Clinical trial NCT04331899
Conditions: COVID-19
Keywords: Coronavirus
Sponsor: Stanford University
Start date: 2020-04-25; Completion date: 2021-05-06
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of a single dose of subcutaneous injections of 180 ug of Peginterferon Lambda-1a, compared with placebo in reducing the duration of viral shedding of SARS-CoV-2 virus in patients with uncomplicated COVID-19 disease.

Detailed description:
Patients will attend up to 9 study visits over a period of up to 28 days.

Arms: arm 1: Study participants assigned to study drug will receive a single subcutaneous dose of Peginterferon Lambda-1a in addition to standard of care treatment. arm 2: Study participants will receive a placebo along with the standard of care treatment.
Interventions: intervention 1: Peginterferon Lambda-1a intervention 2: Placebo
Intervention descriptions: intervention 1: Peginterferon Lambda-1a (180 ug subcutaneous injection) single dose along with Standard of Care intervention 2: Placebo subcutaneous injection along with Standard of Care Treatment for COVID-19 Infection

Protocol documents:
Prot_ICF_002.pdf: 
“A Phase 2 Randomized, Single-Blind Study of a Single Dose of Peginterferon 
 
Lambda-1a (Lambda) Compared with Placebo in Outpatients with Mild COVID-19” 
 
 
ClinicalTrials.gov registration Number: NCT04331899 
 
 
Study Document: Protocol (Version 5.0, August 10th, 2020) 
 
 
Study Phase: 2b 
 
Product Name: Peginterferon Lambda-1a 
 
IND Number: 
 
 
Sponsor: Stanford University 
 
 
Principal Investigator: 
Upinder Singh, M.D. 
Stanford University 


Table of Contents 
PROTOCOL TEAM ROSTER .................................................................................................................................. 4 
1. PROTOCOL SYNOPSIS ...................................................................................................................................... 7 
2 
BACKGROUND ............................................................................................................................................. 11 
2.1 
SCIENTIFIC RATIONALE .................................................................................................................... 11 
2.2. SAFETY AND TOLERABILITY OF LAMBDA ...................................................................................... 13 
2.3 DOSAGE JUSTIFICATION ..................................................................................................................... 14 
2.4 RISK/BENEFIT ASSESSMENT ............................................................................................................. 14 
3. STUDY OBJECTIVES ........................................................................................................................................ 14 
4. STUDY DESIGN .................................................................................................................................................. 14 
5. CRITERIA FOR EVALUATION......................................................................................................................... 15 
6. SELECTION AND ENROLLMENT OF SUBJECTS ...................................................................................... 15 
6.1 STUDY POPULATION ............................................................................................................................................................................. 15 
6.2 INCLUSION CRITERIA ............................................................................................................................................................................ 15 
6.3 EXCLUSION CRITERIA ........................................................................................................................................................................... 15 
6.4. IDENTIFICATION AND RECRUITMENT OF PARTICIPANTS ....................................................................................................... 17 
6.5. PHONE SCREENING INTERVIEW ..................................................................................................................................................... 17 
6.6. STUDY ENROLLMENT PROCEDURES AND BASELINE EVALUATION ................................................................................. 17 
6.6. POTENTIAL LIMITATIONS ON RECRUITMENT AND MITIGATION STRATEGIES ............................................................... 17 
7. CONCURRENT MEDICATIONS....................................................................................................................... 18 
7.1 ALLOWED MEDICATIONS AND TREATMENTS ................................................................................................................................ 18 
7.2 PROHIBITED MEDICATIONS AND TREATMENTS .......................................................................................................................... 18 
8. STUDY TREATMENTS ...................................................................................................................................... 18 
8.1 METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................................................. 18 
8.2 BLINDING .................................................................................................................................................................................................... 18 
8.3 FORMULATION OF TEST AND CONTROL PRODUCTS ................................................................................................................. 18 
8.3.1 Formulation of test product .................................................................................................................. 18 
8.3.2 Formulation of control ........................................................................................................................... 18 
8.3.3 Packaging and labeling ........................................................................................................................ 18 
8.4 STUDY DRUG SUPPLY, DOSAGE, ADMINISTRATION, AND STORAGE .................................................................................. 19 
8.4.1 Supply of study drug at the site ........................................................................................................... 19 
8.4.2 Dosage .................................................................................................................................................... 19 
8.4.3 Dispensing .............................................................................................................................................. 19 
8.4.4 Administration instructions ................................................................................................................... 19 
8.4.5 Storage ................................................................................................................................................... 19 
8.4.6 Study drug accountability ..................................................................................................................... 20 
9 SUBJECT MANAGEMENT ................................................................................................................................ 20 
9.1 SUBJECT FOLLOW-UP .......................................................................................................................................................................... 20 
9.2 CLINICAL LABORATORY MEASUREMENTS ..................................................................................................................................... 21 
9.3 VIROLOGIC ASSESSMENTS ................................................................................................................................................................. 21 
9.4 BIOBANKING/IMMUNE PHENOTYPING ............................................................................................................................................. 22 
9.5 REIMBURSEMENT OF SUBJECTS ...................................................................................................................................................... 22 
9 
ADVERSE EVENT REPORTING AND DOCUMENTATION ................................................................... 22 
10.1. MONITORING AND REPORTING OF ADVERSE EVENTS ...................................................................................................... 22 
10.1.1. 
Definitions ..................................................................................................................................... 22 
10.1.2. 
Identification of Adverse Events ............................................................................................. 23 
10.1.3. 
Reporting of Adverse Events ................................................................................................... 23 
Table 1. Guidelines for reporting adverse events ................................................................................. 23 
10 
WITHDRAWAL OF SUBJECTS AND MANAGEMENT OF PROTOCOL VIOLATIONS ............... 24 


11 DATA SAFETY MONITORING ........................................................................................................................ 25 
12 STATISTICAL METHODS AND CONSIDERATIONS ................................................................................. 27 
13. DATA COLLECTION, RETENTION AND MONITORING .......................................................................... 29 
14. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ..................................................... 30 
15. REFERENCES .................................................................................................................................................. 32 
APPENDIX 1. INFORMED CONSENT ................................................................................................................. 34 
APPENDIX 2. SCHEDULE OF EVENTS ............................................................................................................ 46 
APPENDIX 3. DAIDS TOXICITY TABLE (CLARIFICATION AUG 2017) ...................................................... 47 
Laboratory Values ................................................................................................................................................. 1 


Protocol Team Roster 
 
Investigators 
 
Upinder Singh, MD, Professor, Stanford University, Division of Infectious Diseases and 
Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Phone Number: 1-650-723-4045 
Email: usingh@stanford.edu 
 
Julie Parsonnet, MD, Professor, Stanford University, Division of Infectious Diseases and 
Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Phone Number: 1-650-725-4561 
Email: parsonnt@stanford.edu 
Jason Andrews, MD, Associate Professor, Stanford University, Division of Infectious Diseases 
and Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Phone Number: 
Email: jandr@stanford.edu 
 
Prasanna Jagannathan, MD, Assistant Professor, Stanford University, Division of Infectious 
Diseases and Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Phone Number: 1-650-724-5343 
Email: prasj@stanford.edu 
 
Dean Winslow, Professor, Stanford University, Division of Hospital Medicine and of Infectious 
Diseases and Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Phone Number: 650-723-7912 
Email: dwinslow@stanford.edu 
 
Philip Grant, MD, Assistant Professor, Stanford University, Division of Infectious Diseases and 
Geographic Medicine 
Address: CCSR Building, Rm 1155b, 269 Campus Dr, Stanford, CA 94305 
Phone Number: 1-650-723-7912 
Email: asbhatt@stanford.edu 
 
Ami Bhatt, Assistant Professor, Stanford University, Division of Hematology 
Address: Lane Building, Rm S-101, 300 Pasteur Dr, Stanford, CA 94305 
Email: asbhatt@stanford.edu 
 
Benjamin Pinsky, Associate Professor, Stanford University, Department of Pathology and 
Medicine (Infectious Diseases) 
Address: 300 Pasteur Dr, Rm L235, MC 5324, Stanford, CA 94305 


Phone Number: 650-498-5575 
Email: bpinsky@stanford.edu 
 
Manisha Desai, Professor, Stanford University, Bioinformatics and Biomedical Data Sciences 
Address: 1070 Arastradero Road, Room 305, Palo Alto, CA 94304 
Phone Number: 650-725-1946 
Email: manishad@stanford.edu 
 
Haley Hedlin, Associate Director Clinical Trials Program, Stanford University, Quantitative 
Sciences Unit 
Address: 1070 Arastradero Road, Palo Alto, CA 94304 
Email: hedlin@stanford.edu 
 
Hector Bonilla, Clinical Assistant Professor, Division of Infectious Diseases and Geographic 
Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Phone Number:  650-736-5200 
Email: hbonilla@stanford.edu 
 
Jenna Bollyky, Clinical Assistant Professor, Division of Primary Care and Population Health 
Address: Stanford Express Care, 211 Quarry Rd Ste 102, MC 5989, Palo Alto, CA 94304 
Phone Number:  650-736-5211 
Email: jbollyky@stanford.edu 
 
Joelle Rosser, Postdoctoral Medical Fellow, Division of Infectious Diseases and Geographic 
Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Email: jrosser@stanford.edu 
 
Christiaan Robert de Vries, Postdoctoral Medical Fellow, Division of Infectious Diseases and 
Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Email: devries2@stanford.edu 
 
Karen Jacobson, Medical Fellow, Division of Infectious Diseases and Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Email: kjacobs@stanford.edu 
 
Nicholas Degner, Medical Fellow, Division of Infectious Diseases and Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Email: ndegner@stanford.edu 
 
Orlando Quintero, Medical Fellow, Division of Infectious Diseases and Geographic Medicine 
Address: Lane Building, Suite 154, 300 Pasteur Dr, Stanford, CA 94305 
Email: carloqui@stanford.edu 


Jennifer Newberry, Assistant Professor of Emergency Medicine 
Address: 900 Welch Road, Suite 350, MC5768, Stanfordm CA 94305 
Email: newberry@stanford.edu 
 
Savita Kamble 
Address: 100 Welch Road Suite 202, Stanford, CA 94305 
Phone Number: 1-650-736-7388 
Email: skamble@stanford.edu 


1. PROTOCOL SYNOPSIS 
 
Study Title 
A Phase 2 Randomized, Single-Blind Study of a Single Dose of 
Peginterferon Lambda-1a (Lambda) Compared with Placebo in 
Outpatients with Mild COVID-19 
Sponsor 
Stanford University 
Description 
Single-blind randomized controlled trial 
Study Objectives 
1. To evaluate the efficacy of subcutaneous (SC) injections of a 
single dose of 180 mcg of Peginterferon Lambda-1a compared 
with placebo in reducing the duration of viral shedding of SARS- 
CoV-2 virus in patients with uncomplicated COVID-19 disease. 
2. To evaluate the efficacy of subcutaneous injections of a single 
dose of 180 mcg of Peginterferon Lambda-1a compared with 
placebo, in reducing SARS-CoV-2 viral loads and the duration of 
symptoms, hospitalizations, or ED visits in patients with 
uncomplicated COVID-19 disease. 
3. To evaluate the safety and tolerability of subcutaneous injections 
of a single dose of 180 mcg of Peginterferon Lambda-1a 
compared with placebo. 
Scientific rationale 
Recently, a novel corona virus has been identified as the causative 
pathogen of a rapidly spreading infection associated with pneumonia 
and severe acute respiratory syndrome. COVID-19, originally identified 
in Wuhan in the Hubei province of China, has now spread across the 
globe and has been declared by the WHO as a global pandemic. 
While the majority of infected patients display mild symptoms if any, 
death rates of up to 4% due to development of severe acute 
respiratory syndrome (COVID-19 SARS), have been reported in 
patients with co-morbid conditions and in the elderly population. With 
the unprecedented global health and economic threats imposed by 
COVID-19, development of therapies capable of suppressing or 
eradicating this emerging pathogen has become an urgent unmet 
medical need. 
The interferon (IFN) system represents a major element of the innate 
immune response against viral infections. Virus-induced IFN is a 
complex mixture of biologically active molecules, which includes type I 
and type III IFNs. Binding of type I IFN and type III IFN to their cognate 
receptor complexes triggers signaling cascades that result in the 
activation of a large number of genes, many of which encode antiviral 
proteins. Type III IFN (i.e. IFN-ȜXVHVDGLstinct receptor complex 
(IL28R) for signaling which appears to be expressed on only a few cell 
types, including epithelial cells in the respiratory and gastrointestinal 
tract, resulting in demonstrated improved tolerability profile. Based on 
IFN-Ȝ
VPRUHOimited receptor distribution and therefore expected 
improved tolerability profile, a pegylated form of recombinant 
Peginterferon Lambda-1a (Lambda) has been developed for the 
treatment of chronic viral hepatitides such as hepatitis C, hepatitis B 
and recently also hepatitis D. Lambda has so far been administered in 
over 3000 patients in multiple clinical trials, showing a good safety and 
tolerability profile with varying degrees of antiviral efficacy. The 
presence of IL28R in the epithelial cells of the lungs and respiratory 
tract has also evoked research on the potential role of IFN-Ȝ in 


 
possible mitigation of viral induced respiratory infections. Indeed, 
studies in animal models have shown that IFN-ȜLQKLELWVUHSOLFDWLRQRI 
respiratory viruses such as influenza as well as the SARS-coronavirus. 
The use of Lambda for treatment of COVID-19 infection has not yet 
been explored. 
Participants and 
Sample Size 
We will enroll 120 patients ages 18-64 with confirmed COVID-19 
infection diagnosed by molecular diagnostic assay. 
Clinical Site 
The study will be conducted at the Stanford University School of 
Medicine 
Study duration 
The total anticipated duration of the study for each patient is up to 28 
days, with optional long-term follow-up to 10 months following 
recruitment. The planned duration of the entire study is 12 months. 
Selection Criteria 
Inclusion Criteria 
1. Age  18 years and  75 years at the time of the assessment 
2. Able and willing to understand the study, adhere to all study 
procedures, and provide written informed consent 
3. Diagnosis of COVID-19 disease: 
a. If symptomatic, presence of mild to moderate 
symptoms without signs of respiratory distress, with 
FDA-cleared molecular diagnostic assay positive for 
SARS-CoV-2 within 72 hours from swab to the time of 
commencing informed consent: 
b. If asymptomatic, initial diagnosis of SARS-CoV-2 
infection with positive FDA-cleared molecular diagnostic 
assay obtained no more than 72 hours from initial swab 
to the time of commencing informed consent 
Exclusion Criteria: 
1. Patients who are hospitalized for inpatient treatment or 
currently be evaluated for potential hospitalization at the time of 
initiation of informed consent 
2. Patients with a known allergy to Peginterferon Lambda-1a or 
any component thereof 
3. Display symptoms of respiratory distress (Respiratory rate >20, 
room air oxygen saturation of <94%.) 
4. Participation in a clinical trial with or use of any investigational 
agent within 30 days before screening 
5. Treatment with interferons within 12 months before screening 
6. Previous use of Peginterferon Lambda-1a 
7. History or evidence of any intolerance or hypersensitivity to 
IFNs or other substances contained in the study medication. 
8. Female patients who are pregnant or breastfeeding. Male 
patients must confirm that their female sexual partners are not 
pregnant. 
9. Current or previous history of decompensated liver disease 
(Child-Pugh Class B or C) or hepatocellular carcinoma 
10. Co-infection with human immunodeficiency virus (HIV) 
11. Any of the following abnormal laboratory test results at 
screening: 
 


 
c. Platelet count <75,000 cells/mm3 
d. Absolute neutrophil count <800 cells/mm3 
e. Hemoglobin <11 g/dL for women and <12 g/dL for men 
f. 
6HUXPFUHDWLQLQHFRQFHQWUDWLRQî8/1DQGFUHDWLQLQH 
clearance (CrCl) < 50 mL/min by Cockcroft-Gault 
12. History of liver disease other than viral hepatitis 
13. Prior history or current evidence of any of the following: 
a. Immunologically mediated disease that is uncontrolled 
b. Retinal disorder or clinically relevant ophthalmic disorder 
c. Any malignancy (excluding non-melanoma skin cancer) 
within 5 years before screening 
d. Cardiomyopathy or significant ischemic cardiac or 
cerebrovascular disease. 
e. Chronic uncontrolled pulmonary disease 
f. 
Pancreatitis 
g. Severe or uncontrolled psychiatric disorder 
h. Active seizure disorder 
i. 
Bone marrow or solid organ transplantation 
14. Other significant medical condition that may require 
intervention during the study 
15. Concurrent use of any of the following medications: 
a. Therapy with an immunomodulatory agent 
b. Current use of heparin or Coumadin 
c. Received blood products within 30 days before study 
randomization 
d. Use of hematologic growth factors within 30 days before 
study randomization 
e. Systemic antibiotics, antifungals, or antivirals for treatment 
of active infection within 24 hours before study 
randomization 
f. 
Any prescription or herbal product that is not approved by 
the investigator 
g. Long-term treatment (> 2 weeks) with agents that have a 
high risk for nephrotoxicity or hepatotoxicity unless it is 
approved by the medical monitor 
h. Receipt of systemic immunosuppressive therapy within 3 
months before screening 
Treatment 
assignment 
Study participants will be randomly assigned 1:1 to a single 
subcutaneous dose of Peginterferon Lambda-1a or normal saline 
placebo, along with standard of care 
Treatment arms 
1. Peginterferon Lambda-1a (Lambda), 180 mcg, administered as 
subcutaneous injection 
2. Normal saline, 0.45 ml administered as subcutaneous injection 
Dose Justification 
A single dose PK of Peginterferon Lambda-1a given subcutaneously 
has been assessed in four Phase 1 studies in healthy subjects and in 
two phase 2 studies in subjects with HCV. In these studies, Lambda 
exhibited dose-proportional PK over the dose range of 80 to 240 mcg. 


 
Phase 2 studies established the optimal dose for virologic suppression 
and minimizing treatment-related adverse events for hepatitis C at 180 
mcg; this dose is also currently being used in hepatitis D trials. 
Screening, 
enrolment, 
randomization, and 
follow-up of 
participants 
Patients will be screened, and a baseline physical examination and 
laboratory assessment performed. Eligible patients will be randomized 
1:1 to receive Lambda 180 mcg SC (intervention arm) or normal saline 
placebo (control arm) (Day 0). Patients will complete an at-home 
symptom questionnaire on each day of follow-up, including in-home 
assessments of temperature and O2 saturation and collection of 
anterior nare swabs and stool. Patients will then be seen at follow-up 
visits at Day 1r1, 3r1, 5r1, 7r1, 10r1, 14r1, 21r1, and 28r1. At each 
visit, vital signs (temperature, blood pressure, pulse rate per minute, 
breath rate per minute and oxygen saturation), will be performed. 
Efficacy of Lambda will be assessed by analysis of COVID-19 in 
respiratory secretions obtained by oropharyngeal swabs collected 
consecutively at each visit, and by anterior nare swabs collected daily 
at home. Clinical laboratory measurements (CBC, chemistries, LFTs) 
will be performed at enrollment and Days 5r1, and 14r1. Additionally, 
~25 mL peripheral blood will be collected from study participants at 
enrollment and at Days 5r1, 14r1, and 28r1 for processing and 
cryopreservation into a specimen biobank. Safety and tolerability of 
Lambda will be assessed by adverse event (AE) monitoring, vital signs 
assessment and clinical laboratory tests. Patients will reach the end of 
study at day 28r1 of follow-up. 
Primary Outcome 
Duration of viral shedding of SARS-CoV-2 virus 
Safety monitoring 
Frequency of adverse events and serious adverse events will be 
analyzed in all study participants. 
Planned interim 
analysis 
An interim analysis will be performed and analyzed by a data and 
safety and monitoring board after 50% of study participants are 
enrolled and have completed 1 day of follow-up following study drug 
administration. 
Statistical Analysis 
and Sample Size 
Considerations 
We will evaluate the intention-to-treat (ITT) population, defined as the 
original treatment assignment groups after randomization, for the 
primary efficacy analysis. We will analyze the per-protocol group as 
supportive evidence for the primary efficacy analysis. 
Approximately 120 patients with COVID-19 infection are planned to be 
enrolled and randomized, and we conservatively assume that 90% of 
participants will complete follow-up. The primary endpoint will be 
assessed in all patients. We assume that the mean duration of 
virologic shedding is 14 days in individuals receiving placebo, with a 
standard deviation of 4 days (Zhou et al, Lancet 2020). With 60 
patients randomized per arm, we will have 80% power to detect a 
minimum 50% reduction in virologic shedding in participants receiving 
Lambda. 


2 
BACKGROUND 
 
2.1 
SCIENTIFIC RATIONALE 
 
2.1.1 
COVID-19, a novel coronavirus with an urgent need for novel therapeutics to 
decrease viral shedding and transmission 
 
Recently, a novel coronavirus has been identified as the causative pathogen of a rapidly 
spreading infection associated with pneumonia and severe acute respiratory syndrome. COVID- 
19, originally identified in Wuhan, in the Hubei province of China[1], has now spread across the 
globe and has been declared by the WHO as a global pandemic. While the majority of infected 
patients display mild symptoms if any, death rates of up to 4% due to development of severe 
acute respiratory syndrome (COVID-19 SARS), have been reported in patients with co-morbid 
conditions and in the elderly population[2]. With the unprecedented global health and economic 
threats imposed by COVID-19, development of therapies capable of suppressing or eradicating 
this emerging pathogen has become an urgent unmet medical need. 
 
In a recent report, COVID-19+ patients presenting with mild symptoms had a median viral load 
of 1 X 106 copies in oropharyngeal specimens at diagnosis (an average of 2-4 days post 
symptom onset), and this declined in the subsequent period and correlated with resolution of 
symptoms[3]. All patients had evidence of viral shedding in the oropharynx 7 days following 
symptom onset; by day 14, 22% of patients had evidence of oropharyngeal shedding. In 
contrast, nearly 80% of subjects had evidence of viral shedding in both sputum and stool 
specimens at 14 days, in many patients outlasting the resolution of symptoms and despite the 
development of IgM and IgG seroconversion to the spike protein of SARS-CoV-2. These tissue- 
specific differences in the duration of viral shedding suggest prolonged transmissibility of SARS 
CoV-2 in recovered individuals. Novel therapeutics that can shorten this duration of viral 
shedding could be critically important in reducing transmission. 
 
2.1.2 
Peginterferon Lambda-1a, a broad-spectrum antiviral 
 
Peginterferon Lambda-1a (hereafter referred to as Lambda) is 
a covalent conjugate of human recombinant non-pegylated 
interferon lambda and a 20-kDa linear PEG chain. Lambda is 
a type III interferon (i.e. IFN-ȜWKDWVWLPXODWHVLQQDWHLPPXQH 
responses that are critical for the development of host 
protection during viral infections[4]. Similar to type 1 
interferons (including IFN-a), binding of IFN-ȜWRLWVFRJQDWH 
receptor complexes triggers signaling cascades, including 
those mediated by the JAK/STAT (Janus kinase/signal 
transducer and activator of transcription) pathway, that result 
in the activation of a large number of genes, many of which 
encode antiviral proteins (Fig 1)[5]. However, IFN-ȜXVHVD 
distinct receptor complex (IL28R) for signaling which appears 
to be expressed on only a few cell types, including epithelial cells in the respiratory and 
gastrointestinal tract[4]. Based on IFN-Ȝ
VFRPSDUDEOHDQWLYLUDODFWLYLW\PRUHOLPLWHGUHFHSWRU 
distribution, and improved tolerability profile in comparison to IFN-a, a pegylated form of 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig. 1. Interferon lambda and type 
1 interferons induce similar antiviral 
response 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig. 2 In a study of patients with SARS-CoV, patients given IFN-D and corticosteroids had improved 
clinical outcomes compared with patients given corticosteroids alone. 
recombinant interferon lambda (Lambda) was developed for the treatment of chronic viral 
hepatitides[6, 7]. 
 
 
Lambda was previously investigated by Bristol-Myers Squibb (BMS) for the treatment of chronic 
hepatitis B (HBV) and C (HCV) virus infection. This development was discontinued in 2014 
based on the rapidly evolving landscape of chronic HBV and HCV treatment using non- 
interferon-based regimens, and not due to any new safety or efficacy findings in clinical studies. 
Because of the broad-spectrum antiviral activities of Lambda and fewer side effects of Lambda 
compared with pegylated IFN alfa-2a in HCV and HBV clinical studies, Eiger 
BioPharmaceuticals is investigating Lambda in the treatment of hepatitis D virus (HDV) 
infection, licensing worldwide rights to Lambda from BMS. Lambda has so far been 
administered to over 3743 patients in Phase 1, 2, and 3 clinical trials. 
 
2.1.3 
Interferons, including Lambda, for the Treatment of Respiratory Viruses 
including SARS-CoV 
Type 1 interferons have been shown to induce inhibition of respiratory coronavirus infection[8- 
10]. In in vitro experiments, type 1 interferons were also effective in inhibiting severe acute 
respiratory syndrome-coronavirus (SARS-CoV)[11]. In a study of patients with SARS-CoV, a 
synthetic formulation of IFN-a, when given with corticosteroids, was associated with reduced 
disease-associated impaired oxygen saturation and resolution of radiographic lung 
abnormalities, in comparison with a group receiving corticosteroids alone (Figure 2)[12]. These 
data suggest that therapeutic use of interferon may be efficacious in the treatment of SARS- 
CoV. 
 


The presence of IL28R in the epithelial cells of the 
lungs and respiratory tract has spurred research on 
the potential role of IFN-ȜLQSRVVLEOHmitigation of viral 
induced respiratory infections. In a murine model of 
influenza infection, IFN-ȜWUHDWPHQWSRVW-infection was 
associated with significantly lower mortality compared 
to mice treated with IFN-a, and this was associated 
with lower influenza viral loads[13]. Furthermore, 
studies in animal models have shown that IFN-ȜPD\ 
play an important role in restricting viral replication of 
SARS-coronavirus (Figure 3)[14]. The use of Lambda 
for treatment of COVID-19 infection has to our 
knowledge not yet been explored. 
 
2.2. SAFETY AND TOLERABILITY OF LAMBDA 
 
Approximately 3,743 subjects (including 237 healthy subjects; 3,276 subjects with HCV; 197 
subjects with HBV; and 50 subjects with HDV) have received Lambda to date. 
In a study of healthy volunteers administered a single s.c dose of lambda up to 7.5ug/kg, 
reversible dose-related increases in liver transaminases (ALT and AST) were seen in 5/17 
(29.4%) subjects. One of the 2 subjects treated with Lambda 7.5 ȝJNJ experienced reversible 
Grade 3 elevation of ALT. Transaminase elevations were not associated with increases in 
bilirubin. Mild dose-proportional decreases in serum fibrinogen were reported for 7 subjects. 
 
In a second healthy volunteer study, the most common AEs associated with s.c administration 
of lambda were abdominal pain and venous puncture site hematoma. All AEs were mild in 
intensity. One (3.3%) subject in the 180-ȝJ group had reversible Grade 1 elevations of AST and 
ALT not associated with clinical symptoms or bilirubin elevations. 
 
In a recently completed 48-week study of patients with chronic hepatitis delta virus infection, 
treatment with 180ug lambda, 7/14 (50.0%) patients reported a Grade 3 or 4 treatment-related 
AE with the following frequencies: injection site reaction 1 (7.1%), ALT or AST increase 5 
(35.7%), bilirubin increase 2 (14.3%), decreased neutrophil count 1 (7.1%), flu-like symptoms 
including fever/chills 9 (64.3%), arthralgia or myalgia 7 (50.0%) and fatigue 8 (57.1%). At the 
end-of-treatment ALT or AST >5xULN <10ULN was reported in a single patient. There were no 
increases in bilirubin >2xULN concurrent with increases in ALT or AST at the end-of-treatment. 
In other studies of lambda as a combination therapy for hepatitis B or C, clinically meaningful 
increases in total bilirubin occurred in 7.6% and 2.6% of patients dosed with Lambda/Ribavirin 
(RBV) and Lambda/RBV/Daclatasvir (DCV), respectively. Similarly, increases in serum ALT 
were noted in 6.2% and 3.7% of subjects on Lambda/RBV and Lambda/RBV/DCV, respectively. 
All increases were manageable with dose withholding, reduction, or discontinuation. 
Lymphopenia was not seen with any significance in prior Lambda studies of 48 weeks. Pyrexia 
occurred at a frequency of 9.9% of patients treated with the 180ug lambda + RBV. 
 
IFN-based treatment induces a variety of psychiatric adverse effects, including depression, 
manic condition, acute and chronic cognitive dysfunction, suicidal behavior, and relapse of 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig. 3 In comparison to wild-type mice, mice 
lacking IFN-O or IFN-D had impaired viral 
restriction against SARS-CoV. 


substance abuse. These effects are observed with a much lower frequency than seen with 
interferon alpha. 
 
Injection site reactions including erythema, irritation, inflammation, rash, eczema, pruritus, 
dryness, swelling, and hematoma have been reported (range: 2–15%). 
 
2.3 DOSAGE JUSTIFICATION 
The single dose PK of Peginterferon Lambda-1a given subcutaneously has been assessed in 
four Phase 1 studies in healthy subjects and in two phase 2 studies in subjects with HCV. In 
these studies, Lambda exhibited dose-proportional PK over the dose range of 80 to 240 mcg. 
Phase 2 studies established the optimal dose for virologic suppression and minimizing 
treatment-related adverse events for hepatitis C at 180 mcg; this dose is also currently being 
used in hepatitis D trials. 
2.4 RISK/BENEFIT ASSESSMENT 
As no known effective treatment is available for COVID-19, participants may have access to 
effective therapy in the trial. They may have the added benefit of reducing household and 
community transmission of the virus 
 
3. STUDY OBJECTIVES 
 
3.1 Primary objective 
Ɣ To evaluate the efficacy of subcutaneous injections of a single dose of 180 mcg of 
Peginterferon Lambda-1a compared with placebo in reducing the duration of viral 
shedding of SARS-CoV-2 virus in patients with uncomplicated COVID-19 disease. 
 
3.2. Secondary objectives 
 
Ɣ To evaluate the efficacy of subcutaneous injection of a single dose of 180 mcg of 
Peginterferon Lambda-1a compared with placebo, in reducing the duration of symptoms, 
hospitalizations, or ED visits in patients with uncomplicated COVID-19 disease. 
Ɣ To evaluate the safety and tolerability of subcutaneous injection of a single dose of 180 
mcg of Peginterferon Lambda-1a compared with placebo. 
 
4. STUDY DESIGN 
 
4.1 Study overview 
This is a single center, open-label randomized controlled trial. Each subject will be administered 
either a single subcutaneous dose of study drug or placebo. 
 
Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion 
criteria and none of the exclusion criteria will be entered into the study 
 
The following treatment regimens will be used: 
Ɣ Experimental treatment: Peginterferon Lambda-1a, 180 mcg subcutaneous 
Ɣ Control treatment: Normal saline, 0.45 mL subcutaneous 


The duration of participation for each individual will be up to 28 days, with optional follow-up to 
10 months following randomization. The planned duration for the entire study is 12 months. 
 
5. CRITERIA FOR EVALUATION 
 
5.1. Primary efficacy endpoint 
Ɣ Time to first of two consecutive negative oropharyngeal tests for SARS-CoV-2 by qRT- 
PCR. 
 
5.2. Secondary efficacy endpoints 
Ɣ SARS-CoV-2 RNA levels during follow-up 
Ɣ SARS-CoV-2 viral load area under the curve 
Ɣ Time to alleviation of all symptoms (fever, chills, cough, nasal congestion, muscle pains), 
defined as the time from initiation of treatment until all symptoms are rated as absent or 
mild in symptomatic patients 
Ɣ Incidence of emergency department visits or hospitalizations within 28 days of initiation 
of treatment 
 
5.3. Safety evaluations 
Ɣ Frequency of adverse events and serious adverse events by standardized DAIDS AE 
grading criteria (see appendix) 
 
6. SELECTION AND ENROLLMENT OF SUBJECTS 
 
6.1 Study Population 
Healthy adults ages 18-64 with molecularly confirmed SARS-CoV-2 infection (COVID-19 
disease) who are not currently admitted to a hospital will be eligible for participation in this 
study. 
 
6.2 Inclusion Criteria 
Patients must fulfill all of the following inclusion criteria to be eligible for the study: 
1. Age  18 years and  75 years at the time of the assessment 
2. Able and willing to understand the study, adhere to all study procedures, and provide 
written informed consent 
3. Diagnosis of COVID-19 disease: 
a. If symptomatic, presence of mild to moderate symptoms without signs of 
respiratory distress, with FDA-cleared molecular diagnostic assay positive for 
SARS-CoV-2 within 72 hours from swab to the time of commencing informed 
consent: 
b. If asymptomatic, initial diagnosis of SARS-CoV-2 infection with positive FDA- 
cleared molecular diagnostic assay obtained no more than 72 hours from initial 
swab to the time of commencing informed consent 
 
6.3 Exclusion Criteria 
1. Patients who are hospitalized for inpatient treatment or currently being evaluated for 
potential hospitalization at the time of initiation of informed consent 
2. Patients with a known allergy to Peginterferon Lambda-1a or any component thereof 


3. Display symptoms of respiratory distress (Respiratory rate >20, room air oxygen 
saturation of <94%.) 
4. Participation in a clinical trial with or use of any investigational agent within 30 days 
before screening 
5. Treatment with interferons (IFN) within 12 months before screening 
6. Previous use of Peginterferon Lambda-1a 
7. History or evidence of any intolerance or hypersensitivity to IFNs or other substances 
contained in the study medication. 
8. Female patients who are pregnant or breastfeeding. Male patients must confirm that 
their female sexual partners are not pregnant. 
9. Current or previous history of decompensated liver disease (Child-Pugh Class B or C) or 
hepatocellular carcinoma 
10. Co-infected with human immunodeficiency virus (HIV) 
11. Any of the following abnormal laboratory test results at screening: 
a. Platelet count <75,000 cells/mm3 
b. Absolute neutrophil count <800 cells/mm3 
c. Hemoglobin <11 g/dL for women and <12 g/dL for men 
d. 6HUXPFUHDWLQLQHFRQFHQWUDWLRQî8/1DQGFUHDWLQLQHFOHDUDQFH&U&O 
mL/min by Cockcroft-Gault 
12. History of liver disease other than viral hepatitis 
13. Prior history or current evidence of any of the following: 
a. Immunologically mediated disease that is uncontrolled 
b. Retinal disorder or clinically relevant ophthalmic disorder 
c. Any malignancy (excluding non-melanoma skin cancer) within 5 years before 
screening 
d. Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease. 
e. Chronic uncontrolled pulmonary disease 
f. 
Pancreatitis 
g. Severe or uncontrolled psychiatric disorder 
h. Active seizure disorder 
i. 
Bone marrow or solid organ transplantation 
14. Other significant medical condition that may require intervention during the study 
15. Concurrent use of any of the following medications: 
a. Therapy with an immunomodulatory agent 
b. Current use of heparin or Coumadin 
c. Received blood products within 30 days before study randomization 
d. Use of hematologic growth factors within 30 days before study randomization 
e. Systemic antibiotics, antifungals, or antivirals for treatment of active infection 
within 24 hours before study randomization 
f. 
Any prescription or herbal product that is not approved by the investigator 
g. Long-term treatment (> 2 weeks) with agents that have a high risk for 
nephrotoxicity or hepatotoxicity unless it is approved by the medical monitor 
h. Receipt of systemic immunosuppressive therapy within 3 months before 
screening 


6.4. Identification and Recruitment of Participants 
Flyers will be handed out to anyone being tested at Stanford testing sites (ER, drive-through 
tent, and occupational health), inviting them to call us should their test turn positive. We plan to 
have personnel at the testing sitHKDQGLQJRXWWKHIO\HUV&XUUHQWO\6WDQIRUG
VEORRGWHVWLQJVLWHV 
are identifying 30-50 newly diagnosed patients per day, the great majority of whom are not 
admitted. We are hoping to identify two COVID patients per day. If recruitment is slow in the first 
week, we will also advertise for newly diagnosed COVID cases on social media and hand out 
flyers at other screening sites as possible. We are also exploring the possibility of calling all 
COVID positive patients directly; this recruitment approach will be added to an amended 
protocol if we find it is possible. 
 
6.5. Phone Screening Interview 
Individuals who provide informed consent to be contacted after testing COVID-19 positive via 
the emergency department or occupational health will be contacted by phone. At the initial 
phone call, we will screen for inclusion and exclusion criteria; the clinical research coordinator 
(CRC) will fill out the RedCap screening form and determine if the subject is eligible and 
interested in participating. If the patient meets the criteria in the phone interview, we will invite 
them to the clinical research site (Stanford University) where we will review inclusion criteria 
again at the first patient visit. The subject will also be asked to bring in their proof of infection 
with them or to have it accessible in on-line form. 
 
6.6. Study Enrollment Procedures and Baseline Evaluation 
 
At the initial intake visit, screening eligibility criteria will be reviewed and confirmed. Subjects will 
undergo a standardized history, including time since symptom onset, and physical examination 
and have blood collected by phlebotomy. We will conduct the laboratory screening with 
complete blood count (CBC), comprehensive metabolic panel (CMP) and, in premenopausal 
women, beta HCG. Additional blood will be collected for biobanking. Inclusion/exclusion labs will 
be performed stat in the clinical lab. Participants will be asked whether they are enrolled in 
another study; they cannot be enrolled in other studies of investigational agents. After initial 
screening, the participant will then provide written informed consent to participate in the study 
and for the future use of biological specimens. 
 
6.6. Potential Limitations on Recruitment and Mitigation Strategies 
 
Given the fast-changing landscape during the COVID-19 pandemic, potential alterations are 
considered to mitigate the impact of newly identified therapies that change the standard of care 
and/or slower than planned enrollment. The study team plans to evaluate the rate of enrollment 
two weeks after enrollment opens. If fewer than 10 patients have been enrolled within the first 
two weeks, a potential solution to increase enrollment is to change the randomization ratio to be 
2:1 on treatment:control. We have selected a 1:1 ratio under the assumption of equipoise; 
however, we anticipate that participants may not want to have a 50% chance of being 
randomized to placebo. To address this concern, we could increase the ratio in order to reduce 
the chance of being randomized to placebo to 33%. Under the assumptions described in our 
sample size estimates (Section 12.6 below), the change in the randomization ratio will not 
require a larger sample size. 


7. CONCURRENT MEDICATIONS 
7.1 Allowed medications and treatments 
a. Acetaminophen 
b. Ibuprofen or other non-steroidal anti-inflammatory medications 
c. Symptomatic care for cough/URI (e.g., decongestants/cough syrups) 
 
7.2 Prohibited medications and treatments 
a. Other investigational and/or immunomodulatory agents for treatment of COVID-19, 
including but not limited to chloroquine or hydroxychloroquine. 
b. Heparin or coumadin 
 
8. STUDY TREATMENTS 
 
8.1 Method of assigning subjects to treatment groups 
Up to 120 eligible patients will be randomly assigned to Lambda or placebo in a 1:1 ratio to the 
treatment and control arms using a REDCAP-based computer-generated randomization 
scheme developed by the study data management provider. Randomization will be stratified by 
age (>=50 and <50 years old) and sex. The investigator or designee will complete a password- 
protected electronic spreadsheet containing the randomization allocation, along with the code 
used to generate the allocation along with the seed used in the random number generation, will 
be stored on secure servers at Stanford. 
 
8.2 Blinding 
Administration of all study drugs will be single-blind (blinded to the study participant). All doses 
of study drugs will be prepackaged by the investigational pharmacist and administered by a 
study nurse not involved in data analysis. The study biostatisticians will be blinded to subject 
randomization, with the exception of an unblinded subgroup who will generate the 
randomization scheme and perform unblinded interim analyses. The subgroup will not discuss 
the unblinded data or interim results with the blinded biostatisticians and will save their materials 
on a server that is inaccessible to the blinded members. This study blind will be broken on 
completion of the clinical study and after the study database has been locked. During the study, 
the blind may be broken only in emergencies when knowledge of the patient’s treatment group 
is necessary for further patient management. When possible, the Investigator should discuss 
the emergency with the data safety and monitoring board prior to unblinding. 
 
8.3 Formulation of test and control products 
 
8.3.1 Formulation of test product 
Peginterferon Lambda-1a (Lambda), 180 mcg, administered as a single subcutaneous injection 
 
8.3.2 Formulation of control 
A 0.45mL normal saline in 1 mL syringe sealed with red cap (prevent leaking during transport) 
The placebo syringe product will not match the test product. 
 
8.3.3 Packaging and labeling 
Lambda Injection is a sterile, nonpyrogenic, ready-to-use (RTU) 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-1a drug substance, L- 
histidine, mannitol, polysorbate 80, hydrochloric acid, and water for injection and for a single use 
only. 
 
Normal saline injection is a sterile, nonpyrogenic solution that is clear and will be provided in a 1 
ml BD plastic syringe with a ½ inch, thin-walled needle with safety shield. Syringes are prefilled 
with a 0.9% sodium chloride solution and for a single use only. The injection will be prepared by 
the Stanford Investigational Pharmacy. 
 
8.4 Study drug supply, dosage, administration, and storage 
 
8.4.1 Supply of study drug at the site 
Lambda will be shipped by the manufacturer (Eiger BioPharmaceuticals) and stored at the 
Stanford Health Care Investigational Pharmacy. Normal saline injection will be prepared by the 
Stanford Health Care Investigational Pharmacy 
 
8.4.2 Dosage 
Each participant randomized to receive Lambda will receive a single subcutaneous dose of 
either 180 mcg Peginterferon Lambda-1a or 0.45 mL normal saline. 
 
8.4.3 Dispensing 
Study drug will be dispensed daily by the Stanford Investigational Pharmacy and brought in a 
cooler to the study clinic for administration. 
 
8.4.4 Administration instructions 
Lambda syringes are marked with dose indicator lines, which are used as a reference point for 
administering the correct dose. The clinician 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 Lambda Injection for delivery of up to 180 mcg. 
 
Both lambda and normal saline will be administered subcutaneously in either the lateral or 
posterior aspect of the upper arm or thigh. Injection sites should be clean and free of infection, 
skin lesions, scars, birthmarks, bony prominences, and large underlying muscles, blood vessels, 
and nerves. A lifted skinfold technique (pinching or bunching the skin) will be used to lift the 
subcutaneous layer away from underlying muscle, and the skin will be cleaned with an alcohol- 
impregnated swab before injection at a 90° angle. 
 
Following study drug administration, participants will be observed in the study clinic for thirty 
minutes to assess for any adverse events. 
 
8.4.5 Storage 
Lambda Injection will 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. Lambda injection should not be frozen. 
 
Normal saline injection will be stored in a refrigerator at 2°C to 8°C. 


8.4.6 Study drug accountability 
Study drug accountability and monitoring will be performed by the Stanford Health Care 
Investigational Pharmacy. The Investigational Pharmacy will maintain accurate, complete, and 
current records of receipt, use, or disposition of study drugs, including: 1) dates of receipt, 2) 
dates of dispensing, 3) quantities currently maintained for dispensing, 4) name of participant 
and amount dispensed, and 4) amounts remaining at the end of trial and method of disposition. 
Medications will 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; refrigerators will have temperature logged. 
 
9 SUBJECT MANAGEMENT 
 
9.1 Subject Follow-up 
 
9.1.1. In home assessments. 
Participants will complete an at-home symptom questionnaire by REDcap on each day of follow- 
up through day 28, including in-home assessments of temperature and O2 saturation. These 
assessments will be reviewed daily by a clinical research coordinator, and patients will be 
telephoned by a physician if they report an elevated temperature, diminished O2 sat (<94%), or 
signs/symptoms of respiratory or cardiopulmonary distress (e.g. shortness of breath, dyspnea 
on exertion). 
On each day through day 28, patients will also be instructed to collect an 
anterior nare swab in a pre-labeled container and to store these specimens in a refrigerator at 
2°C to 8°C, and to bring these in to their next scheduled appointment. Prior to the optional follow 
up visits at months 4, 7 and 10, participants will complete an at-home symptom questionnaire 
and will be asked to collect a stool specimen to bring to their next scheduled appointment. 
 
 
9.1.2. Follow-up in-clinic assessments. 
Participants will be seen at follow-up visits at Day 1r1, 3r1, 5r1, 7r1, 10r1, 14r1, 21r1, and 
28r1. At each visit, a subjective medical history will be performed, including assessments for 
use of any concomitant medications. Vital signs will be obtained (temperature, blood pressure, 
pulse rate per minute, breath rate per minute and oxygen saturation), and oropharyngeal and 
anterior nare swabs will be collected. Participants will also submit at-home collected anterior 
nare swab specimens for evaluation. Clinical laboratory measurements will be performed at 
days 5r1 and 14r1 to assess for safety, with additional clinical laboratory assessments 
performed as needed for clinical follow-up and/or patient management. Additionally, ~25 mL 
peripheral blood will be collected from study participants at enrollment and at Days 5r1, 14r1, 
and 28r1 for processing and cryopreservation into a specimen biobank. Safety and tolerability 
of Lambda will be assessed by adverse event (AE) monitoring, vital signs assessment and 
clinical laboratory tests. Patients will reach the end of study at day 28r1 of follow-up. Optional 
long-term follow up visits will be scheduled 4,7, and 10 months post-enrollment. The window of 
r3 weeks is allowed for these long term follow up visits. 
At these long-term follow up visits, patients will undergo a detailed medical history, physical 
exam and psychosocial assessment, as well as specimen collection for biobank, a 6-minute 
walk test, and an olfactory assessment using the NIH toolbox. All patients will receive standard 
supportive care for management of COVID, as defined by clinical practice guidelines: 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig. 4 Laboratory assessments. 
9.2 Clinical laboratory measurements 
All clinical laboratory measurements (CBC and CMP) at enrolment and during follow-up will be 
performed using point-of-care CLIA-waived devices or in the Stanford Hospital clinical 
laboratory. Follow-up clinical laboratory assessments will be performed at Day 5r1 and Day 
14r1 post randomization, with additional clinical laboratory assessments performed as needed 
for clinical follow-up and/or patient management. (Fig 4). 
 
9.3 Virologic assessments 
Oropharyngeal and anterior nare swabs for SARS-CoV2 RNA will be collected using a 
standardized technique at all study visits. Additionally, participants will be instructed in collection 
of anterior nasal swabs at home and asked to collect a swab each day. We will ask participants 
to collect stool at home (between days 0-3, 10-14, and 21-28; and at 4, 7 and 10 months post- 
randomization). All swabs will be collected in viral transport media or phosphate buffered saline. 
Stool will be collected in stabilization tubes, kept at room temperature, and brought to the next 
study visit. Samples collected in the clinic will be refrigerated and transported the same day to 
the Stanford clinical virology laboratory for processing. We will ask that swabs collected at home 
be stored in a 4 degree refrigerator until their study visit, at which point they will be transferred 
to the study team and transported to the clinical virology laboratory. Fridges will be provided to 
the participants at enrolment. In the clinical virology laboratory, samples will undergo 
automated nucleic acid extraction followed by a FDA-cleared quantitative real-time PCR assay 
for SARS-CoV-2, which will generate both qualitative (positive or negative) and quantitative 
(estimated viral copies) results. The assay is validated for nasopharyngeal , oropharyngeal, and 
anterior nare samples. The stool assays have been analytically validated and are undergoing 
clinical validation. 


9.4 Biobanking/Immune phenotyping 
We will biobank longitudinal samples collected from patients enrolled in this trial. This will allow 
for ongoing studies to define the dynamics of the host immune response to COVID-19, with the 
eventual goal of gaining insight into mechanisms by which control or prevention can be 
achieved. For biobanking activities, samples will be collected at enrolment, day 5r1, day 14r1, 
and day 28r1 post-randomization, with optional additional biobanking at 4, 7, and 10 months 
post-randomization (Fig 4). The window of r3 weeks is allowed for these long term follow up 
visits. Stool will be collected as above and biobanked for microbiome assessments. 
 
At the time of blood draw, one 2.5 ml PaxGene tube and two 10 ml CPT (or green-top heparin) 
tubes will be collected for biobanking and brought to the BSL2+ research lab in Grant S146b. 
This whole blood then be stored in either stored in specific fixatives, used directly to assess 
innate immune phenotype and/or the immune response to toll like receptor stimulation, and/or 
separated into plasma and peripheral blood mononuclear cells (PBMC) using a Ficoll gradient, 
following standard protocols. All samples will have unique labels with barcodes and unique 
study identifier. Specimens will be logged into the Stanford Biobank through the OpenSpecimen 
database tracking system. Plasma will be stored at -80°C for future immunologic and/or 
pharmacokinetic studies, which may include measurement of levels of cytokines, antibodies, 
and other features related to the host immune response. PBMCs will be stored in liquid nitrogen 
to maintain viability, and will be evaluated using flow cytometry, RT-PCR, RNA sequencing, and 
other assays to assess the host immune response. 
 
In a subset of patients, we will consider a finger stick blood sample at day 14 and/or 28 to 
collect blood on a dry blood spot to validate performance characteristics of a serologic assay in 
comparison to venipuncture. 
 
9.5 Reimbursement of subjects 
 
Subjects will receive $40 for each visit to support transportation costs and inconvenience of 
frequent visits to the clinic for the first 28 days. For the optional visits at months 4, 7 and 10, 
subjects will receive $100 per visit; this is to encourage study retention. Preferred method of 
payment is gift card after the completion of each study visit. Subjects will receive a thermometer 
and a pulse oximeter for study use which they may keep after study completion. 
 
9 ADVERSE EVENT REPORTING AND DOCUMENTATION 
 
10.1. Monitoring and Reporting of Adverse Events 
 
10.1.1. Definitions 
 
An adverse event is defined as "any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily have a 
causal relationship with this treatment" (ICH Guidelines E2A). An adverse event can further be 
broadly defined as any untoward deviation from baseline health, which includes: 
x 
Worsening of conditions present at the onset of the study 
x 
Deterioration due to the primary disease 


x 
Intercurrent illness 
x 
Events related or possibly related to concomitant medications 
(International Centers for Tropical Disease Research Network Investigator Manual, Monitoring 
and Reporting Adverse Events, 2003). 
 
10.1.2. Identification of Adverse Events 
 
At each scheduled and unscheduled visit to the clinic, study clinicians will assess patients 
according to a standardized case record form. A severity grading scale, based on toxicity 
grading scales developed by the NIH Divisions of AIDS (DAIDS) Toxicity Tables, will be used to 
grade severity of all symptoms, physical exam findings, and laboratory results (Appendix 3). All 
participants, regardless of treatment arm, will be assessed using the same standardized case 
record form. Adverse event monitoring will occur during the period when study drugs are given 
and up to 1 month after cessation of study drugs. 
 
Data will be captured on the incidence of all adverse events, regardless of severity. For each 
adverse event identified and graded as severe or life threatening and felt to be possibly, 
probably or definitely related to study drugs, an adverse event report form will be completed. In 
addition, an adverse event form will be completed for all serious adverse events and 
unexpected events, regardless of severity. An adverse event report form will not be completed 
for events classified as mild or moderate (unless they are serious or unexpected), as mild and 
moderate symptoms are common and difficult to distinguish from signs and symptoms due to 
COVID and other common illnesses. The following information will be recorded for all adverse 
experiences that are reported: 
 
1) Description of event 
2) Date of event onset 
3) Date event reported 
4) Maximum severity of the event 
5) Maximum suspected relationship of the event to study drugs (either SP or DP) 
6) Whether the event is a serious adverse event 
7) Initials of the person reporting the event 
8) Outcome 
9) Date event resolved 
 
10.1.3. Reporting of Adverse Events 
 
Guidelines for reporting of adverse events provided by the Stanford Institutional Review Board 
and the Food and Drug Administration (FDA) in the U.S. will be followed as summarized in 
Table 1 below. 
 
Table 1. Guidelines for reporting adverse events 
 
Institution 
Type of Adverse Events 
When to Report 
Stanford IRB Adverse event that Stanford PI 
determines: 
x 
changes the study risks or 
benefits, 
x 
Within 10 working days of PI’s 
awareness 


 
OR 
necessitates modification to the IRB- 
approved consent document(s) and/or 
the IRB-approved application/protocol 
 
 
 
 
FDA 
 
x 
Definitely, Probably or Possibly 
related AND BOTH Serious* AND 
Unexpected± 
x 
For fatal or life-threatening 
events, by telephone or fax 
within 7 calendar days of first 
awareness 
x 
All other reportable events 
within 15 calendar days of first 
awareness 
 
 
Serious Adverse Event (SAE) is any AE that results in any of the following outcomes: 
• Death, 
• Life-threatening adverse experience. 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• Persistent or significant disability/incapacity, 
• Congenital anomaly/birth defect, or cancer, or 
• Any other experience that suggests a significant hazard, contraindication, side effect or 
precaution that may require medical or surgical intervention to prevent one of the 
outcomes listed above, 
• Event occurring in a gene therapy study 
• Event that changes the risk/benefit ratio of the study. 
 
Unexpected Adverse Event An adverse event is defined as being unexpected if the event 
exceeds the nature, severity, or frequency described in the protocol, consent form and 
investigator brochure (when applicable). An unexpected AE also includes any AE that meets 
any of the following criteria: 
• Results in subject withdrawal from study participation, 
• Due to an overdose of study medication, or 
• Due to a deviation from the study protocol 
 
10 WITHDRAWAL OF SUBJECTS AND MANAGEMENT OF PROTOCOL VIOLATIONS 
 
10.1 Withdrawal of subjects from the study 
 
Participants will be followed until they reach 28 days post-randomization, with optional follow-up 
for up to 10 months. Study participants will be prematurely withdrawn from the study for: 1) 
inability to be located for >7 consecutive days, 2) withdrawal of informed consent, 3) inability to 
comply with the study schedule and procedures (e.g., missing 3 of the first 6 in-person visits), 4) 
at the discretion of the site investigator if the study is not in the best interest of the participant, 5) 
subject judged by the site investigator to be at significant risk of failing to comply with the study 
protocol as to cause them harm or seriously interfere with the validity of study results. If a 
subject is withdrawn for reasons # 1 or 2, we will be unable to perform any additional study 
procedures. If a subject is withdrawn for reasons # 3-5, plans to obtain appropriate follow-up 
tests outside of the study will be individualized for each subject depending on the health status 
of the subject at the time of withdrawal and the willingness of the participant and his or her 
parent/guardian to proceed with additional testing. 


10.2 Protocol Violations 
 
All protocol violations will be noted and reported to the Stanford Institutional Review Board 
within 5 days of the protocol violation report. The PI will develop a corrective action plan to 
present to the IRB for review and approval. 
 
11 DATA SAFETY MONITORING 
 
The proposed study will conform to rigorous standard monitoring procedures, standardized 
reporting of adverse events (Adverse Event Report Forms are completed by study coordinators 
and sent immediately to the investigators), and review of the study by a Data and Safety 
Monitoring Board (DSMB) at both an interim and final analysis. The PI has primary responsibility 
for the overall conduct of the study, including the safety of human subjects. The PI will ensure 
appropriate (1) conduct of the informed consent process (e.g. that informed consent is obtained 
before proceeding with study procedures); (2) enrollment of study subjects; (3) collection and 
analysis of data; (4) implementation of study procedures to ensure consistent monitoring of 
subjects for possible adverse events; (5) review of adverse events and reporting to the DSMB 
and the IRBs; and (6) maintenance of the privacy and confidentiality of study subjects. The PI 
maintains ultimate responsibility for the project and for the safety of study participants. The PI 
will be in contact with the research team on a regular basis to review the progress of the study 
and address any human subject issues that occur. These discussions may involve adverse 
event prevention measures, recruiting of appropriate study subjects, research staff training on 
protection of human subjects, as well as occurrence of adverse events, unexpected incidents, or 
protocol problems. 
 
11.1. Data and Safety Monitoring Board 
 
A DSMB will be established by the study team in cooperation with the sponsor to assess at 
intervals the progress of a clinical trial, safety data, and critical efficacy variables and 
recommend to the sponsor whether to continue, modify or terminate the trial. The DSMB will 
operate according to guidelines documented in a DSMB charter. Minutes will be taken to 
provide a written record of the DSMB meetings, including interim results; these will be available 
for review when the trial is complete. The DSMB will be a separate entity from the Institutional 
Review Board (IRB). The independence of the DSMB is intended to control the sharing of 
important comparative information and to protect the integrity of the clinical trial from adverse 
impact resulting from access to trial information. DSMB members will not participate in the 
study as investigators and will not have conflicts of interest regarding the study or the 
investigational product. The composition of the DSMB will include at minimum: 
 
DSMB Chair, having experience and expertise in clinical trials 
Scientist with expertise in viral infectious diseases. 
Scientist with expertise in pharmacology 
Biostatistician with expertise in clinical trials. 
 
The DSMB will meet before the study, during an interim analysis, and at the conclusion of the 
trial to review progress of the clinical trial and safety data. 


The DSMB will review the study for progress and safety. The PI will provide information that will 
allow the DSMB to review and assess the following: 
· 
The research protocol, informed consent documents and plans for data safety and 
monitoring; 
· 
Periodic assessments of data quality and timeliness, participant recruitment, accrual and 
retention, participant risk versus benefit, and other factors that can affect study outcome; 
· 
Factors external to the study when relevant information, such as scientific or therapeutic 
developments, may have an impact on the safety of the participants or the ethics of the trial; 
· 
Study performance to make recommendations and assist in the resolution of problems; 
· 
The safety of the study participants; 
· 
The safety and scientific progress of the trial; 
· 
The continuation, termination or other modifications of the trial based on the observed 
beneficial or adverse effects of the treatment under study; 
· 
The confidentiality of the data and the results of monitoring; and 
· 
Any problems with study conduct, enrollment, sample size and/or data collection. 
 
The first meeting of the DSMB will take place prior to the initiation of the study to discuss the 
protocol and the Data Safety Monitoring Plan. Meetings of the DSMB shall be held according to 
the plan outlined above. Meetings shall be closed to the public because discussions may 
address confidential patient data. Meetings may be convened as conference calls as well as in 
person. An emergency meeting of the Board may be called at any time should questions of 
patient safety arise. The DSMB may request the presence of study investigators at such 
meetings. 
 
The study PI will distribute study information to the DSMB prior to a scheduled meeting. The 
DSMB may request additions and other modifications to this information on a one-time or 
continuing basis. This information will consist of two parts: (1) information on study progress 
such as accrual, baseline characteristics, and other general information on study status and (2) 
any confidential data on study outcomes, including safety data. A formal report from the DSMB 
should be supplied to the PI within 3 days of each meeting. Each report should conclude with a 
recommendation to continue or to terminate the study. This recommendation should be made 
by formal majority vote. A recommendation to terminate the study should be transmitted to the 
PI and IRBs as rapidly as possible, by immediate telephone and fax if sufficiently urgent. In the 
event of a split vote in favor of continuation, a minority report should be contained within the 
regular DSMB report. At the conclusion of the DSMB meeting for the interim safety review 
planned at 50% enrollment, the DSMB chair will convey the DSMB’s recommendation to the 
study PI in order to minimize the amount of time enrollment is paused. 
 
11.2. Interim analysis 
 
An interim analysis for safety and overwhelming efficacy will be performed once 50% of patients 
have 24 hours of follow-up complete. Enrollment will pause once 50% of patients have received 
treatment and will remain paused until the DSMB makes their recommendation after their safety 
review. The DSMB will meet one or two days after enrollment is paused to review the safety 
data collected within the first 24 hours of follow-up on all enrolled patients. We additionally 


expect blood count labs collected at day 5 to be available in approximately 25% of patients at 
the time of the DSMB review. 
 
The DSMB will also review the efficacy data on all randomized participants at this meeting. The 
interim efficacy analysis will use the same methods as are planned for the final analysis using 
the ITT analysis. Based on the results of the interim analysis, the DSMB will either recommend 
to the sponsor to terminate the study for overwhelming efficacy (p<0.00001 at the interim 
analysis), terminate the study for safety concerns, modify the study, or continue the study as 
planned. No formal stopping rules for futility are planned. 
 
12 STATISTICAL METHODS AND CONSIDERATIONS 
 
12.1 Analysis population 
We will evaluate the intention-to-treat (ITT) population. The intent-to-treat (ITT) population will 
include all randomized patients. Patients will be analyzed according to their assigned treatment 
arm. All efficacy analyses will be completed in the ITT population. The per-protocol (PP) 
population will include all randomized patients who completed follow-up and adhered to study 
procedures. All efficacy analyses will be also be completed in the PP population as supportive 
evidence for the primary efficacy analysis. The safety population will include all patients who 
receive study treatment. Patients will be analyzed according to actual treatment received. All 
safety analyses will be completed in the safety population. 
 
12.2 Descriptive analyses 
Descriptive statistics (proportions for categorical variables, means, medians, standard 
deviations and interquartile ranges for continuous variables) will be reported for all key patient 
variables, including baseline and demographic characteristics, use of medications, compliance, 
and study completion status. Data that are missing on key patient characteristics and the 
outcome will be fully described, including any patterns of missingness (i.e., any relationships 
between missingness of a variable and patient characteristics). 
 
A CONSORT diagram displaying the number of patients screened, eligible, and consented 
along with reasons for ineligibility will be provided. Graphical tools such as histograms, boxplots, 
and scatterplots will be created to assess quality of data and to display patterns over time. 
 
12.3 Analysis of primary endpoint 
Time until shedding cessation will be compared between the two treatment arms using a two- 
sided Cox proportional hazards model adjusted for age and sex. The test will be performed at 
the alpha = 0.05 level of significance. The hazard ratio for shedding cessation will be estimated, 
along with its 95% confidence interval, from a Cox proportional hazards model. If the 
proportional hazards assumption is not met, we will consider an extended Cox model that 
relaxes the proportional hazards assumption. 
 
The distribution of shedding cessation will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves will be presented for each treatment arm. Time to shedding cessation at 
the end of the study period along with 95% confidence intervals will be presented for each 
treatment arm. 


In a subgroup analyses, the time until shedding cessation analyses will be performed separately 
in the symptomatic and asymptomatic participants. 
 
12.4 Analysis of secondary endpoints 
SARS-CoV2 Log10 viral loads at follow-up timepoints will be compared between groups using 
the Wilcoxon rank-sum test and/or generalized estimating equations with robust standard errors. 
The area-under-the-curve (AUC) SARS-CoV2 viral RNA levels during follow-up will be 
estimated using the linear trapezoidal method, and mean AUC levels compared between groups 
using the Wilcoxon rank-sum test. 
 
The distribution of cessation of symptoms will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves will be presented for each treatment arm. Time to cessation of symptoms 
at the end of the study period along with 95% confidence intervals will be presented for each 
treatment arm. The hazard ratio for cessation of symptoms will be estimated, along with its 95% 
confidence intervals, from a Cox proportional hazards model. Time to cessation of symptoms 
will be estimated in the subgroup of patients who are symptomatic at baseline. 
 
The incidence of hospitalizations and emergency department visits will be compared between 
groups using negative binomial regression models, which will account for differing follow-up 
times through an offset term. 
 
12.5 Analysis of safety endpoints 
The frequency of adverse events and serious adverse events will be tabulated by type and by 
treatment arm. AEs will be compared by arm using the Chi-squared test or Fisher’s exact test, 
as appropriate, in the safety analysis set. 
 
12.6 Sample size and randomization 
 
For the primary comparison, the following will be tested: 
 
x 
Null hypothesis: time to cessation of oral shedding is equal in control and treatment; 
x 
Alternative hypothesis: time to cessation of oral shedding differs between control and 
treatment. 
 
Hypothesis tests will be two sided and conducted at an overall alpha = 0.05 level of significance. 
 
We assume that the mean duration of virologic shedding in individuals receiving standard of 
care is 14 days, with a standard deviation of 4 days1. 
 
Assuming 1:1 randomization and the use of a two-sided log rank test at the alpha=0.04999 level 
of significance for the final analysis, 79 events will provide 80% power to detect a hazard ratio of 
2.03. This leaves alpha=0.00001 to check for overwhelming efficacy after 50% of participants 
have completed 24 hours of follow-up. Assuming the control and treatment arm median 
cessation of shedding is 14 and 7 days, respectively, a two-month accrual period, a two-week 
follow-up period after randomization of the last patient, and a drop out of 10% in the control arm, 
it is estimated that the total sample size required to achieve 79 events is 120 (60 patients in 
each arm). 


As described in section 6.6 above, we provide the following power calculations showing how 
potential study alterations due to slow enrolment would impact the study’s operating 
characteristics. If fewer than 10 patients have been enrolled within the first two weeks, a 
potential solution to increase enrollment is to change the randomization ratio to be 2:1 on 
treatment:control, which would reduce the chance of being randomized to placebo to 33%. 
Under the assumptions described above, the change in the randomization ratio will not require a 
larger sample size. 
 
We also consider how a change in the standard of care could impact our study’s power. If the 
standard of care changes and our expected effect size decreases, our expected power would 
decrease to 61%, 41%, or 22% under an assumed hazard ratio of 1.8, 1.6, or 1.4, respectively. 
The impact of the change to the standard of care will depend on what proportion of patients 
have been enrolled. If the standard of care changes before enrollment is 90% complete, we will 
estimate the conditional power based on the current enrollment and the expected decrease in 
the effect size; we would not look at the blinded study data or outcome data to estimate the 
conditional power. If the conditional power is < 70%, the study will be modified by increasing the 
sample size such that the conditional power reaches 80%. If the total required sample size to 
reach 80% conditional power is greater than 180, the study will be stopped for futility. 
 
13. DATA COLLECTION, RETENTION AND MONITORING 
 
13.1 Data collection instruments 
 
Paper data (informed consent documents, screening and contact information) will be maintained 
in a research chart. The remaining clinical data-- daily questionnaires, case record forms 
(CRFs), and laboratory results--ZLOOEHHQWHUHGDQGPDLQWDLQHGLQ6WDQIRUG
V5HG&DSGDWDEDVe 
using the minimum number of personal identifiers (DOB, dates of visit). Physical copies of 
laboratory data from point of care devices will be stored in a file. Specimen containers and blood 
tubes will be labeled by the clinical research coordinator only with study ID and date. Virologic 
measurements will be entered into a database stored on secured servers and provided from the 
clinical laboratory to the study team. Biobanked specimens (e.g. PaxGene, plasma, PBMC) will 
be entered into the Stanford Biobank database stored on secure servers. 
 
13.2 Data management procedures 
 
All subjects will be given a study ID. Symptom questionnaires and CRFs used at clinic visits will 
be completed by subjects and or study personnel using only study ID. Specimen containers will 
be labeled by the CRC only with study ID and date, time of collection. Virologic measurements 
will be provided back to the study team electronically once available, and entered into a RedCap 
database by a CRC. 
 
13.3 Data quality control and reporting 
In order to ensure data quality, the study CRC will perform a nightly data quality audit. For this 
audit all study forms entered into the data management system from that date will be assessed 
for accuracy with source documents. In addition, the study Data Manager will perform monthly 
reviews of the data management system audit trail log to identify potential data quality issues. 
The data will be owned by Stanford University. 


13.4 Archival of data 
Electronic data including all study databases and supporting electronic documentation will be 
archived to cloud-based servers on a daily basis. 
 
13.5 Availability and retention of investigational records 
All data will be kept in secured RedCap and Box servers. Only the research team will have access 
to the data. 
 
13.6 Subject confidentiality 
 
Participants will be asked at screening (after the consent is signed) if it is permissible for the 
VWXG\VWDIIWRFRQWDFWWKHPYLDWHOHSKRQH,IVRWKHSDUWLFLSDQW
VSUHIHUUHGWHOHSKRQHQXPEHUZLOO 
be documented in the research record. Subject identification by phone will require two pieces of 
personal identification (DOB and subject ID#). Computerized questionnaires via redcap are 
password protected, encrypted and monitored by Stanford IT. 
 
Participant interactions (interviews, data collection, PEs, blood draws, etc.) will be completed in 
a private clinic room. The following health information related to this study may be used or 
disclosed in connection with this research study, including, but not limited to, name and initials, 
address, email, phone number(s), date of birth, age, sex, race, ethnicity, medical record 
number, information related to COVID-19 disease, symptoms, physical exams, symptoms that 
might relate to medication side effects, vital signs including temperature and oxygen saturation 
levels laboratory tests, radioimaging results, pregnancy test and tests of viral shedding of Covid- 
19 and other viruses, medications received including study drug, and phone call records. 
 
All subjects will be given a sequential study ID. The code for this ID with personal identifiers will 
be maintained in a locked research file accessible only to study personnel. Only research 
personnel will have access to the research records. The data will be keyed into a secure study 
website in a coded fashion by the study coordinator. Paper research charts will be kept in a 
locked file cabinet with limited access. The study coordinator is the only one that has the key to 
the locked cabinet where the research charts are stored. Laboratory personnel will have access 
to study specimens. The data is transferred by computer via password protected electronic 
network. When transferring via electronic networks a password protected encrypted computer 
will be used. 
 
14. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
 
14.1 Institutional review board 
This study protocol, all procedures and consent forms, and any subsequent protocol 
amendments must be reviewed and approved by the Institutional Review Board of Stanford 
University. 
 
14.2 Informed consent form 
All study participants will provide written informed consent for participation in the study and 
future use of biologic specimens. (Appendix 2) 


14.3 Publications 
The findings from this study may be published in a medical journal. No individual identities will 
be used in any reports or publications resulting from the study. The researchers will publish 
results of the trial in accordance with Stanford guidelines. 
 
14.4 Investigator responsibilities 
The data will be owned by Stanford University. Stanford agrees to provide Eiger 
BioPharmaceuticals quarterly reports on data safety as described in this protocol. Within six 
months after completion of the study, Stanford will provide Eiger with a written report of the 
Study results. The Study Report may take the form of a written manuscript for publication. If 
the Agreement is terminated early, the Study Report should include, at a minimum, the results 
of the Study up until the date of termination. 


15. References 
 
 
1. 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for 
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 
Lancet. 2020. Epub 2020/03/15. doi: 10.1016/S0140-6736(20)30566-3. PubMed PMID: 
32171076. 
2. 
Baud D, Qi X, Nielsen-Saines K, Musso D, Pomar L, Favre G. Real estimates of 
mortality following COVID-19 infection. Lancet Infect Dis. 2020. Epub 2020/03/17. doi: 
10.1016/S1473-3099(20)30195-X. PubMed PMID: 32171390. 
3. 
Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, et al. Virological 
assessment of hospitalized patients with COVID-2019. Nature. 2020. doi: 10.1038/s41586-020- 
2196-x. 
4. 
Kotenko SV. IFN-lambdas. Curr Opin Immunol. 2011;23(5):583-90. Epub 2011/08/16. 
doi: 10.1016/j.coi.2011.07.007. PubMed PMID: 21840693; PubMed Central PMCID: 
PMCPMC3196341. 
5. 
Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R. Type III interferon 
(IFN) induces a type I IFN-like response in a restricted subset of cells through signaling 
pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J 
Virol. 2007;81(14):7749-58. Epub 2007/05/18. doi: 10.1128/JVI.02438-06. PubMed PMID: 
17507495; PubMed Central PMCID: PMCPMC1933366. 
6. 
Pagliaccetti NE, Chu EN, Bolen CR, Kleinstein SH, Robek MD. Lambda and alpha 
interferons inhibit hepatitis B virus replication through a common molecular mechanism but with 
different in vivo activities. Virology. 2010;401(2):197-206. Epub 2010/03/23. doi: 
10.1016/j.virol.2010.02.022. PubMed PMID: 20303135; PubMed Central PMCID: 
PMCPMC2864496. 
7. 
Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus 
replication. J Virol. 2005;79(6):3851-4. Epub 2005/02/26. doi: 10.1128/JVI.79.6.3851- 
3854.2005. PubMed PMID: 15731279; PubMed Central PMCID: PMCPMC1075734. 
8. 
Higgins PG, Phillpotts RJ, Scott GM, Wallace J, Bernhardt LL, Tyrrell DA. Intranasal 
interferon as protection against experimental respiratory coronavirus infection in volunteers. 
Antimicrob Agents Chemother. 1983;24(5):713-5. Epub 1983/11/01. doi: 10.1128/aac.24.5.713. 
PubMed PMID: 6318655; PubMed Central PMCID: PMCPMC185930. 
9. 
Sperber SJ, Hayden FG. Comparative susceptibility of respiratory viruses to 
recombinant interferons-alpha 2b and -beta. J Interferon Res. 1989;9(3):285-93. Epub 
1989/06/01. doi: 10.1089/jir.1989.9.285. PubMed PMID: 2545792. 
10. 
Channappanavar R, Fehr AR, Zheng J, Wohlford-Lenane C, Abrahante JE, Mack M, et 
al. IFN-I response timing relative to virus replication determines MERS coronavirus infection 
outcomes. J Clin Invest. 2019;130:3625-39. Epub 2019/07/30. doi: 10.1172/JCI126363. 
PubMed PMID: 31355779; PubMed Central PMCID: PMCPMC6715373. 
11. 
Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Treatment of 
SARS with human interferons. Lancet. 2003;362(9380):293-4. Epub 2003/08/02. doi: 
10.1016/s0140-6736(03)13973-6. PubMed PMID: 12892961. 
12. 
Loutfy MR, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, et al. Interferon alfacon-1 
plus corticosteroids in severe acute respiratory syndrome: a preliminary study. JAMA. 
2003;290(24):3222-8. Epub 2003/12/25. doi: 10.1001/jama.290.24.3222. PubMed PMID: 
14693875. 
13. 
Davidson S, McCabe TM, Crotta S, Gad HH, Hessel EM, Beinke S, et al. IFNlambda is a 
potent anti-influenza therapeutic without the inflammatory side effects of IFNalpha treatment. 
EMBO Mol Med. 2016;8(9):1099-112. Epub 2016/08/16. doi: 10.15252/emmm.201606413. 
PubMed PMID: 27520969; PubMed Central PMCID: PMCPMC5009813. 
14. 
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(11):5670-7. Epub 2010/03/26. doi: 10.1128/JVI.00272-10. PubMed 
PMID: 20335250; PubMed Central PMCID: PMCPMC2876583. 


Appendix 1. Informed Consent 
 
Are you participating in any other research studies? 
Yes 
No 
 
 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study of Peginterferon Lambda-1a. We hope to learn 
whether a single injection of this medicine decreases the time until you test negative for SARS- 
CoV-2, the virus that causes coronavirus disease (COVID-19). We will also assess whether it 
improves your symptoms and whether it causes any side effects. You were selected as a possible 
participant in this study because you are an outpatient with mild COVID1-9. 
 
If you decide to terminate your participation in this study, you should notify Dr. Upinder Singh at 
650-723-4045 
 
This research study is looking for 120 adults with uncomplicated COVID-19 attending the 
Stanford Hospital and Clinics. Stanford University expects to enroll all 120 research study 
participants. 
 
VOLUNTARY PARTICIPATION 
Your participation in this study is entirely voluntary. Your decision not to participate will not 
have any negative effect on you or your medical care. You can decide to participate now, but 
withdraw your consent later and stop being in the study without any loss of benefits or medical 
care to which you are entitled. 
 
DURATION OF STUDY INVOLVEMENT 
This research study has two parts: the first part—which is required for participation--is expected 
to take approximately 6 months to complete, with each of the 120 participants followed for up to 
28 days. The second part, which is optional for study participation, will require an additional 9 
months of follow-up per participant. The total study will take one year. 
 
PROCEDURES 
This study is to assess whether a new drug, given on one occasion under the skin, can decrease 
the time until you no longer shed the virus SARS-CoV (Coronavirus) from your respiratory 
tract. We will also assess whether it helps you feel better faster and whether it causes any side 
effects. The medication we will use, Peginterferon Lambda 1-a (Lambda), has previously been 
tested in over 200 healthy people and over 3000 people in the treatment of viral hepatitis. 
Because we don’t know if it will work for SARS-CoV2 (COVID-19), we will give the 
medication only to half of the people who join the study. The other half will receive a placebo 
injection of normal saline (salt water). In addition, participants in both groups will receive 
standard of care for COVID-19. The subjects who get the medication will be chosen at random 
and enrolled participants will not know whether they are receiving the drug or the placebo. The 
Lambda and control groups can then be compared to see whether the medication is more 
effective than the symptomatic care at home. You have a 50% chance of receiving Lambda. 
Lambda is experimental and is not approved by the FDA. 
If you choose to participate, the Protocol Director and her research study staff will ask you to do 
the following 
x At the first visit, you will


o Review the research protocol and ask and answer questions confirming that you 
understand it. 
o Be given an ID number that we ask you to save for future use. 
o Provide 30 ml (two tablespoons) of blood by venipuncture. This blood will be 
used to confirm your eligibility for the study. Any remaining blood will be stored 
for future studies of immune responses and viral biology in Biobank 
o Have you throat and anterior (front part) of your nose swabbed for SARS-CoV2 
(the virus that causes COVID-19) and other viruses. 
o Be randomized to either receive a single injection under your skin 
(subcutaneously) of Peginterferon Lambda-1a or placebo along with standard-of- 
care. Because there is no known treatment for this virus, the standard-of-care is 
rest at home, quarantine from others, and follow-up with healthcare providers as 
needed. 
o If you receive the injection, wait in clinic for 30 minute to ensure you don’t have 
an allergy to the medication 
o Be given a thermometer, blood oxygen monitor and mini-fridge for use at home. 
You will be instructed in their use. 
x At home, after the first visit, you will:
o Take your temperature and blood oxygen levels daily and record the time when 
these are obtained 
o Record these values daily in a very short, online questionnaire accessible by 
computer or cell phone. On this questionnaire, you will also be asked to respond 
daily to questions about symptoms of COVID-19 or of medication side effects 
that you experience. 
o Collect a sample of anterior nasal swabs daily in the receptacles provided to. 
o Stool samples (optional) will be collected at home (between days 0-3, 10-14, and 
21-28). 
 
x Eight required follow-up visits (Treatment Study)
o Over the subsequent 28 days, you will be asked to attend 8 follow-up visits. We 
will provide you with a calendar and appointments for these visits. These will 
occur at 
 1 day after enrollment 
 2-4 days after enrollment (no visits will occur on weekends) 
 4-6 days after enrollment. 
 7 days after enrollment 
 9-11 days after enrollment 
 14 days, 21 and 28 days after enrollment 
o At these visits we will obtain: 
 A swab of your throat for SARS-Cov2 
 On days 4-6, 14, and 28, we will ask for 30 ml (two tablespoons of blood) 
by venipuncture. These samples will be used to look for medication side 


effects and to store for future work on immune responses and viral biology 
in Biobank. 
 Optional finger stick blood will be collected at visit Day 14 and Day 28 on 
a dry blood spot to validate performance characteristics of a serologic 
assay in comparison to venipuncture. 
 
o Optional long-term follow-up (Biobank study) 
 If you agree to longer term follow-up, we will collect 30 ml (two 
tablespoon) blood samples on three occasions, 4 months, 7 months and 10 
months after your enrollment, along with additional optional stool samples 
at 4 months, 7 months and 10 months. 
 At each long-term follow up visit, you will be asked to answer questions 
about how COVID-19 has affected your health and your quality of life. 
We will also perform a physical exam, evaluate your oxygen levels after 
walking, and evaluate your sense of smell. 
 
Your specimens will be sent outside of Stanford for analysis 
 
This research might include whole genome sequencing of specimens. Any of your specimens 
which are used in research may result in new products, tests or discoveries. In some instances, 
these may have potential commercial value and may be developed and owned by the 
Investigators, Stanford University and/or others. However, donors of specimens do not retain 
any property rights to the materials. Therefore, you would not share in any financial benefits 
from these products, tests or discoveries. 
· 
Women of Childbearing Potential 
If you are a woman who is able to become pregnant, it is expected that you will use an effective 
method of birth control to prevent exposing a fetus to a potentially dangerous agent with unknown 
risk. If you are pregnant or currently breast feeding, you may not participate in this study. You 
understand that if you are pregnant, if you become pregnant, or if you are breast-feeding during 
this study, you or your child may be exposed to an unknown risk. 
 
To confirm to the extent medically possible that you are not pregnant, you agree to have a 
pregnancy test done before beginning this research study. You must agree to avoid sexual 
intercourse or use a birth control method judged to be effective by the investigator and which will 
not interfere with the proposed investigation for three months after receiving Lambda. You must 
accept the risk that pregnancy could still result despite the responsible use of reliable method of 
birth control. You agree to notify the investigator as soon as possible of any failure of proper use 
of your birth control method, or if you become pregnant, either of which may result in your being 
withdrawn from the study. 
 
If you are a man participating in this study and your partner is able to become pregnant, you and 
your partner must use adequate contraception while you are participating in the study and for at 
least three months Your doctor will discuss with you what methods of birth control are 
considered adequate. You should inform your study doctor if your partner becomes pregnant. 
 
Future Use of Private Information and/or Specimens 


Research using private information and/or specimens is an important way to try to understand 
human disease. You are being given this information because the investigators want to save 
private information and/or specimens for future research. 
 
Your specimens will be stored with a study ID. After the study is complete, all personal 
identifiers linked to the study ID will be destroyed. Because your specimens will not be linked 
to your name after they are stored, you cannot withdraw your consent to the use of the specimens 
after they are taken. 
 
Identifiers might be removed from identifiable private information and/or identifiable specimens 
and, after such removal, the information and/or specimens could be used for future research 
studies or distributed to another investigator for future research studies without additional 
informed consent from you. 
 
Genetic Testing and Future Research 
As part of the analysis on your specimens, the investigators may do genetic testing. Genetic 
research is research that studies genes, including gene characteristics and gene versions that are 
transmitted by parents to children. Genetic research may include looking at information, such as 
personal appearance and biochemistry, gene sequences, genetic landmarks, individual and family 
medical histories, reactions to medications and responses to treatment. Genetic research raises 
certain questions about informing you of any results. Possible risks of knowing results include: 
anxiety; other psychological distress; and the possibility of insurance and job discrimination. A 
possible risk of not knowing includes being unaware of the need for treatment. These risks can 
change depending on the results of the research and whether there is a treatment or cure for a 
particular disease. 
 
Sometimes patients have been required to furnish information from genetic testing for health 
insurance, life insurance, and/or a job. A Federal law, the Genetic Information 
Nondiscrimination Act of 2008 (GINA), generally makes it illegal for health insurance 
companies, group health plans, and employers with 15 or more employees to discriminate 
against you based on your genetic information. 
 
The results of the study of your specimens from this project will be used for research 
purposes only, and you will not be told the results of the tests. 
 
PARTICIPANT RESPONSIBILITIES 
 
As a participant, your responsibilities include 
 
x Follow the instructions of the Protocol Director and study staff.
x Keep your study appointments. If it is necessary to miss an appointment, please contact 
the Protocol Director or research study staff
x Take your temperature and oxygen level daily
x Complete the smart phone/computer questionnaire daily
x Collect anterior nare swab samples daily.
x Tell the Protocol Director or research study staff about any side effects, doctor visits, or 
hospitalizations that you may have.


x Tell the Protocol Director or research staff if you believe you might be pregnant or gotten 
your partner pregnant.
x Ask questions as you think of them.
x Tell the Protocol Director or research staff if you change your mind about staying in the 
study.
 
WITHDRAWAL FROM STUDY 
If you first agree to participate and then you change your mind, you are free to withdraw your 
consent and discontinue your participation at any time. Your decision will not affect your ability 
to receive medical care for your disease and you will not lose any benefits to which you would 
otherwise be entitled. 
 
If you decide to withdraw your consent to participate in this study, you should notify Dr. Upinder 
Singh. 
 
The Protocol Director may also withdraw you from the study without your consent for one or 
more of the following reasons: 
Ɣ Failure to follow the instructions of the Protocol Director and study staff. 
Ɣ The Protocol Director decides that continuing your participation could be harmful to you. 
Ɣ Pregnancy 
Ɣ You need treatment not allowed in the study. 
Ɣ The study is cancelled. 
Ɣ Other administrative reasons. 
Ɣ Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES 
 
There are risks, discomforts, and inconveniences associated with any research study. These 
deserve careful thought. You should talk with the Protocol Director if you have any questions. 
x You will be asked to come to our research clinic on nine occasions (eight more following 
this visit) and twelve occasions if you agree to participate in the longer term follow-up 
study). This is an inconvenience to you.
x We will collect blood samples on four occasions (save if you agree to the longer term 
study). Blood draws can cause discomfort, bruising and very, very rarely, infection at the 
needle site. Some people also feel faint. We will try to minimize these risks by having 
well-trained blood drawing staff draw your blood.
x We will collect throat swabs on 9 occasions. Throat swabs cause some people to gag and 
rarely to vomit. We will minimize these risks by having trained personnel do this as 
rapidly as possible.
x Half of the subjects will receive an experimental drug, Lamda. Those who receive this 
drug may:
o Experience discomfort at the injection site for several days 
o Have abnormalities in liver tests for a short period (expected in 20%). These 
abnormalities are not expected to be severe and the liver tests are expected to 
rapidly return to normal 


o Have other potential side effects including fatigue, headache or diarrhea. Based 
on previous studies of healthy individuals, we do not expect these side effects to 
be common or severe. 
x We do not know if this medication will be effective. All subjects, whether receiving 
treatment or the standard-of-care, may have progression of disease. Because we will be 
monitoring your symptoms daily, and because you can contact us with any concerns, you 
will have rapid access to further medical care
x Any study may have unforeseeable consequences to subjects. By carefully monitoring 
the progress of this study, we will be able to respond to these problems in a timely 
manner.
 
POTENTIAL BENEFITS 
 
We hope that this medicine will reduce shedding of SARS-CoV-2 (the virus that causes 
COVID-19) from your respiratory tract (mouth and nose). Lambda may also reduce the 
duration of symptoms related to COVID-19, reduce the risk of hospitalization or death from the 
virus and decrease the risk of any people in your household contracting COVID-19 within 28 
days. 
 
We cannot and do not guarantee or promise that you will receive any benefits from this study. 
 
ALTERNATIVES 
The alternative to participating is not to participate. 
 
PARTICIPANT’S RIGHTS 
You should not feel obligated to agree to participate. Your questions should be answered clearly 
and to your satisfaction. If you decide not to participate, tell the Protocol Director. 
You will be told of any important new information that is learned during the course of this 
research study, which might affect your condition or your willingness to continue participation in 
this study. 
 
ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the 
Web site will include a summary of the results. You can search this Web site at any time. 
 
CONFIDENTIALITY 
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals. Your identity and/or your personal health information will not be disclosed 
except as authorized by you or as required by law. However, there is always some risk that even 
de-identified information might be re-identified. 
 
Patient information may be provided to Federal and other regulatory agencies as required. The 
Food and Drug Administration (FDA), for example, may inspect research records and learn your 
identity if this study falls within its jurisdiction. 


The purpose of this research study is to obtain information on the safety and effectiveness of 
Peginterferon Lambda-1a. The results will be provided to the sponsor, the Food and Drug 
Administration and other federal and regulatory agencies as required. 
 
CONFLICT OF INTEREST 
Stanford University has a financial interest in the company supplying materials for this study. 
Any equity or royalties will be held in an account managed by an independent third party, which 
will not know about the results of the human subjects research until publicly available. 
 
Authorization To Use Your Health Information For 
Research Purposes 
Because information about you and your health is personal and private, it generally 
cannot be used in this research study without your written authorization. If you 
sign this form, it will provide that authorization. The form is intended to inform 
you about how your health information will be used or disclosed in the study. 
Your information will only be used in accordance with this authorization form and 
the informed consent form and as required or allowed by law. Please read it 
carefully before signing it. 
 
What is the purpose of this research study and how will my health 
information be utilized in the study? 
The purpose of this study is to see if the drug, Peginterferon Lambda-1a (Lambda) 
can reduce shedding of the virus SARS-CoV2 from the respiratory tract. Health 
information you provide will determine whether you are eligible to participate in 
the study and whether the medication has affected your symptoms in any way. 
Blood tests and throat samples you provide will help determine whether the 
medication causes any side effects and whether it can decrease shedding of the 
virus. 
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form. But if you do not, you will not be 
able to participate in this research study, including receiving any research-related 
treatment. Signing the form is not a condition for receiving any medical care 
outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization regarding 
the use and disclosure of your health information (and to discontinue any other 
participation in the study) at any time. After any revocation, your health 
information will no longer be used or disclosed in the study, except to the extent 
that the law allows us to continue using your information (e.g., necessary to 
maintain integrity of research). If you wish to revoke your authorization for the 
research use or disclosure of your health information in this study, you must write 


to: Upinder Singh at Lane L134, 300 Pasteur Dr., Stanford University, Stanford 
CA. 94305-5107. 
 
What Personal Information Will Be Obtained, Used or Disclosed? 
Your health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to, name and initials, 
address, email, phone number(s), date of birth, age, sex, race, ethnicity, medical 
record number, health history and information related to COVID-19 disease and 
symptoms, symptoms that might relate to medication side effects, vital signs 
including temperature and blood oxygen saturation levels, laboratory and 
radioimaging investigation reports, pregnancy test and tests of viral shedding of 
COVID-19 and other viruses, medication received including study drug, and phone 
call records. 
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health information 
in connection with this research study: 
x The Protocol Director Upinder Singh 
x The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as 
necessary 
x Research Staff 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health information 
to the following persons and organizations for their use in connection with this 
research study: 
 
x The Office for Human Research Protections in the U.S. Department of 
Health and Human Services
x Eiger Biopharmaceuticals, the manufacturer of Lambda
x The Food and Drug Administration
x The study’s Institutional Data Monitoring Committee at Stanford
 
Your information may be re-disclosed by the recipients described above, if they are 
not required by law to protect the privacy of the information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information will 
end on May 1, 2050 or when the research project ends, whichever is earlier. 


Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access to any 
health information developed as part of this study until it is completed. At that 
point, you would have access to such health information if it was used to make a 
medical or billing decision about you (e.g., if included in your official medical 
record). 
 
 
 
 
Signature of Adult Participant 
Date 
 
 
 
 
Print Name of Adult Participant 
 
 
 
 
FINANCIAL CONSIDERATIONS 
 
Payment/Reimbursement 
You will be paid $40 for each visit to the clinical site to compensate you for travel expenses and 
inconvenience. For the optional long-term follow up visits at 4, 7 and 10 months, the 
reimbursement will be $100 per visit. Preferred method of payment is gift card after the 
completion of each study visit. Payments may only be made to U.S. citizens, legal resident 
aliens, and those who have a work eligible visa. You may need to provide your social security 
number to receive payment. You will also receive a free thermometer blood oxygen sensor. 
 
Costs 
There is no cost to you for participating in this study, other than basic expenses like 
transportation and the personal time it will take to come to all of the study visits. 
 
If you participate in this study, the study will pay for those services, supplies, procedures, and 
care associated with the study that are not a part of your routine medical care. However, there 
may be additional costs to you. These include basic expenses like transportation and the 
personal time it will take to come to the study visits. You and/or your health insurance must pay 
for services, supplies, procedures, and care that are required during this study for routine medical 
care. You will also be responsible for any co-payments and/or deductibles as required by 
your insurance. Participation in this study is not a substitute for health insurance. 
 
Sponsor 
Eiger Biopharmeuticals is providing the medication, Lambda, for this study. Stanford University 
School of Medicine is providing funding for the conduct of this study via a gift from an unnamed 
donor unrelated to Eiger Biopharmaceuticals but interested in combatting Covid-19. 


A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the 
Web site will include a summary of the results. You can search this Web site at any time. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental – involve some 
risk of injury. In spite of all precautions, you might develop medical complications from 
participating in this study. If such complications arise, the Protocol Director and the research 
study staff will assist you in obtaining appropriate medical treatment. In the event that you have 
an injury or illness that is directly caused by your participation in this study, reimbursement for 
all related costs of care first will be sought from your insurer, managed care plan, or other 
benefits program. You will be responsible for any associated co-payments or deductibles as 
required by your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, managed care plan or 
other benefits program, you may be responsible for these costs. If you are unable to pay for such 
costs, the Protocol Director will assist you in applying for supplemental benefits and explain how 
to apply for patient financial assistance from the hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 
CONTACT INFORMATION 
Questions, Concerns, or Complaints: If you have any questions, concerns or complaints about 
this research study, its procedures, risks and benefits, or alternative courses of treatment, you 
should ask the Protocol Director, Dr. Upinder Singh. You may contact her now or later at 650- 
723-4045. 
 
Injury Notification: If you feel you have been hurt by being a part of this study, please contact 
the Protocol Director, Upinder Singh at 650-723-4045. 
 
Independent Contact: If you are not satisfied with how this study is being conducted, or if you 
have any concerns, complaints, or general questions about the research or your rights as a 
participant, please contact the Stanford Institutional Review Board (IRB) to speak to someone 
independent of the research team at (650)-723-5244 or toll free at 1-866-680-2906. You can also 
write to the Stanford IRB, Stanford University, 1705 El Camino Real, Palo Alto, CA 94306. 
 
Appointment Contact: If you need to change your appointment, please contact Savita Kamble at 
650-736-7388 
 
Alternate Contact: If you cannot reach the Protocol Director, please contact Dr. Julie Parsonnet 
at 650-725-4561. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
As a research participant you have the following rights. These rights include but are not limited 
to the participant's right to: 
Ɣ be informed of the nature and purpose of the experiment; 


Ɣ be given an explanation of the procedures to be followed in the medical experiment, and 
any drug or device to be utilized; 
Ɣ be given a description of any attendant discomforts and risks reasonably to be expected; 
Ɣ be given an explanation of any benefits to the subject reasonably to be expected, if 
applicable; 
Ɣ be given a disclosure of any appropriate alternatives, drugs or devices that might be 
advantageous to the subject, their relative risks and benefits; 
Ɣ be informed of the avenues of medical treatment, if any available to the subject after the 
experiment if complications should arise; 
Ɣ be given an opportunity to ask questions concerning the experiment or the procedures 
involved; 
Ɣ be instructed that consent to participate in the medical experiment may be withdrawn at 
any time and the subject may discontinue participation without prejudice; 
Ɣ be given a copy of the consent form; and 
Ɣ be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion or undue 
influence on the subject's decision. 
 
May we contact you about future studies that may be of interest to you? 
  
 Yes 
No 
 
Signing your name below means you agree to be in the Treatment Part of the study and 
that you will receive a copy of this signed and dated consent form. 
 
 
Signature of Adult Participant 
Date 
 
 
 
Print Name of Adult Participant 
 
 
Signing your name here means you agree to be in the Biobank Part of the study and that 
you will receive a copy of this signed and dated consent form. 
 
 
Signature of Adult Participant 
Date 
 
 
 
Print Name of Adult Participant 
 
 
 
 
 
 


Signature of Person Obtaining Consent 
Date 
 
 
 
Print Name of Person Obtaining Consent 
 
 
The following witness line is to be signed only if the consent is provided as a summary form and 
accompanied by a short form foreign language consent. 
 
 
 
 
Signature of Witness 
Date 
 
 
Print Name of Witness 
 
(e.g., staff, translator/interpreter, family member) 
 
x Translated short form must be signed and dated by both the participant (or their LAR) AND the 
witness. 
x The English consent form (referred to as the "Summary Form" in the regulations): 
 Must be signed by the witness AND the Person Obtaining Consent (POC). 
 The non-English speaking participant/LAR does not sign the English consent. 
 The non-English speaking participant/LAR should not sign the HIPAA participant line 
If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) must ensure that 
1) the LAR's Description of Authority is completed and 2) that any questions or options presented by the 
consent form are documented and initialed by the POC on the Summary Form, per the participant's wishes, 
as they are understood during the consent process. 


 
Appendix 2. Schedule of Events 
 
 


Appendix 3. DAIDS Toxicity Table (clarification Aug 2017) 
 
Division of AIDS Table for Grading the Severity of ADULT AND PEDIATRIC Adverse Events Version 2.1, 
July 2017 
The Division of AIDS (DAIDS) oversees more than 300 clinical trials domestically and 
internationally, which evaluate the safety and efficacy of therapeutic products, vaccines, and 
other preventive modalities. Adverse event (AE) data collected during these clinical trials form 
the basis for subsequent safety and efficacy analyses of pharmaceutical products and medical 
devices. Incorrect and inconsistent AE severity grading can lead to inaccurate data analyses and 
interpretation, which in turn can impact the safety and well-being of clinical trial participants 
and future patients using pharmaceutical products. 
 
Over the years, DAIDS scientific knowledge and experience have expanded, necessitating 
revisions of the DAIDS grading table which serves as a guide for assessing the severity of AEs 
(including clinical and laboratory abnormalities) in participants enrolled in DAIDS-sponsored 
and -supported clinical trials. The Division of AIDS (DAIDS) Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) updates and replaces 
version 2.1 (March 2017). 
 
Glossary/Definitions of terms used in tables: 
AE 
Adverse event; Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or 
procedure. 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
AV 
Atrioventricular 
Basic Self-care 
Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer or movement, continence, and 
feeding. 
 
Young Children 
Activities that are age and culturally appropriate, such as feeding one’s self with culturally 
appropriate eating implements. 
BMI z-score 
Body mass index z- score; A body reference norm. Specifically, the number of standard 
deviations a participant's BMI differs from the average BMI for their age, sex, and ethnicity. 
 
 
BMD t-score 
Bone mineral density t-score; The number of standard deviations above or below the mean 
bone mineral density of a healthy 30 year old adult of the same sex and ethnicity as the 
participant. 
BMD z-score 
Bone mineral density z-score; The number of standard deviations a participant's BMD 
differs from the average BMD for their age, sex, and ethnicity. 


BPAP 
Bilevel positive airway pressure; A mode used during noninvasive positive pressure 
ventilation. 
Chemical 
Pregnancy 
A pregnancy in which a positive pregnancy test is followed by a negative pregnancy test 
without evidence of a clinical pregnancy loss. 
CNS 
Central nervous system 
CPAP 
Continuous positive airway pressure 
DAERS 
DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited Adverse Events (EAEs) to 
DAIDS. It facilitates timely EAE report submission and serves as a centralized location for 
accessing and processing EAE information for reporting purposes. 
 
Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
Hospitalization 
Does not include the following hospital admissions: under 24 hours, unrelated to an adverse 
event (e.g., for labor and delivery, cosmetic surgery, social or administrative for temporary 
placement [for lack of a place to sleep]), protocol-specified, and for diagnosis or therapy of 
a condition that existed before the receipt of a study agent and which has not increased in 
severity or frequency. 
INR 
International normalized ratio 
Intervention 
Medical, surgical, or other procedures recommended or provided by a healthcare 
professional for the treatment of an adverse event. 
IV 
Intravenous 
IVIG 
Intravenous immune globulin 
LDL 
Low density lipoprotein 
LLN 
Lower limit of normal 
Life-threatening 
AE 
Any adverse event that places the participant, in the view of the investigator, at immediate 
risk of death from the reaction when it occurred (i.e., it does not include a reaction that 
would have caused death if it had occurred in a more severe form). 
NA 
Not applicable 
Participant ID 
The identification number assigned to a study participant which is used to track study- 
related documentation, including any reported AEs. 
PR Interval 
The interval between the beginning of the P wave and the beginning of the QRS complex of 
an electrocardiogram that represents the time between the beginning of the contraction of 
the atria and the beginning of the contraction of the ventricles. 
 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc Interval 
The measure of time between the onset of ventricular depolarization and completion of 
ventricular repolarization corrected for ventricular rate. 
RBC 
Red blood cell 
SI 
Standard international unit 
ULN 
Upper limit of normal 


Usual Social & 
Functional 
Activities 
Activities which adults and children perform on a routine basis and those which are part of 
regular activities of daily living, for example: 
 
Adults 
Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, or pursuing a hobby. 
 
Young Children 
Activities that are age and culturally appropriate, such as social interactions, play activities, 
or learning tasks. 
WBC 
White blood cell 
WHO 
World Health Organization 
WNL 
Within normal limits 


Instructions for use 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.1 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs. The term “severe” is not the same as the term “serious” in classifying 
AEs. The severity of a specific event describes its intensity, and it is the intensity which is 
graded. Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
 
Clinical sites are encouraged to report parameters in the DAIDS grading table as they are 
written to maintain data consistency across clinical trials. However, since some parameters can 
be reported with more specificity, clinical sites are encouraged to report parameters that 
convey additional clinical information. For example, diarrhea could be reported as neonatal 
diarrhea; seizures, as febrile seizures; and pain, as jaw pain. 
 
General Considerations 
The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with 
descriptions for each AE based on the following general guidelines: 
Grade 1 indicates a mild event 
Grade 2 indicates a moderate event 
Grade 3 indicates a severe event 
Grade 4 indicates a potentially life-threatening event 
Grade 5 indicates death (Note: This grade is not specifically listed on each page of the grading 
table). 
 
Determining Severity Grade for Parameters “Between Grades” 
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an 
AE could be either Grade 2 or Grade 3), select the higher of the two grades for the AE. If a 
laboratory value that is graded as a multiple of the ULN or LLN falls between two grades, select 
the higher of the two grades for the AE. For example, Grade 1 is 2.5 x ULN and Grade 2 is 2.6 x 
ULN for a parameter. If the lab value is 2.53 x ULN (which is between the two grades), the 
severity of this AE would be Grade 2, the higher of the two grades. 
 
Values Below Grade 1 
Any laboratory value that is between either the LLN or ULN and Grade 1 should not be graded. 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements. Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the clinical case report forms. 
 
Values below Grade 1. Any laboratory value that is between the ULN and grade 1 (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE.  Sites 






Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention 
indicated (e.g., 
oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive 
medications, 
ventricular assist 
device, heart 
transplant) 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion 
indicated 
Symptoms AND 
Transfusion of чϮ 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs 
> 10 cc/kg) indicated 
Prolonged PR Interval 
or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 to 
< 0.25 seconds 
WZŝŶƚĞƌǀĂůшϬ͘Ϯϱ 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree 
AV block or 
ventricular delay of 
3.0 seconds 
Complete AV block 
ч 16 years of age 
1st degree AV block 
(PR interval > 
normal for age and 
rate) 
Type I 2nd degree 
AV block 
Type II 2nd degree 
AV block of 
ventricular delay of 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 
seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR ш 
0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated 
serious ventricular 
dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated 
Symptoms AND 
Intervention 
indicated 
Life-threatening 
embolic event (e.g., 
pulmonary embolism, 
thrombus) 
 
 
 
 
2 As per Bazett’s formula. 






Hypothyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference 
with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR 
Uncontrolled 
Life-threatening 
consequences (e.g., 
myxedema coma) 
 
 
OR Thyroid 
despite 
treatment 
 
 
 
replacement therapy 
modification 
 
 
 
indicated 
 
 
Lipoatrophy4 
Detectable by study 
participant, 
caregiver, 
or 
physician  AND 
Causing  
no  or 
minimal 
interference  with 
usual 
social  & 
functional activities 
Obvious on visual 
inspection 
AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5 
Detectable by study 
participant, 
caregiver, 
or 
physician  AND 
Causing  
no  or 
minimal 
interference  with 
usual 
social  & 
functional activities 
Obvious on visual 
inspection 
AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 SEVERE 
 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
 
 
 
 
 
 
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 
 
= 


Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
Aggressive 
intervention indicated 
(e.g., tube feeding, 
total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical 
intervention 
indicated 
Radiologic, 
endoscopic, or 
operative 
intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
ш 1 year of age 
Transient or 
intermittent 
episodes of 
 
stools over 
baseline per 24- 
hour period 
 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to 6 
stools over baseline 
per 24-hour period 
Increase of шϳ 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number 
of stools OR Mild 
dehydration 
Liquid stools with 
moderate 
dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting 
in severe dehydration, 
hypotensive shock) 


Dysphagia or 
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention 
indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention 
indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no 
intervention 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 






Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and 
attention deficit 
disorder) 
Specify type, if 
applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR 
Specialized 
resources not 
indicated 
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on 
parttime basis 
indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a 
fulltime basis 
indicated 
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
 
Specify type, if 
applicable 
Mild 
developmental 
delay, either 
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for 
the setting 
Moderate 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either 
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated OR 
Headache with 
significant 
impairment of 
alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
decreased 
strength on 
examination 
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual 
social & functional 
activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation 


Neurosensory 
Alteration (includes 
paresthesia and painful 
neuropathy) 
Specify type, if 
applicable 
Minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration 
or paresthesia 
causing inability to 
perform usual 
social & functional 
activities 
Disabling sensory 
alteration or 
paresthesia causing 
inability to perform 
basic self-care 
functions 
 
Seizures 
New Onset Seizure 
ш 18 years of age 
NA 
NA 
1 to 3 seizures 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
< 18 years of age 
(includes new or 
preexisting febrile 
seizures) 
Seizure lasting 
< 5 minutes 
with < 24 hours 
postictal state 
Seizure lasting 5 
to < 
20 minutes with 
< 24 hours 
postictal state 
^ĞŝǌƵƌĞůĂƐƚŝŶŐш 
20 minutes OR > 
24 hours 
postictal state 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Pre-existing Seizure NA 
Increased 
frequency from 
previous level 
of control 
without change 
in seizure 
character 
Change in 
seizure 
character either 
in duration or 
quality (e.g., 
severity or 
focality) 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness 
(e.g., pre- 
syncope) 
Loss of 
consciousness 
with no 
intervention 
indicated 
Loss of 
consciousness 
AND 
Hospitalization 
or intervention 
required 
NA 
 
Psychiatric 










 
usual social & 
functional 
activities 
with usual 
social & 
functional 
activities 
functional 
activities 
 
Cytokine Release Mild signs and 
Therapy (i.e., 
Prolonged severe Life-threatening 
Syndrome7 
symptoms AND 
antibody 
signs and 
consequences (e.g., 
 
Therapy (i.e., 
infusion) 
symptoms OR 
requiring pressor or 
 
antibody 
interruption 
Recurrence of 
ventilator support) 
 
infusion) 
indicated AND 
symptoms 
 
 
interruption not 
Responds 
following initial 
 
 
indicated 
promptly to 
improvement 
 
 
 
symptomatic 
 
 
 
 
treatment OR 
 
 
 
 
Prophylactic 
 
 
 
 
medications 
 
 
 
 
indicated ĨŽƌч  
 
 
 
24 hours 
 
 
Fatigue or 
Symptoms 
Symptoms 
Symptoms 
Incapacitating 
Malaise 
causing no 
causing greater causing inability 
symptoms of 
Report only one 
or minimal 
than minimal 
to perform usual fatigue or malaise 
 
interference with interference 
social & 
causing inability to 
 
usual social & 
with usual 
functional 
perform basic self- 
 
functional 
activities 
social & 
functional 
activities 
activities 
care functions 
Fever (non- 
38.0 to < 38.6°C 
ш 38.6 to < 
ш 39.3 to < 40.0°C ш ϰϬ͘ϬΣŽƌш 
axillary 
temperatures 
only) 
or 100.4 to < 
101.5°F 
39.3°C Žƌш 
101.5 to < 
102.7°F 
or 
шϭϬϮ͘ϳƚŽф 
104.0°F 
104.0°F 
Pain8 (not 
Pain causing no 
Pain causing 
Pain causing 
Disabling pain 
associated with 
or minimal 
greater than 
inability to 
causing inability to 
study agent 
interference with minimal 
perform usual 
perform basic self- 
injections and not usual social & 
interference 
social & 
care functions OR 
specified 
functional 
with usual 
functional 
Hospitalization 
elsewhere) 
Specify location 
activities 
social & 
functional 
activities 
activities 
indicated 
 
 
7 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
8 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 


Serum Sickness9 Mild signs and 
Moderate 
Severe signs and Life-threatening 
 
symptoms 
signs and 
symptoms AND 
consequences 
 
 
symptoms 
Higher level 
(e.g., requiring 
 
 
AND 
intervention 
pressor or 
 
 
Intervention 
indicated (e.g., 
ventilator support) 
 
 
indicated (e.g., 
steroids or IV 
 
 
 
antihistamines) fluids) 
 
Underweight10 
> 5 to 19 years 
of age 
 
WHO BMI z- 
score 
< -1 to -2 
 
WHO BMI z- 
score 
< -2 to -3 
 
WHO BMI z- 
score 
< -3 
WHO BMI z-score 
< -3 with life- 
threatening 
consequences 
2 to 5 years of 
WHO Weight- 
WHO Weight- 
WHO Weight- 
WHO Weight-for- 
age 
for- 
for- 
for- 
height z-score < -3 
 
height z-score 
height z-score 
height z-score < 
with 
 
< -1 to -2 
< -2 to -3 
-3 
lifethreatening 
consequences 
< 2 years of age  
WHO Weight- 
for- 
length z-score 
< -1 to -2 
 
WHO Weight- 
for- 
length z-score 
< -2 to -3 
WHO Weight- 
for- 
length z-score < 
-3 
WHO Weight-for- 
length z-score < -3 
with 
lifethreatening 
consequences 
Unintentional 
NA 
5 to < 9% loss 
ш 9 to < 20% loss ш 20% loss in body 
Weight Loss 
 
in body weight 
in body weight 
weight from 
(excludes 
 
from baseline 
from baseline 
baseline OR 
postpartum 
 
 
 
Aggressive 
weight loss) 
 
 
 
intervention 
 
 
 
 
indicated (e.g., 
 
 
 
 
tube feeding, total 
 
 
 
 
parenteral 
 
 
 
 
nutrition) 
 
Urinary 
 
 
 
9 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or 
dyspnea. 
10 WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ 
for 
participants 
> 
5 
to 
19 
years 
of 
age 
and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those  5 years of age. 
 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 




Redness11 Report 
only one 
> 15 years of age 
social & 
functional 
activities 
 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
 
ч 15 years of age 
чϮ͘ϱ cm in 
> 2.5 cm in 
ш 50% surface 
Potentially 
 
diameter 
diameter with < area of the 
lifethreatening 
 
 
50% surface area extremity 
consequences 
 
 
of the extremity segment 
(e.g., abscess, 
 
 
segment 
involved (e.g., 
exfoliative 
 
 
involved (e.g., 
upper arm or 
dermatitis, 
 
 
upper arm or 
thigh) OR 
necrosis involving 
 
 
thigh) 
Ulceration OR 
dermis or deeper 
 
 
 
Secondary 
tissue) 
 
 
 
infection OR 
 
 
 
 
Phlebitis OR 
 
 
 
 
Sterile abscess 
 
 
 
 
OR Drainage 
 
Injection Site 
Same as for 
Same as for 
Same as for 
Same as for 
Induration or 
Injection Site 
Injection Site 
Injection Site 
Injection 
Swelling 
Erythema or 
Erythema or 
Erythema or 
Site Erythema or 
Report only one 
Redness, > 15 
Redness, > 15 
Redness, > 15 
Redness, > 15 
> 15 years of age 
years of age 
years of age 
years of age 
years of age 
ч 15 years of age 
Same as for 
Same as for 
Same as for 
Same as for 
 
Injection Site 
Injection Site 
Injection Site 
Injection 
 
Erythema or 
Erythema or 
Erythema or 
Site Erythema or 
 
Redness, ч 15 
Redness, ч 15 
Redness, ч 15 
Redness, ч 15 
 
years of age 
years of age 
years of age 
years of age 
 
 
 
 
 
 
 
 
11 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area. 




AST or SGOT, High 
Report only one 
1.25 to < 2.5 
x ULN 
2.5 to < 5.0 x 
ULN 
5.0 to < 10.0 x 
ULN 
ш 10.0 x ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0 to < 16.0 
11.0 to < 16.0 
8.0 to < 11.0 
8.0 to < 11.0 
< 8.0 
< 8.0 
Bilirubin 
Direct Bilirubin13, 
High 
> 28 days of age 
 
NA 
 
NA 
 
> ULN with 
other signs and 
symptoms of 
hepatotoxicity. 
 
> ULN with 
lifethreatening 
consequences 
(e.g., 
signs and 
symptoms of liver 
failure) 
ч 28 days of age 
h>EƚŽчϭ 
mg/dL 
хϭƚŽчϭ͘ϱ 
mg/dL 
хϭ͘ϱƚŽчϮ 
mg/dL 
> 2 mg/dL 
Total Bilirubin, 
High > 28 days of 
age 
 
1.1 to < 1.6 x 
ULN 
 
1.6 to < 2.6 x 
ULN 
 
2.6 to < 5.0 x 
ULN 
 
ш 5.0 x ULN 
ч 28 days of age 
See Appendix 
A. 
Total Bilirubin 
for 
Term and 
Preterm 
Neonates 
See Appendix A. 
Total Bilirubin 
for 
Term and 
Preterm 
Neonates 
See Appendix A. 
Total Bilirubin 
for 
Term and 
Preterm 
Neonates 
See Appendix A. 
Total 
Bilirubin for Term 
and 
Preterm 
Neonates 
 
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited time frame unless it meets protocol-specific reporting 
requirements. 
 
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 
10% of the total bilirubin. 




Creatinine 
Clearance12 or 
eGFR, Low *Report 
only one 
NA 
< 90 to 60 ml/min 
or 
ml/min/1.73 m2 
OR 
10 to < 30% 
decrease from 
participant’s 
baseline 
< 60 to 30 ml/min 
or ml/min/1.73 
m2 
OR 
30 to < 50% 
decrease from 
participant’s 
baseline 
 
< 30 ml/min or
ml/min/1.73 m2 
 
participant’s 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
 
 
110 to 125 
6.11 to < 6.95 
 
 
> 125 to 250 
6.95 to < 13.89 
 
 
> 250 to 500 
13.89 to < 27.75 
 
 
ш 500 
ш 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
ш 500 
ш 27.75 
 
Glucose, Low 
(mg/dL; mmol/L)
ш 1 month of age 
 
55 to 64 
3.05 to <3.55 
 
40 to < 55 
2.22 to < 3.05 
 
30 to < 40 
1.67 to < 2.22 
 
< 30 
< 1.67
< 1 month of age 
50 to 54 
2.78 to < 3.00 
40 to < 50 
2.22 to < 2.78 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High
ULN to < 2.0 x 
ULN without 
acidosis 
шϮ͘Ϭ x ULN 
without acidosis 
Increased 
lactate with pH 
< 7.3 without 
lifethreatening 
consequences 
Increased lactate 
with pH < 7.3 with 
lifethreatening 
consequences 
Lipase, High 
1.1 to < 1.5 x 
ULN 
1.5 to < 3.0 x 
ULN 
3.0 to < 5.0 x 
ULN 
ш 5.0 x ULN 
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, 
Fasting, 
High 
ш 18 years of age 
 
 
 
 
200 to < 240 
5.18 to < 6.19 
 
 
 
 
240 to < 300 
6.19 to < 7.77 
 
 
 
 
ш 300 
ш 7.77 
 
 
 
 
NA 
 
 
 
12 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites should 
choose the method defined in their study and when not specified, use the method most relevant to the study population. 
 
*Reminder: Choose the method that selects for the higher grade. 


< 18 years of age 
170 to < 200 
4.40 to < 5.15 
200 to < 300 
5.15 to < 7.77 
ш 300 
ш 7.77 
NA 
>>͕&ĂƐƚŝŶŐ͕,ŝŐŚш 
18 years of age 
 
130 to < 160 
3.37 to < 4.12 
 
160 to < 190 
4.12 to < 4.90 
 
шϭϵϬ 
шϰ͘ϵϬ 
 
NA 
> 2 to < 18 years of 
age 
110 to < 130 
2.85 to < 3.34 
130 to < 190 
3.34 to < 4.90 
ш 190 
ш 4.90 
NA 
Triglycerides, 
Fasting, 
High 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium13, Low 
(mEq/L; mmol/L) 
1.2 to < 1.4 
0.60 to < 0.70 
0.9 to < 1.2 
0.45 to < 0.60 
0.6 to < 0.9 
0.30 to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
 
2.0 to < LLN 
0.65 to < LLN 
 
1.4 to < 2.0 
0.45 to < 0.65 
 
1.0 to < 1.4 
0.32 to < 0.45 
 
< 1.0 
< 0.32 
1 to 14 years of age 3.0 to < 3.5 
0.97 to < 1.13 
2.5 to < 3.0 
0.81 to < 0.97 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5 to < 4.5 
1.13 to < 1.45 
2.5 to < 3.5 
0.81 to < 1.13 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0 
5.6 to < 6.0 
6.0 to < 6.5 
6.0 to < 6.5 
6.5 to < 7.0 
6.5 to < 7.0 
ш 7.0 
ш 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4 
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5 
2.0 to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150 
146 to < 150 
150 to < 154 
150 to < 154 
154 to < 160 
154 to < 160 
шϭϲϬ 
шϭϲϬ 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135 
130 to < 135 
125 to < 130 
125 to < 130 
121 to < 125 
121 to < 125 
чϭϮϬ 
чϭϮϬ 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0 to < 12.0 
0.59 to < 0.71 
12.0 to < 15.0 
0.71 to < 0.89 
ш 15.0 
ш 0.89 
 
 
Hematology 
 
 
 
13 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 










7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 1.6 to < 2.6 x ULN 2.6 to < 5.0 x ULN ш 5.0 x ULN 
Preterm Neonate20 
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, 
Term Neonate 
(based on days of 
age). 
Same as for Total 
Bilirubin, High, 
Term Neonate 
(based on days of 
age). 
Same as for Total 
Bilirubin, High, 
Term Neonate
(based on days of 
age). 
Same as for Total 
Bilirubin, High, 
Term Neonate
(based on days of 
age). 
32 to < 35 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
10 to < 14 
171 to < 239.4 
ш 14 
ш 239.4 
28 to < 32 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
6 to < 10 
102.6 to < 171 
 
< 28 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
5 to < 8 85.5 to 
< 136.8 
 
7 to 28 days of age 
(breast feeding) 
5 to < 10 
85.5 to < 171 
10 to < 20 
171 to < 342 
20 to < 25 
342 to < 427.5 
ш 25 
ш 427.5 
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 1.6 to < 2.6 x ULN 2.6 to < 5.0 x ULN ш 5.0 x ULN 
 

SAP_001.pdf: 
A Phase 2 Randomized, Single-Blind Study of a Single Dose of 
Peginterferon lambda-1a Compared with Placebo in Outpatients with Mild 
COVID-19 
Statistical Analysis Plan 
NCT04331899 
 September 14, 2020 


 
Electronically signed by: Haley Hedlin 
Reason: I am approving this document. 
Date: Sep 14, 2020 10:57 PDT 
 
 
 
 
 
Statistical Analysis Plan 
 
Study Name 
A Phase 2 Randomized, Single-Blind Study of a Single Dose of Peginterferon 
lambda-1a Compared with Placebo in Outpatients with Mild COVID-19 
 
Version Number 2.0 
 
Date 
14 September 2020 
 
 
 
 
 
Approved by: 
Manisha Desai 
 
 
 
Electronically signed by: Manisha Desai 
Reason: I am approving this document. 
Date: Sep 14, 2020 11:18 PDT 
 
 
Manisha Desai, PhD 
Co-Investigator & Faculty Biostatistician 
 
Haley Hedlin, PhD 
Lead Biostatistician 
 
Upinder Singh 
 
Electronically signed by: Upinder Singh 
Reason: I have reviewed this document. 
Date: Sep 14, 2020 11:32 PDT 
 
 
Upinder Singh, MD 
Principal Investigator 
 
 
 
 
Revision history 
 
Revision 
Date 
Section/Page 
Changes Made -- Reasons for the Change 
2.0 
9/14/20 
Throughout 
Updated to match Protocol version 3 
2.0 
9/14/20 
Sections 2 & 3 
Details added about statistical methods and 
missing data handling 


 
 
 
 
TABLE OF CONTENTS 
1 STUDY DETAILS 
3 
1.1 STUDY DESIGN 
3 
1.2 PRIMARY ENDPOINT 
3 
1.3 SECONDARY ENDPOINTS 
3 
1.4 EXPLORATORY ENDPOINTS 
3 
1.4 SAFETY ENDPOINTS 
4 
1.5 RANDOMIZATION SCHEME 
4 
2 ANALYSIS PLAN 
4 
2.1 ANALYSIS POPULATIONS 
4 
2.2 DESCRIPTIVE ANALYSES 
4 
2.3 PRIMARY EFFICACY ANALYSIS 
5 
2.4 SECONDARY EFFICACY ANALYSES 
5 
2.5 EXPLORATORY EFFICACY ANALYSES 
6 
2.6 SAFETY ANALYSES 
7 
2.7 EFFECT MODIFICATION, SUBGROUP, AND SENSITIVITY ANALYSES 
7 
3 HANDLING OF MISSING AND CENSORED DATA 
7 
4 SAMPLE SIZE CONSIDERATIONS 
8 
4.1 STATISTICAL HYPOTHESIS 
8 
4.2 DETERMINATION OF SAMPLE SIZE 
8 
5 INTERIM ANALYSIS 
8 
6 POTENTIAL LIMITATIONS AND MITIGATION STRATEGIES 
9 
7 REFERENCES 
9 


 
INTRODUCTION 
This statistical analysis plan (SAP) is a comprehensive and detailed description of the strategy, 
rationale, and statistical techniques that will be used in the study. 
1 STUDY DETAILS 
 
1.1 Study design 
This phase 2 randomized, single-blind study intends to evaluate the efficacy of a single dose of 
peginterferon lamba-1a in outpatients with mild COVID-19 compared with placebo in reducing 
the duration of shedding of SARS-CoV-2 virus. 
One hundred and twenty (60 per arm) enrolled patients will be randomized in a 1:1 fashion. 
Thus, there will be two arms: (1) the control arm, comprised of placebo in addition to standard 
supportive care and (2) the treatment arm, comprised of a single dose of peginterferon lamba-1a 
in addition to standard supportive care. An interim analysis for safety and overwhelming efficacy 
will be performed once 50% of patients have 24 hours of follow-up complete. 
The primary analysis is based on intent-to-treat principles in that all patients who are randomized 
to study arm are included in the analysis, where cessation of shedding is assessed according to 
randomized study arm. The secondary analysis of adverse events (AE) are assessed according to 
dose received. 
 
1.2 Primary endpoint 
The primary endpoint is time until cessation of oral shedding of SARS-CoV-2 virus, defined as 
the time in days from randomization to the first of two negative oropharyngeal tests. Patients 
who do not experience the endpoint will be censored at 28 days after randomization (end of 
study) or at the time of premature withdrawal. 
 
1.3 Secondary endpoints 
Secondary endpoints include the following: 
 Time until resolution of all symptoms;
 SARS-CoV-2 viral load over time in oropharyngeal tests;
 SARS-CoV-2 viral load area under the curve in oropharyngeal tests through Day 14;
 Number of emergency department visits or hospitalizations within 28 days of treatment.
 
1.4 Exploratory endpoints 
Exploratory endpoints include the following: 
 Time until sustained symptom resolution;
 Time until resolution of respiratory symptoms (cough, sore throat, runny nose, chest pain, 
and shortness of breath);


 
 
Time until resolution of systemic and respiratory symptoms (headache, fever/chills, 
muscle/joint pain, fatigue and respiratory symptoms described above);
 Time until disease progression;
 SARS-CoV-2 infection-free by negative RT PCR testing results from nasal swabs on 
Days 5, 7, 10, and 14;
 SARS-CoV-2 infection-free by negative RT PCR testing results from oropharyngeal 
swabs on Days 5, 7, 10, and 14;
 SARS-CoV-2 viral load over time in nasal tests;
 SARS-CoV-2 viral load area under the curve in nasal tests through Day 14;
 Seroconversion by Day 28 (presence of IgG antibodies to SARS-CoV-2 Spike Receptor 
Binding Domain, as measured by ELISA);
 Cellular immune responses;
 Host genetics.
 
1.4 Safety endpoints 
 
Safety endpoints include all adverse events by standardized DIADS AE grading criteria, vital 
signs, and clinical laboratory tests from time of randomization until the patient completes their 
study participation. 
 
1.5 Randomization scheme 
Patients will be randomized in a 1:1 ratio to the treatment and control arms. Randomization will 
be stratified by age (>=50 and <50 years old) and sex. 
 
2 ANALYSIS PLAN 
2.1 Analysis populations 
The intent-to-treat (ITT) population will include all randomized patients. Patients will be 
analyzed according to their assigned treatment arm. All efficacy analyses will be completed in 
the ITT population. 
The as-treated population will include all randomized patients. Patients will be analyzed 
according to the treatment actually received. 
 
2.2 Descriptive analyses 
Descriptive statistics (proportions for categorical variables, means, medians, standard deviations 
and interquartile ranges for continuous variables) will be reported for all key patient variables, 
including baseline and demographic characteristics, use of medications, compliance, and study 
completion status. Data that are missing on key patient characteristics and the outcome will be 
fully described, including any patterns of missingness (i.e., any relationships between 
missingness of a variable and patient characteristics). 


 
 
A CONSORT diagram displaying the number of patients screened, eligible, and consented along 
with reasons for ineligibility will be provided. Graphical tools such as histograms, boxplots, and 
scatterplots will be created to assess quality of data and to display patterns over time. 
All tests will be performed at the alpha = 0.05 level of significance unless otherwise noted. 
 
2.3 Primary efficacy analysis 
Time until shedding cessation will be compared between the two treatment arms using a two- 
sided Cox proportional hazards model adjusted for age and sex. The test will be performed at the 
alpha = 0.05 level of significance. The hazard ratio for shedding cessation will be estimated, 
along with its 95% confidence interval, from a Cox proportional hazards model. If the 
proportional hazards assumption is not met, we will consider an extended Cox model that relaxes 
the proportional hazards assumption. 
The distribution of shedding cessation will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves will be presented for each treatment arm. Time to shedding cessation at the 
end of the study period along with 95% confidence intervals will be presented for each treatment 
arm. 
 
2.4 Secondary efficacy analyses 
Time to resolution of all symptoms will be defined as the time from randomization until the first 
study day in which no symptoms are reported. The distribution of time to resolution of symptoms 
will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves will be presented for 
each treatment arm. Time to symptom resolution at the end of the study period along with 95% 
confidence intervals will be presented for each treatment arm. The hazard ratio for resolution of 
symptoms will be estimated, along with its 95% confidence intervals, from a Cox proportional 
hazards model adjusted for age and sex. 
We will model SARS-CoV-2 viral load in oropharyngeal tests over time using a generalized 
mixed effects linear regression model with a random effect for study participant to account for 
correlation within a participant. Viral load with cycle threshold (Ct) values above the limit of 
detection will be calculated by substituting a Ct value of 42 into the equation 10ሺ"#.%&&∗ሺሻ*൅൅.##,ሻ 
∗ 120 to derive viral load from Ct. A logarithmic transformation on viral load will be fit to 
treatment arm, time, armXtime, and adjusted for age and sex to account for the randomization 
stratification variables. The armXtime interaction term will allow us to assess whether the 
trajectory of viral load differs by treatment arm. Time will be defined as days from 
randomization and, depending on model fit, will either be modeled continuously or with a 
flexible approach allowing a non-linear trajectory for the change in viral load over time. Model 
fit will be assessed based on visual inspection of the residuals. Alternative transformations or 
generalized linear models with a link function besides the identity link will be considered if the 
model does not fit the data well. 


 
 
Area under the curve (AUC) will be defined by a single participant’s logarithmic base 10 viral 
load from oropharyngeal tests collected on days 0, 1, 3, 5, 7, 10, and 14. AUC will be calculated 
by the trapezoidal rule, using exact times of collection of each OP swab. Multiple imputation 
using chained equations will be used to impute missing viral load data prior to AUC calculation. 
Five data sets will be imputed, and imputed values will be calculated using non-missing viral 
load on each of the 7 sample collection days, treatment arm, age, sex, and whether or not a 
participant was hospitalized. A pooled linear regression model will be fit to log-transformed 
AUC as a function of treatment, age, and sex using the 5 imputed data sets. Difference in AUC 
by treatment arm and corresponding 95% confidence intervals will be reported using Rubin’s 
Rules. The difference in AUC by treatment arm will also be done after refitting the model 
without participants who were hospitalized to assess sensitivity of results. 
The incidence of hospitalizations and emergency department visits will be estimated for each 
arm, with 95% confidence intervals. 
 
2.5 Exploratory efficacy analyses 
An alternative definition of the secondary endpoint of symptom resolution will be considered in 
an exploratory analysis. We will evaluate time to sustained symptom resolution, defined as time 
from randomization until the first day in which no symptoms are reported and are not reported 
for the duration of the study. The analysis of time to sustained symptom resolution will follow 
the methods described for the secondary endpoint evaluation symptom resolution in the previous 
section. Time to symptom resolution based on symptom subsets (i.e. respiratory, systemic) will 
be similarly analyzed, additionally excluding participants who did not report symptoms from the 
specified subset at screening. 
Time to disease progression will be defined as the time from randomization until the first day of 
a two point or more increase in either cough or shortness of breath persisting for at least 48 hours 
or an increase to a score of 4 or 5, or first day of admission to the emergency department, 
hospitalization, or death. Analysis and reporting of results will be done following methods 
detailed for time to symptom resolution. 
Freedom from SARS-CoV-2 infection by oropharyngeal and nasal swabs at Day 5, 7, 10, and 14 
will be modeled using a multivariable logistic regression model adjusted for age and sex. The 
odds ratio will be presented along with its 95% confidence interval. 
Similar approaches to those used for evaluating SARS-CoV-2 viral load in oropharyngeal tests 
over time and AUC will be used to evaluate viral load in nasal tests. 
Correlation between virology and symptomology will be characterized by evaluating the 
relationship between CT values obtained from the oropharyngeal tests and each symptom 
through two main approaches. For symptoms graded on an ordinal scale, we will calculate a 
Spearman correlation and assess significance with a Z-test. For variables that capture presence of 
a symptom, differences in the median CT values by presence or absence of the symptom will be 
presented and assessed via a Wilcoxon rank sum test. 


 
 
2.6 Safety analyses 
The frequency of adverse events and serious adverse events will be tabulated by type and by 
treatment arm. AEs will be compared by arm using the Chi-squared test or Fisher’s exact test, as 
appropriate, in the safety analysis set. 
 
2.7 Effect modification, subgroup, and sensitivity analyses 
A subgroup analysis will be performed for the primary endpoint using only patients who present 
with symptoms at baseline. 
A statistical interaction term between treatment arm and the following baseline characteristics 
will be added to the Cox proportional hazards model to test for effect modification. 
1) CT value < 30 from the baseline OP swab, 
2) presence of antibodies as defined by presence of IgG antibodies to SARS-CoV-2 Spike 
Receptor Binding Domain (RBD) at baseline, as measured by ELISA. Samples are considered 
seropositive against RBD if their absorbance value was greater than the mean of plus four 
standard deviation (SD) of all negative controls (n=130), 
3) number of risk factors or predictors for severe disease present at baseline (temp 99.5+, cough, 
or shortness of breath present at randomization [symptoms count as a single risk factor], age ≥ 
60, male sex, Black race, Hispanic ethnicity, BMI  30, and lab values of baseline lymphocyte 
counts <1000 and baseline ALT  94), 
4) age ≥ 50, 
5) sex 
A Wald test performed at the alpha = 0.05 level of significance will be used to test whether the 
effect modification is statistically significant. The sensitivity and effect modification analyses 
will be performed in other key endpoints as well. 
 
3 HANDLING OF MISSING AND CENSORED DATA 
All efforts will be made to minimize instances of missing data. However, we expect some 
missing data will occur. Our analyses will assume data are missing at random. For the primary 
endpoint of time to shedding cessation, any participant who drops out prior to having two 
consecutive negative tests will be censored at their last positive test. Participants who have no 
post-randomization test results available or a single test result that is negative will be censored at 
day 1. Similarly, participants will be right censored for the time to symptom resolution or 
progression at the time when their last symptom questionnaire is completed. Participants who are 
asymptomatic at screening and never report symptoms thereafter will be considered to have met 
symptom resolution at study Day 1. For other missing data, we will use multiple imputation- 
based analyses. This approach will be applied to any analysis involving endpoints or key 


 
 
variables where any missing data occurs in order to adhere to the ITT principle. Sensitivity to 
assumptions regarding missingness will be addressed through sensitivity analyses. 
If more than 5% of participants do not have the time of shedding cessation observed (i.e. they are 
right-censored), we will perform a sensitivity analysis to evaluate the robustness of our findings 
to missing data assumptions. In the sensitivity analysis, among those missing timing of shedding 
cessation, we will assume varying proportions (e.g. 25%, 50%) of participants in each arm who 
would have ceased shedding by Day 28. The proportions will differ by arm so we can evaluate 
whether our findings stand if it were true that people who dropped out stopped shedding earlier 
in the placebo arm vs the active arm. 
4 SAMPLE SIZE CONSIDERATIONS 
 
4.1 Statistical hypothesis 
 
For the primary comparison, the following will be tested: 
 
 Null hypothesis: time to cessation of oral shedding is equal in control and treatment;
 Alternative hypothesis: time to cessation of oral shedding differs between control and 
treatment.
 
Hypothesis tests will be two sided and conducted at an overall alpha = 0.05 level of significance. 
 
4.2 Determination of sample size 
We assume that the mean duration of virologic shedding in individuals receiving standard of care 
is 14 days, with a standard deviation of 4 days1. 
Assuming 1:1 randomization and the use of a two-sided log rank test at the alpha=0.04999 level 
of significance for the final analysis, 79 events will provide 80% power to detect a hazard ratio 
of 2.03. This leaves alpha=0.00001 to check for overwhelming efficacy after 50% of participants 
have completed 24 hours of follow-up. Assuming the control and treatment arm median 
cessation of shedding is 14 and 7 days, respectively, a two-month accrual period, a two-week 
follow-up period after randomization of the last patient, and a drop out of 10% in the control 
arm, it is estimated that the total sample size required to achieve 79 events is 120 (60 patients in 
each arm). 
5 INTERIM ANALYSIS 
An interim analysis for safety and overwhelming efficacy will be performed once 50% of 
patients have 24 hours of follow-up complete. Enrollment will pause once 50% of patients have 
received treatment and will remain paused until the DSMC makes their recommendation after 
their safety review. The DSMC will meet one or two days after enrollment is paused to review 
the safety data collected within the first 24 hours of follow-up on all enrolled patients. We 


 
 
additionally expect blood count labs collected at day 5 to be available in approximately 25% of 
patients at the time of the DSMC review. 
The DSMC will also review the efficacy data on all randomized participants at this meeting. The 
interim efficacy analysis will use the same methods as are planned for the final analysis using the 
ITT analysis. Based on the results of the interim analysis, the DSMC will either recommend to 
the sponsor to terminate the study for overwhelming efficacy (p<0.00001 at the interim analysis), 
terminate the study for safety concerns, modify the study, or continue the study as planned. No 
formal stopping rules for futility are planned. 
 
6 POTENTIAL LIMITATIONS AND MITIGATION STRATEGIES 
Given the fast-changing landscape during the COVID-19 pandemic, we provide the following 
power calculations showing how potential study alterations would impact the study’s operating 
characteristics. Potential alterations considered are designed to mitigate the impact of newly 
identified therapies that change the standard of care and/or slower than planned enrollment. 
The study team plans to evaluate the rate of enrollment two weeks after enrollment opens. If 
fewer than 10 patients have been enrolled within the first two weeks, a potential solution to 
increase enrollment is to change the randomization ratio to be 2:1 on treatment:control. We have 
selected a 1:1 ratio under the assumption of equipoise; however, we anticipate that participants 
may not want to have a 50% chance of being randomized to placebo. To address this concern, we 
could increase the ratio in order to reduce the chance of being randomized to placebo to 33%. 
Under the assumptions described above, the change in the randomization ratio will not require a 
larger sample size. 
We also consider how a change in the standard of care could impact our study’s power. If the 
standard of care changes and our expected effect size decreases, our expected power would 
decrease to 61%, 41%, or 22% under an assumed hazard ratio of 1.8, 1.6, or 1.4, respectively. 
The impact of the change to the standard of care will depend on what proportion of patients have 
been enrolled. If the standard of care changes before enrollment is 90% complete, we will 
estimate the conditional power based on the current enrollment and the expected decrease in the 
effect size; we would not look at the blinded study data or outcome data to estimate the 
conditional power. If the conditional power is < 70%, the study will be modified by increasing 
the sample size such that the conditional power reaches 80%. If the total required sample size to 
reach 80% conditional power is greater than 180, the study will be stopped for futility. 
 
7 REFERENCES 
1. 
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID‐19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054‐1062. 
doi:10.1016/S0140‐6736(20)30566‐3