Conditions: COVID-19 COVID
Keywords: COVID Coronavirus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: no

Brief summary:
Prospective randomized trial to assess the antiviral efficacy of Pegylated Interferon Lambda (180 mcg SC injection) vs.placebo in up to 20 subjects with COVID-19 infection.

Detailed description:
The study objective is to assess the efficacy of Pegylated Interferon Lambda (180 mcg) vs. placebo in inducting quantitative PCR negativity at day 7

Arms:
arm 1: Treatment with subcutaneous injection (180 mcg) of pegylated interferon lambda arm 2: Subcutaneous injection of saline placebo

Interventions: intervention 1: Pegylated interferon lambda
Intervention descriptions: intervention 1: 180 mcg subcutaneous injection of pegylated interferon lambda

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2020P001083 
 
 
Version 1.9 dated 07JUN2021 
 
Page 1 of 27 
 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
A Randomized Controlled Trial to Evaluate the Safety and Efficacy of 
Pegylated Interferon Lambda vs. Placebo in Subjects Infected with 
COVID-19 
Sponsor: 
 
 
Raymond Chung, MD 
 
 
 
 
Massachusetts General Hospital 
 
 
 
 
Boston, MA 02114 
 
IND Number: 
 
 
149760  
 
ClinicalTrials.gov 
 
NCT04343976 
Identifier 
 
 
Protocol ID: 
 
 
2020P001083 
Sponsor/Emergency 
 
Raymond Chung, MD 
Contact 
 
 
Gastrointestinal Unit 
 
 
 
 
Massachusetts General Hospital 
 
 
 
 
55 Fruit Street; Boston MA 02114 
 
 
 
 
 
 
 
 
 
 
Co-PI 
 
 
 
Arthur Kim, MD 
 
 
 
 
Infectious Diseases Unit 
 
 
 
 
Massachusetts General Hospital 
 
 
 
 
 
 
 
 
 
 
Co-Investigator  
 
Nikolaus Jilg, MD, PhD 
 
 
 
 
Infectious Diseases Unit 
 
 
 
 
Massachusetts General Hospital 
 
 
 
 
 
 
 
 
Protocol Version/Date:  
Version 1.9: 
 07 June 2021 
 


Protocol 2020P001083 
 
 
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Contents 
Abbreviations ....................................................................................................................................4 
I. 
Introduction ...........................................................................................................................5 
II. 
Objectives...............................................................................................................................6 
Primary Objectives .................................................................................................................................... 6 
Secondary Objectives ................................................................................................................................ 6 
III. 
Study Design ...........................................................................................................................6 
Visit schedule ............................................................................................................................................ 6 
Administration of Treatment ................................................................................................................ 6 
Stopping Rules and Treatment Discontinuation ................................................................................... 7 
Toxicity Based Stopping Criteria ........................................................................................................... 7 
IV. 
Subject Population ..................................................................................................................7 
Inclusion Criteria ....................................................................................................................................... 7 
Exclusion Criteria....................................................................................................................................... 8 
V. 
Investigational Product ...........................................................................................................9 
Randomization, Blinding and Treatment Codes ....................................................................................... 9 
Description and Handling .......................................................................................................................... 9 
Prior and Concomitant Medications ....................................................................................................... 10 
Accountability for Lambda/Placebo ........................................................................................................ 10 
Investigational Product Return or Disposal ............................................................................................ 10 
VI. 
Study Procedures .................................................................................................................. 10 
Subject Enrollment and Treatment Assignment ..................................................................................... 11 
Pretreatment and Baseline Assessments ........................................................................................... 11 
Post-Randomization Visit Assessments .............................................................................................. 12 
Unscheduled Visits .............................................................................................................................. 14 
Early Termination Visit ........................................................................................................................ 14 
VII. 
Adverse Events and Toxicity Management ............................................................................. 14 
Definition of Adverse Events, Adverse Reactions and Serious Adverse Events ..................................... 14 
Adverse Event ..................................................................................................................................... 14 
Serious Adverse Event......................................................................................................................... 15 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or Serious 
Adverse Events .................................................................................................................................... 15 


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Assessment of Adverse Events and Serious Adverse Events .............................................................. 15 
Assessment of Causality for Study Drugs and Procedures ................................................................. 16 
Assessment of Severity ....................................................................................................................... 17 
Reporting of Adverse Events ............................................................................................................... 17 
VIII. 
Statistical Considerations ...................................................................................................... 17 
Data Analysis ........................................................................................................................................... 17 
Sample size and power calculation: ........................................................................................................ 18 
IX. 
References ............................................................................................................................ 19 
Appendices ...................................................................................................................................... 20 
Appendix 1: Investigator Signature Page ................................................................................................ 21 
Appendix 3: GIS Grading Scale for Severity of Adverse Events and Laboratory Abnormalities ............. 23 
Appendix 4: Pregnancy Precautions and Definitions .............................................................................. 24 
Appendix 5: Symptom Questionnaire ..................................................................................................... 25 
Appendix 6: Patient Home Sputum and Saliva Collection Instructions .................................................. 26 
 


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Abbreviations 
 
AE 
Adverse Event 
CBC 
Complete Blood Count 
LFT 
Liver Function Test 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
EDC 
Electronic Data Capture system 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
PICC 
Peripherally inserted central catheter line 
RCT 
Randomized Controlled Trial 
RIC 
Respiratory Illness Clinic 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome 
SC 
Subcutaneous 
WOCBP 
Women of Childbearing Potential 
BMP 
Basic Metabolic Panel 
AST 
Aspartate Aminotransferase 
ALT 
Alanine Transaminase 
AP 
Alkaline Phosphatase 
TBili 
Total Bilirubin 
TCRC 
Translational and Clinical Research Center 
DBili 
Direct Bilirubin 
 
 


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I. 
Introduction 
A novel strain of coronavirus (COVID-19) was recently detected in Wuhan, China and reported to the 
World Health Organization Country Office in China on December 31st 2019. Although respiratory 
symptoms are absent or mild in the majority of patients, COVID-19 infection is associated with a 4% 
mortality rate due to the development of acute respiratory distress syndrome, mainly among elderly 
individuals and those with comorbid conditions. Despite global efforts to contain viral spread, the 
incidence of COVID-19 continues to rise exponentially. The United States has entered an indefinite 
period of lockdown, with the current crisis likely to incur an immense socioeconomic burden. At present, 
there are no vaccines available for disease prevention. Therefore, identifying effective treatment 
strategies to curb human-to-human transmission, while reducing disease severity and shortening 
hospital and ICU admissions, is an area of urgent and unmet clinical need. 
Peginterferon lambda-1a (Lambda) is a conjugate of recombinant human interleukin 29 (rIL-29) and a 
linear polyethylene glycol (PEG) chain, and has been identified as a therapeutic candidate. Lambda has 
been extensively trialled as a treatment for chronic hepatitis B, C and D, and its safety and tolerability 
have been demonstrated for up to 48 weeks of treatment, with over 3000 patients dosed with an 
excellent safety record. Lambda targets type III IFN receptors, whose expression is primarily restricted to 
the lungs, intestine, and liver. This is likely to account for the fewer off-target effects associated with use 
of Lambda versus other trialled interferons.  
Murine studies also indicate robust antiviral effects of IFN lambdas against SARS-CoV, influenza, 
rotavirus, norovirus and reovirus1. Furthermore, SARS-CoV replicated to high titers and induced signs of 
disease in mice lacking both type I and type III IFN receptors. These effects were not observed in single-
knockout mice expressing either type I or type III IFN receptors, indicating protective roles for both type 
I and type III IFNs against SARS-CoV2. In addition, treatment of influenza A-infected mice with IFN 
lambda significantly increased their survival and reduced morbidity. Treatment with IFN alpha 
demonstrated comparable antiviral activity, however it exerted proinflammatory effects on immune 
cells, with an associated increase in mortality. Hence, IFN lambda derivatives may represent a superior 
treatment option compared to IFN alpha. 
The potential benefit of IFN-based therapy in the management of coronavirus infection was evaluated in 
a preliminary study of patients admitted to hospital with probable SARS-CoV in 20033. Administration of 
IFN alfacon-1, a synthetic recombinant type I IFN, plus corticosteroids was associated with more rapid 
resolution of radiographic lung abnormalities and improved oxygen saturation levels compared to 
treatment with corticosteroids alone. 
On the basis of these preliminary findings, it is highly plausible that treatment with Lambda will promote 
COVID-19 clearance and improve clinical outcomes. However, to date, evidence in humans is lacking. 
We propose to evaluate the safety, efficacy and tolerability of Lambda treatment versus standard of 
care in hospitalized patients with confirmed COVID-19 infection. We will conduct a randomized 
controlled trial (RCT) of subjects diagnosed with COVID-19 infection by PCR analysis of nasopharyngeal 
secretions. Subjects will be randomized 1:1 to receive Lambda 180 mcg SC or saline injection. The 
primary endpoint is rate of PCR negativity on post-treatment Day 7. 
 


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II. 
Objectives 
Primary Objectives 
The primary objective of this study is as follows: 
• 
To assess the efficacy of Lambda (180 mcg SC injections) vs. saline placebo injection in inducing 
PCR negativity at day 7 among subjects hospitalized with COVID-19 infection  
 
Secondary Objectives 
The secondary objectives of this study are as follows: 
• 
To assess the efficacy of Lambda (180 mcg SC injections) vs. saline placebo injection in inducing 
PCR negativity at days 3, 7 and 14 among hospitalized subjects with symptomatic COVID-19 
infection  
• 
To assess the efficacy of Lambda (180 mcg SC injections) vs. saline placebo injection in inducing 
symptomatic improvement in subjects with COVID-19 infection, assessed by daily symptom 
questionnaire  
• 
To assess the efficacy of Lambda (180 mcg SC injections) vs. saline placebo injection in improving 
clinical outcomes (death, ICU stay, intubation) in subjects hospitalized with COVID-19 infection  
• 
To evaluate the safety and tolerability of Lambda (180 mcg SC injections) vs. saline placebo 
injection 
III. 
Study Design 
This is a prospective randomized trial to assess the antiviral efficacy of Lambda (180 mcg SC injection) vs. 
standard of care in up to 20 subjects hospitalized with COVID-19 infection. 
Visit schedule 
After referral by the care team and informed consent, and once the subject is confirmed as COVID-19 
positive on clinical testing, patients will have initial clinical lab testing performed during baseline (visit 1).  
After confirmation of inclusion criteria, patients will be randomized 1:1 to receive the first dose of 
Lambda or saline placebo at the baseline visit (visit 1).  Nasal swabs for PCR analysis will be collected for 
all subjects on Days 3, 7 and 14. An optional Day 5 nasal swab collection will occur only for subject who 
remain hospitalized on Day 5.  On day 7, subjects in the treatment arm will receive a second Lambda 
injection and subjects in the control arm will receive a second saline placebo injection. On Day 14, 
subjects will undergo laboratory measurements to confirm CBC and LFT values are within safe 
parameters. Research blood will be collected and stored for future testing to measure levels of pro-
inflammatory cytokines (e.g. IFN- γ, IL-6, IP-10, MCP-1, TNF-α). Measurements will be performed using 
excess blood collected for clinical purposes wherever possible. Subjects will complete a daily symptom 
questionnaire from screening through Day 14 (Appendix 5). 
Administration of Treatment 
Upto an initial 30 hospitalized patients will be enrolled (consented), with a goal of 20 subjects 
randomized 1:1 to receive either Lambda 180 mcg SC injections or saline placebo injections.  


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Administration of first dose Lambda/placebo in relation to initial COVID-19 symptom onset will be 
documented in all subjects. 
Stopping Rules and Treatment Discontinuation 
If a subject discontinues study dosing (for example, as a result of an adverse event [AE] ), every 
attempt should be made to keep the subject in the study, and continue to perform the required 
study-related follow-up procedures (Appendix 2).  If this is not possible or acceptable to the subject or 
Investigator, the subject may be withdrawn from the study 
There is no option for Lambda dose reduction due to toxicity.  If Lambda is withheld due to toxicity, the 
subject must discontinue treatment and be approached for willingness to complete remaining study 
visits as follow-up or to schedule an Early Termination (ET) visit as soon as possible. For subjects 
discharged from the hospital, the ET visit should be conducted over telephone.  An in-person evaluation 
may be scheduled if this is deemed necessary by the overall study PI.  For subjects who elect to 
discontinue treatment and decline the day 7 dose, study staff will confirm willingness to continue on 
protocol and complete all other assessments as listed in the schedule of events.   For subjects unwilling 
to complete these assessments, an ET visit will be completed. 
When medically feasible, the PI must be consulted prior to subject discontinuation. 
Study drug must be discontinued in the following instances: 
• 
Unacceptable toxicity (as defined below) or toxicity that, in the judgment of the investigator, 
compromises the ability to continue study-specific procedures or is considered to not be in the 
subject’s best interest 
• 
Pregnancy in a female subject 
• 
Significant protocol violation that impacts subject safety 
• 
Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason 
• 
Subject noncompliance 
• 
Discontinuation of the study at the request of the study sponsor, regulatory agency or an 
Institutional Review Board (IRB) 
Toxicity Based Stopping Criteria 
Subjects who meet any of the following laboratory or adverse event criteria must stop treatment with 
study drug: 
• 
Any Grade 4 adverse event assessed as related to study drug 
IV. 
Subject Population 
Inclusion Criteria 
1. Willing and able to provide informed consent 
2. Male or female age > 18 years at time of consent 
3. Hospitalized with confirmed COVID-19 infection by PCR analysis of respiratory secretions 


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a. Historic diagnosis by PCR test may be at any time prior to hospitalization but subject 
must have documentation of a positive SARS-CoV-2 RT-PCR test within 72 hours of 
randomization 
4. Female subjects of childbearing potential who engage in heterosexual intercourse must agree to 
use protocol specified method(s) of contraception as described in Appendix 4 
5. Subject must be able to comply with the dosing instructions for study drug administration and 
able to complete the study schedule of assessments 
Exclusion Criteria 
1. Current or prior history of any of the following: 
a. Clinically-significant illness or any other major medical disorder that in the opinion of 
the investigator, may interfere with subject treatment, assessment or compliance with 
the protocol 
b. Treatment with IFN or other immunomodulatory/immunosuppressive agent within 12 
months before screening. 
c. Respiratory compromise requiring ventilatory support other than nasal cannula  (mask, 
bipap or intubation and mechanical ventilation). 
d. History of treatment with any of the following medications within five half-lives or 30 
days before administration of the study drug (whichever is longer): anti-IL-6, anti-IL6R 
antagonists, Janus kinase inhibitors, ustekinumab (anti-IL-12/23), or anti IL-23 agents 
(guselkumab). 
2. Pregnant or Nursing Females (a negative pregnancy test (urine or serum) is required during 
screening [if historic negative result within 48 hours prior to consent is not available] for 
WOCBP) 
3. Life threatening SAE during the screening period 
4. Subjects having the following laboratory parameters at screening 
a. Platelet count <90,000 cells/mm3 
b. WBC count <3,000 cells/mm3 
c. ANC <1,500 cells/mm3 
d. Hb <11 g/dL for women and <12 g/dL for men 
e. CrCl < 50 mL/min 
f. Direct Bilirubin level ≥1.5 x ULN 
g. INR ≥1.5 (except in the setting of concomitant anticoagulant use) 
h. CRP >200 mg/L 
5. Females who may wish to become pregnant and/or plan to undergo egg harvesting during the 
course of the study and up to 30 days of the last dose of study drug.  WOCBP must abstain from 
breastfeeding and be willing to use effective birth control during through the week 4 post 
treatment follow-up visit. 
6. 
Clinically-relevant alcohol or drug abuse within 12 months of screening. Use of any prohibited 
concomitant medications as described in Section V 
7. Known hypersensitivity to IFN 
8. Current or planned participation in an investigational new drug (IND) trial from 30-days prior to 
randomization through Day 14 post treatment. 
9. History of full COVID-19 vaccination 
a. Full vaccination is defined as >2 weeks post final vaccination dose 


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V. 
Investigational Product 
Randomization, Blinding and Treatment Codes 
This is a randomized, single-blinded controlled study. Subjects will be randomized 1:1 to receive Lambda 
180 mcg SC injections vs. saline placebo injections.   
Description and Handling  
Lambda Formulation 
Lambda injection is a sterile, nonpyrogenic, ready to use solution (0.4 mg/mL) that is clear to opalescent, 
colorless to pale yellow, and is essentially free of particles.   Lambda injection is provided in a 1-mL long 
Type I glass syringe with a 29-gauge, ½-inch, thin-walled needle.   The syringes are prefilled with a 
solution of Lambda Injection, mannitol, L-histidine, polysorbate 80, hydrochloric acid, and water for 
injections; they are intended for a single use (180 mcg dose). The study drug will be donated by Eiger 
Biopharmaceuticals. Swab kits and RT-PCR testing will be supplied by a contract research organization, 
Viroclinics.   
Lambda Packaging and Labeling 
Storage of the study drug will be done in the Massachusetts General Hospital Clinical Trials Pharmacy 
(MGH CTP) (directed by Dr. John Vetrano, PharmD).  Study drug will be packaged and labeled per the 
Massachusetts General Hospital Investigational Pharmacy standard procedure and will adhere to federal 
guidelines. 
Lambda Storage and Handling 
Prefilled syringes should be stored in a refrigerator at 2 - 8°C (36 - 46°F) and protected from long-term 
(>24 hours) exposure to light.  Lambda Injections should not be frozen. Until administered to the 
subjects, syringes containing the study drug should be stored in a secure area, accessible only to 
authorized site personnel or vendor (in the case of home health visits). During transport to subject 
homes (via ambulance vehicle for home health visits only), drug should be stored in a cooler with an ice 
pack. To ensure the stability and proper identification, study drugs should not be stored in a container 
other than the container in which they were supplied.  
 
Saline Placebo 
In this single blind study, saline placebo injections will be prepared by the MGH CTP.  Under the 
direction of the lead pharmacist, pharmacy staff will prepare the placebo injections by drawing up 
approximately 0.45 ml of sterile saline into a 1 ml Monoject Tuberculin Safety Syringe with a 28 gauge, ½ 
inch, thin walled needle.  Placebo injections will be labeled with standard MGH research prescription 
EPIC label as peginterferon lambda-1a or placebo however the display name and administration 
instructions will be unblinded for provider to be able to choose the correct treatment. 
Lambda/Placebo Administration 
Each dose of study drug will be dispensed by the MGH CTP in the form of pre-filled syringes.  
Appropriately delegated, trained and credentialed study staff or contracted study vendor (in the case of 
home health visits) will administer the stud drug by subcutaneous injection.  The injection site should be 
documented and entered into the EDC.  The injection site may be any of the following locations: 


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• 
Upper outer arm (right/left) 
• 
Front outer upper thigh (right/left) 
• 
Abdomen 
• 
Upper hip (Right/Left) 
For active Lambda treatment only:  prior to administration, credentialed staff 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 (180 mcg).   
Prior and Concomitant Medications 
Concomitant medications taken within 30 days prior to screening, up to and including 30 days after the 
last dose of study drug, need to be recorded in the source documents and electronic case report form(s) 
(eCRFs). 
In drug-drug interaction studies in healthy subjects, the activity of select CYP enzymes were evaluated 
and suggest that following a single 180μg dose, Lambda is a mild inhibitor of CYP1A2, CYP2C9, and 
CYP3A4 and a moderate inhibitor of CYP2C19 and CYP2D6.  Because the effects of these sensitive CYP 
substrates are mild or moderate, dose adjustments for other concomitant CYP substrates may not be 
necessary, but should be used with caution. 
 
Accountability for Lambda/Placebo 
The investigator or designee (i.e. pharmacist) is responsible for ensuring adequate accountability of all 
used and unused study drug.  This includes acknowledgement of receipt of each shipment of study drug 
(quantity and condition).  Used study drug will be disposed of in the appropriate sharps container.   
Administration of Lambda or saline placebo injections will be performed by site staff and accountability 
of used medication will be documented in the source. 
Lambda/placebo accountability records will be utilized to: 
• 
Record the date received and quantity of study product 
• 
Record the date, subject number, subject initials, the study product dispensed  
• 
Record the date, quantity of used and unused study product returned, along with the initials of 
the person recording the information. 
Investigational Product Return or Disposal 
Due to the nature of the study product (prefilled syringes for injection), used study medication will not 
be returned to the study team or research pharmacy and should be disposed of in the appropriate 
sharps container.   The MGH Clinical Trials Pharmacy Established Site Plan will be followed in regard to 
disposal of unused investigational product. 
VI. 
Study Procedures 
The study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Appendix 2 and described in the text that follows.   
The investigator must document any deviation from protocol procedures and notify the lead PI and IRB. 


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Subject Enrollment and Treatment Assignment 
Study staff, along with the MGH-established COVID Recruitment team, will review patients in the MGH 
ED and current admitted patient charts to identify candidate subjects, ideallywithin the first 24 hours of 
their admission and/or positive COVID PCR test. Upon identification of a potential subject, the COVID 
Recruitment team will notify the study team via email regarding a potentially eligible patient.  Study 
staff will prescreen the chart for eligibility and upon confirmation of presumed eligibility, a physician 
investigator will immediately contact the clinical care team and provide them with information 
regarding the study. A member of the clinical care team who is already known to the patient will gauge 
the appropriateness of approaching them. If they deem it appropriate, the clinical care team member 
will approach the patient to determine if they are willing to learn about this study. If the patient agrees, 
the clinical care team member will authorize the study staff to approach the patient to discuss the study. 
The described process is expected to take place within 48 hours of the most recent positive COVID-19 
PCR test.  
NOTE: per the MGH COVID Recruitment team policy (memo dated 01May2020), any potentially eligible 
subject identified directly by study staff must be referred back to the team who will then distribute the 
potential participant accordingly across recruiting COVID trials.  
Patients will be consented according to the Partners IRB’s Guidelines for Consenting in COVID Research 
that is More than Minimal Risk.  Participants will be enrolled, randomized and dosed from the inpatient 
floors.  In cases with randomized subjects are discharged prior to study completion, home visits with an 
appropriately credentialed and trained provider (paramedic or registered nurse) will be utilized as 
available to limit study specific outpatient visits whenever possible.  NOTE: all Day 0 visits (first dose of 
Lambda/Placebo) must occur onsite at MGH. 
Pretreatment and Baseline Assessments  
Baseline Visit 
Subjects will be screened no later than within 48 hours of their initial hospital presentation to determine 
eligibility and provide informed consent for participation in the study. 
The following will be performed and documented during screening to assess eligibility 
• 
Obtain informed consent 
• 
Determine inclusion and exclusion eligibility 
• 
Obtain relevant medical history 
• 
Obtain details of concomitant medications 
• 
Complete physical examination including vital signs (resting blood pressure, pulse, respiratory 
rate and temperature), body weight, and height 
• 
Collect 30ml research blood for storage and future immune biomarker testing 
o Immune biomarkers include IFN-γ, IL-6, IP-10, MCP-1, TNF-α 
• 
Collect sputum and saliva for storage 
• 
Review of clinical lab results for 
o Chemistry 
o Hematology 
o Coagulation 
o Pregnancy testing in WOCBP 


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Clinical labs drawn within 48 hours prior to consent will be used for screening and as baseline.  If 
clinical labs required to determine protocol eligibility are not available, the clinical care team will 
be notified and if clinically indicated, testing should be ordered by the care team per standard 
practice.  If testing is not clinically indicated, testing may be completed after informed consent is 
obtained as part of study screening. 
• 
Request completion of baseline symptom questionnaire 
o Baseline symptom questionnaire must be completed prior to randomization. 
 
From the time of obtaining informed consent through the first administration of study drug (Lambda or 
saline placebo), all serious adverse events (SAEs), as well as any adverse events related to protocol-
mandated procedures, will be recorded in the source and on the adverse events case report form 
(CRF/eCRF). It is expected the first administration of study drug will occur within 24 hours of informed 
consent but will occur no later than 72 hours after most recent COVID test, as defined by time of clinical 
sample collection.  All other untoward medical occurrences observed during the screening period, 
including exacerbation or changes in medical history are to be captured on the medical history 
CRF/eCRF.   
 
See Appendix 3: Adverse Events and Toxicity Management for additional details. 
 
After review of inclusion and exclusion criteria to confirm continued eligibility, subjects will move into 
the baseline portion of the visit and be randomized to study drug or placebo assignment. Study drug or 
placebo will be administered on-site by appropriately credentialed and trailed staff. Up to 30 patients 
will be consented with a plan of 20 patients randomized to receive Lambda or placebo. A 10 patient cap 
will be placed on the Lambda treatment group, study enrollment will be halted if this cap is reached. 
 
The following will be performed and documented: 
• 
Review of inclusion/exclusion criteria 
• 
Review of concomitant medications taken since previous visit 
• 
Randomization to study drug or standard of care (placebo) arm 
• 
Obtain nasopharyngeal swab for COVID-19 PCR testing (pre-dose) 
• 
Administration of first dose of study drug (Lambda) or placebo (saline) 
 
Nasopharyngeal samples will be collected using a standardized method and will be sent to a central 
laboratory for processing.  Both nostrils may be sampled. 
 
Post-Randomization Visit Assessments  
Days 3*, 7* and 14* 
The following will be performed and documented: 
• 
Symptom driven physical exam, as needed 
o 
Clinically performed physical exams may be used in place of research exam when performed same 
day of visit during inpatient stay 
• 
Vital signs as recorded by hospital care team 
• 
Obtain nasopharyngeal swabs for COVID-19 quantitative PCR testing 
• 
Request completion of symptom questionnaire 


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• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring since the Screening visit 
• 
Blood samples for clinical testing (Day 14 only): 
o Chemistry 
o Hematology 
o Coagulation 
• 
Provide subject with home sputum and saliva collection instructions (as needed) 
• 
Collect sputum and saliva and 30ml research blood for storage (Day 7 and 14 only) 
o Future testing of immune biomarker will be performed off Day 12 research sample 
• 
Administration of Lambda/placebo injection (Day 7 only) 
*All post randomization visits will have a +/- 1 day window. 
 
Day 5 (Optional, inpatients only) 
The day 5 visit is applicable only to subjects who remain hospitalized on study Day 5.  Subjects 
discharged prior to day 5 will not complete this visit 
The following will be performed and documented: 
• 
Obtain nasopharyngeal swabs for COVID-19 quantitative PCR testing 
• 
Request completion of symptom questionnaire 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring since the Screening visit 
 
In the event that study subjects are discharged before the end of follow up, they will be requested to 
present to the RACC or the outpatient COVID research clinic for the remaining study time points, where 
a research nurse will conduct the study visit and obtain swab samples.  Subjects will be strongly 
discouraged from using taxi or rideshare services to return for outpatient visits.  Parking vouchers 
(purchased with study funds) will be provided to subjects to cover out of pocket cost of parking.   For 
subjects who are unable to return to MGH for outpatient visits, home visits will be made an option 
through the established vendor.  Subjects who confirm inability to return to MGH for outpatient visits 
and do not live within the service area of the established vendor will be excluded from the study (under 
inclusion criteria #5). 
 
Upon completion of the Day 14 visit, subjects will be instructed their study participation has ended and 
will be referred back to their care team for any necessary clinical follow-up, inclusive of additional 
clinical COVID PCR testing, as needed.  Subjects will be instructed to follow the clinical 
recommendations and CDC guidelines provide at time of hospital discharge by their treating team 
regarding COVID-19 vaccination timing and reminded that study participation should not impact these 
clinical recommendations.   Although there is a possibility of interface of pegylated interferon lambda 
with the immune response to COVID-19 vaccines and vaccination is recommended to be delayed for 2 
weeks after last dose of peginterferon lambda (given potential to interfere with vaccine effectiveness) 


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this is not expected to impact clinical eligibility for vaccination due to the short duration of study 
participation and timing of last dose at day 7. 
 
Female subjects of childbearing potential will be instructed to self-report a pregnancy that occurs within 
30 days of their day 7 dose, but study staff will not directly query subjects regarding pregnancy after Day 
14.  
 
 
For those participants who require home visits, study drug administration and sample collections will be 
conducted by the appropriately trained and credentialed staff from the vendor. 
The location of the study visit (home vs. RACC) will be captured in the study source. 
 
 
Blood draws will be performed by qualified personnel at the request of study staff. Research 
coordinators will never perform blood draws. Blood samples may be drawn from arterial or central lines 
or PICC catheters and will not be drawn from peripheral lines, except at the time of placement of a new 
peripheral line. Blood samples for research purposes will be drawn alongside clinical samples, wherever 
possible. Alternatively, lab results obtained close to study time points for clinical purposes may be used, 
if available. 
Unscheduled Visits 
Additional unscheduled assessments may be performed at the discretion of the investigator. 
 
Early Termination Visit 
In the event a subject terminates the study prior to completion of the 14 day follow up period, the Early 
Termination (ET) visit should be scheduled as soon as possible.  The early termination visit procedures 
are outlined in Appendix 2 and mirror the day 14 visit but without research archive sample collection. 
 
VII. Adverse Events and Toxicity Management 
Definition of Adverse Events, Adverse Reactions and Serious Adverse Events 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered a 
medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. AEs may 
also include pre- or post-treatment complications that occur as a result of protocol specified procedures, 
overdose, drug abuse/misuse reports, or occupational exposure. Preexisting events that increase in 
severity or change in nature during or as a consequence of participation in the clinical study will also be 
considered AEs. 
An AE does not include the following: 
• 
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
• 
The condition that led to the procedure may be an adverse event and must be reported 


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• 
Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
Screening visit that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
• 
elective surgery, social and/or convenience admissions) 
• 
Overdose without clinical sequelae  
• 
Any medical condition or clinically significant laboratory abnormality with an onset date before 
the consent form is signed and not related to a protocol-associated procedure is not an AE. It is 
considered to be pre-existing and should be documented on the medical history case report 
form (CRF) 
 
Serious Adverse Event 
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following: 
• 
Death 
• 
Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe) 
• 
In-patient hospitalization or prolongation of existing hospitalization 
o Hospitalization for an elective procedure is not considered an SAE for the purposes of 
this study 
• 
Persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
A medically important event or reaction: such events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the subject or may require intervention 
to prevent one of the other outcomes constituting SAEs. Medical and scientific judgment must 
be exercised to determine whether such an event is a reportable under expedited reporting 
rules. 
 
Examples of medically important events include: 
- 
intensive treatment in an emergency room or at home for allergic bronchospasm 
- 
blood dyscrasias or convulsions that do not result in hospitalization 
- 
development of drug dependency or drug abuse 
 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or Serious 
Adverse Events 
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. However, 
laboratory abnormalities (e.g., clinical chemistry, hematology) that require medical or surgical 
intervention or lead to investigational medicinal product (IMP) interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or 
other abnormal assessments (e.g., vital signs) that are associated with signs and/or symptoms must be 
recorded as an AE or SAE if they meet the definition of an AE or SAE as described above.   If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin). 
 
Assessment of Adverse Events and Serious Adverse Events 
The investigator or qualified sub investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 


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and assessments. 
 
Assessment of Causality for Study Drugs and Procedures 
Assessment of relatedness will be made by a physician investigator with respect to the stage of the trial 
that the subject is in (screening, on-treatment, post-treatment) and further with respect to whether the 
event was related to Lambda/placebo where applicable. The following will be used to assess the 
relationship of the adverse event to the use of Lambda/placebo: 
 
1. Probably related 
- 
Event or laboratory test abnormality, with reasonable time relationship to drug intake  
- 
Unlikely to be attributed to disease or other drugs  
- 
Response to withdrawal clinically reasonable  
- 
Rechallenge not required 
2. Possibly related 
- 
Event or laboratory test abnormality, with reasonable time relationship to drug intake  
- 
Could also be explained by disease or other drugs   
- 
Information on drug withdrawal may be lacking or unclear 
 
3. Unlikely related 
- 
Event or laboratory test abnormality, with a time to drug intake that makes a relationship 
improbable (but not impossible)   
- 
Disease or other drugs provide plausible explanations 
 
4. Unrelated 
- 
Event assessed as having no reasonable possibility of being related to study drug 
 
5. Unclassified 
- 
Event or laboratory test abnormality  
- 
More data for proper assessment needed, or additional data under examination 
- 
Report suggesting an adverse reaction  
- 
Cannot be judged because information is insufficient or contradictory  
- 
Data cannot be supplemented or verified 
 
 
The relationship of an AE or SAE to study procedures (e.g., invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations: 
- 
No: Evidence exists that the adverse event has an etiology other than the study procedure 
 
- 
Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture) 
 
Extra consideration will be made regarding fever as an adverse event.  Fever is noted as a less common 
(<10%) potential side effect of Lambda, as well as a common expected symptom of COVID-19 infection.  
To best distinguish between fever associated with COVID-19 and Lambda treatment emergent or 
exacerbation of fever, study investigators will adjudicate suspected causality by reviewing time elapsed 


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between Lambda administration and onset/exacerbation of fever.  We acknowledge that this distinction 
cannot be made with complete accuracy. 
Assessment of Severity 
The severity grading of AEs will be assessed as Grade 1, 2, 3, 4, or 5 according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be found 
at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 8.5x11.pdf. 
 
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality. 
 
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed above. 
 
Reporting of Adverse Events 
The Principal Investigator (Dr. Raymond Chung) will be immediately notified of any adverse events. 
These will be documented in detail in the Adverse Events Tracking Log and submitted each year at the 
time of continuing review. Adverse events will be reported to the PHRC as described in the PHRC policy 
on Unanticipated Problems Involving Risks to Subjects or Others. 
VIII. Statistical Considerations 
Data Analysis 
All subjects will be included in the primary intention-to-treat analysis as well as the analyses of 
secondary outcomes and observed safety events.  The primary analysis will compare the proportion of 
subjects who are PCR negative at post-treatment Day 7 between subjects receiving Lambda vs. standard 
of care using Fisher’s exact test, and the difference between the treatment groups will be estimated 
using the difference in proportions. Subjects who die during follow up will be considered not to have 
achieved viral clearance, for the purposes of statistical analysis. Subjects who are lost to follow up will 
be removed from the analysis, since we consider loss to follow up as being unrelated to our outcome of 
interest. A key secondary analysis will compare the mean change in quantitative PCR from baseline to 
Day 7 in the treatment group and placebo group using a two-sample t-test. This analysis will likely have 
more power to detect a treatment effect compared to the PCR negative analysis since a continuous 
outcome will be used. 
Additional secondary analyses will compare the proportion of subjects who are PCR negative at post-
treatment Days 3, 5, and 14 and the mean magnitude of viral load reduction using the same approach at 
Day 7.  In addition, the time to PCR negativity will be compared using a log-rank test, and the difference 
between the treatment groups will be estimated using a Cox proportional hazards model.  To compare 
changes in symptom scores over time, a linear mixed model will be used to estimate the difference in 
the change with time between the two treatment groups at each of the post-baseline timepoints.  For 
safety endpoints, the proportion of subjects who experience each type of event will be compared 
between the Lambda vs. standard of care groups at Day 14 using Fisher’s exact test. Additional analysis 


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will compare proportions of hospitalized subjects who experience progression of disease as reflected by 
transfer to ICU or intubation, and the length of stay among hospitalized subjects will be compared using 
the log-rank test. Subjects who die will be analyzed as having a length of stay censored at one day past 
the last follow-up date. Hence, subjects who die will be considered as having a greater length of stay 
than subjects who remain alive for the duration of the study. Statistical analyses will be completed using 
SAS (SAS Institute 2011, Version 9.4, Cary, NC).  
Sample size and power calculation: 
This is a pilot study to assess the ability of Lambda to increase the proportion of subjects with PCR 
negativity at Day 7 compared to standard of care (placebo group) as a primary endpoint.  We anticipate 
that no subjects in the standard of care arm will be PCR negative at Day 7, and we anticipate that 50% of 
subjects in the Lambda arm will be PCR negative at Day 7.   
 
The treatment will be considered for further study if the proportion of subjects who achieve PCR 
negativity will be 30% higher at Day 7 in the Lambda arm compared to the standard of care arm.  This 
would correspond to 3/10 subjects in the Lambda arm if 0/10 subjects were PCR negative in the 
standard of care (placebo) arm.  Assuming 50% of subjects will be PCR negative, we have a 94% chance 
of observing 3 or more subjects who are PCR negative at Day 7.   This shows that our sample size of 10 
subjects per group is sufficient to have a reasonable chance to support further study given the proposed 
treatment effect.   Additionally, demonstration of a reduction in viral load relative to the placebo arm 
will be factored into decisions to pursue further trials. 
 
 


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IX. 
References 
 
1. Read SA, Wijaya R, Ramezani-Moghadam M, Tay E, Schibeci S, Liddle C, Lam VWT, Yuen L, Douglas MW, 
Booth D, George J, Ahlenstiel G. Macrophage Coordination of the Interferon Lambda Immune Response. 
Front Immunol. 2019 Nov 19; 10:2674. 
2. Mordstein M, Neugebauer E, Ditt V, Jessen B, Rieger T, Falcone V, et al. Lambda interferon renders 
epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol. 
2010;84:5670–7. 
3. Loutfy MR et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: A 
preliminary study. JAMA 2003 Dec 24/31; 290:3222-8. 
 


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Appendices 
 
Appendix 1: Investigator signature page 
Appendix 2: Study procedures table for hospitalized subjects (schedule of events) 
Appendix 3: GSI Grading scale for Severity of Adverse Events and Lab Abnormalities 
Appendix 4: Pregnancy precautions/definition of Woman of Childbearing potential/contraceptive 
requirements 
Appendix 5: Symptom Questionnaire 
 
Appendix 6: Patient Home Sputum Collection Instructions


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Appendix 1: Investigator Signature Page 
Investigator Signature Page 
MASSACHUSETTS GENERAL HOSPITAL 
55 FRUIT STREET 
BOSTON, MA 02114 
STUDY ACKNOWLEDGEMENT 
A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Pegylated Interferon Lambda vs. 
Standard Supportive Care in Subjects Infected with COVID-19 
Protocol Version 1.9 dated 07 June 2021 
INVESTIGATOR STATEMENT 
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 a 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 Massachusetts General Hospital.   I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
___________________________________ 
_______________________________ 
Principal Investigator Name (Printed)  
Signature 
____________________________________ 
_______________________________ 
Date 
 
Site Name/Location 
Raymond Chung, MD
Massachusetts General Hospital
Raymond T Chung (Jun 7, 2021 16:59 EDT)
Raymond T Chung
Jun 7, 2021




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Appendix 3: GIS Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities 
 
https://www.fda.gov/media/73679/download 
 
 


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Appendix 4: Pregnancy Precautions and Definitions 
The below listed methods meet the requirements for contraception as per the CTFG guidance. 
If female, subject must be either postmenopausal defined as:  
• 
Age ≥ 55 years with no menses for 12 or more months without an alternative medical cause.  
• 
Age < 55 years with no menses for 12 or more months without an alternative medical cause 
AND an FSH level > 40 IU/L.  
OR  
• 
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy  or 
hysterectomy).  
Agreeing to practice one effective method of birth control while receiving study drug (as outlined in the 
subject information and consent form or other subject information documents), starting with Day 1 and 
for at least 30 days after stopping study drug.  
• 
Bilateral tubal occlusion/ligation.  
• 
Vasectomized partner(s), provided the vasectomized partner has received medical assessment 
of the surgical success and is the sole sexual partner of the WOCBP trial participant.  
• 
Hormone-releasing Intrauterine device (IUD)  
• 
Hormone-releasing Intrauterine hormone-releasing system (IUS)  
• 
Male or female condom with spermicide (male and female condom must not be used together)  
• 
Diaphragm with spermicide  
• 
Cervical cap with spermicide  
• 
Contraceptive sponge with spermicide  
• 
True abstinence:  
o Refraining from heterosexual intercourse when this is in line with the preferred and 
usual lifestyle of the subject (periodic abstinence, e.g., calendar, ovulation, 
symptothermal, post-ovulation methods, “rhythm method,” or pre-ejaculation 
withdrawal, are not acceptable forms of contraception).  
o Sexually active with female partners only


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Appendix 5: Symptom Questionnaire 
Symptom questionnaire will be available as a paper tool as well as an electronic tool (RedCap survey).  Patients may 
complete electronically and submit to study team (preferably via RedCap, email alternative option) or have the 
option to complete via interview and answers will be dictated onto the paper form by a caregiver, member of the 
study team or member of the clinical team.  Subjects who cannot read English will complete the questionnaire via 
interview with study team and interpreter present.   
 
 
 
 


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Appendix 6: Patient Home Sputum and Saliva Collection Instructions 
 


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