Interferon Lambda for Immediate Antiviral Therapy at Diagnosis (ILIAD): A Phase II Randomized, Double-blind, Placebo-controlled, Multicenter Trial to Evaluate the Effect of Peginterferon Lambda for the Treatment of COVID-19
Phase: PHASE2
Conditions: Sars-CoV2, Covid-19
Sponsor: University Health Network, Toronto

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STUDY TITLE: 
 
 
 
 
Interferon Lambda for Immediate Antiviral therapy at Diagnosis 
(ILIAD): A phase II randomized, double-blind, placebo-
controlled, multicenter, trial to evaluate the effect of 
peginterferon lambda for the treatment of COVID-19. 
 
SHORT TITLE:  Interferon Lambda for Immediate Antiviral therapy at Diagnosis 
(ILIAD) 
PROTOCOL ID:  JF-4-2020 
 
SPONSOR: Jordan Feld, MD MPH 
Toronto General Hospital, University Health Network 
VERSION NO.: 2.2 
VERSION DATE: January 24, 2021 
PREVIOUS VERSIONS: 1.0 April 6, 2020 
1.1 April 20, 2020 
1.2 April 27, 2020 
1.3 April 30, 2020 
1.4 May 1, 2020 
1.5 May 2, 2020 
1.6 May 7, 2020 
1.7 June 8, 2020 
1.8 July 01, 2020 
1.9 August 29, 2020 
2.0 October 15, 2020 
2.1 December 22, 2020 
 

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PROTOCOL: 
 
Interferon Lambda for Immediate Antiviral therapy at Diagnosis (ILIAD): A phase II 
randomized, double-blind, placebo-controlled, multicenter, trial to evaluate the effect of 
peginterferon lambda for the treatment of COVID-19. 
 
 
This protocol has been approved by the Toronto Centre for Liver Disease, University Health 
Network.  The following signature documents this approval. 
 
 
 
 
 
 
 
 
 
__________________________ 
 
__________________________ 
Dr. Jordan Feld, MD                                                   Date 
 
 
 
 
INVESTIGATOR SIGNATURE OF AGREEMENT FOR PROTOCOL 
 
I have read the protocol, including all appendices, and I agree that it contains all necessary details 
for me and my staff to conduct this study as described. I will conduct this study as outlined herein 
and will make reasonable effort to complete the study within the time designated. 
 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by the Toronto Centre for Liver Disease, University Health Network. I will 
discuss this material with them to ensure that they are fully informed about the drugs and the study. 
  
 
 
 
 
 
 
 
___________________________________  
_____________________________ 
Site Principal Investigator Name (Printed)                 Signature 
 
 
 
 
                                                                                     ___________________________ 
                                                                                      Date 
 
 
 
 

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Interferon Lambda for Immediate Antiviral therapy at Diagnosis (ILIAD): A phase II 
randomized, double-blind, placebo-controlled, multicenter, trial to evaluate the effect of 
peginterferon lambda for the treatment of COVID-19. 
 
 
Principal Investigator: Jordan J Feld MD MPH 
Co-PI:  Christopher Kandel (MGH site lead) 
Co-I:   Darrell Tan (SMH site lead) 
Atul Humar 
 
Deepali Kumar 
Bryan Coburn 
 
Marcelo Cypel 
 
Mario Ostrowski 
 
David Wong 
 
Harry Janssen 
 
Eddy Fan 
 
Tony Mazzulli 
 
Robert Kozak 
 
Evaldo Stanislau 
Statistician: Bettina E Hansen 
 
 
 
 
 
 

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Table of Contents 
1. Title Page  
 
 
 
 
 
1 
2. Investigator Signature Page 
 
 
 
2 
3. Investigator List  
 
 
 
 
3 
4. Protocol Synopsis  
 
 
 
 
8 
5. Abbreviations and Definitions 
 
 
 
16 
6. Background 
 
 
 
 
 
18 
7. Study outline 
 
 
 
 
 
19 
7.1. Hypothesis 
 
 
 
 
 
19 
7.2. Objectives 
 
 
 
 
 
19 
7.3. Study Populations 
 
 
 
 
19 
7.4. Study Design  
 
 
 
 
19 
8. Study Medication  
 
 
 
 
21 
8.1. Peginterferon lambda overview 
 
 
21 
8.2. Composition  
 
 
 
 
21 
8.3. Use 
 
 
 
 
 
 
22 
8.4. Mechanism of action  
 
 
 
22 
8.5. Contraindications 
 
 
 
 
22 
8.6. Summary 
 
 
 
 
 
22 
8.7. Special populations  
 
 
 
23 
8.8. Drug-drug interactions 
 
 
 
23 
8.9. Clinical trial data 
 
 
 
 
24 
8.10. 
Safety data summary  
 
              25 
8.11. 
Pregnancy 
 
 
 
              27 
8.12. 
Placebo 
 
 
 
 
27 
9. Cohort A  
9.1. Inclusion/Exclusion Criteria  
 
 
27 
9.2. Study Procedures 
 
 
 
 
29 
9.2.1. Consent 
 
 
 
 
29 
9.2.2. Enrolment & randomization  
            29 
9.2.3. Study interventions 
 
 
 
30 
9.2.4. Nasal Swabs & Saliva Collection 
 
32 
9.2.5. Home visits                                                     33 
9.2.6. Household contacts                                         33 
9.2.7. Participant compensation                                34 
9.2.8. Standard Operating Procedures for Clinic      34 
    Visits                                                               
9.2.9. Safety assessment                                           34 
9.3. Outcomes 
 
 
 
 
 
35 
9.4. Sample Size Calculations 
 
 
 
36 
10. Cohort B 
10.1. 
Safety Assessment 
 
 
 
37 
10.2. 
Inclusion/Exclusion Criteria  
 
37 
10.3. 
Study Procedures 
 
 
 
39 
10.3.1. Consent 
 
 
 
 
39 
10.3.2. Enrolment & randomization  
 
40 

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10.3.3. Study interventions 
 
 
 
40 
10.4. 
Outcomes 
 
 
 
 
42 
10.5. 
Sample Size Calculations 
 
 
43 
10.6. 
Rationale for Primary Endpoint Cohort B 
43 
11. Optional Consents 
 
 
 
 
43 
11.1. 
Genetics 
 
 
 
 
43 
11.2. 
PBMC  
 
 
 
 
44 
11.3. 
Antibody Testing 
 
 
 
44 
12. Sample Processing  
 
 
 
 
45 
12.1. 
Swabs  
 
 
 
 
45 
12.2. 
PBMC collection 
 
 
 
45 
13. Study Withdrawal  
 
 
 
 
45 
14. Data Safety and Monitoring Committee  
 
46 
15. Trial Oversight 
 
 
 
 
 
46 
 
 
16. Data Analysis 
 
 
 
 
 
46 
17. Symptom Reporting 
 
 
 
 
47 
18. Adverse/Severe Adverse Events  
 
 
48 
19. Ethical & Regulatory Considerations 
 
 
49 
20. Schedule of events –  
20.1           Cohort A                                                         51 
20.2           Cohort B 
 
                                           52 
21. Flowcharts 
 
 
 
 
 
 
21.1. 
Cohort A 
 
 
 
 
53 
21.2. 
Cohort B 
 
 
 
 
54 
22. References  
 
 
 
 
 
55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Amendment 6 
 
 
Amendment rationale 
 
Changes to the protocol 
The major changes made to the protocol, and sections affected listed below 
 
 
Section 
Changes made 
Cohort B Primary Outcome 
The primary has been revised to a clinical 
endpoint along an ordinal scale from a 
virologic endpoint. This change was made 
to reflect the importance of clinical 
outcomes for individuals hospitalized with 
COVID-19. A recently reported 
randomized trial of inhaled interferon-beta 
among inpatients with COVID-19 was 
associated with an improved odds of a 
beneficial outcome.  
Cohort B Study Procedures 
Reduced the number of sampling to align 
with the new primary endpoint and limit 
the need to expose research personnel to an 
individual with COVID-19. Replaced saliva 
sampling with mid-turbinate swabbing to 
allow for easier self-collection.   
 
 
 

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4.0 Study Synopsis 
OBJECTIVES 
Cohort A – Ambulatory 
1. To evaluate the safety and tolerability of immediate treatment 
with Peginterferon Lambda 180 mcg in patients with mild to 
moderate COVID-19 discharged to home isolation. 
2. To compare the proportion of individuals with a nasopharyngeal 
swab negative for SAR-CoV-2 RNA at day 7 post-treatment in 
those treated with peginterferon lambda 180 mcg vs. placebo. 
Cohort B - Hospitalized 
1. To evaluate the safety and tolerability of immediate treatment 
with peginterferon-lambda 180 mcg on days 0 and 5 in patients 
hospitalized with moderate COVID-19 admitted to hospital. 
2. To compare clinical outcomes on an ordinal scale in those 
treated with peginterferon lambda 180 mcg at Days 0 and 5 vs. 
placebo. 
STUDY DESIGN 
AND 
INTERVENTION 
The study uses an adaptive design.  An ambulatory cohort (Cohort 
A) will be recruited first. Individuals diagnosed with COVID-19 in 
an Assessment Centre/Emergency Department who are deemed well 
enough for discharge to home isolation will be provided information 
related to the study through recruitment materials (posters) at the 
site. Participants that are interested in participating will contact the 
study coordinator through the contact information provided on the 
recruitment material at the site or found through study 
advertisements. Providers caring for patients with COVID-19 may 
also refer patients to the study team after obtaining verbal consent 
to share contact information with the study team.  After speaking 
with research staff, eligible consenting participants confirmed to be 
COVID-19 positive will come to the ambulatory clinic and be 
randomized to receive a single subcutaneous (SC) injection of 

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peginterferon lambda 180 mcg or placebo. Patients will be observed 
for one hour in the clinic before discharge and followed through 
phone/videoconferencing at 4-6 hours post injection and then daily 
and will perform self-administered mid-turbinate nasal swabs on 
days 1, 2 and 3. For participants who cannot return to the outpatient 
clinic; a study nurse will perform a home visit on day 3 for 
nasopharyngeal swab collection and clinical assessment. Additional 
self-swabs will be taken on days 5 and 7 with a second clinic/home 
visit on day 7 and 14 for nasopharyngeal swab. Virtual visits will 
occur on the days of self-swabs until day 14. Self-swabs will be 
performed on days 0,1, 2, 3, 5, 7, 10 and 14. The primary endpoint 
will be the proportion in both groups negative for SARS CoV-2 RNA 
by nasopharyngeal swab on day 7. 
After 50% enrollment (n=30) in Cohort A, the Data Safety 
Monitoring Committee will review safety data.  If deemed safe, 
Cohort B (Hospitalized) will begin enrollment. Patients diagnosed 
with COVID-19 without evidence of severe disease but requiring 
hospitalization will be consented and randomized to receive a SC 
dose of peginterferon-lambda 180 mcg on Days 0 and 5 or placebo 
Patients will be monitored with blood tests and mid-turbinate swabs 
from day 0 to  day 28, with swab frequency decreasing after day 7. 
The primary endpoint will be clinical status on an ordinal scale at 
Day 14. Numerous secondary endpoints will be evaluated.   
STUDY 
POPULATION AND 
NUMBER OF 
PATIENTS 
Cohort A – Ambulatory – 60 
Cohort B – Hospitalized - 200 
ROLL-IN PHASE 
After the first 10 patients randomized (Cohort A) have completed 7 
days of follow-up, the independent DSMC will review the totality of 
the safety data. Review will occur after each 10 patients complete 7 

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days of follow-up until 50% enrollment.  The DSMC will advise the 
steering committee whether to halt or continue enrollment based on 
their findings. After 50% enrollment, if the DSMC recommends 
continued enrollment, recruitment in Cohort B will begin.  
STUDY DURATION 
Approximately 3 months (2 months for enrollment, 1-2 weeks of 
treatment, 1-2 weeks of follow-up). 
ELIGIBILITY 
CRITERIA 
Inclusion Criteria Cohort A 
1. Adult patients between the ages of 18 and 75 years. 
2. Confirmed COVID-19 infection by PCR within 7 days of 
symptom onset. 
3. Discharged to home isolation. 
4. Willing and able to sign informed consent. 
5. Willing and able to follow-up by daily phone videoconference. 
6. Female patients of childbearing potential and male patients with 
partners of childbearing potential must agree to use adequate 
methods of contraception during the study and through 90 days 
after the last dose of study medication. Female patients of 
childbearing potential are all those except patients who are 
surgically sterile, who have medically documented ovarian 
failure, or who are at least 1 year postmenopausal.   
Exclusion Criteria Cohort A 
1. Requirement for hospital admission 
2. Current immunosuppression due to medication (steroids, 
biologics, chemotherapy) or underlying condition such as  
organ/bone marrow transplant or untreated HIV or HIV 
infection with detectable HIV RNA and/or CD4 count of <500. 
3. Pregnancy (or positive urine pregnancy test) or lactating 
4. The following pre-existing medical conditions: 

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a. Known seizure disorder 
b. Known retinal disease requiring therapy 
c. Known autoimmune condition requiring therapy more 
intensive 
than 
intermittent 
non-steroidal 
anti-
inflammatories in the prior 6 months (rheumatoid 
arthritis, lupus, inflammatory bowel disease) 
d. Known history of chronic obstructive pulmonary disease 
(COPD) 
or 
asthma 
associated 
with 
functional 
impairment  
e. Known cirrhosis with any history of decompensation 
(ascites, variceal bleeding or hepatic encephalopathy) 
f. Known chronic kidney disease with estimated creatinine 
clearance < 50 mL/minute or need for dialysis 
g. Severe psychiatric disorder – schizophrenia, bipolar 
disorder, depression with prior suicidality 
h. Any other underlying medical (cardiac, liver, renal, 
neurological, respiratory) or psychiatric condition that 
in the view of the investigator would preclude use of 
peginterferon lambda 
5. Advanced cancer or other illness with life expectancy of < 1 year 
6. Known alcohol or drug dependence that in the opinion of the 
investigator would impair study participation 
7. Known prior intolerance to interferon treatment 
8. Enrolment in another clinical trial with use of any 
investigational agent in the prior 30 days 
9. Use of off-label therapy for COVID-19 
Cohort B Inclusion Criteria 
1. Adult patients over age 18  
2. SARS-CoV-2 RNA-positive on nasopharyngeal swab/respiratory 
specimen within 10 days of symptom onset 

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3. Admitted to hospital for management of COVID-19 
4. Willing and able to provide informed consent  
5. Female patients of childbearing potential and male patients with 
partners of childbearing potential must agree to use adequate 
methods of contraception during the study and through 90 days 
after the last dose of study medication. Female patients of 
childbearing potential are all those except patients who are 
surgically sterile, who have medically documented ovarian 
failure, or who are at least 1 year postmenopausal.   
 
Cohort B Exclusion Criteria 
1. Severity of illness 
a. Respiratory failure (requiring>6L O2 or intubation in the 
ER) 
b. Shock – systolic BP<90 mmHg or mean arterial BP<60 
mmHg after fluid resuscitation 
2. Current immunosuppression due to medication (steroids, 
biologics, chemotherapy) or underlying condition such as 
organ/bone marrow transplant or untreated HIV or HIV 
infection with detectable HIV RNA and/or CD4 count of <500. 
3. Pregnancy (or positive urine pregnancy test) or lactating 
4. The following pre-existing medical conditions: 
a. Known seizure disorder 
b. Known retinal disease requiring therapy 
c. Known autoimmune condition requiring therapy more 
intensive 
than 
intermittent 
non-steroidal 
anti-
inflammatories in the prior 6 months (rheumatoid 
arthritis, lupus, inflammatory bowel disease) 
d. Known cirrhosis with any history of decompensation 
(ascites, variceal bleeding or hepatic encephalopathy) 
e. Known chronic kidney disease with estimated creatinine 
clearance < 30 mL/minute or need for dialysis 

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f. Severe psychiatric disorder – uncontrolled schizophrenia 
or bipolar disorder or depression with prior suicidality 
g. Any other underlying medical (cardiac, liver, renal, 
neurological, respiratory) or psychiatric condition that 
in the view of the investigator would preclude use of 
peginterferon lambda 
5. Known prior intolerance to interferon treatment 
6. Enrolment in another clinical trial with use of an antiviral agent 
in the prior 30 days (co-enrollment with immunomodulatory 
agents permitted) 
7. Use of off-label therapy for COVID-19 
8. Any of the following abnormal laboratory indices 
a. Hemoglobin < 100 mg/dL 
b. Platelet count < 75,000 cells/mm3 
c. Absolute neutrophil count < 1,000 cells/mm3 
d. Estimated creatinine clearance < 30 cc/mL 
e. Total bilirubin > 2x upper limit of normal (ULN) 
f. Alanine aminotransferase (ALT) > 5x ULN 
g. Aspartate aminotransferase (AST) > 5x ULN 
h. Lipase or amylase > 2x ULN 
i. Random blood glucose > 20 mmol/L 
PRIMARY 
ENDPOINTS 
Cohort A  
Primary efficacy endpoint: 
The proportion of participants with negative SARS-CoV-2 RNA on 
nasopharyngeal swab at day 7 post-randomization. 
Primary safety endpoint:  
The rate of treatment-emergent and treatment-related serious 
adverse events (SAEs)  
Cohort B 

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Primary clinical endpoint: 
Clinical status on an ordinal scale at Day 14. 
Scale: 1 death; 2 hospitalized with invasive ventilation; 3 
hospitalized on non-invasive ventilation or high flow oxygen; 4 
hospitalized on supplemental oxygen; 5 hospitalized not on 
supplemental oxygen; 6 not hospitalized with limitation of activity; 
7 not hospitalized without limitation in activity 
Primary safety endpoint:  
The rate of treatment-emergent and treatment-related serious 
adverse events (SAEs).  
SECONDARY 
ENDPOINTS 
Cohort A 
Secondary Endpoints: 
Clinical 
1. Time to resolution of symptoms (fever, cough, diarrhea) 
2. Change in symptom scores (respiratory, gastrointestinal, 
fever) from day 0 to day 7 
3. Need for hospital admission from day 0 to 14 
4. Adverse events and serious adverse events by day 14 
Virologic/Immunological 
5. Proportion 
negative 
for 
SARS-CoV-2 
RNA 
by 
nasopharyngeal swab on day 3 
6. Proportion 
negative 
for 
SARS-CoV-2 
RNA 
by 
nasopharyngeal swab on day 14 
7. Time to SARS-CoV-2 RNA negativity on mid-turbinate nasal 
swab  
8. Proportion with SARS-CoV-2 RNA in blood at day 0 and 7 
9. Proportion with SARS-CoV-2 antibodies in blood at day 0 
and 7 

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10. Correlation of response with interferon lambda 4 (IFNL4) 
genotype 
11. Change 
in 
laboratory 
and 
inflammatory 
markers 
(hemoglobin, white blood cell count, lymphocyte count, liver 
profile, ferritin, lactate dehydrogenase, c-reactive protein, 
D-dimers, amylase) from day 0 to day 7 and day 7 to 14 
12. Confirmed diagnosis of COVID-19 in household contacts 
from day 0 – 30.  
 
Cohort B 
Secondary Endpoints 
1. Clinical status on the ordinal scale at Day 7, 21, and 28 
2. ICU admission during hospitalization 
3. Need for intubation from day 0 to 14 and to 28 
4. Length of hospital stay 
5. Change in respiratory symptom score from day 0 to 7, day 0 
to 14, and day 0 to 28 (Appendix A) 
6. All-cause mortality at day 28 and day 90 
7. Readmission to hospital from day 0 - 28 and from day 0 - 90 
8. COVID-19-related mortality at day 28 
9. Adverse (AEs) and Serious Adverse Events (SAEs) from day 
0 - 28 
10. Frequency of dose reduction or dose omission for the second 
dose of peginterferon lambda 
Virologic/Immunological 
11. Time to SARS-CoV-2 negativity 
12. Proportion negative for SARS-CoV-2 RNA by mid-turbinate 
swab on days 0-7, 10, 12, 14, 18, 21, 25, 28 

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13.  Change in quantitative SARS-CoV-2 RNA by mid-turbinate 
swab over time 
14. Correlation of clinical and virologic response with interferon 
lambda 4 (IFNL4) genotype 
15. Change 
in 
laboratory 
and 
inflammatory 
markers 
hemoglobin, white blood cell count, lymphocyte count, liver 
profile, ferritin, lactate dehydrogenase, c-reactive protein, 
D-dimers, amylase) from day 0 to day 7 and to day 14, 21, 
and 28  
16. Proportion with SARS-CoV-2 antibody at day 7, 14, 21, and 
28 
17. Proportion with SARS-CoV-2 RNA in blood at day 0, 7 and 
14, 21, and 28 
SAMPLE SIZE  
Cohort A 
With an expected clearance rate of 40% by day 7 in the placebo arm 
and 80% in the treatment arm, 23 patients are required in each arm 
for 80% power at alpha 0.05. With potential dropout of 20% due to 
either logistical problems or loss-to-follow-up, this translates to 30 
patients per arm or 60 patients. 
Cohort B 
Powered based on the estimated odds of improvement on an ordinal 
scale using the distribution of outcomes from previous randomized 
treatment trials for COVID-19. For a suspected odds ratio of 2.1, 
similar to that observed for inhaled interferon-beta, and with 80% 
power the estimated sample size is 200, assuming 5% drop-out.  
RANDOMIZATION 
AND TREATMENT 
ASSIGNMENT 
In both cohorts, patients will be randomly assigned 1:1 in blocks of 
4 using centralized computer-generated randomization to receive 
either 
treatment 
with 
peginterferon 
lambda 
or 
placebo. 

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Randomization in Cohort B will be stratified by sex (male/female) 
and country of site. 
DATA TO 
CAPTURE 
Demographic data: Age, sex, ethnicity, country of birth 
Living arrangements: house/apartment, long-term care, number of 
household contacts 
Medical history – any pre-existing medical conditions with specific 
focus on history of diabetes, heart disease, lung disease 
Current prescribed medications and any drug allergies. 
Habits: smoking (none/current/past), recreational drug and alcohol 
use (none/current/past) 
Physical examination: Cohort A: Vital signs, weight & height 
Cohort B: Full physical examination, weight & height 
Routine blood tests: complete blood count, biochemistry (blood 
glucose, electrolytes, creatinine, liver enzymes, total and direct 
bilirubin and albumin) and inflammatory markers including D-
Dimers, LDH, ferritin, amylase c-reactive protein, and troponin.  
DATA 
MANAGEMENT 
AND ANALYSIS 
The study will be overseen by the study steering committee including 
PIs, site PIs and statistician. Data will be stored in a secure REDCap 
database through UHN.  Analysis will be carried out by the study 
team statistician. 
 
 
 

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5.0 Abbreviations & Definitions 
AE – adverse events 
ALT – alanine aminotransferase 
AST – aspartate aminotransferase 
ASV – asunaprevir 
AUC – area under the curve 
Beta-hCG – beta human choriogonadotropin 
BP – blood pressure 
CI – confidence interval 
Co-I – co-investigator 
COPD – chronic obstructive pulmonary disease 
COVID-19 – Coronavirus disease 19 
CTN – Clinical Trials Network 
CXR – chest x-ray 
CYP – cytochrome P-450 
DCV – daclatasvir 
DSMC – Data Safety Monitoring Committee 
eGFR – estimated glomerular filtration rate 
ER – emergency room 
ESRD – end-stage renal disease 
GMR – geometric mean ratio 
HBeAg – hepatitis B e antigen 
HBV – hepatitis B virus 
HCV – hepatitis C virus 
HDV – hepatitis D virus 
HIV – human immunodeficiency virus 
IFN - Interferon  
IFN-λ - interferon lambda 
IFNL4 – interferon lambda 4 
Mcg – micrograms 
MGH – Michael Garron Hospital 
NOAEL – no-observed-adverse-event-level 
NP – nasopharyngeal 
PBMC - peripheral blood mononuclear cells 
PCR – polymerase chain reaction 
pDILI – presumed drug-induced liver injury 
PEG – polyethylene glycol 
PegIFN-λ - peginterferon lambda 
PI – principal investigator 
PK - pharmacokinetic 
RBV – ribavirin 
RNA – ribonucleic acid 
SAE – serious adverse events 
SARS-CoV-2 – Severe Acute Respiratory Syndrome – Coronavirus 2 
SC – steering committee 
SMH – St. Michael’s Hospital 

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Sub-I – sub-investigator 
SVR – sustained virologic response 
TCLD – Toronto Centre for Liver Disease 
UHN – University Health Network 
ULN – upper limit of normal 
WBC – white blood cell count 
 
 

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6.0 Background/Rationale 
SARS-CoV-2 is a novel coronavirus that has led to a global pandemic due to its relatively high 
transmissibility and potential to cause severe acute respiratory disease1. There are currently no 
approved therapies for coronavirus disease-19 (COVID-19) and although various antiviral 
strategies are under evaluation, none has shown significant benefits in early phase trials2. 
 
The cornerstone of the innate antiviral immune response is the interferon (IFN) system. Sensing 
of viral infection leads to production of Type I (alpha, beta) and Type III (lambda) IFNs, which 
drive a potent antiviral response through the induction of a wide array of genes, collectively known 
as IFN-stimulated genes (ISGs)3. Both Type I and Type III IFNs signal through the JAK-STAT 
pathway to drive ISG induction with comparable antiviral activity, however their systemic effects 
differ markedly due to the use of distinct receptors with different tissue distributions3. The Type I 
IFN receptor is highly expressed on all cells in the body, whereas the IFN-λ (lambda) receptor is 
primarily expressed on epithelial cells with high expression in lung, intestine and liver and very 
limited expression in hematopoietic and central nervous system cells4.  As a result, production of 
or treatment with Type I IFNs leads to significant off-target effects, which have limited the safety, 
tolerability and ultimately clinical use of this class of agents. Interferon-alpha was used with some 
evidence of clinical efficacy in a pilot trial during the first SARS outbreak5, however, concerns 
have been raised of the toxicity of a Type I IFN for COVID.  IFN-λ was developed as a therapeutic 
to overcome the toxicity seen with IFN alpha and beta. Conjugation of IFN-λ to polyethylene 
glycol increases the half-life and allows for once weekly dosing. PegIFN-λ has been studied in 
Phase 1, 2 and 3 clinical trials in over 3000 patients for the treatment of hepatitis C virus6, hepatitis 
B virus7 and most recently hepatitis delta virus8 infections, showing comparable antiviral activity 
to IFN-α, but with a much better safety and tolerability profile. 
 
IFN-λ is particularly attractive for acute respiratory disease due to the high expression of the IFN-
λ receptor in lung epithelia. In vitro and mouse studies have shown that IFN-λ is strongly induced 
in influenza, SARS-CoV-1 and other respiratory virus infections9.  More importantly, IFN-λ 
treatment has been shown to be highly effective in a mouse model of severe influenza A infection. 
In mice challenged with influenza A, pre-treatment with either IFN-α or IFN-λ prevented 
mortality10. However, when the IFNs were given after infection, IFN-α worsened outcome, 
whereas IFN-λ treatment improved survival10. IFN-λ is particularly attractive as a treatment 
strategy for SARS-CoV-2 infection because in addition to its anticipated effect in the lung, the 
IFN-λ receptor is highly expressed in intestine and liver11, which would address intestinal and 
hepatic involvement documented in patients with COVID-191,12. Furthermore, the lack of the 
lambda receptor on hematopoietic cells limits concerns about the potential to worsen cytokine 
storm syndrome13.  
 

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Based on extensive human safety data using PegIFN-λ and strong mouse data supporting the use 
of IFN-λ in acute respiratory infection, this study will evaluate PegIFN-λ in patients with mild to 
moderate COVID-19.   
 
7.0 Study Outline 
  
7.1 Hypothesis: Treatment with peginterferon lambda 180µg SC in patients with mild to moderate 
COVID-19 will accelerate viral clearance compared to best supportive care. 
 
7.2 Objectives 
Cohort A - Ambulatory 
1. To evaluate the safety and tolerability of immediate treatment with Peginterferon Lambda 180 
mcg in patients with mild to moderate COVID-19 discharged to home isolation. 
2. To compare the proportion of individuals with a nasopharyngeal swab negative for SARS-
CoV-2 RNA at day 7 post-treatment in those treated with peginterferon lambda 180 mcg vs. 
those who receive placebo. 
 
Cohort B - Hospitalized 
1. To evaluate the safety and tolerability of immediate treatment with peginterferon-lambda 180 
mcg in patients hospitalized with moderate COVID-19 admitted to hospital. 
2. To compare the time until the first negative mid-turbinate swab for SARS-CoV-2 RNA by day 
28 in those treated with peginterferon lambda 180 mcg on Days 0 and 5 vs. those receiving 
placebo. 
 
7.3 Study Populations 
The study population will include 2 cohorts and will follow an adaptive design with initial safety 
data in Cohort A guiding the initiation of Cohort B. 
 
7.4 Study Design 
Cohort A – Ambulatory 
Individuals who are seen at the assessment centre who are swabbed for possible COVID-19 and 
deemed well enough for home isolation will be informed about the study.  They will be provided 
with contact information for the study team (email and phone number) and will contact the study 
team if interested in learning more about the study.  Interested participants who contact study staff 
will be confirmed to be COVID-19 positive by research staff as soon as results are available 
(turnaround time ~12 hours) and if confirmed will be further screened for eligibility criteria by 
research study staff.  Providers caring for patients with COVID-19 may refer patients to the study 
after obtaining verbal consent for sharing of contact information with the study time.  The study 
team will contact referred patients by phone to describe the study and assess eligibility.  After 
review, a consent form will be emailed to the participant and informed consent will be obtained 

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(see ‘Consent Process’) though witnessed telephone consent.  Consenting individuals will be 
provided with instructions for follow-up. Participants who consent will come to the outpatient 
office and be randomized to receive a single dose of peginterferon lambda 180µg SC or placebo 
(see ‘Study Procedures’).                 
 
Cohort B – Hospitalized 
Patients with confirmed SARS-CoV-2 infection admitted to hospital will be screened for inclusion 
and exclusion criteria and if eligible will be offered study enrolment. Written informed consent 
will be obtained (see ‘Consent Process’). Consenting eligible patients will be randomized to 
receive peginterferon lambda 180µg SC or placebo and a second dose on day 5.   
 
Study procedures, eligibility criteria and outcomes will be described for the 2 cohorts 
separately. 
 
8.0 Study Medication 
8.1 Peginterferon lambda overview 
 
- Administered subcutaneously in the lower abdomen 
- Dose 180 µg SC weekly (in ambulatory arm of the study only 1 dose is given, which may 
last up to 1 week) 
- Composition: according to the manufacturer’s specifications. 
- Expiry date: mentioned on the label or package. 
8.2 Composition: Peginterferon lambda Injection is a sterile, nonpyrogenic, ready-to-use solution 
(0.4 mg/mL) that is clear to opalescent, colorless to pale yellow, and essentially free of particles. 
Lambda Injection is provided in a 1-mL long Type I glass syringe (0.18 mg/syringe) with a staked 
29-gauge, 1/2- inch, thin-walled needle. The syringe has a rigid needle shield and is stoppered with 
a plunger stopper. Syringes are prefilled with a solution of Peginterferon lambda Injection, 
mannitol, L-histidine, polysorbate 80, hydrochloric acid, and water for injection; they are intended 
for a single use at adjustable doses. The syringe is marked with dose indicator lines, which are 
used as a reference point for administering the correct dose.  
 
The coordinator will expel the air bubble from the syringe and set the dose by aligning the front 
edge of the stopper with the correct dose indicator line. A sufficient overfill is included in each 
syringe for needle/syringe, dose adjustment, and bubble expulsion losses, leaving a sufficient 
amount of Peginterferon lambda Injection for delivery of up to 180 μg. Peginterferon lambda 
Injection should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from long-
term (> 24 hours) exposure to light. Peginterferon lambda injection should not be frozen. 

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8.3 Use 
 
Peginterferon lambda is currently not approved for clinical use in Canada.  Eiger 
BioPharmaceuticals, Inc (manufacturer) is providing the drug for study purposes. The syringes 
will be covered and dispensed from the study pharmacy at UHN to the participating hospitals 
and offsite clinic. 
8.4 Mechanism of Action 
 
- Peginterferon lambda is a covalent conjugate of human recombinant non-pegylated IFN lambda 
(IFN L) and a 20-kDa linear PEG chain. 
 
- Peginterferon lambda binds to the interferon lambda receptor expressed on epithelial cells in the 
lung, intestine, liver and skin and activates a signaling pathway leading to the production of a 
variety of genes with antiviral and anti-proliferative effects, collectively known as interferon-
stimulated genes (ISGs). 
8.5 Contraindications 
 
- Hypersensitivity to peginterferon lambda 
 
8.6 Summary 
 
As of 11-May-2018, approximately 3,743 subjects (including 237 healthy subjects; 3,276 subjects 
with HCV; and 197 subjects with HBV; and 33 subjects with HDV) have received peginterferon 
lambda or comparator in 19 Phase 1, 2, or 3 studies. 
 
Identified risks associated with treatment with peginterferon lambda based on nonclinical and/or 
clinical data, as well as potential class effects, include hepatobiliary toxicity (transaminase 
elevations with or without hyperbilirubinemia) and injection site reactions. Potential risks include 
neuropsychiatric 
disorders 
(including 
depression), 
cardiovascular 
events, 
immunogenicity/hypersensitivity reactions, autoimmune disorders, elevated amylase/lipase, 
dermatitis, reproductive risk, and pediatric growth inhibition. Overall, peginterferon lambda was 
well tolerated at single SC doses of up to 5 μg/kg and multiple SC doses of up to 180 μg 
administered weekly for 48 weeks. The primary safety finding observed has been dose-dependent 
and reversible elevations in serum transaminases, with the majority of events observed across 
studies in the highest (240 μg) dose group, which were accompanied, in some cases, by increases 
in total and conjugated (direct) bilirubin. The dose of 240 μg has been discontinued from further 
development. Increases in total and direct bilirubin have also been noted with doses of 180 μg that 
may be accompanied by mild increases in transaminases. These increases were not accompanied 
by evidence of loss of synthetic function of the liver and were readily reversible with dose 
withholding and/or dose reduction. Currently available data from peginterferon lambda clinical 

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studies indicate that cirrhotic patients with portal hypertension are at greater risk for hepatic 
decompensation. 
 
8.7 Special Populations  
 
Renal Impairment: The PK of peginterferon lambda in subjects with normal renal function or 
impaired renal function (IR) was measured in a total of 43 subjects (age 18–75 years, BMI 18–35 
kg m–2) enrolled into one of 5 renal function groups: normal (n = 12), mild RI (n = 8), moderate 
RI (n = 8), severe RI (n = 7), end-stage renal disease (ESRD, n = 8 (Study AI452019, Hruska 
2015). Subjects received a single dose of peginterferon lambda (180 μg) subcutaneously on day 1 
followed by PK serum sample collections through day 29. Safety, tolerability and immunogenicity 
data were collected through day 43. PK parameters were estimated and summarized by group. 
Geometric mean ratios (GMR) and 90% confidence intervals (CIs) were calculated between 
normal and RI groups. With decreasing eGFR, peginterferon lambda exposure (Cmax, AUC) 
increased while apparent clearance (CL/F) and apparent volume of distribution (V/F) decreased. 
Relative to subjects with normal renal function (geometric mean AUC= 99.5 ng ml–1 h), 
peginterferon lambda exposure estimates (AUC) were slightly increased in the mild RI group 
(geometric mean [90% CI]: 1.20 [0.82, 1.77]) and greater in the moderate (1.95 [1.35, 2.83]), 
severe RI (1.95 [1.30, 2.93]) and ESRD (1.88 [1.30, 2.73]) groups. Peginterferon lambda was 
generally well tolerated. 
 
In conclusion, the data show that following single dose peginterferon lambda administration, mild 
renal impairment appears to slightly increase exposure, but may not be clinically significant, while 
subjects with moderate and severe renal insufficiency and ESRD had approximately two-fold 
increases in exposures. These results suggest that subjects with mild renal impairment could use 
the same dosing regimen as subjects with normal renal function.  
Similar to the other pegylated interferons, patients with moderate to severe renal impairment and 
ESRD most likely would require dose modifications of peginterferon lambda.  
 
Hepatic Insufficiency: No data are available for comparative PK in subjects with hepatic 
insufficiency.  
 
8.8 Drug-Drug Interactions: The effect of a single dose of peginterferon lambda on a cocktail of 
CYP substrates was assessed in healthy subjects. The activity of select CYP enzymes were 
evaluated using the following probe substrates: caffeine (CYP1A2), warfarin (CYP2C9), 
omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). Subjects 
received the cocktail on Day 1 followed by PK sample collection for 5 days; the subjects then 
received a single dose of peginterferon lambda 180 μg on Day 8, followed by a second dose of the 
cocktail on Day 15 with subsequent PK sample collection for 5 days. Peginterferon lambda 
increased the AUC of the probe drugs as follows: caffeine ~73%, warfarin ~40%, omeprazole ~2-
fold, dextromethorphan ~2- fold, and midazolam ~75%. These results suggest that following a 
single 180μg dose, peginterferon lambda is a mild inhibitor of CYP1A2, CYP2C9, and CYP3A4 

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and a moderate inhibitor of CYP2C19 and CYP2D6. Because the effects on these sensitive CYP 
substrates are mild or moderate, dose adjustments for other concomitant CYP substrates may not 
be necessary, but such agents should be used with caution.  Given that only a single or two doses 
will be used in this trial, concern about drug interactions is limited compared to other settings in 
which peginterferon lambda is given weekly for long durations. 
 
8.9 Clinical Trial Data 
Clinical Activity in Chronic HCV and HBV Infection  
The clinical activity of peginterferon lambda in combinations with direct-acting anti-viral agents 
is summarized in Table 8 The antiviral activity of peginterferon lambda against HCV was 
demonstrated in 2 Phase 2 studies investigating peginterferon lambda regimens in treatment-naive 
subjects with chronic HCV. The regimens included peginterferon lambda/ribavirin (RBV) in 
EMERGE Phase 2a/2b (526H04, N = 624) and peginterferon lambda/RBV/DCV (daclatasvir) and 
Lambda/RBV/ASV (asunaprevir) in D-LITE (AI452008, N = 140). Initial doses tested in the Phase 
2a/2b study EMERGE were 80, 120, 180 or 240 µg per week for 24 weeks (GT 2/4) or 48 weeks 
(GT 1/4). Pharmacodynamic modeling to derive the optimal dose and duration of peginterferon 
lambda treatment for Phase 3 studies has been described in 2 publications (Wang 2014, Hruska 
2014). Wang et al (2014) derived a population model of peginterferon lambda exposure; adapting 
a previously published viral dynamic model for peginterferon lambda treatment and host genotype 
and using it to simulate sustained virologic responses (SVR). peginterferon lambda population 
pharmacokinetics were described by a one compartment model with first-order absorption, and 
33.0 L per day clearance with 47% interindividual (36% intra-individual) variability. Weight 
explained a negligible proportion of the variability. Based on SVR predictions, optimum treatment 
durations were 48 weeks for HCV genotypes 1 or 4 (SVR estimates for 120, 180, and 240 µg 
peginterferon lambda: 58%, 54%, 47%, respectively) and 24 weeks for genotypes 2 or 3 (75%, 
72%, 67%). SVR predictions for 240 mg were lower due to dropout predictions. The SVR model 
established the optimum treatment duration for Phase 3 studies but did not differentiate between 
120 and 180 mg dosing. Hruska et al (2014) described the derivation of regression models for 12-
week on-treatment virologic response and safety outcomes at 120, 180, and 240 µg peginterferon 
lambda with ribavirin. In patients with HCV genotypes 1 or 4, there was a significant (P=0.024) 
relationship between undetectable HCV-RNA at Week 4 and peginterferon lambda exposure 
(AUC or Cmax), with the largest difference between adjacent dose levels between the 180 and 120 
µg exposure ranges. The risk of Grade 3-4 aminotransferase or bilirubin elevations relative to a 
peginterferon alfa-2a/ribavirin control were related to peginterferon lambda exposure for all 
patients, and the largest increase between adjacent dose levels was seen for 240 versus 180 µg. 
Anemia and neutropenia events were lower than control across all doses and exposures.  
 
Based on these finding, the Phase 3 studies for HCV were designed to evaluate fixed 180 µg doses 
of peginterferon lambda in combination with ribavirin and a direct-acting antiviral for 24–48 
weeks in HCV genotypes 1 or 4 or 12–24 weeks in genotypes 2 or 3.  

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The antiviral activity of peginterferon lambda as a monotherapy against HBV was investigated in 
1 dose-ranging study in IFN-naïve patients (LIRA-B). Initial treatment groups received weekly 
peginterferon lambda 180 µg or 240 µg, or IFN-alfa at 180 µg for 48 weeks. The 240 µg dose was 
discontinued for development during the study and only 13 patients received this dose. The 
primary endpoint was HBeAg seroconversion at week 24. HBeAg seroconversion rates were 
comparable for peginterferon lambda and alfa at week 48 (17.5% vs. 16.9%, respectively); 
however, lambda non-inferiority was not met at week 24 posttreatment (13.8% vs. 30.1%, 
respectively; lambda vs. alfa 80% CI). 
 
8.10 Summary of Safety  
Peginterferon lambda has been generally well tolerated in clinical studies. A lower frequency of 
musculoskeletal (myalgia, arthralgia, and back pain) and flu-like symptoms (chills, pyrexia, and 
pain) was observed across Phase 2 studies in subjects receiving interferon regimens peginterferon 
lambda compared with alfa. In addition, there was a notable lack of hematologic toxicity in the 
WBC or platelet lineages in subjects receiving peginterferon lambda regimens.  
 
Laboratory abnormalities have generally been of low grade and self-limited. When study regimens 
included concomitant RBV administration, decreases in hemoglobin levels were observed as 
expected; however, anemia was less frequent and milder with peginterferon lambda /RBV than 
with alfa/RBV. Hematologic toxicity was also reported less frequently in groups treated with 
Lambda compared with alfa.  
 
The main safety finding associated with peginterferon lambda treatment has been the higher 
frequency of transaminase elevations, accompanied, in some cases, by increases in total and 
conjugated (direct) bilirubin, but without evidence for impaired liver synthetic function such as 
decreased albumin or increased INR. The hyperbilirubinemia cases resolved with no laboratory 
evidence of sustained hepatic dysfunction following dose reduction or discontinuation of study 
drug. In EIGLMD-001 study, the frequency of liver related SAEs (jaundice) was 7/15 (46.7%) at 
the Pakistan site compared to 0/18 (0.0%) at the other three sites, and 2.7% to the rate described 
in PEDESTAL study. Further evaluation of the potential pharmacogenomic or environmental basis 
for the higher frequency of these events in Pakistani patients is warranted. In one study, 3 cases of 
concurrent ALT and TBILI elevations in patients with HCV treated with peginterferon 
lambda/RBV/asunaprevir (ASV) met program-defined criteria for pDILI; this led to 
discontinuation of this regimen in future development plans. Frequencies of concurrent ALT/AST 
and TBILI elevations across studies were as follows: 18.2% for peginterferon lambda /RBV/ASV, 
3.6% for peginterferon lambda/RBV, 2.3% for alfa-2a/RBV/ASV, and 3.5% for alfa-2a/RBV. In 
another study in patients with HBV, 4 subjects (5.0%) in the peginterferon lambda 180-µg group 
and 1 subject (7.7%) in the 240 µg group, and 1 subject (1.2%) in the alfa group met the laboratory 
criteria for pDILI. In 5 of the 6 cases, an alternative explanation (early, on-treatment, host-
mediated ALT flare) was identified. In vitro data did not suggest a hypothesis-driven metabolism- 
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hyperbilirubinemia between subjects treated with alfa-2a or peginterferon lambda, but 
retrospective analysis of safety data from the EMERGE study (Zwirtes 2016) found that 
hyperbilirubinemia events occurred within the first 12 weeks of treatment, and the temporal pattern 
of mean total bilirubin level in the Alfa/RBV group was similar to that observed in the 
peginterferon lambda 120 and 180 mg groups (although with lower quantitative values for Alfa), 
suggesting a similar underlying mechanism of hyperbilirubinemia, probably RBV-induced 
hemolysis, for peginterferon lambda and Alfa treatments during the first 4–6 weeks of therapy. 
For the peginterferon lambda 240 mg group, however, a second peak occurred after week 12 
suggesting additional reasons for increases in bilirubin levels, probably as a result of direct toxicity 
to hepatocytes with that dose.  
 
Decompensation of cirrhosis has been observed with peginterferon lambda, as with alfa 
interferons. A total of 4 cases have been reported. One subject with baseline cirrhosis and Gilbert’s 
disease developed Grade 1 hepatic decompensation and ascites while receiving peginterferon 
lambda 120 μg in the EMERGE Phase 2b study. The events resolved with drug interruption, and 
the subject subsequently resumed therapy at a lower dose. In the Phase 3 study (AI452017) in GT-
2, -3 HCV-infected subjects, 3 of approximately 70 randomized subjects with pre-existing 
compensated cirrhosis developed decompensated cirrhosis while on treatment with peginterferon 
lambda. All 3 subjects were Child-Pugh Class A at entry and had evidence of portal hypertension. 
Two of these subjects subsequently recovered; however, 1 subject died of infectious 
complications. No cases of acute liver failure or hepatic decompensation in the absence of pre-
existing cirrhosis with portal hypertension have been reported with use of peginterferon lambda.  
Based on these data, peginterferon lambda appears to be associated with decompensation of 
cirrhosis especially in the context of portal hypertension. Enrollment of cirrhotic subjects in current 
studies is restricted to compensated cirrhotic subjects (Child-Pugh Class A) without evidence of 
portal hypertension.  
 
Prior studies of peginterferon lambda included patients with ALT values up to 5 times the upper 
limit of normal (HCV) and 10 times the upper limit of normal (HBV) and excluded patients with 
evidence of cirrhosis and with current or past hepatic decompensation. 
 
In analyses of the cardiac effects of peginterferon lambda, no evidence of a clinically meaningful 
impact on QT/QTc interval or other key ECG parameters was detected in 32 healthy subjects given 
a single dose of peginterferon lambda 80 to 240 µg or in 176 patients with HBV treated with 
peginterferon lambda 180 µg for 24 weeks. A slight increase in mean ΔQTcF was seen in the HBV 
patients. Peginterferon lambda was not associated with AEs of ventricular arrhythmias or QT/QTc 
prolongation. 
 
 
 
 

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8.11 Pregnancy 
 
Reproductive Risk Potential  
Peginterferon lambda has not been tested in pregnant or lactating women; however, in the embryo-
fetal development study in pregnant mice, peginterferon lambda was determined to be a selective 
developmental toxicant with increased embryo mortality when administered at ≥ 0.02 mg/kg/day 
(maternal AUC0-24h = 0.232 µg×h/mL) during the period of organogenesis. There was no 
identified maternal toxicity. The NOAEL for female reproductive toxicity was 0.01 mg/kg/day 
(AUC0-24 h = 18 ng×h/mL), which is approximately 0.9´ the maximum AUC of 143 ng×h/mL in 
humans following a weekly dose of 180 μg peginterferon lambda. 
 
Female subjects should not be pregnant or lactating at the time of exposure to peginterferon-
lambda. Female and male subjects should use appropriate measures to avoid pregnancy during the 
administration of peginterferon lambda and for up to 3 months after the last dose of peginterferon 
lambda. 
 
8.12 Placebo 
The placebo will be 0.9% sodium chloride (normal saline) solution. A plastic 1 mL syringe will 
be prefilled by the study pharmacy. Each syringe will contain 0.5 mL (0.45 mL to match the 
volume of the Interferon plus 0.05 mL overfill) to allow for needle priming by the unblinded study 
nurse.  
 
The syringes will be stored in a refrigerator at 2 to 8 degrees Celsius (36 to 46 Fahrenheit) after 
preparation and should not be frozen. The study nurse will attach a staked 25-gauge needle and 
needle shield at the time of administration.  It will be handled and administered by the study 
coordinator in a fashion analogous to Peginterferon lambda injection. 
 
9.0 A. Cohort A – Ambulatory 
 
9. 1 Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
1. Adult patients between the ages of 18 and 75 years. 
2. Confirmed COVID-19 infection by PCR within 7 days of symptom onset (fever, respiratory 
symptoms, sore throat). 
3. Discharged to home isolation. 
4. Willing and able to sign informed consent. 
5. Willing and able to follow-up by daily phone or videoconference. 
6. Female patients of childbearing potential and male patients with partners of childbearing 
potential must agree to use adequate methods of contraception during the study and through 
90 days after the last dose of study medication. Female patients of childbearing potential are 

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all those except patients who are surgically sterile, who have medically documented ovarian 
failure, or who are at least 1 year postmenopausal.  Adequate methods of contraception are: 
a. For female patients 
i. Hormonal contraceptives including progestogen injection (eg, Depo-Provera®), 
combined oral contraceptive pill or vaginal ring for ≥ 3 months before screening 
AND a barrier method (use of condom [male partner] or diaphragm with 
spermicide or cervical cap with spermicide) from screening, or 
ii. Intrauterine device (IUD) or intrauterine system (IUS) in place ≥ 3 months 
before screening AND a barrier method (use of condom [male partner] or 
diaphragm with spermicide or cervical cap with spermicide) from screening, or 
iii. Surgical sterilization of the partner (vasectomy ≥ 1 month before screening) 
AND a barrier method (use of condom [male partner] or diaphragm with 
spermicide or cervical cap with spermicide) from screening, or 
iv. Double-barrier methods (use of condom [male partner] with either diaphragm 
with spermicide or cervical cap with spermicide) from screening. 
b. For male patients 
i. Surgical sterilization (vasectomy ≥ 1 month before screening) AND a barrier 
method (use of condom or diaphragm with spermicide or cervical cap with 
spermicide) from screening, or 
ii. Consistently and correctly use a condom from screening AND female partner 
must agree to use a hormonal contraceptive, a nonhormonal nonbarrier method 
(eg, copper IUD), or a nonhormonal barrier method (eg, diaphragm with 
spermicide or cervical cap with spermicide). 
 
Exclusion Criteria  
1. Requirement for hospital admission 
2. Current immunosuppression due to medication (steroids, biologics, chemotherapy) or 
underlying condition such as organ/bone marrow transplant or untreated HIV or HIV infection 
with detectable HIV RNA and/or CD4 count of <500. 
3. Pregnancy (or positive urine pregnancy test) or lactating 
4. The following pre-existing medical conditions: 
a. Known seizure disorder 
b. Known retinal disease requiring therapy 
c. Known autoimmune condition requiring therapy more intensive than intermittent non-
steroidal anti-inflammatories in the prior 6 months (rheumatoid arthritis, lupus, 
inflammatory bowel disease) 
d. Known history of chronic obstructive pulmonary disease (COPD) or asthma associated 
with functional impairment  
e. Known cirrhosis with any history of decompensation (ascites, variceal bleeding or 
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f. Known chronic kidney disease with estimated creatinine clearance < 50 mL/minute or 
need for dialysis 
g. Severe psychiatric disorder – schizophrenia, bipolar disorder, depression with prior 
suicidality 
h. Any other underlying medical (cardiac, liver, renal, neurological, respiratory) or 
psychiatric condition that in the view of the investigator would preclude use of 
peginterferon lambda 
5. Advanced cancer or other illness with life expectancy of < 1 year 
6. Known alcohol or drug dependence that in the opinion of the investigator would impair study 
participation  
7. Known prior intolerance to interferon treatment 
8. Enrolment in another clinical trial with use of any investigational agent in the prior 30 days 
9. Use of off-label therapy for COVID-19 
 
9.2 Study Procedures (Cohort A) 
 
9.2.1 Consent Process 
Individuals at the COVID-19 assessment centres or emergency departments will be provided 
with information related to the study through study recruitment materials (posters) and instructed 
to contact study staff by email or telephone if they are interested in study participation. The study 
will also be advertised on social media with contact information of the study team.  Providers 
caring for patients with COVID-19 may also refer patients to the study after obtaining verbal 
consent to share contact information with the study team.  Those interested in the study who 
contact or are contacted by study staff will be confirmed to be COVID-19 positive based on 
nasopharyngeal swab results and screened by study staff for other inclusion/exclusion criteria 
and will be provided a consent form electronically for review.  The study coordinator will 
explain the rationale and the risks and benefits of the study. A sub-investigator/principal 
investigator will be available to answer any questions by phone.  In addition to the consent to the 
trial, participants will be offered an additional optional consent for genetic testing (see ‘Genetic 
Testing’) and a second optional consent for collection of peripheral blood mononuclear cells 
(PBMCs) (see ‘PBMCs’).  In keeping with REB adapted consenting process, the study 
coordinator will read the consent form verbatim while the patient reads along.  When the patient 
consents, the study coordinator will sign his/her copy of the document and this will be witnessed 
and signed by an impartial witness. This document will stay in the patient’s study file.  Upon 
coming to the clinic, the study team will provide the patient a paper copy to keep and not return 
to the study team. Those with a positive test for SARS-CoV-2 and who meet all 
inclusion/exclusion criteria and have signed consent will be asked to come to the outpatient 
office at a designated time (see ‘Standard Operating Procedures for Outpatient Visits’). 
 
9.2.2 Enrolment and randomization  
Those who test positive will be invited to attend the outpatient clinic for completion of screening, 
enrolment and randomization (see Standard Operating Procedures for Clinic Visits).  Consenting 
individuals will undergo a medical history including current medication use and complete a 
symptom survey to be recorded on the Baseline Case Report Form (Appendix A).  Women of 

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childbearing potential will take a urine pregnancy test to confirm eligibility.  Female participants 
who are concerned they may be pregnant will not be enrolled even if the test is negative (in case 
it is too early for a positive result). Female and male subjects will be advised to use appropriate 
measures to avoid pregnancy during the week following administration of peginterferon lambda 
and for up to 3 months after the dose of peginterferon lambda. 
 
Vital signs, including blood pressure, temperature, pulse, respiratory rate and oxygen saturation in 
ambient air will be recorded. The eligibility checklist will be reviewed by a site sub-
investigator/principal investigator and if deemed to be necessary, a history and physical 
examination will be performed by the sub-I/PI.  Potential participants meeting all inclusion and no 
exclusion criteria will be offered study enrolment.   Eligible participants will have blood drawn for 
routine laboratory (CBC, creatinine, liver profile) and inflammatory markers (LDH, ferritin, D-
Dimers, c-reactive protein, amylase), a research sample for plasma to be stored for future use, as 
well as optional blood for genetic and PBMC sub-studies for those who consent. The genetic and/or 
PBMC sample will replace the research plasma sample, as plasma can be used after PBMC 
isolation or preparation for extraction of genetic material.  Patients will also provide a baseline 
saliva sample and self-collected mid-turbinate nasal swab.  
 
Randomization will be centralized at TCLD (at UHN) and eligible patients included in the study 
will be assigned to one of the 2 treatment arms according to a standard computer-generated 
randomization schedule 1:1 in blocks of 4, stratified by site.  
 
To randomize a subject into the study, after completion of the above procedures, the coordinator 
will send the completed eligibility checklist to the TCLD (at UHN) by e-mail/fax. Once reviewed 
and approved by the PI or designate sub-I, the coordinator will be contacted by SMS to randomize 
the patient. Numbered opaque envelopes with treatment arm allocation will be stored at the 
outpatient site.  Upon instruction to randomize from the PI or designate sub-I, the coordinator will 
open the envelope to reveal the treatment allocation.  The study ID, month and year of birth and 
initials will be recorded on the randomization form as a unique identifier and emailed/faxed to the 
TCLD.  The treatment codes will be maintained by the trial statistician in a password-protected 
file which cannot be accessed by other study personnel or subjects. In future study materials and 
analyses, the subject will be referred to only by the study identification number.  
 
9.2.3 Study Interventions (See Schedule of Events – Ambulatory) 
Those randomized to the peginterferon lambda arm will receive a single SC injection in the lower 
abdomen of peginterferon lambda 180µg and those randomized to placebo will receive a single 
SC injection of saline (and this will count as Day 0 of the study for the Schedule of Events). After 
the injection, participants will be observed for 30 minutes to ensure there are no immediate 
complications from the medication.  After 30 minutes of observation, participants will be 
discharged.  Prior to discharge, patients in both arms will be taught self-collection technique of 
mid-turbinate nasal swabs and how to properly collect saliva specimens with observation by the 
coordinator of a collection of each specimen. Participants will be provided with 5 additional swabs 
for mid-turbinate nasal swabs and 5 sterile specimen containers (see ‘Nasal Swabs and Saliva 
Collection’) to be collected by self-collection as well as a sealable cooler for home swab storage 
until collection.  The coordinator will confirm contact information for the participant with the 
number of an emergency contact as well, and the participants will be provided with the contact 

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information to reach the study team.  A detailed daily schedule for follow-up will be provided to 
the participant.  If participants do not own a digital thermometer, they will be given one by the 
study team. 
 
After discharge, participants will follow the standard-of-care advice given to all individuals with 
presumed/confirmed COVID-19 at the Assessment Centre/ER. Participants will return home and 
remain in home isolation for at minimum 14 days from symptom onset according to current 
Toronto Public Health recommendations.  The exception to home isolation will be for study visits, 
as permitted by Public Health (for example, people with COVID-19 may attend medical 
appointments provided proper precautions are taken including wearing a mask at all times).   
 
A study coordinator will contact the participant by phone/videoconference 4-6 hours post-injection 
to record symptoms and potential adverse events (AEs) related to the treatment because of the 
known early side effects reported in previous trials with initial dosing of peginterferon lambda6.  
Symptoms/AEs will be recorded using the Symptom Assessment form (below) - the questions will 
be asked by the study coordinator and recorded in REDCap.   
 
Participants will be contacted at a pre-specified time on days 1, 2, 3, 5, 7, 10 and 14 by a study 
coordinator by phone/videoconference to review the same symptom and AE survey, concomitant 
medications and to record the digital oral temperature.  During the call, results will be recorded 
onto case report forms by the study coordinator and entered into the secure REDCap electronic 
case report form (eCRF) database. Participants will collect a mid-turbinate nasal swab and saliva 
specimen on Days 1 and 2 after speaking to the study coordinator and, wherever possible, 
collection will be observed by the study coordinator using videoconferencing (see ‘Nasal Swabs 
and Saliva Collection’). The viral media with the swab and the sterile specimen containers will be 
stored in a plastic container inside a cooler that will be provided to the participant and stored until 
collection. 
 
On Day 3, the participant will return to the outpatient clinic for symptom, AE, concomitant 
medications and temperature recording.  The participant will bring the self-collected nasal swabs 
and saliva specimens to the clinic in the sealed cooler following the written instructions for 
transport (see ‘Nasal Swabs and Saliva Collection’).  During the visit, the participant will self-
collect a mid-turbinate nasal swab and the study coordinator will perform a nasopharyngeal swab 
as well as collect a saliva specimen.  Blood will be drawn for routine laboratory and inflammatory 
markers, a research sample to be stored for future use and additional samples for those who 
consented to PBMC collection.  The coordinator will bring the Day 3 swabs as well as the stored 
swabs from Days 1 and 2 and return them to the Mount Sinai Hospital Microbiology laboratory 
(T. Mazzulli) for processing.  The samples will be labeled and transported in 2 sealed clean 
biospecimen bags inside a sealed plastic container, in line with Infection Protection and Control 
recommendations. 
 
On Day 5, a coordinator will contact the participant by phone/videoconference for symptom, AE, 
concomitant medications and temperature recording.  A self-collected mid-turbinate nasal swab 
and saliva specimen will be taken and stored as above.  
 
On Day 7, the participant will return to the outpatient clinic and similar to the Day 3 visit, a self-

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collected mid-turbinate nasal swab, a coordinator-collected nasopharyngeal swab and a saliva 
specimen will be collected.  Blood will be drawn for routine laboratory and inflammatory markers, 
a research sample to be stored for future use and additional samples for those who consented to 
PBMC collection.  
 
On Days 10, a coordinator will contact the participant by phone/videoconference for symptom, 
AE, concomitant medications and temperature recording.  Self-collected mid-turbinate nasal 
swabs and saliva specimens will be collected on Days 10 and stored as above.   
 
On Day 14, the participant will return to the outpatient clinic and similar to the Day 3 visit, a self-
collected mid-turbinate nasal swab, a coordinator-collected nasopharyngeal swab and a saliva 
specimen will be collected.  Blood will be drawn for routine laboratory and inflammatory markers, 
a research sample to be stored for future use and additional samples for those who consented to 
PBMC collection.  
 
On Day 90+ (up to one year), participants who consented to a final symptom survey and PBMC 
collection (even if they did not consent to PBMC collection during the treatment phase of the 
study) will return to the outpatient clinic for a final blood draw and to complete the symptom 
survey. Up to 8 tubes of blood will be collected. 
 
For participants who cannot travel to the clinic, the option of home visits by the study team will 
be discussed for the Day 3, 7, 14 and 90+ visits (See ‘Home Visits’). 
 
9.2.4 Nasal Swabs and Saliva Collection 
The rationale for self-collection of mid-turbinate nasal swabs and saliva is to allow for more 
frequent sampling to determine the time of viral clearance and quantitative viral kinetics. 
Understanding how quickly individuals clear SARS-CoV-2 is very important for determining 
when people could potentially return to work/public.  It is possible that peginterferon lambda will 
be highly effective and lead to rapid clearance, which can only be recognized if frequent early 
sampling is conducted.  In addition, viral kinetics using quantitative PCR may provide insights 
into the mechanisms of clearance, as has been successfully done with other viral infections14,15.  A 
previous study done by our group has shown that mid-turbinate nasal swabs can be reliably self-
collected with only marginally lower sensitivity (69/71 91% concordance) for influenza, 
rhinovirus and respiratory syncytial virus detection than standard nasopharyngeal swab16.  Because 
nasopharyngeal swabs are considered the gold standard for SARS-CoV-2 diagnosis, we will 
collect these on days 3, 7 and 14 for the primary (day 7) and key secondary (day 3 and 14) 
endpoints.  Self-collection of nasopharyngeal swabs is not feasible16.  To directly compare the 
methods for SARS-CoV-2 recovery, on Day 3, 7 and 14, a self-collected mid-turbinate nasal swab, 
a coordinator-collected nasopharyngeal swab and saliva will be tested.   
 
Detecting SARS-CoV-2 using saliva specimens may be equivalent to detection rates of 
nasopharyngeal swab early in the course of the disease.  Our group has recently shown that by day 
14 of symptom onset saliva specimens were positive in 17/24 individuals with COVID-19 as 
compared to 18/24 by nasopharyngeal swab (Jamal A et al, unpublished data). A preprint report 
from Wyllie et al at Yale found that saliva was actually marginally superior to nasopharyngeal 
swab with higher sensitivity and higher SARS CoV-2 RNA levels on a quantitative assay from 

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samples taken on the same day17. Additional benefits from using saliva for SARS-CoV-2 detection 
includes the ease of self-collection while lowering potential patient discomfort and, more 
importantly, a microbiological swab is not required, which are currently in limited supply during 
the COVID-19 pandemic.  
 
Participants will be instructed and observed at the first visit on the collection of mid-turbinate nasal 
swabs and saliva and if possible, the subsequent self-collection samples will be observed by the 
coordinator during the daily videoconferencing visits. Participants will be given written 
instructions on how to store the swabs and saliva.  After putting the swab into the viral culture 
media, the swab will be placed into two clear biohazard bags inside the provided sealed cooler.  
Saliva will be collected in sterile collection containers and placed into two clear biohazard bags 
inside the provided sealed cooler. At the day 3, 7 and 14 clinic visits, the participant will place the 
cooler into 2 provided clear biohazard bags and bring the bags to the clinic.  Upon receipt of the 
bags in the clinic, the outer bag will be decontaminated and then the specimens will be taken to 
Toronto General Hospital for storage at -80C in the laboratory of the PI (J Feld).  PCR for SARS-
CoV-2 will be performed in the future when there is no longer concern for reagent use at the 
microbiology laboratory.    
 
9.2.5 Home Visits 
For participants unable to travel to clinic visits, home visits by study staff will be provided as an 
alternative, provided participants live within a 30-minute drive of the site from which they were 
recruited and are agreeable to having study staff visit their home.  Prior to home visits, study staff 
will review and follow UHN standard operating procedures for ‘Working safely while alone at 
KITE or Offsite’ (SOP Number: SRRL0008 version 3.0).  They will also complete the UHN 
Occupational Health and Safety Off-Site Work PRE-VISIT ASSESSMENT CHECKLIST for 
each specific visit and review with the PI to determine if risks to staff safety have been identified. 
If risks cannot be mitigated, the visit will not be undertaken and will be recorded as a missed visit 
in the trial documents. If the staff member and PI agree with proceeding with the visit, the 
precautions outlined will be taken to ensure staff safety including: maintain and provide schedule 
of visits to PI/site PI, verbally check in and check out with PI/site PI, wear a hospital identification 
at all times during the visit as required by UHN, ensure that cellular phone is charged for the home 
visit. Staff will be advised not continue a home visit if situations and/or conditions become unsafe 
and to report all work related incidents immediately to the PI/site PI and submit an online 
Employee Incident Report (EIR) within 24 hours. For home visits, the study coordinator will drive 
to the participant home at an agreed up pre-specified time.  Upon arrival, the coordinator will call 
the participant as notification.  The coordinator will don personal protective equipment (mask, 
gown, gloves and face shield) and enter the home to carry out the study visit.  Upon completion of 
the study visit, the coordinator will doff personal protective equipment and place it in a clear plastic 
bag.  It will then be transported back to the hospital/clinic for appropriate disposal. 
 
9.2.6 Household contacts 
For participants with household contacts, the coordinator will ask the participant to report a 
confirmed diagnosis of COVID-19 in any household contacts.  Participants will be contacted at 
Days 14 and 30 to specifically ask if any household contacts have been diagnosed with COVID-
19.   
 

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9.2.7 Participant Compensation 
Participants will be reimbursed $50 CAD for each of the study clinic visits (Day 0, 3, 7 and 14) 
for transportation and parking expenses.  For the day 90+ visit, participants will be reimbursed 
$100 for their time and costs associated with the visit.  Any extra expenses incurred related to 
attending study visits will be paid upon invoice. 
 
9.2.8 Standard Operating Procedures for Clinic Visits 
To ensure that clinic visits are carried out safely minimizing exposure to the public and study staff, 
the following procedures will be followed.  Participants will be provided with hospital masks for 
themselves and their chauffeurs (if applicable) to be worn during travel to and from the clinic.  
Participants will be encouraged to attend clinic visits by car, if possible.  If arriving by car, a 
parking spot outside the clinic will be reserved in advance.  Upon arrival, the participant will call 
the study coordinator from the car.  The coordinator will advise the participant when to come into 
the clinic.  Entry will only occur when there are no other study participants or other individuals in 
the pharmacy to avoid interaction between infected and potentially uninfected individuals.  Upon 
entry into the clinic, the participant will perform hand hygiene (hand sanitizer) and the study staff 
in appropriate personal protective equipment will guide the participant to one of the clinic rooms 
where the participant will wait to be seen.  For participants who are unable to drive to clinic visits, 
a chauffeur will be arranged (and costs covered through taxi chit or mailed reimbursement) by the 
study team.  The chauffeur/taxi company will be informed that the individual is known to have 
COVID-19 and the individual driver will be informed of this prior to the trip. A surgical mask will 
be provided for the driver. The participant will wear a mask during the drive to and from the clinic 
visits. The study staff will wipe the seat of the taxi with disinfectant after the participant leaves the 
car.   
 
The study staff will wear masks, gloves, gowns and face shields for all visits and will follow 
directions of Infection Protection and Control from UHN in the event that guidance changes. 
(https://intranet.remote.uhn.ca/cvpn/tlJTnOjlDlsJLjHQDzsvAj6HOjg8ig/departments/infection_
control/covid-19/IPAC.asp). 
 
 
9.2.9 Safety Assessment  
Peginterferon lambda has been given to >3,000 patients with chronic viral hepatitis for up to 48 
weeks duration without major safety concerns, however, it has not been used in COVID-19 
previously.  We do not expect major safety concerns however, we will follow patients in the 
ambulatory arm closely to document adverse events during treatment.  Blood work will be 
collected prior to the peginterferon lambda injection but will not be used to determine eligibility 
in the ambulatory cohort.  Hepatotoxicity has been noted in studies of peginterferon lambda in 
patients with chronic viral hepatitis.  Transaminase elevations were reported, and hepatic 
decompensation has been reported but only in people with a prior history of decompensation prior 
to dosing.  The study team has extensive experience managing patients with underlying liver 
disease (3 investigators are hepatologists) and multiple investigators have experience with 
peginterferon lambda use as well.  If baseline laboratory results are suggestive of cirrhosis 
(unlikely), patients will be informed of this and followed carefully for signs of hepatic 

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decompensation (ascites, hepatic encephalopathy, variceal hemorrhage) during follow-up, with 
prompt referral to the hospital should these signs/symptoms occur.   
 
The most relevant other concern would be unrecognized renal impairment.  Dosing advice is 
unclear for patients with estimated glomerular filtration rate (eGFR) below 50 mL/min.  
Participants found to have a reduced eGFR (<50 mL/min) after dosing will be advised of the test 
result and the need for follow-up.  The consequences of dosing during renal impairment are not 
well understood but may lead to increased concentrations of systemic interferon lambda.  
Participants will be followed virtually frequently with in-person visits at day 3, 7 and 14 with 
repeat blood tests on those days.  Those with unexpected renal impairment will be followed 
according to the standard follow-up in the protocol, however, additional investigations may be 
performed at the discretion of the treating physician. 
 
9.3 Outcomes (Cohort A)  
Primary efficacy endpoint: 
The proportion of participants with negative SARS-CoV-2 RNA on nasopharyngeal swab at day 
7. 
Primary safety endpoint:  
Rate of treatment-emergent and treatment-related serious adverse events (SAEs)  
 
Secondary Endpoints: 
Clinical 
1. Time to resolution of symptoms (fever, cough, diarrhea) 
2. Change in symptom scores (respiratory, gastrointestinal, fever) from day 0 to day 7 
3. Need for hospital admission by day 14 
4. Adverse events and serious adverse events by day 14 
Virologic/Immunological 
5. Proportion negative for SARS-CoV-2 RNA by nasopharyngeal swab on day 3 
6. Proportion negative for SARS-CoV-2 RNA by nasopharyngeal swab on day 14 
7. Time to SARS-CoV-2 RNA negativity on mid-turbinate nasal swab or saliva 
8. Proportion with SARS-CoV-2 RNA in blood at day 0 and 7  
9. Proportion with SARS-CoV-2 antibodies in blood at day 0, 7 and 14 
10. Correlation of response with interferon lambda 4 (IFNL4) genotype 

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11. Change in laboratory and inflammatory markers (hemoglobin, white blood cell count, 
lymphocyte count, liver profile, ferritin, lactate dehydrogenase, c-reactive protein, D-
dimers, amylase) from day 0 to day 7 and day 7 to 14  
Transmission 
12. Confirmed diagnosis of COVID-19 in household contacts by day 30 
 
9.4 Sample Size Calculation 
 
Cohort A 
Existing data from France and China were used to estimate the effect size. In a recent French study 
comparing chloroquine to no treatment, 2 of 16 (12.5%) untreated patients were SARS-CoV-2 
negative at day 618. Although no studies have been performed with peginterferon lambda a small 
Chinese study compared interferon-α alone or with chloroquine19. By day 7, 14 of 15 (94%) in the 
IFN-only arm were RNA negative. To be conservative, if we estimate a clearance rate of 40% by 
day 8 (equivalent to day 7 in the Chinese study) in the placebo arm and 80% in the peginterferon 
lambda arm, 23 patients are required in each arm for 80% power at alpha 0.05. With potential 
dropout of 20% due to either logistical problems or loss-to-follow-up, this translates to 30 patients 
per arm or 60 patients total across 3 sites (UHN, SMH, MGH). 
 
Rationale for Primary Endpoint Selection 
The primary endpoint for the study is the proportion of people with a negative nasopharyngeal 
swab for SARS-CoV-2 at Day 7.  This endpoint was selected based on existing data about the 
natural history of SARS-CoV-2 infection and practical considerations.  As noted above in the 
Sample Size calculations, in the untreated arm of the French chloroquine study by Gautret et al, 2 
of 16 (12.5%) patients were SARS-CoV-2 negative at day 6 of follow-up.  Similarly, in a study 
from China of 113 patients with COVID-19 of varying severity, the median time to viral clearance 
by nasopharyngeal swab was 17 (IQR 13-22) days, with approximately 20% clearing by day 12, 
18% clearing by day 10 and 7% by day 7.  Notably some patients received treatments in this study, 
but the data were not presented by treatment regimen making it difficult to discern the time to 
clearance with no treatment.  Time to clearance was calculated from the time of symptom onset 
whereas in our study we will determine the proportion with negative nasopharyngeal swabs from 
7 days after randomization.  In our study, patients must be enrolled within 7 days of symptom 
onset, meaning for our placebo group, patients could be up to 14 days since symptom onset when 
they reach day 7 post-enrollment.  Both studies would suggest that the probability of clearance by 
that point would be 12-20% and thus our estimate for the sample size calculation of 40% clearance 
is appropriately conservative.  As noted, in patients treated with interferon alpha, ~90% had cleared 
by day 7, giving us confidence that our estimate of 80% clearance in the treatment arm is realistic.    
 
In addition to the natural history, we took into account practical considerations as well.  The 
purpose of treatment in the ambulatory arm in patients who do not require hospitalization is to 

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prevent progression of illness but also to accelerate viral clearance to reduce viral shedding and 
thus onwards transmission.  If treatment does not lead to high rates of clearance by day 7, it is 
unlikely to be of significant clinical or practical value, as patients discharged are advised to remain 
in home isolation for 10-14 days depending on the jurisdiction.  If treatment does not lead to 
clearance by day 7 in the vast majority of patients, it will be of questionable benefit.  We are 
evaluating the earlier timepoints with self-collected mid-turbinate nasal swabs and saliva 
specimens (days 1, 2 and 3), and a coordinator-performed nasopharyngeal swab 3 days post-
randomization to determine if patients may indeed clear much earlier than study day 7.  Self-
collected mid-turbinate nasal swabs and saliva specimens will also be collected after day 7 to 
determine the ultimate time to viral clearance in both groups.  The collection of mid-turbinate nasal 
swabs and saliva specimens is described in detail in the study procedures.   
 
10. B. Cohort B - Hospitalized 
 
10.1 Safety Assessment 
Prior to initiating screening for Cohort B, the Data Safety and Monitoring Committee (DSMC) 
will review data from Cohort A. They will review data after every 10 randomized participants 
Cohort A complete 7 days of follow-up until 50% of Cohort A has been recruited (n=30).  After 
50% of Cohort A has been enrolled and completed 7 days of follow-up, the DSMC will review all 
available safety data and will advise the steering committee whether Cohort A may continue 
enrolment and whether Cohort B may initiate enrolment (see DSMC). The DSMC will review data 
from Cohort B after 25% have enrolled and completed 14 days of follow-up and after 50% have 
enrolled and completed 14 days of follow-up. 
 
Exclusion criteria were selected to ensure that patients with an increased risk of adverse events 
from peginterferon lambda use are excluded.  These included comorbidities that may be worsened 
by peginterferon lambda and thresholds on screening blood tests.  The threshold for transaminase 
elevation of 5 times the upper limit of normal was selected because of the frequency of liver 
enzyme elevation in patients with COVID-19.  Two recent studies reported that liver enzyme 
elevation was common, occurring in 43% of 70, and 76% of 417, hospitalized individuals in 
China20,21.  Most patients had mild enzyme elevations but 33 (10.4%) in the larger study had ALT 
above 3 times the upper limit of normal.  Enzyme elevation was associated with a more severe 
disease course, but not with liver failure or hepatic decompensation20. Prior studies of 
peginterferon lambda in chronic viral hepatitis allowed patients with ALT values up to 5 times the 
upper limit of normal (HCV) and 10 times the upper limit of normal (HBV) with no cases of 
hepatic toxicity detected in the absence of current or past decompensated cirrhosis6,7.  To avoid 
missing patients who may be at risk of more severe COVID-19 and thus might derive greater 
benefit of antiviral therapy, patients with ALT or AST values up to 5 times the upper limit of 
normal without a history of decompensated cirrhosis are eligible.  Other laboratory values are in 
line with prior studies of peginterferon lambda.    

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10.2 Inclusion/Exclusion Criteria 
Inclusion Criteria 
1. Adult patients over age 18  
2. SARS-CoV-2 RNA-positive on nasopharyngeal swab/respiratory specimen within 10 days of 
symptom onset 
3. Admitted to hospital for management of COVID-19 
4. Willing and able to provide informed consent  
5. Female patients of childbearing potential and male patients with partners of childbearing 
potential must agree to use adequate methods of contraception during the study and through 
90 days after the last dose of study medication. Female patients of childbearing potential are 
all those except patients who are surgically sterile, who have medically documented ovarian 
failure, or who are at least 1 year postmenopausal.  Adequate methods of contraception are: 
a. For female patients: 
i. Hormonal contraceptives including progestogen injection (eg, Depo-Provera®), 
combined oral contraceptive pill or vaginal ring for ≥ 3 months before screening 
AND a barrier method (use of condom [male partner] or diaphragm with 
spermicide or cervical cap with spermicide) from screening, or 
ii. Intrauterine device (IUD) or intrauterine system (IUS) in place ≥ 3 months 
before screening AND a barrier method (use of condom [male partner] or 
diaphragm with spermicide or cervical cap with spermicide) from screening, or 
iii. Surgical sterilization of the partner (vasectomy ≥ 1 month before screening) 
AND a barrier method (use of condom [male partner] or diaphragm with 
spermicide or cervical cap with spermicide) from screening, or 
iv. Double-barrier methods (use of condom [male partner] with either diaphragm 
with spermicide or cervical cap with spermicide) from screening. 
b. For male patients: 
i. Surgical sterilization (vasectomy ≥ 1 month before screening) AND a barrier 
method (use of condom or diaphragm with spermicide or cervical cap with 
spermicide) from screening, or 
ii. Consistently and correctly use a condom from screening AND female partner 
must agree to use a hormonal contraceptive, a nonhormonal nonbarrier method 
(eg, copper IUD), or a nonhormonal barrier method (eg, diaphragm with 
spermicide or cervical cap with spermicide). 
 
Exclusion Criteria 
1. Severity of illness 
a. Respiratory failure (requiring>6L O2 or intubation in the ER) 
b. Shock – systolic BP<90 mmHg or mean arterial BP<60 mmHg after fluid resuscitation 

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2. Current immunosuppression due to medication (steroids, biologics, chemotherapy) or 
underlying condition such as organ/bone marrow transplant or untreated HIV or HIV 
infection with detectable HIV RNA and/or CD4 count of <500. 
3. Pregnancy (or positive urine pregnancy test) or lactating 
4. The following pre-existing medical conditions: 
a. Known seizure disorder 
b. Known retinal disease requiring therapy 
c. Known autoimmune condition requiring therapy more intensive than intermittent non-
steroidal anti-inflammatories in the prior 6 months (rheumatoid arthritis, lupus, 
inflammatory bowel disease) 
d. Known cirrhosis with any history of decompensation (ascites, variceal bleeding or 
hepatic encephalopathy) 
e. Known chronic kidney disease with estimated creatinine clearance < 30 mL/minute or 
need for dialysis 
f. Severe psychiatric disorder – uncontrolled schizophrenia, bipolar disorder, depression 
with prior suicidality 
g. Any other underlying medical (cardiac, liver, renal, neurological, respiratory) or 
psychiatric condition that in the view of the investigator would preclude use of 
peginterferon lambda 
5. Known prior intolerance to interferon treatment 
6. Enrolment in another clinical trial with use of an antiviral agent in the prior 30 days (co-
enrollment with immunomodulatory agents permitted) 
7. Use of off-label therapy for COVID-19 
8. Any of the following abnormal laboratory indices 
a. Hemoglobin < 100 mg/dL 
b. Platelet count < 75,000 cells/mm3 
c. Absolute neutrophil count < 1,000 cells/mm3 
d. Estimated creatinine clearance < 30 cc/mL 
e. Total bilirubin > 2x upper limit of normal (ULN) 
f. Alanine aminotransferase (ALT) > 5x ULN 
g. Aspartate aminotransferase (AST) > 5x ULN 
h. Lipase or amylase > 2x ULN  
i. Random blood glucose > 20 mmol/L 
 
10.3 Study Procedures (Cohort B) 
 
10.3.1 Consent Process 
Potential participants meeting all inclusion and no exclusion criteria will be offered study 
enrolment.   The study coordinator will explain the rationale and the risks and benefits of the study.  
A study investigator will be available to answer any questions related to the study.  In addition to 
the consent to the trial, participants will be offered an additional optional consent for genetic testing 

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(see ‘Genetic Testing’ below) and a second optional consent for collection of peripheral blood 
mononuclear cells (PBMCs) (see ‘PBMCs’ below).  A study coordinator or other team member 
(except PI) will obtain written informed consent.  
 
10.3.2 Enrolment and randomization  
Consenting individuals will undergo a medical history, focused physical examination, complete a 
symptom survey and have blood drawn for routine laboratory and inflammatory markers (if not 
already performed as standard of care).  Female participants of childbearing potential will have a 
blood pregnancy test (serum beta hCG). Female and male subjects will be advised to use 
appropriate measures to avoid pregnancy during the 2 weeks of administration of peginterferon 
lambda and for up to 3 months after the last dose of peginterferon lambda. 
 
Vital signs, including blood pressure, temperature, pulse, respiratory rate and oxygen saturation in 
ambient air will be recorded. The eligibility checklist will be reviewed by a site sub-
investigator/principal investigator and eligible participants will then be randomized 1:1 using 
centralized randomization in blocks of 4, stratified by country of site and sex, with numbered 
opaque envelopes to treatment or no treatment.  
 
The participant’s study ID, month and year of birth and initials will be recorded on the 
randomization form and emailed/faxed to the TCLD.  The treatment codes will be maintained by 
the trial statistician in a password-protected file which cannot be accessed by other study personnel 
or subjects. In future study materials and analyses, the subject will be referred to by the study 
identification number. 
 
10.3.3 Study Interventions (See Schedule of Events – Hospitalized) 
On Day 0, those randomized to the peginterferon-lambda arm will receive a SC injection in the 
lower abdomen of peginterferon lambda 180µg and those randomized to the placebo arm will 
receive a SC injection of saline. Participants will be seen on each study day by a study team 
member to record symptoms, temperature and adverse events, which will be captured on a paper 
Case Report Form (CRF) before being entered into the REDCap database.   
 
Standard-of-care laboratory results (hematology, chemistry, renal and liver profiles) will be 
collected at the frequency performed by the admitting team. If these laboratory tests are not 
performed more frequently by the admitting team, they will be done on days 3, 5 (prior to injection 
if Day 3 tests are abnormal), 7, 10 (if hospitalized), 14, 21, and 28. Inflammatory markers (ferritin, 
lactate dehydrogenase, D-Dimers, C reactive protein, amylase, troponin) will be measured on days 
3, 7, 10 (if hospitalized), 14, 21, and 28; or more frequently if clinically indicated.  A research 
sample will be collected at baseline and on days 3, 7, 14, 21, 28, and 90 (optional) from which 
serum will be extracted and stored at -80C for future use.   
Self-collected mid-turbinate swabs will be collected daily from Days 0-7 then Day 10, 12, 14, 18, 

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21, 25, and 28.  
 
On Day 5 (+/- one day), a second dose of peginterferon lambda 180µg SC or placebo (saline) will 
be given.  Day 5 blood will only be collected for dosing eligibility if the dosing eligibility 
laboratory results from day 3 are abnormal.  If all eligibility laboratory results from day 3 are in 
the normal range, dosing may proceed prior to obtaining Day 5 results. In those with abnormal 
Day 3 eligibility labs, Day 5 blood and swab should be collected prior to injection of peginterferon 
lambda or placebo.  Results from Day 5 labs will be used to assess eligibility for the second dose 
with the same thresholds as used for the first dose.  For participants with hematology values outside 
of the accepted thresholds, the second dose may be omitted, or the following dose reductions may 
be considered, with the final decision made by the investigator: 
 
1. If Day 5 hemoglobin is < 100 mg/dL but ≥ 80 mg/dL, a half dose of peginterferon lambda 
(90 µg) or placebo (half volume) SC may be given. If Day 5 hemoglobin is < 80 mg/dL, 
the second dose must be omitted. 
 
2. If the Day 5 platelet count is < 75,000 cells/mm3 but ≥ 50,000 cells/mm3, a half dose of 
peginterferon lambda (90 µg) or placebo (half volume) SC may be given. If the Day 5 
platelet count is < 50,000 cells/mm3, the second dose must be omitted. 
 
3. If the Day 5 absolute neutrophil count is < 1,000 cells/mm3 but ≥ 750 cells/mm3, a half 
dose of peginterferon lambda (90 µg) or placebo (half volume) SC may be given. If the 
Day 5 absolute neutrophil count is < 750 cells/mm3, the second dose must be omitted. 
 
4. If the Day 5 creatinine clearance is < 50 but ≥ 30 cc/minute, a half dose of peginterferon 
lambda (90 µg) or placebo (half volume) SC may be given. If the Day 5 creatinine clearance 
is < 30 cc/minute, the second dose must be omitted. 
 
 
If the second dose is omitted at Day 5, a full or reduced dose (half volume - 90 µg SC or half dose 
placebo) may be given if the laboratory parameters return to within the specified thresholds by 
Day 9 at the discretion of the investigator.  If the laboratory values remain out of the specified 
ranges at Day 9, the second dose will be omitted.  The second dose may be omitted at the discretion 
of the investigator for reasons other than laboratory value thresholds.  If the dose is reduced or 
omitted, the reason for the change must be documented.  For participants who have a dose 
reduction or dose omission, the primary and secondary endpoints will remain unchanged. 
 
If participants are discharged by the medical team prior to Day 28, follow-up with calls on each 
study day by phone or videoconference will be arranged for symptom/AE collection, concomitant 
medications and temperature recording.  Participants will be taught to self-collect mid-turbinate 
nasal swabs (see ‘Nasal Swab Collection’) and will be given enough swabs to collect a self-swab 

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for each day remaining in the study.  An outpatient office visit will be arranged for collection of 
swabs and blood on day 3, 5, 7, 14, 21, and 28. Participants discharged before day 5, will receive 
the second dose of study medication at the day 5 outpatient visit with the same criteria used to 
determine eligibility for inpatient dosing.  Participants will be called at day 21, 28 and 90 to record 
any persistent symptoms and any additional complications after study completion. All of these 
visits will have a window of +/- one day.  
 
Participant Compensation 
Participants in Cohort B will not receive financial compensation for study participation unless they 
are discharged before completion. If discharged with ambulatory follow-up, they will receive 
compensation following the schema for Cohort A. 
 
10.4 Outcomes 
 
Cohort B 
Primary efficacy endpoint: 
Clinical status on an ordinal scale at Day 14. 
 
Primary safety endpoint:  
The rate of treatment-emergent and treatment-related serious adverse events (SAEs) 
 
Secondary Endpoints: 
1. Clinical status on an ordinal scale at Day 7, 21 and 28 
2. ICU admission during hospitalization 
3. Need for intubation by day 14 and day 28 
4. Length of hospital stay 
5. Change in respiratory symptom on ordinal scale score day 0 to 7 and day 0 to 14 and 0 to 
28 
6. Readmission to hospital by day 28 and day 90 
7. All-cause mortality at day 28 and day 90 
8. COVID-19-related mortality at day 28 
9. Adverse (AEs) and Serious Adverse Events (SAEs) by day 28 
10. Frequency of dose reduction or dose omission for the second dose of peginterferon-lambda 
Virologic/Immunological 
18. Time to SARS-CoV-2 negativity 
19. Proportion negative for SARS-CoV-2 RNA by mid-turbinate swab on days 0-7, 10, 12, 
14, 18, 21, 25, 28 

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20. Change in quantitative SARS-CoV-2 RNA by mid-turbinate swab over time 
21. Correlation of clinical and virologic response with interferon lambda 4 (IFNL4) genotype 
22. Change in laboratory and inflammatory markers hemoglobin, white blood cell count, 
lymphocyte count, liver profile, ferritin, lactate dehydrogenase, c-reactive protein, D-
dimers, amylase) from day 0 to day 7 and to day 14, 21, and 28  
23. Proportion with SARS-CoV-2 antibody at day 7, 14, 21, and 28 
24. Proportion with SARS-CoV-2 RNA in blood at day 0, 7 and 14, 21, and 28 
 
10.5 Sample Size Calculation 
The sample size was re-calculated based upon a change in the primary outcome to the score on an 
ordinal scale. Using the outcomes from the ORCHID trial evaluating the utility of 
hydroxychloroquine in hospitalized patients the following proportions at day 14 were identified; 
6% died, 8% on invasive ventilation, 3% non-invasive ventilation or high-flow oxygen,  8% 
hospitalized with oxygen, 8% hospitalized without oxygen, 36% outpatient without activity 
limitation 
and 
31% 
outpatient 
without 
activity 
limitation 
(https://jamanetwork.com/journals/jama/fullarticle/2772922). Using this distribution of outcome 
in the study population and an estimated odds ratio of benefit of 2.1, based upon the odds of 
improvement in an ordinal scale from a trial assessing inhaled interferon-beta the estimated sample 
size is 190, based on a power of 0.8 (lancet ifn-beta inhaled rct).  With an estimate 5% loss to 
follow up the total sample size is 200. 
 
10.6 Rationale for Primary Endpoint Selection for Cohort B 
The clinical manifestations of COVID-19 are myriad, but the main symptom necessitating 
hospitalization is respiratory distress. An ordinal scale captures the spectrum of the clinical care 
received by an individual hospitalized with respiratory failure. Furthermore, this scale has been 
adopted by multiple randomized COVID-19 therapeutic trials for hospitalized patients (ORCHID 
trial) and is the recommended outcome as outlined by the WHO Research and Development 
Blueprint for COVID-19 (https://www.who.int/teams/blueprint/covid-19). Adopting this 
commonly used scale will permit comparisons between this and other treatment trials. Moreover, 
the use of death or ICU admission will ultimately require a larger sample size that could 
overlook a beneficial effect of peginterferon-lambda for reasons that contribute to a prolonged 
hospitalization, which are worthwhile in their own right. Lastly, given that rapidly changing 
treatment paradigm for COVID-19 the estimates of mortality and ICU admission are sure to 
change as new treatments, such as dexamethasone, become the standard of care.  
 
11. Optional Consents 
11.1 Genetic Testing 
A genome-wide association study (GWAS) performed on people treated with interferon-alpha 
therapy for hepatitis C virus (HCV) infection identified a single nucleotide polymorphism (SNP) 
near the interleukin 28B (IL28B) gene that was strongly associated with response to treatment22.  

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Subsequent studies confirmed the association and found that this SNP was also associated with 
spontaneous HCV clearance23.  Although the originally identified SNP was in a non-coding region, 
a later study identified a novel mRNA transcript induced by viral infection in hepatocytes.  The 
transcript codes for a novel Type III interferon called interferon lambda 4 (IFNL4)24.  A deletion 
in the IFNL4 gene prevents production of a functional protein.  The lack of the functional IFNL4 
is associated with HCV treatment response to interferon-based therapy and with spontaneous HCV 
clearance.  In contrast, production of functional IFNL4 is associated with non-response to 
interferon-based therapy for HCV24.  The prevalence of the IFNL4 mutation varies by ethnicity, 
with 80% of East Asians producing no functional IFNL4 whereas approximately 75% of Africans 
produce the functional protein22.  The difference in prevalence explains the bulk of the difference 
in HCV treatment response by ethnicity.  It is unknown whether the IFNL4 genotype affects 
response to interferon lambda treatment and/or the natural course of COVID-19.  Currently no 
other genes have been identified that modify the course or response to treatment of COVID-19.   
 
Study participants will be asked to sign an optional consent giving permission to study genetic 
associations between disease outcome and treatment response during COVID-19 infection.  
Participants in either cohort who agree to genetic testing will have a tube of whole blood taken on 
Day 0 for DNA extraction and storage.  The IFNL4 genotype will be determined in all consenting 
participants and DNA will be stored for future analysis in case other relevant genes are identified. 
 
 
11.2 Peripheral Blood Mononuclear Cell (PBMC) 
To evaluate SARS-CoV-2-specific immune responses, a subset (~30%) of participants in each 
cohort will be asked to consent to provide additional blood for PBMC isolation.  Those who agree 
will have 5 tubes collected on Day 0, 3, 7 and 14 in Cohort A and Day 0, 1, and 14 in Cohort B.  
The magnitude and change in SARS-CoV-2-specific immune responses will be evaluated using 
standard interferon-gamma ELISPOT assays to over-lapping peptides of SARS-CoV-2.  
Participants in both Cohorts will be asked to consent to provide additional blood for PBMC 
isolation at Day 90+ post-dosing (up to 1-year post-dosing).  Provision of blood for the Day 90+ 
PBMCs will be requested of all participants in both cohorts irrespective of whether they agreed to 
PBMC collection during the course of treatment. The rationale for the late PBMC collection is to 
assess the degree of T cell immunity and antibodies targeting SARS-CoV2 and to determine 
whether the PBMC responses are influenced by peginterferon lambda treatment.   
 
11.3 Antibody Testing 
Currently there are three Health Canada approved testing platforms for antibodies against COVID-
19. Although the clinical significance of the presence of IgM/IgG antibodies is not fully 
understood, the presence and quantity of anti-COVID-19 antibodies up to day 28 of the study to 
day 90+ visits will be compared; including assessing whether the administration of Interferon-
Lambda may affect expression. In addition to collecting plasma, the utility of collecting blood by 
finger-prick onto a dried blood spot card will be assessed. The sample would be eluted from the 

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card and will also be analyzed on one of the three Health Canada approved platforms. Dried blood 
spots have been widely used in resource limited countries for the presence of hepatitis B and C 
antibodies, and several countries are also implementing this collection method for seroprevalence 
studies of COVID-19. However, to date, there are few head-to-head comparisons of venipuncture 
to finger-prick collection for COVID-19 antibodies; and the ability to collect by both methods in 
this study will provide data as to whether this method is feasible and comparable to testing from 
plasma.   
 
 
12. Sample Processing 
12.1 Swabs and Saliva 
Collection of nasopharyngeal and mid-turbinate nasal will follow the instructions on the label of 
each specific swab. Immediately after the swab is completed, the swab should be placed in viral 
culture media.  Saliva will be collected by filling one-third of sterile specimen container with spit. 
Self-collected samples should be stored in the sealed cooler provided to the participants until pick-
up.   
 
The swabs in viral culture media and saliva in specimen collection containers will be transported 
in a sealed plastic container to the Mount Sinai microbiology lab for SARS-CoV-2 testing using 
the Seegene Allplex SARS-CoV-2 PCR (limit of detection 100 copies/mL), which is Health 
Canada approved. 
 
12.2 PBMC Collection 
Samples for PBMCs will be transported to the laboratory of Dr. Adam Gehring for PBMC 
isolation, storage and downstream analysis using standard Ficoll PBMC isolation techniques 
following specific handling laid out by Infection Prevention and Control for UHN. 
 
 
13. Study Withdrawal 
Study Discontinuation 
The investigator may advise the participant to withdraw from the study if there are concerns for 
participant safety.  In Cohort B, if there are concerns that the participant’s condition worsened 
after the first injection and it would not be safe to give a second injection, the day 5 dose may be 
withheld.  This decision will be made at the discretion of the treating physician.  Data from 
participants who discontinue for safety will still be collected unless the participant withdraws 
consent.  Participants who discontinue prematurely before assessment of the primary endpoint will 
be counted as treatment failures for analysis.  Participants who discontinue prematurely due to 
safety concerns will not be replaced. 
 
Participant Withdrawal from the Study 
Participants may withdraw from the study at any time.  The reason for withdrawal must be 
documented.  Participants who discontinue prematurely will be included in the analysis of results 

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(as appropriate) and may be replaced in the enrollment.  If agreeable, participants who choose to 
discontinue the study prematurely, will be asked to have a final study visit to document final 
virologic results.  Participants may decline the final study visit at the time of withdrawal. 
 
14. Data Safety and Monitoring Committee (DSMC) 
To evaluate safety of this investigational agent, the Data Safety and Monitoring Committee 
(DSMC) of the Canadian HIV Clinical Trials Network (CTN) will be used.  The DSMC consists 
of 6 members including a community member and follows an established charter. 
 
The DSMC will review safety data after the first 10 randomized participants complete 7 days of 
follow-up after treatment.  They will review after every 10 randomized participants in Cohort A 
until 50% of the cohort has been enrolled.  Once 50% of Cohort A have completed 7 days of 
follow-up, the entire safety dataset will be reviewed by the DSMC.  After review, the DSMC will 
notify the sponsor/steering committee to indicate whether the trial may proceed.  The DSMC will 
specifically evaluate any change in liver enzymes from Day 0 to 7, given the known association 
of peginterferon lambda with mild hepatotoxicity.  The trial will be stopped for safety if the DSMC 
notes >1 treatment-related SAE or apparent worsening of the disease course based on increased 
symptoms in at least 5 individuals in the treatment arm or based on other unexpected safety 
concerns identified by the DSMC.  If approved for continuation, recruitment will continue in 
Cohort A and in parallel, recruitment will begin in Cohort B.   
 
The DSMC will review after 25% of randomized patients in Cohort B have completed 14 days of 
follow-up.  They will again review at 50% enrollment in Cohort B or more frequently at their 
discretion based on AE/SAEs reported.  The treatment will be halted if >1 treatment-related SAE 
is reported or based on other unexpected safety concerns identified by the DSMC  
 
15. Trial Oversight 
A Steering Committee (SC) will consist of the overall study PIs, the site PI at each site, as well as 
study statistician.  The SC will meet once weekly by teleconference for the first 4 weeks and then 
will adjust the frequency of meetings based on need.  The DSMC will instruct the SC about 
continuation of the trial in both Cohorts and initiation of enrolment in Cohort B after their 
evaluations of safety and efficacy. 
 
Eiger Biosciences will provide adequate study medication for all enrolled participants to complete 
the study dosing according to the Study Contract with UHN.  Eiger Biosciences will be provided 
with aggregate study data, but not individual patient-level data.  They will have the right to review 
study publications 30 days prior to submission. 
 
16. Data Analysis 
The assessment of endpoints – both safety and efficacy – will be determined by study staff blinded 
to the treatment assignment of the participant.  Descriptive statistics will be used to summarize 
demographic and clinical baseline characteristics of enrolled participants in Cohorts A and B. 

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Continuous variables will be summarized with mean, median, SD, quartiles, and minimum and 
maximum values, as appropriate. Categorical variables will be summarized using counts and 
proportions. The primary outcome in cohort A will be assessed using Chi-squared with 95% 
confidence intervals (CI) on the intention-to-treat (ITT) population. Once Day 14 information has 
been collected for the last participant in cohort A, the study will be unblinded and the data will be 
made available for analysis to allow for prompt dissemination of the results. Day 30 information 
will still be collected thereafter for the remaining participants, but this only pertains to outcomes 
of potential home transmission so will not influence the primary or key secondary outcomes. The 
primary outcome for cohort B will be analyzed with a global odds ratio comparing the 
peginterferon-lambda arm to the control arm. RNA negativity for determination of the key 
secondary endpoint will require two consecutive negative mid-turbinate swab specimens. Patients 
who die before reaching RNA negativity will be counted as never reaching negativity.  Patients 
who withdraw from the study prior to reaching RNA negativity will be counted as never reaching 
negativity for the ITT analysis.   
 
A secondary analysis will be performed on the modified ITT population, including anyone who 
took at least a single dose of peginterferon lambda or placebo. Factors associated with severity of 
disease and clinical course will be evaluated by uni- and multivariable logistic regression for 
cohort A and with Cox regression for cohort B.  Secondary endpoints will be described and 
analysed depending on the outcome with chi-2 test for proportions, log-rank test for time to event 
and repeated measurement modelling for multiple outcomes per patient over time. Viral kinetics 
will be determined using quantitative SARS-CoV-2 RNA and correlated with inflammatory and 
cytokine profiles. If feasible, quantitative results will be plotted to develop a model of 
peginterferon lambda activity against SARS-CoV-2. A complete statistical analysis plan will be 
created prior to data analysis. 
 
17. Symptoms and AE/SAE Reporting 
 
Symptom Score 
Symptoms will be collected by phone/videoconference.  Participants will be asked about specific 
symptoms known to be common in COVID-19 or to be reported with interferon use. Symptoms 
will be rated as: none, mild, moderate or severe and will be compared to the day prior as: better, 
unchanged or worse. They will also be asked an open-ended question about additional symptoms 
and again rate them by severity and change over time.  The following symptoms will be 
specifically explored: 
 
1. Respiratory symptoms  
 
- Cough 
 
- Shortness of breath 
 
- Chest pain 
 
- Sore throat 

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- Runny nose/congestion 
2. Fever  
 
- Objective temperature measurement 
 
- Chills 
 
- Rigors 
3. Gastrointestinal side effects 
 
- Loss of appetite 
 
 - Nausea 
 
- Vomiting 
 
- Diarrhea 
 
- Abdominal pain 
4. Sensory 
            - Loss of sense of taste 
 
- Lose of sense of smell  
5. Dermatological  
  
- Rash 
- Pruritus (itch) 
- Injection site reaction 
6. Headache 
7. Depression 
8. Muscle pain/aches 
9. Confusion 
10. Fatigue/weakness 
11. Changes in the colour of fingers/toes 
12. Light-headedness/dizziness 
13.. Other symptoms (open-ended) 
18. Adverse Events and Serious Adverse Events 
 
An adverse event (AE) is any adverse change from the participant’s baseline (pre-treatment) 
condition, including intercurrent illness which occurs during the course of the trial, after the 
consent form has been signed, whether the event is considered related to treatment or not.  
 
The Common Terminology Criteria for Adverse Events CTCAE v 5.0 will be used for grading 
severity of AEs.  
 
A serious adverse event (SAE) is any adverse event that at any dose: 
• results in death (grade 5 event) 
• is life-threatening (grade 4 event) 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability or incapacity 

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• is a congenital anomaly/birth defect 
Unexpected adverse events are those which are not consistent in either nature or severity with 
information contained in the investigator brochure or product monograph. 
  
Adverse events considered related to protocol treatment are those for which a relationship to the 
protocol agent cannot reasonably be ruled out. 
  
All serious adverse events which are unexpected and related to protocol treatment must be 
considered reportable, and therefore be reported in an expedited manner.   
  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. These should also be considered serious. 
 
All SAEs meeting the above criteria must be reported to the sponsor site to either Dr. Jordan Feld 
or the TCLD research coordinator in an expedited fashion.  The completed SAE form should be 
faxed to TCLD at 416-340-4533.  The TCLD research coordinator or Dr. Feld (416-340-3155 and 
ask hospital operator to page Dr. Feld) should be notified by telephone.  SAEs should be reported 
to the sponsor within 24 hours.  In many instances, complete clinical information may not be 
available.   Whatever information is available on the SAE should be provided to the sponsor within 
24 hours.  As new information becomes available, it should be forwarded to the sponsor.  Each 
site will report unexpected AEs or SAEs to their REB as per their local site regulations.  
  
A serious adverse event, which is unexpected and is related, will require expedited reporting to the 
appropriate oversight committees or entities, as per local site regulations. 
19. Ethical and Regulatory Considerations 
Confidentiality 
Participant confidentiality will be maintained by generating a unique participant identification 
code that will be stored separately from the anonymized study database.   
Data relating to the study might be made available to third parties (for example in case of an audit 
performed by regulatory authorities) provided the data are treated confidentially and that the 
participant’s privacy is guaranteed. 
Sources of Materials 
Research material obtained from study participants includes medical information, blood specimens 
and swab samples obtained for laboratory analysis.   

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All of the data obtained for this study will be obtained prospectively. 
Copies of data obtained as part of the study will be retained by the clinical research centre, with 
appropriate source documentation, on all patients that sign informed consent. The data utilized in 
this study are described above and consist of information from medical records, or study-specified 
measures and interventions.  
Maintaining Records  
The principal investigator will maintain copies of all study-related correspondence, regulatory 
documents, data, shipment of supplement accountability logs, adverse supplement effects and other 
records related to the clinical study. The principal investigator will maintain records related to the 
signed Investigator Agreements. 
Site Record Retention Policy  
All core laboratories and clinical sites will maintain study records until the principal investigator 
notifies them and the reviewing regulatory authorities that research is completed or terminated 
under the clinical investigation in compliance with national law. Record retention dates will be 
provided to study sites by the principal investigator at the onsite closeout visit. 
Informed Consent and Ethics Committee 
All participants must provide written informed consent in accordance with the local clinical site’s 
REB. A signed Informed Consent must be obtained from each participant prior to commencing 
screening evaluations. One copy of the Informed Consent document will be given to the participant 
and another retained by the Investigator. 
Protocol Deviation  
Any incident in which the investigator or site personnel did not conduct the study according to the 
clinical protocol or the investigator agreement. Protocol deviations are classified into three 
categories:  
• Major deviation: Any deviation from participant inclusion and exclusion criteria or 
participant-informed consent procedures. 
• Critical finding: any deviation that can affect the wellbeing of the participant, or the 
reliability of the data collected is compromised. 
• Minor deviation: Deviation from a clinical protocol requirement such as 
incomplete/inadequate testing procedures, follow-ups performed outside specified time 
windows, etc.  
20. Schedule of Events 
 
20.1 Cohort A – Ambulatory 
 

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Group A - Ambulatory Cohort
Screening
Day 0
Day 1
Day 2
Day 3
Day 5
Day 7
Day 10
Day 14
Day 30
Day 90+
Informed Consent 
X
Medical History
X2
Determine Eligibility (Inclusion/Exclusion Criteria)
X
X2
Nasopharyngeal Swab
X1
X
X
X
Urine Pregnancy Test*
X2
Randomization
X2
Study Drug Administration
X
Symptom/Temperature Survey**
(video/teleconference)
Midturbinate Nasal Swab
X2
X
X
X
X
X
X
X
Saliva Collection
X2
X
X
X
X
X
X
X
Adverse Event/Serious Adverse Event assessment
X2,3
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Lab Tests***
 
X2
X
X
X
Inflammatory Markers****
X2
X
X
X
Research Plasma Sample
X2
X
X
X
Peripheral Blood Mononuclear Cell collection*****
X2
X
X
X
X4
Genetic Sample*****
X2
Finger-prick blood test
X4
Household diagnoses of COVID-19
X
X
* for women of childbearing potential
**hematology, chemistry, renal and liver profiles 
*** ferritin, lactate dehydrogenase, D-Dimers, C reactive protein, amylase
**** Peripheral Blood Mononuclear Cell (PBMC) and genetic samples are optional for those who agree
1. Collected if not already performed by the assessment centre
2. To be performed prior to randomization and dosing 
3. To be performed 4-6 hours after study drug administration
4. Can be performed up to 1 year post enrollement. 
X2,3
X
X
X
X4
X
X
X
X

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20.2 Cohort B – Hospitalized 
 
 
 
  
 
 

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21. Flow Diagram  
21.1Cohort A: Ambulatory 
                                                                   
 
 
 
 
 
 
 
 
     
 
 
 
                   
                                                                                 
 
 
 
 
 
  
 
Interferon Lambda for Immediate Antiviral therapy at Diagnosis (ILIAD): A phase II randomized, open-
label, multicenter, trial to evaluate the effect of peginterferon lambda for the treatment of COVID-19. 
Randomization 
Screening: 
Determine eligibility, informed consent, nasopharyngeal swab (if not 
already collected by assessment centre) 
Arm 1:  
Single dose 
PegIFN-λ 
30 subjects 
Discharged home for 14 days of self-quarantine (days 1-14) 
    *call from nurse required 4-6 hours after discharge for symptom survey, AE/SAE assessment 
Daily 
-AE/SAE assess 
-con meds 
-symptom/temp 
survey 
 
Day 30  
Determine if any household diagnoses of Covid-19 
Day 0 procedures: 
Medical history, Urine pregnancy test (if applicable), con meds, symptom/temp survey, saliva collection, MT 
nasal swab, labs, inflammatory markers, research sample, PBMCs and genetic testing (optional)  
Arm 2: 
Placebo 
30 subjects 
Day 3, 7, 14 
-research sample 
-NP swab 
-labs 
-inflammatory markers 
- PBMC (optional) 
Day 1-3, 5, 7, 
10, 14, 17, 25 
-MT nasal 
swabs 
-saliva sample 
 
Day 14 
-call to determine 
household 
diagnoses of 
Covid-19 
 
Day 90+ 
PBMC collection + finger-prick blood-spot test + symptom survey (optional) 

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21.2 Cohort B: Hospitalized  
 
 
 
Interferon Lambda for Immediate Antiviral therapy at Diagnosis (ILIAD): A phase II randomized, open-
label, multicenter, trial to evaluate the effect of peginterferon lambda for the treatment of COVID-19. 
Randomization 
Arm 1:  
Two doses PegIFN-λ 
(day 0 and day 5) 
100 subjects 
Screening procedures: 
Determine eligibility, informed consent, medical history, physical exam, blood pregnancy test (if 
Inpatient Hospitalization Stay (days 1-14) 
Every study 
day 
-AE/SAE assess 
-con meds  
-symptoms/temp  
-MT swab  
 
Day 21, 28   
Clinical status, AE/SAE assessment, concomitant medications, labs, research sample, MT swab 
Arm 2: 
Two doses of placebo 
(day 0 and day 5) 
100 subjects 
Day 0 procedures: 
Symptom/temp survey, physical exam, labs, inflammatory markers, research sample, PBMCs 
(optional), genetic testing (optional)  
Day 5 
- second dose 
of PegIFN-
λ or placebo 
-labs (if 
abnormal d3) 
 
Day 1 and 14 
-PBMC (optional) 
 
 
Day 90 – End of Study 
 Mortality assessment, PBMC collection + finger-prick blood-spot test + symptom survey 
(optional) 
Day 3, 7, 10, 
14 
-labs 
-research 
sample 
 
 

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22. References 
 
1. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet. 2020;395(10223):497-506. 
2. 
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe 
Covid-19. N Engl J Med. 2020. 
3. 
Hermant P, Michiels T. Interferon-λ in the context of viral infections: production, response and 
therapeutic implications. J Innate Immun. 2014;6(5):563-574. 
4. 
Syedbasha M, Egli A. Interferon Lambda: Modulating Immunity in Infectious Diseases. Front 
Immunol. 2017;8:119. 
5. 
Loutfy MR, Blatt LM, Siminovitch KA, et al. Interferon alfacon-1 plus corticosteroids in severe 
acute respiratory syndrome: a preliminary study. JAMA. 2003;290(24):3222-3228. 
6. 
Muir AJ, Arora S, Everson G, et al. A randomized phase 2b study of peginterferon lambda-1a for 
the treatment of chronic HCV infection. J Hepatol. 2014;61(6):1238-1246. 
7. 
Chan HLY, Ahn SH, Chang TT, et al. Peginterferon lambda for the treatment of HBeAg-positive 
chronic hepatitis B: A randomized phase 2b study (LIRA-B). J Hepatol. 2016;64(5):1011-1019. 
8. 
Etzion O, Hamid S, Lurie Y, et al. End of study results from LIMT HDV study: 36% durable 
virologic response at 24 weeks post-treatment with pegylated interferon lambda monotherapy in 
patients with chronic hepatitis delta virus infection. International Liver Congress 2019; 2019; 
Vienna, Austria. 
9. 
Crotta S, Davidson S, Mahlakoiv T, et al. Type I and type III interferons drive redundant 
amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. 
PLoS Pathog. 2013;9(11):e1003773. 
10. 
Davidson S, McCabe TM, Crotta S, et al. IFNλ is a potent anti-influenza therapeutic without the 
inflammatory side effects of IFNα treatment. EMBO Mol Med. 2016;8(9):1099-1112. 
11. 
Mordstein M, Neugebauer E, Ditt V, et al. Lambda interferon renders epithelial cells of the 
respiratory and gastrointestinal tracts resistant to viral infections. J Virol. 2010;84(11):5670-5677. 
12. 
Jin X, Lian JS, Hu JH, et al. Epidemiological, clinical and virological characteristics of 74 cases of 
coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut. 2020. 
13. 
Zhang W, Du RH, Li B, et al. Molecular and serological investigation of 2019-nCoV infected 
patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020;9(1):386-389. 
14. 
Guedj J, Dahari H, Pohl RT, Ferenci P, Perelson AS. Understanding silibinin's modes of action 
against HCV using viral kinetic modeling. J Hepatol. 2012;56(5):1019-1024. 
15. 
Guedj J, Dahari H, Rong L, et al. Modeling shows that the NS5A inhibitor daclatasvir has two 
modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci 
U S A. 2013;110(10):3991-3996. 
16. 
Larios OE, Coleman BL, Drews SJ, et al. Self-collected mid-turbinate swabs for the detection of 
respiratory viruses in adults with acute respiratory illnesses. PLoS One. 2011;6(6):e21335. 
17. 
Wyllie A, Fournier J, Cassanovas-Massana A, Campbell M, al. e. Saliva is more sensitive for 
SARS-CoV-2 detection in COVID-19 patients than nasopharyngeal swabs. MedRxIV. 
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