, limitation on activities;  
3. Hospitalized, not requiring supplemental oxygen;  
4. Hospitalized, requiring supplemental oxygen;  
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;  
6. Hospitalized, on invasive mechanical ventilation;  
7. Hospitalized, on mechanical ventilation plus organ support: RRT or ECMO;  
8. Death. 
3.4.2 Secondary outcome measures 
 Clinical status at Day 28 as measured by WHO 9-point ordinal scale: 
0. No detectable infection;  
1. Not hospitalized, no limitations on activities;  
2. Not hospitalized, limitation on activities;  
3. Hospitalized, not requiring supplemental oxygen;  
4. Hospitalized, requiring supplemental oxygen;  


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5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;  
6. Hospitalized, on invasive mechanical ventilation;  
7. Hospitalized, on mechanical ventilation plus organ support: RRT or ECMO;  
8. Death. 
 Outcome measures relating to the efficacy of IFN beta-1a treatment: 
o In-hospital mortality at Day 28 and Day 90 
o Overall (all-cause) mortality at Day 28 and Day 90 
3.4.3 Exploratory outcome measures 
 Incidence of ARDS 
 Incidence of Acute Kidney Injury (AKI) 
 Incidence of new mechanical ventilation 
 Days alive and free of renal support at Day 28 
 Days alive and free of ECMO at Day 28 
 Days alive and free of oxygen support, Day 28 
 ICU-days at Day 28 
 Days on mechanical ventilation on Day 28 
 Length of Hospital stay among survivors at Day 90 
 Incidence of study treatment discontinuation and transition to an open label corticosteroid 
 PD markers (CD73 and MxA) possibly related to the natural IFN responses, as well as to 
the IFN beta-1a treatment 
 Potential inflammatory and interferon signalling (e.g., IL-6, IL-8) markers at a protein 
and RNA level (Nanostring) in response to treatment. 
 Quantitative analysis (PCR) for SARS-CoV-2 from serum samples. 
 Genetic susceptibility to IFN beta-1a treatment, including but not limited to, by screening 
for SNP rs9984273 and surrounding area which is the glucocorticoid regulatory motif 
area of IFN alpha/beta receptor subunit 2 (IFNAR2) 
 Association of the efficacy outcome measures of study treatment with  the variant of 
SARS-CoV-2 
 Association of the efficacy outcome measures of study treatment with the vaccination 
status  
4 
OVERALL DESIGN AND PLAN OF THE STUDY 
4.1 Overview 
This is a multicentre Phase II, double-blind, randomized and controlled, study of the safety and 
preliminary efficacy of IV IFN beta-1a compared with dexamethasone in adult patients diagnosed 
with COVID-19 needing hospitalization, but not invasive mechanical ventilation or high 
flow/pressurized supplemental oxygen. The primary endpoint safety and tolerability of IV IFN beta-


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1a, and primary efficacy endpoint is WHO ordinal scale for clinical improvement (WHO OSCI) score 
at D14.  Both treatment groups will receive standard care according to current treatment guidelines, 
except open-label corticosteroids during study days D1-D6 (or other co-medication with potential of 
interacting with IFN beta-1a; Section 5.7). If the patient receives (oral or intravenous) glucocorticoids 
during study days D1-D6, the IMP will be discontinued, and the patient will continue with in all 
follow-up study assessments. 
Approximately 140 subjects are planned. Patients with COVID-19 admitted to hospital will undergo 
screening during which written informed consent will be obtained and eligibility assessed. Not more 
than 48 hours may elapse between arrival to hospital and administration of the first dose of study 
drug. An interactive web-response system (IWRS) will be used to randomise the patients using age 
and gender as stratification parameters. 
Following randomization, patients will be treated daily with IFN beta-1a 10 µg or dexamethasone 6 
mg as an IV bolus for 6 days and will undergo daily assessments while hospitalized. The main 
analysis and reporting will use D14 and D28 data. D90 data will be analysed separately. Final follow-
up will occur at D90 by phone or through medical records. The overall duration of the study for a 
patient is therefore 3 months. During the long-term follow-up periods patient care will follow normal 
hospital procedures, as appropriate. The study will be completed when the last patient completes D90 
study assessment. The study design is summarised in Figure 1. 
Discontinuation criteria for individual patients and the entire study are described in Section 4.8.1. 
The study design incorporates an Independent Data Monitoring Committee (IDMC) that will review 
ongoing safety (i.e., adverse events [AEs] and serious AEs [SAEs]) and will also make 
recommendations to the Sponsor as described in the IDMC charter. Details of the IDMC are given 
in Section 8.8. 
A schedule for the tests and assessments to be conducted during this study is given in Section 6 
(Table 2). 
 
 
 
 
 
IV IFN beta-1a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IV Dexamethasone 
 
 
 
 
 
 
 
 
 
 
Day 
 
 
D1 pre-dose
D1 - - - - - - - - - - - - - - - - - D6 
D7 D28 
D90 
 
 
 
 
 
 
 
Visit
Screening 
Randomisation
 
Double-blind treatment period
Short-term FU 
Long-term FUc 
 
Baseline 
includes D1 pre-dosea 
Daily assessments while hospitalizedb 
 
 
 
Figure 1. Study Design 
a 
Not more than 48 hours may elapse between arrival to hospital and administration of the first dose of study drug on 
D1. Once eligibility has been met, randomization can occur during screening or pre-dose on D1. 
b 
Assessments are described in the Schedule of Procedures in Table 2. 
c 
Telephone contact or searched from medical records if the patient cannot be contacted. 
Abbreviations: D=day; FU=follow-up 


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4.2 Criteria for Evaluation of the Safety and Efficacy 
4.2.1 Criteria for Evaluation of Safety 
 AEs up to D28, AEs occurring after D28 if the investigator considers there is a causal 
relationship with the study drug and all deaths up to D90. 
 Physical examination to the extent available, vital signs and available laboratory results 
(biochemistry and haematology including pre-dose D1, D2-D7, D10, D14, D28/last day 
in hospital laboratory tests (Table 2)) while hospitalized. 
 Immunogenicity as measured by anti-drug antibodies (ADA) 
4.2.2 Criteria for Evaluation of Efficacy 
Primary Efficacy Endpoint:  
 Clinical status at D14 as measured by WHO 9-point ordinal scale: 
0 -  No detectable infection; 
1 -  Not hospitalized, no limitations on activities; 
2 -  Not hospitalized, limitation on activities; 
3 -  Hospitalized, not requiring supplemental oxygen; 
4 -  Hospitalized, requiring supplemental oxygen;  
5 -  Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
6 -  Hospitalized, on invasive mechanical ventilation; 
7 -  Hospitalized, on mechanical ventilation plus additional organ support: renal 
replacement therapy, ECMO 
8 -  Death 
Secondary Efficacy Endpoints:  
 
Clinical status at D28 as measured by WHO 9-point ordinal scale (above) 
 
Secondary endpoints relating to the efficacy of IV IFN beta-1a treatment: 
- 
In-hospital mortality at Day 28 and Day 90 
- 
Overall (all-cause) mortality at Day 28 and Day 90 
4.2.3 Criteria for Evaluation of Exploratory Endpoints 
Exploratory Efficacy Endpoints:  
 Exploratory endpoints relating to the efficacy of IV IFN beta-1a treatment in comparison 
to dexamethasone: 
- 
Incidence of ARDS 
- 
Incidence of AKI 
- 
Incidence of new mechanical ventilation 
- 
Days alive and free of renal support at Day 28 
- 
Days alive and free of ECMO at Day 28 
- 
Days alive and free of oxygen support at Day 28 
- 
ICU-days at Day 28 
- 
Days on mechanical ventilation on Day 28 
- 
Length of Hospital stay among survivors at Day 90 


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- 
Incidence of study treatment discontinuation and transition to an open label 
corticosteroid  
- 
Association of efficacy outcome measures of study treatment with the vaccination 
status 
Exploratory Laboratory Endpoints: 
- 
Change in the treatment-specific exploratory biomarkers (MxA and CD 73) and PIMs 
(pre-dose on D1, D3, D5 and D7 for hospitalized patients) and Interferon beta (pre-dose 
on D1, D1 (5 minutes after study drug dosing), D3 and D7. 
- 
Viral clearance for SARS-CoV-2 infection by D14 (viral RNA copy number pre-dose D1 
and D4, D7, D10 and D14 
also on the day of discharge)) 
- 
A blood sample will be taken for pharmacogenetic analysis of the genetic susceptibility 
in responding to IFN beta-1a treatment. Under specific examination is SNP rs9984273 
and surrounding area which is the glucocorticoid regulatory motif area of IFN alpha/beta 
receptor subunit 2 (IFNAR2). According to the previous Phase III Study (FPCLI002) this 
polymorphic site may determine responsiveness to IFN beta-1a treatment and outcome. 
The sub-groups carrying polymorphism in this region will be analysed separately for the 
Study outcome measures. 
- 
Association of efficacy outcome measures of study treatment with the variant of SARS-
CoV-2  
4.3 Justification of the Study Design 
This is a Phase II study to evaluate the safety and efficacy of IFN beta-1a in comparison to 
dexamethasone in the treatment of subjects with COVID-19. The study is designed as a double-blind, 
randomized, parallel-group, controlled, multicentre clinical study. 
At present there is no approved pharmacological treatment for the prevention of ARDS. The only 
currently available treatment for mechanically ventilated COVID-19 patients is dexamethasone, but 
still COVID-19 mortality to ARDS remains high. Because of the lack of an effective pharmacological 
agent, glucocorticoids are widely used because of their anti-inflammatory properties. However, they 
may dampen natural anti-viral response of IFN beta signalling. Further, overlapping use of 
glucocorticoids may block IFN beta-1a from up-regulating CD73 on the lung endothelium. 
Therefore, the current approach is to investigate the use of IFN beta-1a before corticosteroids (or 
other medications with immunosuppressive activity) are indicated for COVID-19 and to prevent 
disease aggravation to ARDS. 
The study target population is defined to subjects requiring oxygen supplementation (< 8 l/min) in 
order 
to 
comply 
with 
the 
treatment 
guidelines 
(https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/). The IFN beta-1a 
treatment arm is not to receive dexamethasone for study days D1-D6. This is justified with the 
anticipated anti-viral effects of IFN beta and clinical observations of severity of the disease associated 
with a deficiency in IFN signalling, and uncertainty of the benefit from dexamethasone in mild 
COVID-19 (see Section 2.6 for detailed justification for the study setting). However, should the study 
subjects condition worsen during the early course of the study, while the IMP is being administered 
(Study days D1-D6), the IMP can be discontinued and dexamethasone initiated according to the 
discretion of the attending physician, ideally after a discussion with the local study investigator, if 
the clinical condition of the patient permits it.  


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4.4 Study Population 
The study population will consist of hospitalized patients due to confirmed SARS-CoV2 infection 
during the previous 7 days. Study subjects must meet all the inclusion criteria and none of the 
exclusion criteria to be enrolled in the study. The inclusion and exclusion criteria apply during 
screening and prior to administration of the first dose of study drug on D1. 
4.5 Inclusion Criteria 
The inclusion and exclusion criteria apply during screening and prior to administration of the 
first dose of study drug on study Day 1. 
1. Age 
 years 
2. Positive SARS-CoV-2 test by PCR or other diagnostic method within the past 7 days  
3. Admission to hospital with respiratory symptoms of COVID-19 requiring hospital care and 
oxygen supplementation (  8L/min) 
4. Respiratory symptom onset no more than 7 days prior to hospital admission  
5. Informed consent from the subject or 
legal representative must be available  
4.6 Exclusion Criteria 
1. Unable to screen, randomize and administer study drug within 48 hours from arrival to hospital   
2. Systemic corticosteroid, baricitinib or tofacitinib (or other JAK-STAT signalling pathway 
inhibitors) therapy within 7 days prior to arrival to hospital or planned for the next days  
3. Known hypersensitivity or contraindication to natural or recombinant IFN-beta-1a or its 
excipients, or to dexamethasone or its excipients 
4. Currently receiving IFN-beta-1a therapy 
5. Home assisted ventilation (via tracheotomy or non-invasive) except for Continuous positive 
airway pressure (CPAP) / Bilevel Positive Airway Pressure (BIPAP) used only for sleep-
disordered breathing 
6. Participation in another concurrent interventional pharmacotherapy trial during the study 
period  
7. Decision to withhold life-sustaining treatment; patient not committed to full support (except 
DNR after cardiac arrest only)  
8. Woman known to be pregnant, lactating or with a positive pregnancy test (urine or serum test)  
9. Subject is not expected to survive for 24 hours 
10. Subject has liver failure (Child Pugh grade C) 
11. Any clinical condition that in the opinion of the attending clinician or Investigator would present 
a risk for the patient to participate in the study 
4.7 Confirmation of Patient Eligibility 
To ensure appropriate enrolment into the study there will be a formal confirmation of eligibility 
process utilising the following procedure: 


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An electronic Case Report Form (e-CRF) with mandatory fields for completion and a checklist of 
inclusion and exclusion criteria; all items will need to be completed. The IWRS System will prompt 
the Investigator to confirm eligibility before allowing a patient to progress to randomization. 
With this method, only those patients whose data are recorded as meeting eligibility criteria can be 
randomized.  
4.8 Patient Withdrawal and Replacement 
4.8.1 Discontinuation Criteria 
Subject may withdraw from the entire study, including follow-up, at any time without penalty and 
for any reason without prejudice to their future medical care; they are not obliged to state their reasons 
for withdrawing. The decision to withdraw can be made by the subject or their Personal Legal 
Representative (PerLR) or Professional Legal Representative (PrfLR). 
Subjects may be withdrawn from the study under the following circumstances: 
 Protocol violations including non-compliance with study procedures or subject lost to 
follow-up 
 Subject, PerLR or PrfLR request 
 
The Investigator must ensure that the status page in the e-CRF for the end of the study is completed.  
Necessity for concomitant glucocorticoid treatment during study days D1-D6 may occur (for treating 
conditions listed in the Table 1 
necessitating systemic (oral or intravenous) glucocorticoid treatment) or deterioration of the study 
subjects condition due to COVID-19 may lead to IMP discontinuation and initiation of open label 
corticosteroids for COVID-19, neither of these are a condition for withdrawal. 
Subject may be required to withdraw from study drug after discussion with the Sponsor and/or 
Investigator for the following reasons: 
 Safety issues  
 At the discretion of the attending physician if it is considered to be in the subject
interest 
Subjects who discontinue study drug should continue in the study for follow-up to D90. The 
Investigator must ensure that the status page in the e-CRF is completed and every effort should be 
made to minimize missing data. 
In all cases, the reason(s) for withdrawal, including the primary reason, must be recorded in the e-
CRF. If a subject is prematurely withdrawn from the study drug for any reason, the Investigator must 
make every effort to perform the evaluations described for the follow-up visits. Any on-going AEs 
should be followed up to resolution or D28 whichever is the sooner. D90 assessment for mortality 
should be sought to the extent possible. See also Sections 8.6.2 and 8.6.3. 
If a subject (or their representative) withdraws consent and still agrees to undergo a final examination, 
this will be documented in the e-
(ICD), which will be countersigned and dated by the subject (or PerLR or PrfLR). 
Subjects who have discontinued or withdrawn their consent will not be replaced. Data and 
biospecimen collected before withdrawal will be used. 


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The study will be terminated if, in the opinion of the Sponsor, significant safety concerns arise during 
the conduct of the study. 
4.8.1.1 Non-attendance of Follow-up Assessments 
Attempts should be made to contact subjects discharged from hospital who do not attend their study 
follow-up assessments to ensure their well-being. In such cases, the subject will be contacted at least 
twice by telephone and once by letter to request that they attend the scheduled follow-up assessment. 
If subjects do not respond they will be considered as withdrawn at that time point (lost to follow-up). 
If a subject is lost to follow-up, wherever possible mortality data will be sought at all remaining 
mortality time points from alternative sources such as the subjec
 or health records. 
4.8.2 Replacement Policy 
A screen failure subject is defined as any subject who did not comply with the inclusion and exclusion 
criteria during screening and prior to receiving the first dose of study drug. Subjects who become 
ineligible after consenting, and before treatment, will be deemed to be screen failures and will be 
replaced. 
Subjects who complete screening and are randomized and receive the first dose of study drug will 
not be replaced even if later withdrawn or lost to follow-up. 
It is possible that a subject may be randomized to a study group following successful screening but 
may become ineligible prior to administration of the first dose of study drug. For example, prior to 
the first dose of study drug a subject may deteriorate and require mechanical ventilation. Such 
subjects will be classed as screen failures and will be replaced. 
Subject numbers (and randomization numbers if applicable) of screen failures will not be reallocated. 
A new subject will be enrolled and assigned the next available number. 
4.9 Planned Sample Size and Number of Study Centres 
It is planned to randomise and dose 140 subjects at approximately 5-15 centres in the USA and 
possibly also in other countries. See Section 7.4 for a discussion of sample size. 
4.10 Subject Identification and Randomization 
4.10.1 Subject Identification 
A unique subject number (subject identification number) will be allocated to study patients. The 
subject number will be assigned at the study centre on enrolment (i.e., provision of written informed 
consent) in chronological order of screening and will be used throughout the study. If a subject is not 
subsequently randomized, their screening number will not be reallocated. Each screened subject will 
therefore have a unique identifier. 
4.10.2 Randomisation Scheme 
Subjects will be randomized on a 1:1 basis to FP-1201-lyo or dexamethasone. IWRS will be used to 
obtain randomisation details. 
To ensure that conclusions are not dominated by data from a small number of centres, and also to 
obtain a broad spread of subjects and centres within the constraints of the inclusion/exclusion criteria, 
each centre will be allowed to include up to, but no more than, 30 patients. 


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Randomisation will be stratified by gender and age (under 70 years and 70 years and older). A 
sequence of randomisation numbers will be assigned to each study centre. 
Refer to Section 5.4 for details of blinding and breaking the blind. 
4.10.3 Randomisation of Subjects to Treatment 
Randomisation of patients to treatment will occur during screening or on D1 after all screening 
procedures have been performed and eligibility for inclusion in the study has been confirmed. Each 
randomized subject will receive a unique randomisation number. Randomized subjects who 
terminate their study participation for any reason, regardless of whether study drug was taken or not, 
will retain their randomisation number. 
The Investigator will use IWRS for randomisation of study subjects, details can be found in the study 
file. 
4.11 Minorities and Women 
No patients will be excluded on the basis of race, ethnicity, or sex. The Steering Committee and the 
Sponsor will monitor recruitment of minorities and women, and this recruitment will also be 
reviewed by the IDMC.  
5 
STUDY DRUG 
5.1 Identity 
Pharmacy manual contains the relevant information on the study IMP manufacturers, packagers and 
distributors.  
5.2 Packaging, Labelling and Storage 
FP-1201-lyo is provided by Faron to clinical sites. Dexamethasone (commercially available) and 
0.9% Saline solution will be sourced locally by the sites. 
FP-1201-lyo is secondary packaged in a carton, containing one vial. The dexamethasone packaging 
configuration may vary based on the source chosen by the clinical site. 
Six investigational medicinal kits are provided per patient. These are reserved for each patient to 
cover the 6-day treatment period. 
Labelling will be prepared to meet the local regulatory requirements. 
All study drug supplies must be stored in accordance with 
uctions, e.g., FP-
1201-lyo kits are to be stored at 2 8°C (35.6°F 46.4°F) until dispensed to the patients. The study 
drug is to be stored in a securely locked area, accessible to authorised personnel only. The IMPs are 
dispensed and prepared only after approval by the Investigator or by a member of staff specifically 
authorised by the Investigator, or by a pharmacist, as appropriate.  
5.3 Administration 
Study IMP FP-1201-lyo (IFN beta-1a) 10 µg or dexamethasone 6 mg will be prepared for clinical 
application according to the instructions provided in the Pharmacy Manual. The IMP will be prepared 
by an unblinded site staff (i.e. Pharmacist) according to the randomization code and dispensed into a 
blinded syringe. The prepared IMPs will be administered as two intravenous bolus injections via a 
central or peripheral line. To maintain blinding at administration, every study subject will receive 
two separate bolus injections of IMP (either IFN-beta -1a/Saline, and another injection of 


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Saline/Dexamethasone). The exact time of both injections will be recorded and the injections will be 
followed with a 5 mL flush of sterile saline (not provided). Administration should be performed by 
blinded site personnel. 
IMP injections will be given once daily for 6 days, unless the patient is discharged from the hospital. 
The injections should be given at the same time each day ±1 hour 
allows this. If for any reason this is not possible, the treatment should be given as soon as possible. 
The reason for the delay must be entered in the e-CRF. Subsequent doses should not be delayed and 
should revert to the original time schedule (e.g., if the D1 dose was at 13:00, the D2 dose was delayed 
and given at 17:00, the D3 dose should be given at 13:00 ±1 hour). No dose modifications or 
temporary cessations of IMP administration are allowed. If a delay is more than 12 hours, the patient 
must discontinue from study IMP, but all data must continue to be collected per protocol. 
Administration of a second 6-day course of study IMP is not permitted. 
5.4 Blinding and Breaking the Blind 
The study will be performed in a double-blind and randomized manner. IMP (IFN beta-1a and 
dexamethasone) will be prepared in identical syringes by an unblinded person, thereby enabling fully 
blinded conditions. 
The treating physician is responsible for the medical care of the trial patient and the study set up 
allows the investigator/treating physician to rapidly break the treatment code in an emergency 
situation. 
The study blind should only be broken in a medical emergency (where knowledge of the study drug 
received would affect the treatment of the emergency) or as a regulatory requirement (e.g., for SAEs 
or death). Note that there is no specific antidote or method of removing the study drug from the body 
(such as dialysis) and the best available care for the patient should be continued.  
e-CRF and any 
associated AE report. It is the responsibility of the investigator to promptly document and explain 
any unblinding to the sponsor/CRO. 
Detailed instructions for the use of the IWRS in order to break the study blind for a patient are 
provided in a separate document that will be filed in the Site File and Trial Master File. As well as 
the IWRS, a backup system enabling unblinding of treatment is provided to the sites. 
After a patient has been unblinded data collection should continue as per protocol.  
Suspected unexpected serious adverse reactions (SUSARs), which are subject to expedited reporting, 
should be unblinded by the Pharmacovigilance group before submission to the regulatory authorities 
and IECs/IRBs (Independent Ethics Committee/Institutional Review Boards). 
The overall randomisation code will be opened only for reporting purposes. This will occur when all 
D28 clinical data have been entered into the database and all data queries related to D28 have been 
resolved, and the assignment of patients to the analysis sets and database lock has been completed. 
After completion of the extended follow up of 90 days and resolving related queries the database is 
locked again for D90 analyses. 
5.5 Drug Accountability 
The Investigator is responsible for maintenance of accurate study drug accountability records 
throughout the study. 
Each dispensing of study drug will be documented. 


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The Investigator is responsible for ensuring all unused medication is destroyed at the investigational 
site following the appropriate drug accountability procedures. 
5.6 Compliance 
The study drugs are administered intravenously at the study site, so it is not necessary to monitor 
patient compliance with the study drug regimen. 
5.7 Previous and Concomitant Medications 
Any medication the patient takes other than the study drug between screening and D28, including 
herbal and other non-traditional remedies, is considered to be a concomitant medication. All 
concomitant medications (for previous 7 days) must be recorded in the e-CRF except for nutritional 
and volume therapy, electrolyte support, vitamins and supportive therapies such as artificial tears, 
ointments, etc. The following information must be recorded in the e-CRF for each concomitant 
medication: generic name, route of administration, start date, stop date, dosage and indication. Any 
changes in the dosage or regimen of a concomitant medication must be recorded in the e-CRF. If a 
patient is discharged from the hospital prior to D28 then the patient must be instructed that the 
Investigator should be informed about additional medication up to D28. 
Concomitant medications or therapies that are considered necessary for the patient s welfare and that 
will not interfere with the study drug may be given at the discretion of the attending physician. 
All patients in this study will be managed with supportive care measures according to the best practice 
established locally in study centre and in accordance with the treatment guidelines 
(https://www.covid19treatmentguidelines.nih.gov/therapeutic-management). 
There are no prohibited co-medications in this study, except for systemic corticosteroids, baricitinib 
and tofacitinib (and other JAK-STAT signalling pathway inhibitors) as these agents have been 
demonstrated to have potential inhibitory effect on IFN beta. 
6 
STUDY CONDUCT AND ASSESSMENTS 
6.1 General Considerations 
The study will utilize standard clinical care laboratory assessments for safety, in order to avoid 
excessive sampling of blood in hospitalized subjects. Complete Blood Count (CBC), White Blood 
Cells (WBC) differential and biochemistry, for example, will be collected from clinical routine if 
available; if not then these will be collected as protocol specific assessments from pre-dose D1, D2-
D7, D10, D14, D28/last day in hospital. The timing of the assessments is shown in the Table 2 
Schedule of Procedures (below). Laboratory assessments needed for CBC, differential and chemistry 
should be taken on the timepoints indicated in the Table 2, if not available by clinical standard of 
care (i.e., analyses should not be duplicated if available by clinical routine). 
For the purposes of this study, study day 1 (D1) is defined as the first calendar day (from midnight 
to the following midnight) of treatment with IFN beta-1a or dexamethasone. All days thereafter are 
 
Baseline assessments are defined as those assessments carried out in the screening period and pre-
dose D1 (before the first dose of study drug on D1). Unless withdrawn from study or discharged from 
the hospital, all patients will receive study drug for 6 consecutive days (D1-D6). All assessments in 
the period up to D28 are only to be performed when a patient is in hospital. Study assessment at D14, 
D28 and D90 are performed by phone call if the patient is not any longer present at the hospital, or 
sought through records if the patient cannot be contacted. The end of the study will be the date of last 
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6.2.2 Pre-dose D1  
1. Inclusion and exclusion criteria 
2. Randomization (if feasible can be done also during screening) 
3. Specimen collection including genetic sample per Table 2. 
4. COVID-19 specimen collection (blood sample and nasopharyngeal swab) 
5. WHO 9-point ordinal scale  
6. Concomitant medications and therapies. Note that use of systemic glucocorticoids, 
baricitinib and tofacitinib (or other JAK-STAT signalling pathway inhibitors) at 
randomization is an exclusion criteria 
7. Clinical status assessments 
8. Vital signs 
9. Adverse events  
Screening assessments will be carried out after informed consent has been obtained and must be 
completed before the first dose of the study drug is administered. If a patient continues to meet all 
entry criteria (including negative pregnancy test and not receiving systemic glucocorticoids, 
baricitinib or tofacitinib (or other JAK-STAT signalling pathway inhibitors)), study drug will be 
administered. The first dose of study drug must be administered within 48 hours of admission to 
hospital, preferably as soon as possible. 
 
The specimen collections and assessments at pre-dose D1 should be within 4 hours prior to the 
administration of study drug.  
6.3 Study Assessments During Hospital stay  
The following in-hospital data will be collected to assess trial efficacy and safety endpoints. Most 
data may be assessed by medical record review.  
1. Administration of study drug once daily for 6 days 
2. Close monitoring of vital signs for the 60 minutes following study drug administration 
3. Specimen collection including COVID-19 sample per Table 2. 
4. WHO 9-point ordinal scale 
5. Concomitant medications and therapies 
6. Clinical status assessments 
7. Adverse events 
8. Hospital discharge disposition. 
 
The specimen collection should be prior to the administration of study drug and within +/-2 hours of 
the sampling time at D1.  
 
If a subject has been discharged from the hospital but is re-admitted before Day 28 to the study site 
for COVID-19 associated reasons, the data for the visits assessments are recorded in CRF. Laboratory 
samples are not taken from re-admitted subjects, but, if possible, a  serum sample for determining 
the viral load should be taken according to the timepoints in Table 2. The re-admission to hospital is 
reported as a SAE. 


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6.3.1 Vital Signs 
Vital signs will be measured supine pre-dose on D1 (baseline) and daily while hospitalized as detailed 
in the Schedule of Procedures (Section 6, Table 2). The date and time of collection of each parameter 
will be recorded in the e-CRF. 
Vital sign variables are: 
 Blood pressure (BP; systolic, diastolic and mean; mmHg) 
 Heart rate (HR; bpm): measured as per clinical practice in each hospital  
 Total respiratory rate (breaths per minute) 
 
for temperature recording and the site used for measurement should be recorded in the e-
CRF 
6.3.2 Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Procedures (Table 2) 
and as applicable to subjects  condition. 
A physical examination covering the major body systems (general appearance, head [ear, nose and 
throat], cardiovascular, eyes, respiratory, abdomen, urogenital, musculoskeletal, neurological, lymph 
nodes and skin) will be performed at screening (baseline) and following according to standard 
clinical practice and at D28 or Day of discharge from hospital (whichever is earlier). 
At screening the physical examination will also include:  
 Actual body weight measured or provided by the subject 
 Actual height measured or provided by the subject. 
6.3.3 Clinical status assessments 
Clinical status assessments include survival, hospital status, ICU status, renal support, ECMO, 
oxygen support, and mechanical ventilation. Assessments for D14 and D28 are made by phone for 
non-hospitalized subjects. On D90 only survival and hospital status will be collected. Information 
will be sought from health records if patient cannot be contacted by phone. 
6.3.4 Hospital Laboratory Assessments 
6.3.4.1 Biochemistry and Haematology  
The biochemistry and haematology analysis will be performed at the hospital laboratories of the 
individual Investigator sites. Copies of laboratory accreditation and relevant reference ranges will be 
provided to the Sponsor or representative prior to the analysis of the first patient sample at that site. 
The laboratory variables measured in the study will be as detailed in Table 3. 
Blood samples for determination of biochemistry and haematology (CBC, WBC Differential) will be 
taken at pre-dose on D1 (baseline value), D2-D7, D10 and D14 while the patient is in the hospital, 
and on D28 or the last day in hospital. The date and time of sample collection and the results will be 
recorded in the e-CRF (results for analysis performed routinely at the site on other days will also be 
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Table 3. Biochemistry and haematology variables  
Haematology: 
Haemoglobin 
Haematocrit 
Erythrocytes 
MCV 
Platelets 
Leukocytes 
Differential counts of: 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
  Biochemistry: 
Albumin 
Creatine kinase 
Creatinine 
Bilirubin 
Alkaline phosphatase 
AST 
ALT 
Lactate 
Sodium (blood gas value acceptable) 
Potassium 
Bicarbonate 
Calcium (total calcium corrected for albumin 
level) 
 Pregnancy test: 
In women with child-bearing potential only. A urine pregnancy test will be performed unless the 
patient is not producing urine in which case a serum pregnancy test will be performed instead 
Abbreviations: AST=aspartate transaminase; ALT=alanine transaminase; MCV=mean corpuscular volume. 
6.3.4.2 COVID-19 confirmation test  
A positive SARS-CoV-2 test result no older than 7 days should be available for inclusion in the study. 
The test can have been taken as part of the standard care or is performed for the study and the analyse 
method is according to the hospital laboratory routines. If information on the virus variant is 
available, it should be recorded in the e-CRF. 
6.3.5 Central Laboratory Assessments 
A maximum of 73 mL of blood will be taken for study-specific testing during the study in addition 
to sampling for routine local analysis of haematology and biochemistry variables. One 
nasopharyngeal swab is taken for determination of SARS-CoV-2 variants. 
6.3.5.1 Anti-drug Antibodies to Interferon Beta-1a 
For serum samples 5.0 mL of blood will be taken on D1 pre-dose (baseline) and D28 (or on last day 
in hospital or at withdrawal, if earlier) to determine the presence of anti-drug antibodies to IFN beta-
1a. 
Anti-drug antibody sample preparation and sample storage details are provided in the Laboratory 
Manual. It is essential that the actual time and date of collection of each antibody sample will be 
recorded in the sample collection form provided with the laboratory kits. 
Anti-drug antibody samples will be analysed centrally at Wieslab AB, Malmö, Sweden. 
6.3.5.2 Myxovirus Resistance Protein A 
Whole blood samples (2 mL) will be taken pre-dose on D1, D3, D5 and on D7 for hospitalized 
patients for analysis of MxA levels. For details of sample preparation and storage refer to the 
Laboratory Manual. MxA samples will be analysed centrally at Wieslab AB, Malmö, Sweden. 
6.3.5.3 Cluster of differentiation 73 (CD73), Potential Inflammatory Markers (PIMs) and 
Interferon Signalling Markers 
Samples for the CD73 and PIM assessments will be collected pre-dose on D1 (baseline), D3, D5 and 
D7 for hospitalized patients as detailed in the Schedule of Procedures (Section 6, Table 2). Blood 


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samples of 2.5 mL will be collected for CD73; from these, serum samples will be prepared for the 
testing. Blood samples of 6.0 mL will be collected for PIM sample preparation; from these, plasma 
and cell samples will be prepared for the testing of the potential inflammatory markers, interferon 
signalling markers and genetics. Sample preparation and storage details are provided in the 
Laboratory Manual. It is essential that the actual time and date of collection of each sample is 
recorded in the sample collection form provided with the laboratory kits. 
CD73 samples will be analysed centrally by Wieslab AB, Malmö, Sweden. 
PIMs may include (but are not limited to): Interleukin-6, Interleukin-8, von Willebrand Factor, 
Hypoxia-inducible factor 1-alpha, Angiopoietin-2, IFN- , 
-1, and TNF- , and interferon 
signalling markers. Inflammatory markers and interferon signalling will be analyzed both on a 
protein and RNA expression level using plasma and peripheral blood mononuclear cells (PBMCs) 
using Nanostring analyses. Inflammatory markers will be anaysed at MediCity Research Laboratory, 
University of Turku, Turku, Finland. Nanostring analyses will be performed at Wake Forest 
University Medical School after RNA and DNA extraction has been performed at MediCity for 
pharmacogenetics (see below).  
6.3.5.4 Interferon beta (IFN beta) 
A 2 mL venous blood sample for the determination of IFN beta in serum will be collected on pre-
dose D1 (baseline), D1 (5 minutes after dosing), pre-dose D3 and D7 for hospitalised patients as 
detailed in the Schedule of Procedures (Section 6, Table 2).  Blood sample preparation and sample 
storage details are provided in the Laboratory Manual. It is essential that the actual time and date of 
the collection of each sample is recorded in the sample collection form provided with the laboratory 
kits and in eCRF. 
The post-dose sample taken 5 minutes after study drug administration on D1 must be taken from 
another extremity than the site where the study drug was administrated. 
IFN beta in serum will be analysed centrally by Syrinx Bioanalytics Oy, Turku, Finland. 
6.3.5.5 Pharmacogenetics 
The genetic sample must be taken for a patient to enter the study. According to the previous Phase 
III Study (FPCLI002) there may be significant genetic variability in response to the investigational 
treatment. We specifically aim to investigate whether a specific genetic polymorphism rs9984273, 
which is the glucocorticoid regulatory motif area of IFN alpha/beta receptor subunit 2, defines 
responsiveness to treatment, and whether this sub-groups should be a targeted population for the 
investigational medicinal product. 
PIM sample collected pre-dose on D1 will be used for genetic analyses; sample preparation and 
sample storage details are provided in the Laboratory Manual. Genetic analyses will be done at 
MediCity Research Laboratory, University of Turku, Turku, Finland. 
The samples and data for genetic analysis in this study will be coded. Samples will not carry any 
personal identifiers. DNA samples will be destroyed 15 years after completion of this study. 
6.3.5.6 SARS-CoV-2 viral burden 
A 2.5 mL blood sample for SARS-CoV-2 viral burden in serum are collected on pre-dose Day 1 and 
on Day 3, Day 7, Day 10 and on Day 14 (only for hospitalized patients, 
discharge is before 
D14, the specimen is obtained also on the day of discharge). The date and time of sample collection 
will be recorded in the-CRF. 


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6.3.5.7 SARS-CoV-2 variants  
A nasopharyngeal swab is taken on pre-dose Day 1 for central analysis of variants of SARS-CoV-2.   
6.3.6 Lung X-ray/CT scan 
For the purpose of diagnostic accuracy, the study will utilize only documentation of lung X-ray/CT 
scan performed as part of standard clinical care; separate X-ray/CT scans are not performed for study 
purpose. No separate imaging manual exists for the Study, and images will not be collected. 
6.4 Post-Discharge Assessments 
Patients will be contacted at D14, D28 (if discharged; assessment window of +/- 3 days permitted, 
but with exact assessments for D14 and D28 conditions) and D90 (if discharged; assessment window 
of +/- 1 week permitted) to assess for health status, including mortality. At D14 and D28 the patient 
will be assessed on changes in the concomitant medications and on possible adverse events. On D90 
only survival and hospital status will be collected. At the time of enrolment, subjects will be asked 
to provide at least two methods of contact, as well as contact information for a caregiver, to facilitate 
contact at Day 90. Patients who cannot be reached by phone will be mailed a follow up letter. The 
information is sought through records if the patient cannot be contacted. 
Please see section 6.3. for patients that have been discharged from the hospital but are re-admitted 
due to COVID-19 before D28 to the study site. 
6.5 Withdrawal Prior to Day 28 
For patients withdrawing from the study, procedures for the last day of study involvement should be 
followed. 
In the case of an ongoing AE, appropriate safety evaluations and/or additional tests may be performed 
at any time when clinically indicated at the discretion of the attending physician or Investigator, until 
resolution or Day 28, whichever is first. Any ongoing AEs should be followed up to resolution or 
Day 28, whichever is the sooner. 
If the patient refuses to have any of the above assessments, or if the patient is lost to follow-up, then 
this should be noted in the e-CRF. If a patient is lost to follow-up, wherever possible, mortality data 
databases and all data obtained reported as SAEs. 
6.6 Safety Variables 
6.6.1 Adverse Events 
6.6.1.1 Collection of Adverse Events 
It is the responsibility of the Investigator to collect all AEs (both serious and non-serious) derived by 
observation, by spontaneous unsolicited reports of patients, and, where appropriate, by routine open 
questioning, e.g., How have you felt since I last saw you?  
6.6.1.2 Definitions 
Definitions of AEs and SAEs and their documentation and reporting within this study follow 
International Conference on Harmonisation (ICH) Good Clinical Practice, European Union, and 
national regulations and requirements. 


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An AE is defined as any untoward medical occurrence that occurs in a patient or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the use 
of an investigational product, whether or not considered related to the product. 
All AEs up to D28 are collected. AEs occurring after D28 should be reported to the Sponsor if the 
Investigator considers there is a causal relationship with the study drug. All AEs up to D90, which 
lead to death, are reported as SAEs. Concomitant illnesses, which existed before entry into the study, 
will not be considered AEs unless there is any deterioration from baseline that is considered clinically 
relevant or significant during treatment or follow-up period until D28. All AEs must be documented, 
regardless of the source of identification (e.g., physical examination, laboratory assessment, ECG, 
reported by patient).   
Pre-existing conditions will be recorded in the e-CRF on the Medical History or appropriate page. 
A TEAE (Treatment-Emerged Adverse Event) is defined as an AE that begins or that worsens in 
severity after at least one dose of study drug has been administered up to D28. 
See 6.1 for the schedule of collection of adverse events 
6.6.1.3 Assessment of Adverse Events 
It is recognised that the patient population in the hospital will experience a number of common 
aberrations in laboratory values, signs and symptoms due to the severity of their underlying disease 
and the impact of standard therapies. These will not necessarily constitute an AE unless they require 
intervention, lead to discontinuation of blinded study drug or are considered to be of concern in the 
 
Each AE will be assessed by the Investigator with regard to the following categories: 
6.6.1.3.1 Seriousness 
An SAE is defined as any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening. This means that the patient is at risk of death at the time of the event. 
It does not mean that the event hypothetically might have caused death if it were more 
severe 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalisation but that may jeopardise the patient or require intervention to 
prevent one of the above outcomes. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalisation; or development of drug dependency or drug abuse 
Medical and scientific judgment should be exercised in deciding whether a case is serious and 
whether expedited reporting is appropriate. However, all deaths up to D90 will be reported as a SAE. 


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the event. 
Study drug doses may have been given during treatment cycles or interrupted temporarily prior to 
the onset of the SAE, but may have contributed to the event. 
6.6.1.3.2 Intensity 
Investigator will be responsible for the assessment of severity, using the categories of mild, moderate 
or severe to describe each AE as: 
 Mild: Does not interfere 
 
 Moderate: 
n 
 Severe: 
 
Note the distinction between serious and severe AEs. Severe is a measure of intensity whereas an 
event must meet one of the criteria for serious events listed in Section 6.6.1.3.1 to be considered 
serious; thus, a severe reaction is not necessarily a serious reaction. For example, a headache may 
be severe in intensity, but would not be classified as serious unless it met one of the criteria for serious 
events listed in Section 6.6.1.3.1. 
6.6.1.3.3 Causality 
The Investigator will assess the causality/relationship between the study drug and the AE and record 
that assessment in the e-CRF. Causality will be assessed as: 
 Not related: AE is obviously explained by another cause; OR the time of occurrence of AE is 
not reasonably related to administration of the study drug 
 Possibly related: Study drug administration and AE occurrence are reasonably related in time; 
AND AE is explained equally well by causes other than study drug 
 Probably related: Study drug administration and the occurrence of the AE are reasonably related 
in time; AND the AE is more likely explained by exposure to study drug than by other 
mechanisms 
The most likely cause of an AE (e.g., disease under treatment, concomitant disease, concomitant 
medication, other) will be indicated in the e-CRF with details of the concomitant disease or 
medication or other cause.  
6.6.1.3.4 Adverse events related to laboratory assessments  
Abnormal laboratory findings (e.g., biochemistry, haematology, urinalysis) or other abnormal 
assessments (e.g., vital signs) that are judged by the Investigator as clinically significant will, if 
certain requirements are met, be recorded as AEs or SAEs. Clinically significant abnormal laboratory 
findings or other abnormal assessments that meet the definition of an AE or SAE and are detected 
during the study, or are present at baseline and significantly worsen following the start of the study, 
will be reported as AEs or SAEs.  
The Investigator will exercise their medical and scientific judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant and as such an AE. 
6.6.1.4 Recording Adverse Events 
AE reporting will extend from signing of informed consent. AEs occurring after D28 should be 
reported to the Sponsor by the Investigator if the Investigator considers there is a causal relationship 
with the study drug. However, all deaths will be recorded and reported as SAEs throughout the study 
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All AE reports should contain a brief description of the event, date and time of onset, date and time 
of resolution, intensity, treatment required, relationship to study drug, action taken with the study 
drug, outcome, and whether the event is classified as serious. 
Recording a diagnosis (when possible) is preferred to recording a list of associated signs and 
symptoms. However, if a diagnosis is known but there are associated signs or symptoms not generally 
attributed to the diagnosis, the diagnosis and each sign or symptom must be recorded separately. 
6.6.1.5 Reporting Serious Adverse Events 
According to applicable US and European Union regulations and requirements, an SAE must be 
reported to the Sponsor from the trial site as soon as possible within 24 hours of becoming aware of 
the SAE. A medically qualified person at the trial site identified on the Delegation of Authority Log 
with this responsibility must assess the SAE. Any member of the clinical trial site staff can assist in 
reporting an initial SAE. The Principal Investigator or delegated sub-investigators are responsible for 
the SAE reporting procedures at the site during the trial, and must always sign-off on each SAE even 
if other site staff have reported the event on behalf of the investigators. A delegation log at each trial 
site will clearly show delegation of responsibilities regarding SAE reporting. 
The SAE reporting is done via the eCRF system. Paper forms are available as back-ups. 
The Investigator and the Sponsor (or 
the seriousness and the causal relationship of the event to study treatment will be evaluated. In 
 
the reference document (Investigator Brochure). Based on the Investigator 
of the event, a decision will be made concerning the need for further action. 
If consensus on the assessment cannot be reached between the parties (e.g., Investigator and 
Sponsor/Sponsor s delegate), all opinions will be provided in the Council for International 
Organizations of Medical Sciences Form I report and reporting to the CA and IEC/IRB should be 
based on the highest degree of causality provided. 
Details for reporting SUSARs can be found in Section 6.6.1.7. 
All SAEs will be recorded that occur between signing of informed consent and D28. Events occurring 
after D28 and coming to the attention of the Investigator should be reported only if they are 
considered in the opinion of the Investigator to be causally related to the investigational drug.  
However, all deaths up to D90 will be reported as SAEs. 
All SAEs occurring as described above, must be reported within 24 hours. 
The minimum information required for an initial report is: 
 Details of person sending the report (i.e., name and address of Investigator) 
 Patient identification details (screening/randomization number, age, sex, NOT patient 
name) 
 Protocol number 
 Description of SAE 
 Causality assessment 
However, all points on the SAE report should be covered in the initial report. 
After receipt of the initial report, Pharmacovigilance (PV) will review the information and, if 
necessary, contact the Investigator to obtain further information for assessment of the event. PV CRO 
will be responsible for all information processing and reporting according to local legal requirements.  


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Detailed instructions concerning SAE reporting procedures will be described in a Safety 
Management Plan written by PV CRO. SAE Report Form and contact information for reporting SAEs 
will be provided to the sites. 
6.6.1.6 Follow-up of Adverse Events  
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored until: the 
AE has resolved or any abnormal laboratory values have returned to baseline, or stabilised at a level 
acceptable to the Investigator and Medical Monitor; there is a satisfactory explanation for the changes 
observed; the follow-up period is completed (D90) or the patient is lost to follow-up; or the patient 
has died. 
6.6.1.7 Suspected Unexpected Serious Adverse Reactions  
Any AE that is serious, associated with the use of the study drug, and unexpected (SUSAR) has 
additional reporting requirements, as described below. 
 If the SUSAR is fatal or life threatening, associated with use of the study drug and 
unexpected, regulatory authorities and IECs/IRBs must be notified within 7 calendar 
days after the Sponsor learns of the event. Additional follow-up information (cause of 
death, autopsy report and hospital report) should be reported within an additional 8 days 
(15 days total). 
 If the SUSAR is not fatal or life threatening but is otherwise serious, associated with the 
use of the study drug and unexpected, regulatory authorities and IECs/IRBs must be 
notified within 15 calendar days after the Sponsor learns of the event. 
The Sponsor will notify the Investigators in a timely fashion of relevant information about SUSARs 
that could adversely affect the safety of patients. Follow-up information may be submitted if 
necessary. 
The Sponsor will also provide annual safety updates to the regulatory authorities and IECs/IRBs 
responsible for the study. These updates will include information on SUSARs and other relevant 
safety findings. 
6.7 Pregnancy 
Pregnancy is an exclusion criterion, and a pregnancy test is performed in all women of childbearing 
potential at screening. Owing to the nature of the study involving short (6-day) treatment with the 
study drug in a hospital setting, it is not practically possible for women to become pregnant during 
treatment and for there to be any foetal exposure to the study drug. Study subjects and their partners 
are advised not to become pregnant for 2 months after the study drug exposure and to use appropriate 
contraception. Any pregnancy during the study (for 2 months after the study drug exposure) that 
becomes to the knowledge of an investigator during the study, should be reported as an SAE and 
followed-up for the outcome. Any pregnancy, which onset is after 2 months from the study drug 
exposure, until the end of the study, will be reported (as a non-SAE) and followed-up for the outcome. 
7 
STATISTICAL METHODS 
The statistical considerations summarised in this section outline the plan for data analysis of this 
study.  


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The main analysis and reporting will use D14 and D28 data after last study subject has completed 
D28 assessment and the data has been verified and locked. D90 follow-up data is analysed separately. 
Before unblinding/database lock, a separate Statistical Analysis Plan (SAP) will be finalised, 
providing detailed methods for the analyses outlined below. Before the conduct of interim analysis, 
an Interim Analysis (IA) plan will be finalised. After the clinical parts of the study have been 
completed, a blinded review of the data will be undertaken according to the SAP/IA plan. This review 
will make decisions regarding: the handling of missing data and data for withdrawn patients; and the 
definition of the Per-Protocol Set (PPS) at the patient level.
Any deviations from the planned analyses will be described and justified in the final integrated study 
report. 
7.1 Study Patients  
7.1.1 Disposition of Patients 
Disposition and reasons for discontinuation will be summarised for all patients together with study 
drug exposure and study duration by treatment group. 
The number and percentage of patients entering and completing each phase of the study will be 
presented by treatment group. Reasons for withdrawal pre- and post-randomization will also be 
summarised. 
The disposition of patients will also include information on the number and percentage of patients 
who: 
 completed study drug and follow-up 
 withdrew from study drug but completed follow-up 
 withdrew from study drug and from follow-up 
7.1.2 Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will be classified as 
njunction with the Sponsor and Medical Monitor. Relevant major deviations 
from the protocol will lead to the exclusion of that patient from the PPS. Deviations will be defined 
prior to unblinding. 
7.1.3 Analysis Sets 
The following analysis sets will be defined for statistical analysis: 
The Full analysis set (FAS) will consist of all randomized patients who have been received at least 
one dose of study drug. If a randomized subject becomes ineligible before dosing the subject will be 
replaced and is excluded from the FAS. The primary efficacy analyses will be based on this data set. 
Patients will be included in the analysis according to the treatment to which they were randomized. 
The Per-Protocol Set (PPS) will consist of patients in the FAS excluding patients with major 
protocol violations. A list of major protocol violations relevant for excluding data from the PPS will 
be detailed in the SAP before the interim analysis. The precise definition of the PPS at the patient 
level will be identified at the blinded data review meeting before the interim and final analyses.  
Statistical analyses for the primary and secondary endpoints will be performed on both the FAS and 
PPS. 


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The safety set will consist of all patients who receive at least one dose of study drug. All safety and 
tolerability analyses will be based on this analysis set. A patient who receives the wrong treatment 
according to their randomisation will be analysed for safety and tolerability in the treatment group 
corresponding to the treatment received. 
Statistical analyses for the primary and secondary endpoints will be performed on both the FAS and 
PPS. The primary efficacy endpoint analysis will be based on the FAS; a secondary analysis will also 
be performed based on the PPS to assess the sensitivity of the analysis to the choice of analysis set. 
All safety analyses will be based on the safety set. Demographic and baseline characteristics will be 
evaluated for the FAS. 
7.2 General Considerations 
All statistical tests will be two sided and will be performed at the significance level of 0.05, unless 
otherwise stated. 
Continuous data will be summarised by treatment group using descriptive statistics (number, mean, 
median, standard deviation [SD], minimum and maximum). Categorical data will be summarised by 
treatment group using frequency tables (frequencies and percentages). 
7.2.1 Analysis and Data Conventions 
7.2.1.1 Definition of Baseline 
The baseline assessment, where relevant, will be the latest available valid pre-dose assessment. 
7.2.1.2 Visit Windows 
Assessments made outside of protocol-mandated windows will be displayed according to the e-CRF 
assessment recorded by the Investigator. 
7.2.1.3 Unscheduled Assessments 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing AEs) will be included in listings, but not 
summaries. If more than one laboratory value is available for a given visit, the first valid observation 
will be used in summaries and all observations will be presented in listings. It is noted that invalid 
laboratory data will not be used (from haemolysed samples, mishandled samples, quantity not 
sufficient, or other conditions that would render values invalid). 
7.2.1.4 Missing Data Handling 
In general, data will not be imputed for the primary efficacy analysis or the safety analysis. For other 
efficacy analyses, where relevant, imputations will use the last observation carried forward method 
for patients in the analysis. Additional details will be given in the SAP. 
7.2.1.5 Intercurrent events 
Use of open label corticosteroids (i.e., discontinuation of study IMP during D1-D6 and initiation of 
corticosteroids due to deterioration of the study 
 condition, or initiation of corticosteroids 
D7 onwards) is an intercurrent event anticipated to affect the study outcomes. The primary analysis 
is planned to follow the treatment policy strategy (using FAS dataset). As sensitivity analyses, also 
other strategies under the estimands framework (ICH E9 (R1) addendum) will be applied to account 


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for this intercurrent event. Details of these analyses will be described in SAP. The frequency and 
magnitude of the effect of the use of corticosteroids to the study outcomes will be also evaluated 
during the planned Interim Analysis.    
7.3 Demographics, Medical History, Baseline Characteristics and Concomitant 
Medications 
Baseline assessments will consist of those assessments carried out in the screening period and those 
carried out prior to the first dose of study drug on D1. 
Demographic and baseline characteristics will be summarised by treatment group and overall. No 
formal statistical comparisons will be undertaken to compare treatment groups for any of these 
parameters. 
Demographic data, medical history, concomitant disease and concomitant medication will be 
summarised by descriptive statistics (number, mean, SD, median, minimum and maximum) or 
frequency tables, overall and stratified by treatment. 
A medication given prior to the first injection of study drug will be classified as a prior medication. 
A medication given with or after the first injection of study drug will be classified as concomitant. 
Prior medications continuing during the study will be labelled accordingly in the listings. 
7.4 Determination of Sample Size 
140 patients will be randomised 1:1 for active: comparator. Conditional Power re-assessment will be 
conducted at interim analysis after circa 70 patients have been enrolled and followed up for the 
primary efficacy endpoint variable. The primary variable is the clinical status at Day 14 using the 
WHO 9-point scale (0=no detectable infection to 8=death). It will be analysed using ordinal logistic 
regression model comparing the odds of having better clinical status (smaller number in the 9-point 
scale) at Day 14 between treatment groups. The sample size is based on an assumption of odds ratio 
of 0.43 between groups leading to a power of 80% with 70 evaluable patients per group. In the interim 
analysis the conditional power will be calculated based on the observed result and the sample size 
will be increased in case the conditional power is in the predefined promising zone. The details of 
interim analyses will be given in IDMC charter created at the study initiation and in an interim 
analysis plan which will be finalised before breaking the blind for interim analysis. 
7.5 Efficacy Analyses 
7.5.1 Primary Efficacy Analysis 
For the Primary Efficacy Endpoint the following hypotheses will be tested: 
 Null hypothesis H0: the WHO OSCI at D14 in the IFN beta-1a treatment group is equal to 
that in the control group 
 Alternative hypothesis HA: the WHO OSCI at D14 in the IFN beta-1a treatment group is 
not equal to that in the control group 
The primary analysis of this endpoint will be based on the FAS, with a sensitivity analysis based on 
the PPS providing supportive information. Each of these analyses will be undertaken at the two-sided 
significance level of 0.05. For powering of the primary efficacy endpoint see chapter 7.4. 
The primary variable will be analysed using ordinal logistic regression model comparing the odds of 
having better clinical status (smaller number in the scale from 0 to 8) between the groups. The 
primary model will include baseline OSCI score and age, gender and ethnicity as a covariate. In 


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addition, also a model without covariates will be applied and the results provided as sensitivity 
analysis. The percentages in each category for both groups will be presented descriptively including 
95% confidence intervals.  
Primary endpoint as well as other efficacy endpoints will also be presented for key predefined 
subgroups of patients (such as SNP rs9984273, see Section 4.2.3) together with 95% CIs for the 
difference in those rates to supplement the investigation of homogeneity. 
7.5.2 Secondary Efficacy Analyses 
For the Secondary Efficacy Endpoint WHO OSCI score at Day 28 will be analysed in a similar 
ordinal logistic regression model than the primary endpoint.  
The primary analysis of the mortality endpoints (in-hospital and overall (all-cause) mortality at Days 
28 and 90) will be based on the FAS and will be undertaken using COX proportional hazards 
regression model adjusting for age, gender and ethnicity key baseline characteristics. This analysis 
will be repeated using the PPS as a sensitivity analysis. Hazard ratios comparing the treatment groups 
will be reported using 95% CI for these endpoints. Data for these efficacy endpoints will also be 
presented for key predefined subgroups of patients (such as SNP rs9984273, see Section 4.2.3 
together with 95% CIs for the difference in those rates to supplement the investigation of 
homogeneity. 
7.5.3 Exploratory Efficacy Endpoints  
 
The binary variables for incidence of mechanical ventilation, ARDS and AKI (until Day 28) will be 
analysed with logistic regression model with similar covariates than used for the primary endpoint 
analysis. Odds ratios comparing the treatment groups will be reported using 95% CI for these 
endpoints. 
 
Renal support -free days alive are defined as the number of days in the first 28 days after the first 
dose of study drug that the patient is alive and free of renal support (renal replacement therapy).  
In similar fashion days alive and free from mechanical ventilation, ECMO, oxygen support, length 
of hospital and of ICU stay at D28 will be evaluated. 
General linear mixed model will be used for the analysis of these endpoints. However, if there is no 
valid distribution assumption, then Wilcoxon rank sum test will be applied. The statistical methods 
to be used for these exploratory efficacy endpoints will be detailed further in the SAP. 
 
 
 
Descriptive statistics (mean, median, SD, minimum and maximum) for laboratory variables will be 
obtained and tabulated by treatment group. The statistical methods to be used for the analysis of 
laboratory exploratory endpoints will be detailed in the SAP. 


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Effect of SARS-CoV-2 variant and SARS-CoV-2 vaccination status on the primary and secondary 
efficacy endpoints will be explored using these variables as subgroups and presenting the results for 
each subgroup with 95% confidence intervals.  
7.6 Safety Analyses 
These summaries will be based on the safety set. The presence of anti-drug antibodies to IFN beta-
1a at D28 will be summarised by treatment groups in terms of counts. 
7.6.1 Adverse Events 
AEs and SAEs will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA) and will be classified by system organ classes and preferred terms. In the event 
that intensity or relationship of an AE to the study drug is missing, a worst-case scenario will prevail 
(severe in intensity or probably related). Only TEAEs (AEs that occur after the first study drug 
administration, that were not pre-existing or that increased in intensity) will be included in the 
summary tables. Counting will be performed for patients and events separately. Patients experiencing 
the same event more than once will have that event counted once within the corresponding system 
organ class and with a unique preferred term. All AEs will be included in the data listings. Listings 
of SAEs, of AEs leading to study drug withdrawal and of AEs leading to death will also be provided. 
7.6.2 Independent Data Monitoring Committee 
An IDMC will be established for the study to monitor safety (see Section 8.8). 
8 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
8.1 Data Quality Assurance 
The Sponsor 
 will verify the qualifications of each Investigator, inspect the site 
facilities and inform the Investigator of their responsibilities and the procedures for ensuring adequate 
and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each study participant. All information 
recorded in the e-CRF 
medical records). 
8.1.1 Database Management and Quality Control 
All study-related data generated by site personnel will be captured electronically at each study centre 
using the e-CRF. 
Central laboratory assays (e.g., PD, genetic analyses) will be managed by the central laboratories and 
results will be transferred for inclusion in the study analysis database. 
Once the e-CRF clinical data have been submitted, corrections to the data fields will be captured in 
an audit trail. The reason for change, the name of the person who performed the change, and the time 
and date will be logged to provide an audit trail. 
The specific procedures to be used for data entry and query resolution using the e-CRF will be 
provided to study sites in CRF completion instructions. In addition, site personnel will receive 


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training on the e-CRF. Once the source data verification is complete and all queries are closed, Data 
Management will freeze the e-CRF page. 
8.2 Case Report Forms and Source Documentation 
All data obtained during this study must be promptly entered in the e-CRF. All source documents 
from which e-CRF 
Measurements for which source documents are usually available include laboratory assessments and 
x-ray/CT scans. 
Data that will be entered directly into the e-CRF (i.e., for which there is no prior written or electronic 
record) are considered to be source data. 
The e-CRF entries for each patient will be checked against source documents at the study site by the 
CRA. 
8.2.1 Data Collection  
The Investigators (and appropriately authorised staff) will be given access to an online web-based 
electronic data-capture system that is compliant with US Food and Drug Administration Title 21 
Code of Federal Regulations Part 11. This system is specifically designed for the collection of clinical 
data in electronic format. Access rights to the electronic data-capture system will be carefully 
throughout the study. Only the 
Investigator and authorised staff will be able to enter and correct data in the e-CRF. Protocol 
deviations can be recorded within the e-CRF system also by the Sponsor/CRO CRA. 
The e-CRF should be completed for each patient included in the study and should reflect the latest 
observations on the patients participating in the study. Therefore, the e-CRF is to be completed as 
Investigator must 
verify that all data entries in the e-CRF are accurate and correct. If some assessments cannot be done, 
or if certain information is unavailable, not applicable or unknown, the Investigator should indicate 
this in the e-CRF. 
Computerised data-check programs and manual checks will identify any data discrepancies for 
resolution. Corresponding queries will be generated in the system and the site will be informed online 
about new issues to be resolved. All discrepancies must be resolved online directly by the Investigator 
or by staff authorised to do this by Delegation of Authority. 
After completion, the Investigator will be required to electronically sign off the clinical data. 
8.3 Access to Source Data 
During the study, the Sponsor/CRO site CRA will make regular site visits to review protocol 
compliance, conduct source data verification by comparing e-CRF entries 
medical records, assess drug accountability and management, assess laboratory procedures and 
ensure that the study is being conducted according to pertinent regulatory and protocol requirements. 
The review of medical records will be performed in a manner that ensures patient confidentiality is 
maintained. Remote review of source data can be performed if permitted by the study site. 
Source data verification will be required to monitor the progress of the study. Moreover, regulatory 
authorities in certain countries, IECs/IRBs 
or designee may wish to carry out such source data checks and/or on-site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out giving 
due consideration to data protection and medical confidentiality. The Investigator must assure the 


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CRO and the Sponsor that they will provide the necessary support at all times. Also U.S. Department 
of Defense providing funding for the study can access source records as part of study oversight.  
8.4 Archiving Study Records 
It is the responsibility of the Principal Investigator to ensure all essential trial documentation and 
source records (e.g., signed Patient Information and Consent Documents, Investigator Site Files, 
hives for 25 
years after the end of the trial. However, these documents should be retained for a longer period if 
destruction of the documents.  
8.5 Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and Investigator 
abide by the principles of the Good Clinical Practice guidelines of the ICH and the Declaration of 
Helsinki (Declaration of Helsinki 2013). The study will also be carried out in keeping with local legal 
requirements. 
8.6 Informed Consent  
The Investigator at each investigational site is responsible for ensuring that written informed consent 
for study participation is given by each patient or their legal representative prior to collection of study 
data and administration of the study drug. Unless the study site is in a country where consent can 
only be obtained from the patient but can be waived and obtained retrospectively, according to local 
IEC rules, the Investigator will not undertake any investigation specifically required only for the 
clinical study until valid consent has been obtained. If consent has not been obtained, a patient cannot 
be enrolled into the study. 
Consent will be sought from the patients themselves, if this is possible. However, it is recognised 
that some patients may be unable to give written informed consent themselves due to severity of the 
clinical condition. For these patients, written informed consent will be sought from a PerLR or PrfLR. 
The PerLR may be a relative, partner or close friend. Any country-specific guidance on who may act 
as a PerLR will be followed. If the patient is unable to give consent and no PerLR is available then a 
doctor at the investigational site who is not connected with the conduct of the study may act as a 
PrfLR (in countries where this process is acceptable). Any country-specific guidance on who may 
act as a PrfLR will be followed. In some countries, according to IEC rules, consent can only be 
obtained from the patient. In these countries, if the patient is unable to give consent, their relatives 
and the patient  own family doctor will be informed about the study. Consent from the patient will 
be obtained as soon as the patient is able to understand the study and sign the consent form. The 
appropriate guidances and laws will be followed for each country participating in the study. 
If a protocol amendment is required, the ICD may need to be revised to reflect those changes. If the 
ICD is revised, it must be reviewed and approved by the appropriate IEC/IRB and signed by all 
patients (or their representatives) subsequently enrolled in the study as well as those currently 
enrolled in the study where relevant. 
8.6.1 Consent Procedure 
The person giving consent will be informed about the study by the Investigator or by a member of 
the research team to whom the Investigator has delegated the consent process. The patient will also 
be given a copy of the ICD. 


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To provide all the necessary information, clinical study information and ICDs are quite lengthy. For 
this study, dependent on country or site specific regulations, an abbreviated initial section of the ICD 
will provide a short summary of key information, followed by the detailed information for those 
interested in receiving further information. 
The patient, PerLR or PrfLR must be given adequate time to consider their decision about entering 
the study. However, the requirement to initiate study treatment within 48 hours of admission to 
hospital meeting inclusion criteria will of necessity be a consideration. 
In all cases, the patient, PerLR or PrfLR will be asked to sign two copies of the ICD, which will then 
be countersigned by the Investigator or the member of the study team to whom obtaining consent has 
been delegated.  One copy of the document will be retained by the person giving consent (patient, 
PerLR or PrfLR). The second copy will be photocopied. The photocopy will be 
medical records
and the original will be retained in the 
Investigator Site File. Alternative practical arrangements, including electronic consent processes, 
might be used due to e.g., COVID-19 restrictions at the hospitals.  
A similar procedure will be followed for retrospective patient informed consent, which will be an 
additional section at the end of the ICD (see Section 8.6.2). 
The terms of the consent and details of the informed consent discussions should be recorded in the 
e consent was given and the short name of the 
study or protocol code. 
8.6.2 Retrospective Patient Informed Consent 
Patients for whom consent was given by a PerLR or a PrfLR will be informed of their participation 
in the study by the Investigator or by a member of the research team to whom the Investigator has 
delegated the consent process. This process will take place once the patient has regained the capacity 
to understand the details of the study. The timing of this process will thus vary between patients. 
Howe
-consent process occurring by D90 
(3 months), then no further attempts will be made to re-consent the patient. 
Once informed, patients will be given an adequate amount of time to consider their decision to 
consent to continued participation in the study and to sign the re-consent section of the ICD. 
If the patient does not give retrospective consent then the patient will be informed of the importance 
to collect the data and that the data collected from the patient to that time point will be entered into 
the analyses as the withdrawal does not extend to the data already obtained during the time the subject 
was enrolled. Blood samples already collected up to the time of withdrawal will be analyzed. Genetic 
samples collected will be analysed per protocol. No further data will be collected; the patient will be 
 
 
8.6.3 Withdrawal of Consent 
Patients may withdraw or be withdrawn (by the PerLR or PrfLR) from the study at any time, for any 
reason and such a decision will not affect the ongoing care given to the patient. Data recorded and 
biospecimen collected up to the point of withdrawal will be included in the study analyses.  
If a patient or PerLR/PrfLR requests termination of the administration of study drug during the 
treatment period, then the administration of study drug will be stopped but the patient will continue 
in the study and all follow-up assessments will be performed. 


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If a patient or a PerLR/PrfLR withdraws consent during or after the treatment period then the 
administration of study drug will be stopped and no further active study assessments will be 
records to obtain data relevant to the study and safety evaluation (e.g., mortality, etc.). If a patient (or 
their representative) withdraws consent and still agrees to undergo a final examination, this will be 
documented in the e-
which will be countersigned and dated by the subject (or PerLR or PrfLR). 
8.7 Protocol Approval and Amendment 
For the study to start, all required documentation must be approved by the IEC/IRB and Competent 
Authority, in accordance with local legal requirements. The Sponsor must ensure that all ethical and 
legal requirements have been met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, substantial amendments must be written, 
receive approval from the appropriate personnel, and receive IEC/IRB/competent authority approval 
prior to implementation (if appropriate). 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the need 
for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
8.8 Independent Data Monitoring Committee 
An IDMC will be established for the study. The IDMC and associated parties (CRO, PV, Data 
management and the Sponsor) will function under the terms of an IDMC Charter. The IDMC will 
comprise three members, including one independent biostatistician and two senior clinicians with 
significant experience in clinical management of critically ill patients and who are not involved in 
the study. The duty of this IDMC is to protect the safety interests of patients and all others who may 
possibly be exposed to the study drug and to make recommendations to the Sponsor. The IDMC will 
review ongoing safety data (all SAEs) in an unblinded manner. IDMC meetings are scheduled to take 
place after the data has been received for the last patient of approximately 20 and 40 subjects and at 
an interim analysis at 70 subjects who either have completed 14 days in the study following their first 
dose of study medication or have been withdrawn for any reason (including death). The IDMC will 
not review efficacy data, other than how it relates to the safety of the therapy. However, the IDMC 
will  review the efficacy data at interim analysis after 70 evaluable subjects, where the sample size 
re-assessment will be conducted. From each meeting, the IDMC will make a blinded 
recommendation to the Sponsor regarding the study to continue without change, modify study or 
enrolment to be placed on hold, or study termination. The sponsor is obligated to inform the study 
sites, IECs/IRBs and Competent Authorities of the IDMC recommendations according to country 
specific requirements. 
8.9 Steering Committee 
A Steering Committee will be established for this study. Members of the Steering Committee may 
also be Investigators or Sub-investigators. Face-to-face meetings will be held as determined by need. 
Routine business will be conducted by email, post or teleconferencing. 
The Steering Committee will provide advice and support to the study in matters concerning: 
 Communicating with sites (e.g., in the instance of recruitment or quality issues) 
 Oversight of the progress of the study 


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 Informing and advising on all aspects of the study  
8.10 Duration of the Study 
For an individual patient, the maximum duration of the study will be up to 99 days, including up to 
48 hours for screening, 6 days  treatment and follow-up at 3 months (D90 with a ±7-day window). 
The study will close when all patients have completed the 3-month follow-up visit. 
8.11 Premature Termination of the Study 
The Sponsor reserves the right to stop the study at any time on the basis of new information regarding 
safety or efficacy (e.g., discovery of an unexpected, significant or unacceptable risk to the patients 
enrolled in the study), or if study progress is unsatisfactory (e.g., failure to enrol patients at an 
acceptable rate), or for other valid reasons (e.g., Sponsor decides to suspend or discontinue 
development of the drug). After such a decision is made, the Investigator must inform all on-study 
patients within 1 week. All delivered study materials must be collected and all e-CRF pages 
completed to the extent possible. 
8.12 Confidentiality  
All study findings and documents will be regarded as confidential. The Investigator and members of 
their research team must not disclose any information without prior written approval from the 
Sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be identified on the e-
CRF and other documents submitted to the Sponsor/CRO by their study subject number, not by name. 
Documents that identify the subject must not to be submitted to the Sponsor/CRO (e.g. the ICD) and 
must be maintained in confidence by the Investigator. In the case of specific issues and/or queries 
from the regulatory authorities, it will be necessary to have access to the complete trial records, 
provided that subject confidentiality is protected. 
8.13 Other Ethical and Regulatory Issues 
If a significant safety issue is identified, either from an individual case report or review of aggregate 
data, then the Sponsor will issue prompt notification to all parties 
 regulatory authorities, 
Investigators and IEC/ IRB. 
A significant safety issue is one that has a significant impact on the course of the clinical study or 
programme (including the potential for suspension of the development programme or amendments 
to protocols) or warrants immediate update of informed consent. 
8.14 Publication Policy 
Any manuscript, abstract or other publication or presentation of results or information arising in 
connection with the study (including any ancillary study involving study subjects) must be submitted 
to the Sponsor for review and comment at least 14 days prior to submission for publication or 
presentation. No single centre or groups of centres may publish individually without review and 
approval from the trial Steering Committee. 
shall be considered in good faith by the authors. The Sponsor may delay such submission by a 
maximum of 90 days if it reasonably believes that publication of results may compromise its 
intellectual property rights or may insist that such information or data is removed from the proposed 


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publication. Publication of the results will not include confidential information without the 
permission of the Sponsor. 
The original eCRF pages and all data generated during the study under this protocol will become the 
property of the Sponsor. 
The Sponsor may announce quality-assured summary data in order to comply with the requirements 
of financial regulatory authorities, while ensuring so far as possible that such announcements will 
not compromise the Investigators  ability to publish the data in appropriate scientific forums. 
Authorship of communications arising from the trial-related data and subsequent analysis may 
include members from the contributing site(s) including basic research laboratories 
 
personnel. 


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Bellingan et al. 2017. Comparison of the efficacy and safety of FP-1201-lyo (intravenously 
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Buchwalder et al. 2000. Pharmacokinetics and pharmacodynamics of IFN-beta 1a in healthy 
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Chan et al. 2015. Treatment With Lopinavir/Ritonavir or Interferon-
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Solidarity Trial Results. N Engl J Med. 2021 Feb 11;384(6):497-511. 
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Science 2020 Oct 23;370(6515):eabd4570. doi: 10.1126/science.abd4570. Epub 2020 Sep 24.  
Zhou et al. 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. 
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SAP_001.pdf: 
Title: A Phase II Multi-Center, Double-Blind, Randomized and Controlled Study of the Safety and 
Efficacy of Intravenous Recombinant Human Interferon Beta-1a in Comparison to Dexamethasone 
for the Treatment of Hospitalized Patients with COVID-19 Infection  
 
NCT number: NCT04860518 
 
Document date: 21April2022 


 
 
 
 
 
 
 
 
 
 
A Phase II Multi-Center, Double-Blind, Randomized and Controlled Study of the Safety 
and Efficacy of Intravenous Recombinant Human Interferon Beta-1a in Comparison to 
Dexamethasone for the Treatment of Hospitalized Patients with COVID-19 Infection 
 
 
 
Study code: HIBISCUS (Human intravenous Interferon Beta-Ia Safety and preliminary 
efficacy in hospitalized subjects with CoronavirUS) 
 
Phase II study 
 
 
 
STATISTICAL ANALYSIS PLAN 


Statistical Analysis Plan 
            Page 2 (7)
 
Sponsor: Faron Pharmaceuticals Ltd 
Final 21.4.2022 
Study: HIBISCUS
 
 
 
 
 
Signatures: 
 
 
Statistical Analysis Plan was prepared by: 
 
 
 
Statistical Analysis Plan was reviewed/approved by: 
 
 
 


Statistical Analysis Plan 
            Page 3 (7)
 
Sponsor: Faron Pharmaceuticals Ltd 
Final 21.4.2022 
Study: HIBISCUS
 
 
 
 
 
Table of Contents 
 
1 
Abbreviations................................................................................................................................. 4 
2 
Early termination of the study ....................................................................................................... 4 
3 
Study objective(s) .......................................................................................................................... 4 
4 
Design and type of the study ......................................................................................................... 4 
5 
Sample size considerations ............................................................................................................ 5 
6 
General statistical considerations .................................................................................................. 5 
7 
Hardware and software .................................................................................................................. 6 
8 
References ..................................................................................................................................... 6 
9 
Appendices .................................................................................................................................... 6 
9.1 
Data listing plan ...................................................................................................................... 6 
9.2 
Tabulation plan ....................................................................................................................... 7 
 


Statistical Analysis Plan 
            Page 4 (7)
 
Sponsor: Faron Pharmaceuticals Ltd 
Final 21.4.2022 
Study: HIBISCUS
 
1 
Abbreviations 
Describe all the abbreviations used in the statistical analysis plan. E.g. 
AE 
 
Adverse event 
ANOVA 
Analysis of variance 
CD73  
Cluster of differentiation 73 
IV 
 
Intravenous 
IFN 
 
Interferon 
MxA  
Myxovirus resistance protein A 
PIM 
 
Potential inflammatory marker 
PT 
 
Preferred term 
SOC 
 
System organ class 
TEAE  
Treatment-Emergent Adverse Events 
2 
Early termination of the study 
 
The study was 
 to changes in the pandemic resulting in 
difficulties recruiting eligible patients. There were only five patients enrolled and dosed at the time 
of termination. 
3 
Study objective(s) 
The primary objective of this study was to demonstrate the safety and tolerability of early IV IFN 
beta-1a administration in hospitalized patients with COVID-19 infection compared to 
dexamethasone, and to investigate the efficacy of IV IFN beta-1a to improve clinical status in 
hospitalized patients with COVID-19 compared to dexamethasone. 
The secondary objectives of this study were to assess the immunogenicity of IFN beta-1a and to 
investigate the efficacy of IV IFN beta-1a on clinical outcomes in hospitalized patients with 
COVID-19 compared to dexamethasone. 
The exploratory objectives of this study were to investigate the efficacy of IV IFN beta-1a on 
clinical outcomes in hospitalized patients with COVID-19 compared to dexamethasone, to measure 
the pharmacodynamic (PD) effects of IFN beta-1a (MxA and CD73), to measure IFN beta levels 
during the treatment, to evaluate potential inflammatory markers (PIMs) response to treatment, and 
to evaluate genetic susceptibility to IFN beta-1a treatment. 
4 
Design and type of the study 
This was a multicentre Phase II, double-blind, randomized and dexamethasone controlled, study of 
the safety and preliminary efficacy of IV IFN beta-1a compared with dexamethasone in adult 
patients diagnosed with COVID-19 needing hospitalization, but not invasive mechanical ventilation 
or high flow/pressurized supplemental oxygen. The primary endpoint safety and tolerability of IV 
IFN beta-1a, and primary efficacy endpoint is WHO ordinal scale for clinical improvement (WHO 


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Study: HIBISCUS
 
OSCI) score at D14.  Both treatment groups received standard care according to current treatment 
guidelines. If the patient was subjected for systemic (oral or intravenous) glucocorticoids during the 
study days D1-D6, the IFN IMP is discontinued, and the patient continued in all follow-up study 
assessments. 
The study population consisted of patients that came into the emergency department for a 
deteriorated condition due to a suspected or already confirmed SARS-CoV2 infection during the 
previous 7 days. Approximately 140 subjects were planned to be recruited. 
Following randomization, patients were treated daily with IFN beta-1a 10 µg or dexamethasone as 
an IV bolus for 6 days and undergone daily assessments while hospitalized. The main analysis and 
reporting were meant to use D14, D28 and D90 data. Final follow-up occurred at D90 by phone or 
through medical records. During the long-term follow-up periods patient care will follow normal 
hospital procedures, as appropriate. 
5 
Sample size considerations 
140 patients were to be randomised to active and dexamethasone with 1:1 ratio. Conditional power 
re-assessment was planned to be conducted at interim analysis after 70 patients have been enrolled 
and followed up for the primary efficacy endpoint variable. 
Sample size calculations were performed and documented earlier, see Appendix A. 
6 
General statistical considerations 
No formal statistical hypotheses are set to be analysed due the early termination of the study with 
only 5 recruited subjects. 
Collected data will be listed and presented descriptively only. Following summary tables will be 
presented in support to patient listings: 
 
Study termination and primary reason for discontinuation 
 
Patient disposition 
 
Demographic characteristics 
 
Study drug exposure 
 
Summary of Treatment-Emergent Adverse Events (TEAEs) 
 
Deaths 
Summary tables regarding adverse events (AEs) will be presented at least by system organ class 
(SOC), preferred term (PT) and severity including number of patients and events for all TEAEs, 
severe TEAEs, serious TEAEs, drug-related TEAEs, serious drug-related TEAEs and TEAEs 
leading to study drug discontinuation. 
Based on the data from only 5 individual subjects some of the tables may be left out from the final 
table package due the sparsity of the table to be meaningful to produce, for example, deaths will not 
be tabulated if all study participants are alive. 


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Study: HIBISCUS
 
7 
Hardware and software 
Tables and patient data listings are produced with SAS® 9.4 TS1M6 for Windows (SAS Institute 
Inc., Cary, NC, USA). 
8 
References 
1. HIBISCUS Study Protocol, version 4.0 (27th September 2021), Faron Pharmaceuticals Ltd. 
9 
Appendices 
A. HIBISCUS updated sample size calculation, final version (1st April 2021). 
9.1 
Data listing plan 
Listing 1 Demographics 
Listing 2 Disposition 
Listing 3 Termination 
Listing 4 Deaths 
Listing 5 Adverse events 
Listing 6 Exposure 
Listing 7 Deviations 
Listing 8 Symptoms 
Listing 9 Concomitant medications 
Listing 10 Medical history 
Listing 11 Questionnaires 
Listing 12 CD73 
Listing 13 Anti-drug antibodies 
Listing 14 ARDS 
Listing 15 Acute kidney injury 
Listing 16 New mechanical ventilation 
Listing 17.1 Labs - Chemistry 
Listing 17.2 Labs - Hematology 
Listing 17.3 Labs - Interferon beta 


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Study: HIBISCUS
 
Listing 17.4 Labs - Myxovirus resistance protein A 
Listing 17.5 Labs - Pregnancy 
Listing 18 Physical examination 
Listing 19 Pharmacogenetics 
Listing 20 Scans 
Listing 21 Vital signs 
 
9.2 
Tabulation plan 
1 Demographic Tables 
Table 1.1 Demographics 
 
Table 1.2 Disposition 
 
Table 1.3 Termination 
 
Table 1.4 Deaths 
2 Safety Tables 
Table 2.1 Adverse events 
 
Table 2.2 Exposure