A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Study of Baricitinib in Patients With COVID-19 Infection
Phase: PHASE3
Conditions: COVID-19
Sponsor: Eli Lilly and Company

I4V-MC-KHAA Protocol (e) 
 
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Study of Baricitinib in Patients with 
COVID-19 Infection 
 
NCT04421027 
 
Approval Date: 25-Nov-2020 
 

CONFIDENTIAL
Protocol I4V-MC-KHAA(e)
1
Title Page
Confidential Information
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of baricitinib (LY3009104), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 
Study of Baricitinib in Patients with COVID-19 Infection
Protocol Number: I4V-MC-KHAA
Protocol Amendment Number:  E
Compound: baricitinib (LY3009104)
Study Phase: 3
Acronym: COV-BARRIER
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Regulatory Agency Identifier Numbers
IND: 149279
EudraCT: 2020-001517-21
Approval Date: Protocol Amendment (e) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 25-Nov-2020 GMT

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Protocol I4V-MC-KHAA(e)
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Medical monitor name and contact information will be provided separately.

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Protocol I4V-MC-KHAA(e)
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
18 May 2020
Amendment A
27 May 2020
Amendment B
03 Jun 2020
Amendment C
12 Aug 2020
Amendment D
20 Oct 2020
Amendment E
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
This protocol amendment addresses the sample size re-estimation and the addition of a 
subpopulation for the primary endpoint.  
Sections # and Name
Description of Change
Brief Rationale
1.1 Synopsis
Updated primary endpoint to match 
Section 3.0.
To provide additional data for the 
treatment of COVID-19
1.1 Synopsis
Changed sample size to 
approximately 1400 patients 
To evaluate disease progression in 
additional subpopulation of patients. 
3.0 Objectives and Endpoints
Added subpopulation for the primary 
endpoint to evaluate disease 
progression in all randomized 
patients or patients who, at baseline, 
require oxygen supplementation and 
are not receiving dexamethasone or 
other systemic corticosteroids for the 
primary study condition.
To provide additional data for the 
treatment of COVID-19.
4.1 Overall Design
Updated description to include the
two populations for the primary 
endpoint
To provide clarification of 
populations being evaluated.
4.2 Scientific Rationale
Added rationale for inclusion of 
additional subpopulation in the 
primary endpoint
To evaluate disease progression in 
patients requiring oxygen 
supplementation without use of 
dexamethasone or systemic 
corticosteroids at baseline. 
5.2 Exclusion Criteria
Added exclusion criteria for 
neutralizing antibodies
Based on recent Emergency Use 
Authorization approvals in the 
United States and potential to 
confound assessment of baricitinib’s 
antiviral activity.
9.1 Statistical Hypotheses
Added primary endpoint population
and hypotheses, and testing scheme.
To update statistical methods

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Protocol I4V-MC-KHAA(e)
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Sections # and Name
Description of Change
Brief Rationale
9.2 Sample Size Determination
Provided new assumptions for 
amendment E
To update the assumptions used to 
calculate the new sample size based 
on scenarios with two primary 
endpoints and differing assumptions 
about the effect of 
dexamethasone/corticosteroids on 
the treatment effect.
9.4.2 Primary Endpoint
Added statement about populations 
assessed
To reflect the inclusion of two 
populations for the primary 
endpoint.
Throughout the protocol
Minor editorial and formatting 
changes
Minor, therefore not described

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Protocol I4V-MC-KHAA(e)
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Table of Contents
1.
Protocol Summary......................................................................................................8
1.1.
Synopsis.......................................................................................................................8
1.2.
Schema.......................................................................................................................11
1.3.
Schedule of Activities (SoA) ......................................................................................12
2.
Introduction..............................................................................................................22
2.1.
Study Rationale ..........................................................................................................22
2.2.
Background ................................................................................................................23
2.3.
Benefit/Risk Assessment ............................................................................................24
3.
Objectives and Endpoints.........................................................................................27
4.
Study Design .............................................................................................................29
4.1.
Overall Design............................................................................................................29
4.2.
Scientific Rationale for Study Design .........................................................................30
4.3.
Justification for Dose..................................................................................................31
4.4.
End-of-Study Definition .............................................................................................32
5.
Study Population ......................................................................................................33
5.1.
Inclusion Criteria........................................................................................................33
5.2.
Exclusion Criteria.......................................................................................................34
5.3.
Lifestyle Considerations .............................................................................................36
5.4.
Screen Failures...........................................................................................................36
5.4.1.
Allowed Retesting of Screening Investigations ...........................................................36
5.4.2.
Rescreening of Individuals Who Failed Screening ......................................................36
6.
Study Intervention....................................................................................................37
6.1.
Study Interventions Administered...............................................................................37
6.2.
Preparation/Handling/Storage/Accountability.............................................................37
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................38
6.4.
Study Intervention Compliance...................................................................................39
6.5.
Concomitant Therapy .................................................................................................39
6.5.1.
Prior Medications .......................................................................................................40
6.5.2.
Required and Permitted Concomitant Therapy............................................................40
6.5.3.
Prohibited Concomitant Therapy ................................................................................40
6.6.
Dose Modification......................................................................................................41
6.7.
Intervention after the End of the Study........................................................................41
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................42
7.1.
Discontinuation of Study Intervention ........................................................................42
7.1.1.
Criteria for Permanent Discontinuation of Study Drug................................................42
7.1.2.
Criteria for Temporary Interruption (Withholding) of Study Drug...............................44
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................44
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................45
7.3.
Lost to Follow-up .......................................................................................................45
8.
Study Assessments and Procedures .........................................................................46
8.1.
Efficacy Assessments .................................................................................................46

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Protocol I4V-MC-KHAA(e)
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8.1.1.
COVID-19 Clinical Status Assessment .......................................................................46
8.1.2.
Ordinal Scale..............................................................................................................46
8.1.3.
Other Efficacy Assessments........................................................................................47
8.2.
Safety Assessments ....................................................................................................49
8.2.1.
Vital Signs..................................................................................................................50
8.2.2.
Physical Examinations................................................................................................50
8.2.3.
Electrocardiograms.....................................................................................................51
8.2.4.
Chest Imaging Studies ................................................................................................51
8.2.5.
Laboratory Tests.........................................................................................................51
8.2.6.
Hepatic Safety Monitoring..........................................................................................52
8.3.
Adverse Events and Serious Adverse Events ..............................................................52
8.3.1.
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ............................................................................53
8.3.2.
Method of Detecting Adverse Events and Serious Adverse 
Events.........................................................................................................................53
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events .........................................53
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events................................54
8.3.5.
Pregnancy...................................................................................................................54
8.3.6.
Special Assessments of Infections and Venous Thromboembolic 
Events.........................................................................................................................54
8.3.7.
Complaint Handling ...................................................................................................54
8.4.
Treatment of Overdose ...............................................................................................55
8.5.
Pharmacokinetics........................................................................................................55
8.6.
Pharmacodynamics.....................................................................................................56
8.7.
Genetics .....................................................................................................................56
8.8.
Biomarkers.................................................................................................................56
8.9.
Immunogenicity Assessments.....................................................................................57
8.10.
Medical Resource Utilization and Health Economics..................................................57
9.
Statistical Considerations.........................................................................................58
9.1.
Statistical Hypotheses.................................................................................................58
9.2.
Sample Size Determination.........................................................................................59
9.3.
Populations for Analyses ............................................................................................60
9.4.
Statistical Analyses.....................................................................................................60
9.4.1.
General Considerations...............................................................................................60
9.4.2.
Primary Endpoint........................................................................................................63
9.4.3.
Secondary Endpoints ..................................................................................................63
9.4.4.
Safety Analyses ..........................................................................................................63
9.4.5.
Pharmacokinetic Analysis...........................................................................................64
9.5.
Interim Analyses.........................................................................................................64
9.6.
Data Monitoring Committee (DMC)...........................................................................65
10.
Supporting Documentation and Operational Considerations ................................66
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................66
10.1.1.
Regulatory and Ethical Considerations........................................................................66
10.1.2.
Financial Disclosure ...................................................................................................66
10.1.3.
Informed Consent Process ..........................................................................................67

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Protocol I4V-MC-KHAA(e)
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10.1.4.
Data Protection...........................................................................................................67
10.1.5.
Committee Structure...................................................................................................68
10.1.6.
Dissemination of Clinical Study Data .........................................................................68
10.1.7.
Data Quality Assurance ..............................................................................................68
10.1.8.
Source Documents......................................................................................................70
10.1.9.
Study and Site Start and Closure.................................................................................70
10.1.10. Publication Policy.......................................................................................................71
10.1.11. Investigator Information .............................................................................................71
10.1.12. Long-Term Sample Retention.....................................................................................71
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................72
10.2.1.
Clinical Laboratory Tests............................................................................................72
10.2.2.
Clinical Laboratory Calculations.................................................................................74
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................75
10.3.1.
Definition of AE.........................................................................................................75
10.3.2.
Definition of SAE.......................................................................................................76
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................77
10.3.4.
Reporting of SAEs......................................................................................................78
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................79
10.4.1.
Definitions..................................................................................................................79
10.4.2.
Contraception .............................................................................................................79
10.4.3.
Collection of Pregnancy Information ..........................................................................80
10.5.
Appendix 5: Abbreviations .........................................................................................82
10.6.
Appendix 6: Protocol Amendment History .................................................................86
11.
References.................................................................................................................96

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Protocol I4V-MC-KHAA(e)
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 
Study of Baricitinib in Patients with COVID-19 Infection
Rationale: 
Baricitinib, an approved therapy for the treatment of moderately to severely active rheumatoid 
arthritis (RA) in adults, is being proposed as a potential therapy for patients with COVID-19
infection. The proposed mechanism of action in COVID-19 infection includes reduction of
cytokine-mediated inflammation and the potential for antiviral activity.
There are currently no approved therapies for the treatment of COVID-19 infection. 
Management of COVID-19 is supportive, and respiratory failure from acute respiratory distress 
syndrome (ARDS) is the leading cause of mortality. The cause of ARDS is a hyperinflammatory 
state characterized by upregulation of multiple cytokines. Baricitinib, an orally administered 
inhibitor of JAK1 and JAK2, could be a therapeutic option for this condition because of the 
potential to inhibit signaling from multiple cytokines that are implicated in COVID-19 ARDS
(McInnes et al. 2019). In patients with RA, treatment with the 4-mg dose of baricitinib resulted 
in a reduction from baseline in serum IL-6 at Week 12 in a Phase 2, randomized, placebo-
controlled study of baricitinib (Stebbing et al. 2020). The potent anti-inflammatory effects of 
baricitinib have also been demonstrated by the reduction of serum levels of IFN-γ, IP-10, GM-
CSF and MCP-1 in pediatric patients with steroid-dependent chronic inflammation, resulting in 
the ability to wean or taper steroids (Sanchez et al. 2018).
In addition to the anti-cytokine effect, baricitinib has recently been hypothesized (Richardson et 
al. 2020) and shown (Stebbing et al. 2020) to be a potent inhibitor of numb-associated kinases 
(NAKs), which include AAK1, GAK, and BIKE. These proteins play a critical role in the host 
epithelial cell to facilitate propagation of viruses, including SARS-CoV-2, that rely on the 
scaffold protein known as activator protein 2 (AP2). Inhibiting the NAK proteins that activate 
the AP2 scaffolding protein vital to viral entry and propagation could be one therapeutic 
approach to managing COVID-19 infection.
The rationale for study treatment for up to 14 days is based on the known onset of efficacy in the 
RA population, which is as early as 1 week (Olumiant Summary of Product Characteristics), and
on the expected duration of treatment needed for an acute infection such as COVID-19. 
Recently, data were published on a case series describing a 14-day treatment course of baricitinib 
in patients with mild to moderate COVID-19 infection (Cantini et al. 2020).
Baricitinib is administered orally once a day. It has a short half-life (approximately 12 hours in 
RA patients), so treatment can be interrupted or stopped if necessary. It has few drug-drug 
interactions (due to low CYP inhibitory activity) so it can be given concomitantly with 
background therapies. Baricitinib has a well-established safety profile, based on clinical trial data 
and postmarketing data in patients with RA.
This profile, together with the observation that baricitinib is a potent AAK1/BIKE/GAK 
inhibitor with known anti-cytokine profile, provide the rationale to study baricitinib in the 
context of a randomized, controlled clinical trial in patients with COVID-19 infection.

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Protocol I4V-MC-KHAA(e)
9
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the effect of baricitinib 4-mg once 
daily (QD) compared to placebo on disease 
progression in patients with COVID-19 infection
Proportion of patients who die or require non-invasive 
ventilation/high-flow oxygen or invasive mechanical ventilation 
(including extracorporeal membrane oxygenation [ECMO]) by Day 
28 in these 2 populations

Population 1 - all randomized patients 

Population 2 – patients who, at baseline, require oxygen 
supplementation and are not receiving dexamethasone or 
other systemic corticosteroids for the primary study 
condition.
Key Secondary
To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on clinical outcomes in 
patients with COVID-19 infection
Proportion of patients with at least 1-point improvement on NIAID-
OS or live discharge from hospital at Day 4, Day 7, Day 10, Day 14
Number of ventilator-free days (Day 1 to Day 28)
Time to recovery (NIAID-OS) (Day 1 to Day 28)
Overall improvement on the NIAID-OS evaluated at Day 4, Day 7, 
Day 10, Day 14
Duration of hospitalization (Day 1 to Day 28)
Proportion of patients with a change in oxygen saturation from 
<94% to ≥94% from baseline to Day 4, Day 7, Day 10, Day 14
All-cause mortality (Day 1 to Day 28)
Overall Design
Study I4V-MC-KHAA (KHAA) is Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of 
baricitinib 4-mg given once daily (QD). The primary endpoint is the proportion of patients who 
die or require non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation 
(including extracorporeal membrane oxygenation [ECMO]) by Day 28.
The study duration will be up to approximately 60 days over 3 study periods:
Screening: on Day 1 prior to dosing
Treatment period: treatment is administered for up to 14 days, or up to the day of hospital 
discharge, whichever comes first, followed by treatment evaluations up to Day 28
Follow-up: Period starting after treatment evaluation, with a follow-up visit 
approximately 28 days after last dose of study drug and another follow-up visit at
approximately Study Day 60.
Disclosure Statement: 2-arm parallel treatment period, participant-blinded and 
investigator-blinded.

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Protocol I4V-MC-KHAA(e)
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Number of Participants: Approximately 1400 patients are planned to be randomized, with the 
potential to increase the final sample size, if indicated, at an interim analysis to maintain an 
adequately powered study.
Intervention Groups:
At baseline, participants will be randomized in a 1:1 ratio to one of two treatments groups: either 
baricitinib or placebo.
Both treatment groups will receive background therapy in keeping with local clinical practice for 
management of COVID-19 infection.
Data Monitoring Committee: Yes

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Protocol I4V-MC-KHAA(e)
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1.2.
Schema
Note: Dosing occurs from the day of randomization until Day 14, or until hospital discharge, whichever comes first.  
Placebo or baricitinib are given with background therapy in keeping with local clinical practice for management of COVID-19, as defined in the protocol.
Abbreviations: D = study day; QD = once daily.
Figure 1. Schema of Study I4V-MC-KHAA.

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Protocol I4V-MC-KHAA(e)
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1.3.
Schedule of Activities (SoA)
Day 1 procedures may be conducted over more than 1 day, as long as all activities are completed within the allowed interval tolerance.
Activities at the first follow-up visit (28 days after last dose) are required for all randomized patients and can be conducted as a 
telephone visit. Activities at the second follow-up visit (on Study Day 60) are also required for all randomized patients and can be 
conducted as a telephone visit. If a telephone visit is conducted after hospital discharge, assessments will include: concomitant 
medications, adverse events, COVID-19 clinical symptoms, and Clinical Status Assessment. Collection of laboratory samples is 
preferred at designated timepoints, but it will not be a protocol deviation if, after hospital discharge, phone visits are conducted and
laboratory samples are not collected because the visits are by telephone. See the Comments column for details about daily collection 
of clinical assessments and vital signs.
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Informed consent
X
Inclusion and exclusion criteria
X
Demographics
X
Pre-existing conditions and 
medical history, including 
relevant surgical history
X
Obtained from interview or available 
information, for example, medical 
records.

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Protocol I4V-MC-KHAA(e)
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Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Prespecified medical history: 
comorbidities
X
Includes comorbidities such as, but not 
limited to, diabetes, hypertension, 
cardiovascular disease, underlying 
pulmonary disease.
Prespecified medical history: 
COVID-19
X
Includes COVID-19 diagnosis date and 
onset of COVID-19 symptoms.
Prior treatments of special 
interest within last 2 weeks
X
Includes NSAIDs, antivirals, 
antibiotics, antimalarials, 
corticosteroids, herpes zoster vaccine, 
immunosuppressive medications.
Substance use (tobacco use)
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Assess daily. Includes medications of 
interest: background therapy, 
supportive care, sedating/paralytic
drugs, and VTE prophylaxis.
Adverse events (AEs)
X
X
X
X
X
X
X
X
X
Assess daily. AE collection begins 
when ICF is signed. For infections and 
VTEs, additional data are collected
(Section 8.3.6).
COVID-19 clinical symptoms
X
X
X
X
X
X
X
X
X
Assess daily while hospitalized and on 
day of visits after discharge.

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Protocol I4V-MC-KHAA(e)
14
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Clinical Assessments
Height
X
May be as measured or reported.
Weight
X
Vital signs
X
X
X
X
X
X
X
Assess and document daily while 
hospitalized. Includes: respiratory rate 
and oxygen saturation, blood pressure, 
body temperature, heart (pulse) rate. 
See Section 8.2.1.
Physical examination
X
The complete physical exam is 
performed if feasible (excludes pelvic, 
rectal, and breast exams). An
assessment of risk factors for 
tuberculosis (TB) is included (Section 
8.2.2).
Symptom-directed physical 
examination 
X
X
X
X
X
X
See Section 8.2.2.
Chest imaging (CT scan or 
x-ray) (local)
X
X
X
X
Assessed by radiologist or 
pulmonologist (Section 8.2.4).
Documentation of hospital-based 
imaging prior to study entry, obtained 
up to 24 hours prior to study entry is 
acceptable.

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Protocol I4V-MC-KHAA(e)
15
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
12-lead ECG (local)
X
Performed and assessed locally. 
Documentation of hospital-based ECG 
prior to study entry, up to 24 hours 
prior to study entry is acceptable 
(Section 8.2.3).
Clinician-Administered 
Assessments Paper
Clinical Status Assessment
X
X
X
X
X
X
X
X
Document daily through Day 29. 
Includes status of oxygen/life support 
procedures and proning.
Assessment for the NEWS
X
X
X
X
X
X
X
Document daily.
Laboratory Tests and Sample 
Collections
For laboratory tests and sample 
collections, the timing can be +1 day or 
-1 day from the designated day, unless 
otherwise specified.
Hematology
X
X
X
X
X
X
X
X
Performed locally. Tests performed in 
the 24 hours prior to study entry will be 
accepted for determination of 
eligibility. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF.

CONFIDENTIAL
Protocol I4V-MC-KHAA(e)
16
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Laboratory Tests and Sample 
Collections (continued)
For laboratory tests and sample 
collections, the timing can be +1 day or 
-1 day from the designated day, unless 
otherwise specified.
Clinical chemistry, including 
creatine kinase (CK)
X
X
X
X
X
X
X
X
Performed locally. Tests performed in 
the 24 hours prior to study entry will be 
accepted for determination of 
eligibility. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF.
Lactate dehydrogenase (LDH)
X
X
X
X
X
X
X
X
Performed locally. Test performed 
within 2 days prior to study entry will 
be accepted for determination of 
eligibility. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF.
Cardiac troponin
X
X
X
X
X
X
X
X
Performed locally. Tests performed in 
the 24 hours prior to study entry will be 
accepted. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF.

CONFIDENTIAL
Protocol I4V-MC-KHAA(e)
17
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Laboratory Tests and Sample 
Collections (continued)
For laboratory tests and sample collections, 
the timing can be +1 day or -1 day from the 
designated day, unless otherwise specified.
eGFR (MDRD)
X
X
X
X
X
X
X
X
Performed locally. Test performed in 
the 24 hours prior to study entry will be 
accepted for determination of 
eligibility. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF. If eGFR ≥30 to <60 
mL/min/1.73 m2 at screening, patient 
will receive blinded 2-mg dose 
(baricitinib or placebo) for the duration 
of the treatment period. See Sections 
6.1 and 6.6 for dose modification if 
eGFR decreases to <60 mL/min/1.73 
m2 after study entry. See Section 7.1.2
for temporary interruption criteria.
Serum pregnancy
X
Required prior to randomization. 
Performed locally. Test performed in 
the 24 hours prior to study entry will be 
accepted for determination of 
eligibility. Only for WOCBP (Section 
8.2.5.1, Appendix 10.4).

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Protocol I4V-MC-KHAA(e)
18
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Laboratory Tests and Sample 
Collections (continued)
For laboratory tests and sample collections, 
the timing can be +1 day or -1 day from the 
designated day, unless otherwise specified.
Pharmacokinetic (PK) samples
X
Samples should be collected on all 
intubated patients in ICU if lab kits 
available. Timing starts on the first day 
of invasive mechanical ventilation.
Samples on first day of intubation:
15 minutes, 1 hour, and any time 
between 2-4 hours (all post-dose).
Samples on third day of intubation: 
pre-dose; then 30 minutes, and any 
time between 6-10 hours post-dose.
If collection on the third day of 
intubation is not possible, PK 
sample collection can be done on a 
later day.
Central laboratory.
Erythrocyte sedimentation rate 
(ESR)
X
X
X
X
X
X
X
X
Performed locally. Test performed in 
the 24 hours prior to study entry will be 
accepted. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF.

CONFIDENTIAL
Protocol I4V-MC-KHAA(e)
19
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Laboratory Tests and Sample 
Collections (continued)
For laboratory tests and sample collections, 
the timing can be +1 day or -1 day from the 
designated day, unless otherwise specified.
C-reactive protein (CRP)
X
X
X
X
X
X
X
X
Performed locally. If available, 
high-sensitivity (hs-CRP) is preferred. 
Test performed within 2 days prior to 
study entry will be accepted for 
determination of eligibility. 
Unscheduled collection, if clinically 
warranted, will be entered into the 
eCRF.
Ferritin
X
X
X
X
X
X
X
X
Performed locally. Test performed 
within 2 days prior to study entry will 
be accepted for determination of 
eligibility. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF.
D-dimer
X
X
X
X
X
X
X
X
Performed locally. Test performed 
within 2 days prior to study entry will 
be accepted for determination of 
eligibility. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF.

CONFIDENTIAL
Protocol I4V-MC-KHAA(e)
20
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Laboratory Tests and Sample 
Collections (continued)
For laboratory tests and sample collections, 
the timing can be +1 day or -1 day from the 
designated day, unless otherwise specified.
Procalcitonin
X
X
X
X
X
X
X
X
Performed locally. Test performed in 
the 24 hours prior to study entry will be 
accepted for determination of 
eligibility. Unscheduled collection, if 
clinically warranted, will be entered 
into the eCRF.
SARS-CoV-2 viral infection 
confirmation via NP swab
X
X
X
X
X
X
X
Performed locally. Test performed 
during current hospitalization (prior to 
study entry) will be accepted for 
determination of eligibility per 
inclusion criteria requirements.
Collection of NP swab is at 
investigator’s discretion at other 
timepoints and will not be considered 
protocol deviation if not done.
Exploratory biomarker 
samples: serum, whole blood
X
X
X
X
X
Obtained and sent to the Lilly-
designated laboratory. Refer to Section 
8.8 for additional information.
Exploratory biomarker sample: 
nasopharyngeal swab
X
X
X
X
X
X
Obtained and sent to the Lilly-
designated laboratory. Refer to Section 
8.8 for additional information.

CONFIDENTIAL
Protocol I4V-MC-KHAA(e)
21
Study day
1
4
7
10
14
28
Follow-up 
(28 Days 
after Last 
Dose)
Follow-up 
Day 60
ETV
Unsched
uled
Comments
Interval tolerance (days)
≤3
—
—
—
—
—
±4
+7
—
—
If patient is discharged from hospital, the 
study visit may include a visit interval 
tolerance (window) of ±2 at Study Day 4, 
Day 7, Day 10, Day 14, and Day 28.
Site Visit
X
X
X
X
X
Site visit is preferred after discharge, but 
telephone visit is acceptable after discharge 
and should include collection of 
concomitant medications, adverse events, 
COVID-19 clinical symptoms, and Clinical 
Status Assessment. Failure to conduct 
activities that cannot be reasonably 
performed over the telephone will not be 
considered a protocol deviation.
Telephone Visit
X
X
Randomization
X
Dosing daily from randomization 
through Day 14, or until patient is 
discharged from hospital, whichever 
comes first.
Abbreviations: CT = computerized tomography; eCRF = electronic case report form; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; 
ETV = early termination (discontinuation) visit; ICU = intensive care unit; ICF = informed consent form; MDRD = Modification of Diet in Renal Disease; 
NEWS = National Early Warning Score; NP = nasopharyngeal; NSAIDs = nonsteroidal anti-inflammatory drugs; VTE = venous thromboembolism; WOCBP 
= women of childbearing potential.

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Protocol I4V-MC-KHAA(e)
22
2.
Introduction
2.1.
Study Rationale
Baricitinib, an approved therapy for the treatment of moderately to severely active rheumatoid 
arthritis (RA) in adults, is being proposed as a potential therapy for patients with COVID-19
infection. The proposed mechanism of action in COVID-19 infection includes reduction of 
cytokine-mediated inflammation and the potential for antiviral activity.
There are currently no approved therapies for the treatment of COVID-19 infection.
Management of COVID-19 is supportive, and respiratory failure from acute respiratory distress 
syndrome (ARDS) is the leading cause of mortality. The cause of ARDS is a hyperinflammatory 
state characterized by upregulation of multiple cytokines. For example, COVID-19 infected 
patients admitted to the intensive care unit (ICU) in Wuhan, China, exhibited increased plasma 
concentrations of IL-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP1A, and TNFα, compared to the 
non-ICU patients (Huang et al. 2020). Elevated IL-6 and hyperferritinemia were predictors of 
death in COVID-19 patients in China (Chen X et al. 2020; Chen T et al. 2020; Mehta et al. 2020; 
Ruan et al. 2020). 
Baricitinib, an orally administered inhibitor of JAK1 and JAK2, could be a therapeutic option for 
this condition because of the potential to inhibit signaling from multiple cytokines that are 
implicated in COVID-19 ARDS (McInnes et al. 2019). In patients with RA, there was a dose-
dependent reduction in plasma IL-6 at Week 12 in a Phase 2, randomized, placebo-controlled, 
study of baricitinib (Stebbing, et al. 2020). In ex vivo studies, there was a similar dose-dependent 
effect on inhibition of multiple cytokines implicated in COVID-19 infection. The potent 
anti-inflammatory effects of baricitinib have also been demonstrated by the reduction of serum 
levels of IFN-γ, IP-10, GM-CSF and MCP-1 in pediatric patients with steroid-dependent chronic 
inflammation, resulting in control of disease activity and the ability to wean or taper steroids
(Sanchez et al. 2018).
In addition to the anti-cytokine effect, baricitinib has recently been hypothesized (Richardson 
et al. 2020) and shown (Stebbing et al. 2020) to be a potent inhibitor of numb-associated kinases 
(NAKs), which include AAK1, GAK, and BIKE. These proteins play a critical role in the host 
epithelial cell to facilitate propagation of viruses, including SARS-CoV-2, that rely on the 
scaffold protein known as activator protein 2 (AP2). Inhibiting the NAK proteins that activate 
the AP2 scaffolding protein vital to viral entry and propagation could be one therapeutic 
approach to managing COVID-19 infection.
The rationale for study treatment for up to 14 days is based on the known onset of efficacy in the 
RA population, which is as early as 1 week (Olumiant Summary of Product Characteristics), and
on the expected duration of treatment needed for an acute infection such as COVID-19. 
Recently, data were published on a case series describing a 14-day treatment course of baricitinib 
in patients with mild to moderate COVID-19 infection (Cantini et al. 2020).
Baricitinib is administered orally once a day. It has a short half-life (approximately 12 hours in 
RA patients), so treatment can be interrupted or stopped if necessary. It has few drug-drug 
interactions (due to low CYP inhibitory activity) so it can be given concomitantly with 

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Protocol I4V-MC-KHAA(e)
23
background therapies. Baricitinib has a well-established safety profile, based on clinical trial data 
and postmarketing data in patients with RA (Olumiant United States package insert, 2020; 
Olumiant Summary of Product Characteristics).
This profile, together with the observation that baricitinib is a potent AAK1/BIKE/GAK 
inhibitor and the known anti-cytokine profile, provide the rationale to study baricitinib in the 
context of a randomized, controlled clinical trial in patients with COVID-19 infection.
2.2.
Background
In December 2019, a life-threatening infectious disease first observed in Wuhan, China, and later 
identified as COVID-19 has rapidly spread, causing a global pandemic. According to the World 
Health Organization (WHO), as of 20 April 2020, 2,314,621 confirmed cases have been reported 
worldwide with 157,847 deaths (WHO COVID-19 Situation Report 91).
COVID-19 belongs to the coronavirus family of single-stranded RNA viruses that can cross 
species barriers and can cause illness ranging from the common cold to more severe diseases 
such as SARS and MERS. Transmission of COVID-19 is believed to occur through respiratory 
droplets from coughing and sneezing. The pathogenesis is unclear, but the virus seems capable of 
producing an excessive immune reaction, which results in extensive tissue damage (Rothan and 
Byrareddy 2020).
The majority of individuals infected with COVID-19 experience a mild respiratory disease 
generally affecting the lower airways; symptoms usually appear after an incubation period of 
approximately 5 days. The most common symptoms at onset include fever, fatigue, and dry 
cough. Other signs and symptoms include myalgia, headache, diarrhea, nausea, dyspnea, 
lymphopenia, prolonged thrombin time, elevated lactate dehydrogenase, elevated alanine 
transaminase, and creatine kinase, and bilateral infiltrates on chest imaging. Patients can 
deteriorate rapidly. The median time from first symptoms to hospitalization is 7 days (Wang D et 
al. 2020).
Huang et al. (2020) reported that 27% of hospitalized patients diagnosed with COVID-19
infection in China developed ARDS after 9 days from onset of symptoms requiring oxygen 
therapy and intensive care. Some patients have laboratory evidence of a severe inflammatory 
response, similar to the cytokine release syndrome, with persistent fever, elevated inflammatory 
markers (hs-CRP, D-dimer, ferritin), and multiple organ dysfunction (Guan et al. 2020; Chen T 
et al. 2020). The major complications during hospitalization include ARDS, arrhythmia, and 
shock. Disease severity and mortality appears to be associated with those over the age of 70 and 
individuals with underlying comorbidities such as diabetes, hypertension, cardiovascular disease, 
chronic renal disease, and chronic lung disease (Chen N et al. 2020; Guan et al. 2020; Rothan 
and Byrareddy 2020; Wang W et al. 2020).
There is no approved or standard-of-care treatment for COVID-19 infection; medical 
management is based on supportive care. As stated in the guidelines of the United States
Institutes of Health (NIH) and the World Health Organization (WHO), no drug to date has been 
proven safe and effective for treating COVID-19 infection. Furthermore, there are insufficient 
data to recommend either for or against the use of any antiviral or immunomodulatory therapy in 
patients with COVID-19 infection. As a result of the RECOVERY trial (NCT04381936; Horby 
et al. 2020), the WHO and NIH guidelines recommend use of corticosteroids in patients with

CONFIDENTIAL
Protocol I4V-MC-KHAA(e)
24
severe COVID-19 infection, specifically for patients who require oxygen supplementation or 
who are on invasive mechanical ventilation. (WHO 2020b; NIH 2020b). The use of NSAIDs has 
been questioned since patients who were treated with NSAIDs early in their course of infection 
have progressed.
2.3.
Benefit/Risk Assessment
Baricitinib, which is an approved therapy for the treatment of moderately to severely active RA 
in adults, is being proposed as a potential therapy for COVID-19. The proposed mechanism of 
action includes reduced cytokine-mediated inflammation and the potential for antiviral activity.
Patients diagnosed with COVID-19 infection who are candidates for entry into Study KHAA 
will be at an elevated risk for excess morbidity and mortality due to the underlying SARS-CoV-2 
infection and subsequent cytokine activation. Of hospitalized patients with COVID-19 infection 
in Wuhan, China, 26% were transferred to the intensive care unit (ICU), and of those patients in 
the ICU, complications included acute respiratory distress syndrome (61.1%), arrhythmia 
(44.4%), and shock (30.6%) (Wang D et al. 2020). In addition, these patients will inherently be 
at higher risk for venous thromboembolism (VTE) due to immobilization and the 
hyperinflammatory state (Klok et al. 2020; Chen N et al. 2020; Huang et al. 2020). 
As stated in the study rationale, the cytokine storm that may be responsible for the significant 
complications will potentially be ameliorated by immunomodulators such as the use of
baricitinib. The potential benefit of baricitinib in the treatment of COVID-19 infection is 
described further in the study rationale (Section 2.1).
Baricitinib is a Janus kinase (JAK) inhibitor approved for the treatment of RA. In the US, 
baricitinib 2-mg is indicated for the treatment of adult patients with moderately to severely active 
RA who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist 
therapies. In Europe, baricitinib 4-mg is indicated for the treatment of moderate to severe active 
RA in adult patients who have responded inadequately to, or who are intolerant to one or more 
disease-modifying anti-rheumatic drugs. Baricitinib is currently under development in other 
autoimmune conditions including atopic dermatitis, alopecia areata, systemic lupus 
erythematosus, and juvenile idiopathic arthritis.
The United States product labeling indicates a boxed warning for the risk of serious infections, 
malignancies, and thrombosis, while warnings and precautions include serious infections, 
thrombosis, gastrointestinal perforations, abnormal laboratory assessments (potential changes in 
lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids), and avoidance with the use of 
live vaccines.
The Summary of Product Characteristics indicates as special warning and precautions for 
infections, including tuberculosis (TB), hematological abnormalities, viral reactivation, use of 
live vaccines, increase in blood lipid parameters, increase in hepatic transaminase, malignancy, 
VTE, hypersensitivity, and use of baricitinib with potent immunosuppressive medications.
Baricitinib has an established safety profile with a positive benefit/risk profile in RA. An 
integrated analysis of patients with active RA exposed to baricitinib with 3770 patients and 
10,127 patient-years for a maximum exposure of 7 years (as of February 2018) was recently 
published (Genovese et al. 2019). No significant differences were seen for baricitinib 4-mg 
versus placebo in adverse events leading to permanent drug discontinuation, death, malignancy, 

CONFIDENTIAL
Protocol I4V-MC-KHAA(e)
25
serious infection, or major adverse cardiovascular events. Malignancy (excluding non-melanoma 
skin cancer) incidence rates (IRs) per 100 patient-years were 0.8 (2-mg) and 1.0 (4-mg; as-
randomized analysis). Fewer than 1% of patients discontinued due to abnormal laboratory 
results.
Specifically regarding VTE, during the 16-week placebo-controlled period of RA studies, the IRs
per 100 patient-years for deep vein thrombosis (DVT)/pulmonary embolism (PE) were 
numerically higher in baricitinib 4-mg (IR=1.7) versus both baricitinib 2-mg and placebo (IR=0). 
With long-term exposures, the exposure-adjusted IR of VTE for baricitinib-treated patients with 
RA was similar to the background rates published in the literature for the target population. 
Cases observed with baricitinib were confounded by 1 or more recognized risk factors for VTE 
and the time to onset of an event ranged from 37 to 1658 days.
VTE has been classified as an important potential risk for baricitinib and is also an adverse drug 
reaction. Mitigation of the risk of venous thromboembolism will be managed through the 
appropriate exclusion and discontinuation criteria which limit participation of patients who are at 
an increased risk of VTE (Section 5.2, Section 7.1.1). The addition of VTE prophylaxis to all 
patients enrolled in this study unless there is a contraindication will also reduce the potential risk
(Section 6.5.2).
During the 16-week treatment period of RA studies, overall infections were numerically 
increased with IRs per 100 patient-years of 100.1 events, 99.1 events and 82.1 events in 
baricitinib 4-mg, baricitinib 2-mg, and placebo respectively. However, serious infections for the 
16-week treatment period were similar between baricitinib 4-mg, baricitinib 2-mg, and placebo 
(IRs per 100 patient-years 3.7, 3.6 and 4.2 respectively). The frequency of Herpes zoster was 
higher for baricitinib 4-mg versus placebo (1.4 vs 0.4) and for baricitinib 4-mg versus
baricitinib 2-mg (1.4 vs 1.0).  
There are provisions in the protocol to mitigate risk from potential concurrent infections,
including allowance of appropriate use of standard-of-care for treatment of infections and criteria 
for permanent discontinuation of study drug if the patient is diagnosed with active tuberculosis, 
hepatitis B, or hepatitis C (Section 6.5.2, Section 7.1.1). Permanent discontinuation of study drug
will also occur if a participant develops a serious adverse event which, in the opinion of the 
investigator or sponsor, would preclude the participant from continuing to receive study drug
(Section 7.1.1).
It is difficult to extrapolate the potential risks of baricitinib in a disease state very different than a 
chronic autoimmune disease such as RA. However, baricitinib has an established safety profile 
for RA, with approximately 10,034 patients having received baricitinib in all clinical trials and 
150,000 patients estimated to have been treated with baricitinib (based on postmarketing 
sources) worldwide. In RA, baricitinib was approved for long-term chronic use whereas the 
duration of baricitinib treatment in this COVID-19 study will be short (up to 14 days). The half-
life of the molecule is approximately 12 hours, which will lead to a very short washout period 
once discontinued and has few drug-drug interactions (due to low CYP inhibitory activity) so it 
can be given concomitantly with background therapies.
More detailed information about the known risks and reasonably expected adverse events of 
baricitinib may be found in the Investigator’s Brochure (IB).

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Protocol I4V-MC-KHAA(e)
26
In summary, in the context of the cumulative knowledge for baricitinib with respect to the 
established safety profile, the potential to mitigate the hyperinflammatory state and cytokine 
storm associated with SARS-CoV-2, and the high unmet need for a treatment to slow the 
progression of COVID-19 infection, the benefit/risk balance for this study is assessed to be 
favorable.

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Protocol I4V-MC-KHAA(e)
27
3.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the effect of baricitinib 4-mg once 
daily (QD) compared to placebo on disease 
progression in patients with COVID-19 infection
Proportion of patients who die or require non-invasive 
ventilation/high-flow oxygen or invasive mechanical ventilation 
(including extracorporeal membrane oxygenation [ECMO]) by 
Day 28 in these 2 populations

Population 1 - all randomized patients 

Population 2 – patients who, at baseline, require oxygen 
supplementation and are not receiving dexamethasone or 
other systemic corticosteroids for the primary study 
condition.
Key Secondary
To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on clinical outcomes in 
patients with COVID-19 infection
Proportion of patients with at least 1-point improvement on NIAID-
OS or live discharge from hospital at Day 4, Day 7, Day 10, Day 14
Number of ventilator-free days (Day 1 to Day 28)
Time to recovery (NIAID-OS) (Day 1 to Day 28)
Overall improvement on the NIAID-OS evaluated at Day 4, Day 7, 
Day 10, Day 14
Duration of hospitalization (Day 1 to Day 28)
Proportion of patients with a change in oxygen saturation from 
<94% to ≥94% from baseline to Day 4, Day 7, Day 10, Day 14
All-cause mortality (Day 1 to Day 28)
Other Secondary
To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on other clinical outcomes 
in patients with COVID-19 infection
Treatment Period – (Day 1 to Day 28, unless otherwise specified)

Time to recovery (NIAID-OS) by disease duration of < 7 days 
or ≥7 days

Duration of stay in the intensive care unit (ICU) in days

Time to clinical deterioration (one-category increase on the 
NIAID-OS)

Time to clinical improvement in one category of the NIAID-
OS

Time to resolution of fever, in patients with fever at baseline

Overall improvement on the NIAID-OS evaluated at Day 21, 
Day 28

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Protocol I4V-MC-KHAA(e)
28
Objectives
Endpoints

Mean change in National Early Warning Score (NEWS)

Time to definitive extubation

Time to independence from non-invasive mechanical 
ventilation

Time to independence from oxygen therapy in days

Time to oxygen saturation of ≥94% on room air in days

Number of days with supplemental oxygen use 

Number of days of resting respiratory rate <24 breaths per 
minute 
Landmark analysis – Day 4, Day 7, Day 10, Day 14, Day 28

Proportion of patients in each severity category on the NIAID-
OS

Proportion of patients with at least 2-point improvement on the 
NIAID-OS or live discharge from the hospital

Proportion of patients with at least 1-point improvement on 
NIAID-OS or live discharge from hospital
Exploratory
Exploratory objectives and endpoints may include the following:

C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), ferritin

Virologic measures

Characterization of the pharmacokinetics of baricitinib in intubated patients with COVID-19 infection

Long-term (at least Day 60) clinical outcomes.
Notes: 
   The Day 28 Clinical Status Assessment is entered for midnight to midnight for the previous day. Therefore, the 
Day 28 Clinical Status Assessment is entered on Day 29.
   Recovery is defined as the first day or time from study start on which the participant satisfies 1 of the following 3 
categories from the ordinal scale: Hospitalized, not requiring supplemental oxygen – no longer requires ongoing 
medical care; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized, no 
limitations on activities (applies to live discharge from hospital to home as well).

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Protocol I4V-MC-KHAA(e)
29
4.
Study Design
4.1.
Overall Design
Study I4V-MC-KHAA (KHAA) is Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of
baricitinib 4-mg given once daily (QD). The primary endpoint is the proportion of patients who 
die or require non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation 
(including ECMO) by Day 28.  Two populations will be evaluated, all randomized patients and a 
subset of patients who, at baseline, require oxygen supplementation and are not receiving 
dexamethasone or other systemic corticosteroids for the primary study condition.
The study duration will be up to approximately 60 days over 3 study periods:
Screening: on Day 1 prior to dosing
Treatment period: treatment is administered for up to 14 days, or up to the day of hospital 
discharge, whichever comes first, followed by treatment evaluations up to Day 28
Follow-up: Period starting after treatment period, with a follow-up visit approximately 
28 days after last dose of study drug and another follow-up visit at approximately 
Study Day 60.
Patients will be enrolled if they are hospitalized with coronavirus (SARS-CoV-2) infection and 
meet other study entry criteria, including requiring oxygen supplementation. Patients requiring
invasive mechanical ventilation (including ECMO) at the time of study entry are not eligible.
While hospitalized, enrolled patients will receive either baricitinib or placebo until Day 14 or 
until the day of hospital discharge, whichever comes first.
Participants may remain on stable background therapy per local guidelines, including 
antimalarials (hydroxychloroquine), and/or antivirals, and/or azithromycin. Hydroxychloroquine 
and chloroquine are not approved to treat COVID-19 infection. Recently published data suggest 
that chloroquine and hydroxychloroquine may be associated with increased risk in patients with 
COVID-19 infection (Mehra et al. 2020; Tang et al. 2020). Hydroxychloroquine and chloroquine 
are only permitted as concomitant medication if these are recommended or required by local 
COVID-19 treatment guidelines. Concomitant biologics (including interferon, tocilizumab, 
sarilumab, TNFi) or Janus kinase (JAK) inhibitors [except for study drug]) are not permitted (see 
Section 6.5).
A follow-up visit approximately 28 days after last dose is required for all randomized patients, 
including those discharged from hospital before Day 14. Another follow-up visit occurs at 
approximately Study Day 60. These follow-up visits can be conducted as telephone visits.
Discharge from the hospital prior to Day 14 is not considered early discontinuation from the 
study drug or from the study. All randomized patients, including patients meeting criteria for 
early discontinuation of study drug, as specified in Section 7.1, should be encouraged to remain 
in the study for the scheduled study assessments specified in the Schedule of Activities (SoA)
(Section 1.3). Patients who prematurely discontinue from the study should have an ETV and 
follow-up visits, if possible, as shown in the SoA.
The study schema is presented in Section 1.2.

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4.2.
Scientific Rationale for Study Design
The double-blind, placebo-controlled design of this study limits potential bias in investigator 
assessments and enables a clearer interpretation of the effects of active drug compared to placebo 
(background therapy).
The primary endpoint of this study is the proportion of patients who die or require non-invasive 
ventilation/high-flow oxygen or invasive mechanical ventilation (including ECMO) by Day 28.
Progression to requiring non-invasive or invasive mechanical ventilation is an indicator of 
critical disease and can occur at any timepoint after hospitalization. 
Time on ventilation increases the patient’s risk of complications, including pneumothorax, 
airway injury, alveolar damage, ventilator-associated pneumonia, and ventilator-associated 
tracheobronchitis, which are associated with higher death rates and longer hospital stays (Craven 
et al. 2009; Hess 2011; Patel 2020). An effective treatment should be able to halt progression of 
patients to ventilation at any time. A primary endpoint capturing progression to death or non-
invasive ventilation/high-flow oxygen or invasive ventilation (including ECMO) by Day 28 
(rather than at Day 28) is clinically meaningful because it utilizes all available data about the 
course of disease progression or resolution in response to treatment.
The addition of the subpopulation of patients requiring oxygen supplementation at baseline to the 
primary analysis is based on the National Institute of Allergy and Infectious Diseases (NIAID)
Adaptive COVID-19 Treatment Trial 2 (ACTT-2). Patient recovery and mortality in ACTT 2 
indicated treatment effect was the largest in this subset of patients. The use of dexamethasone is 
recommended for patients requiring oxygen supplementation or invasive mechanical ventilation
per the NIH and WHO guidelines and is allowed in this study per the protocol. The impact of 
dexamethasone on the efficacy of baricitinib is unknown and further evaluations in the two 
subpopulations will provide additional results relevant to the treatment of COVID-19.
In addition, an observation of treatment effect for baricitinib to 28 days is based on US 
regulatory and WHO recommendations, and allows comparisons across different therapeutic 
agents in COVID-19 studies. Based on regulatory feedback, an additional evaluation of patients’ 
clinical status and safety assessments will be conducted at Day 60 to evaluate safety and 
effectiveness for this patient population.
The rationale for study treatment for up to 14 days is based on the known onset of efficacy in the 
RA population, which is as early as 1 week (Olumiant Summary of Product Characteristics), and 
on the expected duration of treatment needed for an acute infection such as COVID-19. 
Recently, data were published on a case series describing a 14-day course of baricitinib in 
patients with mild to moderate COVID-19 infection (Cantini et al. 2020).
A key secondary objective is improvement on an ordinal scale. The ordinal scale used in this 
study (NIAID-OS) has been used in the NIAID ACTT study and is similar to the WHO ordinal 
scale recommended for use in the assessment of therapeutics for the treatment of COVID-19 
infection (WHO R&D). Clinical improvement as described by a similar ordinal scale was used in 
a study comparing the effectiveness of combined favipiravir and oseltamivir therapy versus 
oseltamivir monotherapy in critically ill patients with influenza virus infection (Wang Y et al. 
2019), and was an endpoint recommended by the WHO R&D Blueprint expert group (WHO 
R&D).

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To ensure that sufficient patients enrolled are in the hyperinflammatory state which correlates
with progression to severe disease and ventilation requirements, patients are required to have at 
least one inflammatory marker (CRP, D-dimer, LDH, ferritin) that is greater than the upper limit 
of normal (ULN). 
In this study, collection of demographic information includes race and ethnicity. The scientific 
rationale is based on the possible need to assess variable response in safety and/or efficacy based 
on race or ethnicity. Such a need can be addressed only if all the relevant data are collected.
The post-treatment follow-up period allows for continued safety and efficacy monitoring after 
the last dose.
4.3.
Justification for Dose
The 4-mg QD dose of baricitinib selected for this study in a patient population with COVID-19 
infection is based on clinical data showing an effect of baricitinib on inhibition of cytokine 
signaling. Upregulation of multiple proinflammatory cytokines has been shown in patients with 
COVID-19 infection admitted to ICU units in Wuhan, China, and elevated IL-6 was a predictor 
of mortality in COVID-19 patients in another China-based study. 
In patients with RA, there was a dose-dependent reduction in plasma IL-6 levels, assessed after 
12 weeks of treatment. In ex vivo studies, there was a similar dose-dependent effect on inhibition 
of multiple cytokines implicated in COVID-19 infection. In a compassionate use program in 
pediatric patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated 
temperature (CANDLE) syndrome, patients on a mean dose of baricitinib 6-mg QD showed a 
striking reduction in cytokine signaling (Sanchez et al. 2018). In healthy volunteers, exposures 
observed at the baricitinib 4-mg (or higher) doses are associated with reduction of IL-6 induced 
ex vivo pSTAT3 activation (Shi et al. 2014).
In terms of risk considerations, the proposed duration of treatment with baricitinib 4-mg in the 
setting of COVID-19 infection is brief (up to 14 days); to date, baricitinib has been studied and 
approved for long-term use in the setting of chronic autoimmune conditions. In a vaccine 
response study, individuals treated with baricitinib 4-mg can mount an appropriate immune 
response to a pneumococcal vaccine, suggesting that transient exposure to baricitinib will not 
result in clinically meaningful changes to adaptive immunity (Winthrop et al. 2019).
In addition, the choice of the 4-mg dose is supported by efficacy and safety data for baricitinib in 
Phase 2 and Phase 3 RA studies. In the RA population, there was a dose-dependent reduction in
plasma IL-6 levels, assessed after 12 weeks of treatment (Stebbing et al. 2020). In ex vivo 
studies, there was a similar dose-dependent effect on inhibition of multiple cytokines. The 
baricitinib 4-mg dose is approved in multiple regions globally for the treatment of RA and is 
currently being studied in large ongoing global Phase 3 studies of RA, systemic lupus 
erythematosus, atopic dermatitis, and alopecia areata.
In summary, the potential benefit of the 4-mg dose in reducing the hyperinflammatory state 
caused by COVID-19 infection, and the short duration of treatment with this dose with a 
well-established safety profile, provides the rationale for the assessment of the benefit/risk 
profile of the baricitinib 4-mg dose in the setting of a randomized, controlled clinical trial in a 
hospital setting.

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Dose Adjustment for Renal Impairment
As detailed in the IB, baricitinib exposure increases with decreased renal function (Study I4V-
MC-JADL [JADL]). Based on PK simulations, dose adjustment is not required for patients with 
estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2. Patients with eGFR
≥30 mL/min/1.73 m2 to <60 mL/min/1.73 m2 at screening who are randomized to the 4-mg 
QD dose will receive a 2-mg QD dose, to avoid exposures that exceed those of the 4-mg QD 
dose in patients with eGFR ≥60 mL/min/1.73 m2. Patients will remain on the 2-mg dose
during treatment.
4.4.
End-of-Study Definition
A participant is considered to have completed the study if he or she has completed the last 
scheduled procedure shown in the SoA (Section 1.3).
The “end of the study” is defined as the date of the last visit or last scheduled procedure shown 
in the SoA for the last participant in the study globally.

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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
All screening evaluations must be conducted and reviewed to confirm that potential participants 
meet all eligibility criteria.
The investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable.
Due to the criticality of participant health and the setting of this research study, verbal interview 
of the potential participant, or his or her legal representative or family member, may be the 
source for pre-existing conditions and prespecified medical history, unless otherwise specified 
within the eligibility criteria.
For screen failures and rescreening activities within the screening period, see Section 5.4.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if they meet all of the following criteria 
during the screening period, unless otherwise specified below:
Informed consent
[1]  Patient (or legally authorized representative) who gives informed consent as described in 
Appendix 10.1, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol.
Participant characteristics
[2] Are male or female patients from 18 years of age (inclusive), at the time of enrollment.
Note:  Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. There are no 
contraceptive requirements for men. See Appendix 10.4 for contraception requirements.
COVID-19 pulmonary infection-related inclusion criteria
[3]  Hospitalized with coronavirus (SARS-CoV-2) infection, confirmed by polymerase chain 
reaction (PCR) test or other commercial or public health assay in any specimen, as 
documented by either of the following:
●  PCR positive in sample collected <72 hours prior to randomization; OR
●  PCR positive in sample collected ≥72 hours prior to randomization (but no more than 14 
days prior to randomization), documented inability to obtain a repeat sample (for 
example, due to lack of testing supplies, limited testing capacity, results taking >24 
hours, etc.) AND progressive disease suggestive of ongoing SARS-CoV-2 infection
[4]  Require supplemental oxygen at the time of study entry and at randomization.
[5]  Have indicators of risk of progression: at least 1 inflammatory markers >ULN (CRP, 
D-dimer, LDH, ferritin) with at least 1 instance of elevation >ULN within 2 days before
study entry.

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5.2.
Exclusion Criteria
Participants will be excluded from study enrollment if they meet any of the following criteria 
within the screening period, unless otherwise specified:
Prior or concomitant therapy
[6] Are receiving cytotoxic or biologic treatments (such as TNF inhibitors, anti-interleukin-1
[IL-1], anti-IL-6 [tocilizumab or sarilumab], T-cell or B-cell targeted therapies (rituximab), 
interferon, or Janus kinase (JAK) inhibitors for any indication at study entry.
Note: A washout period 4 weeks (or 5 half-lives, whichever is longer) is required prior to 
screening, with the following exceptions:
●  B-cell targeted therapies: a washout period of 24 weeks or 5 half-lives (whichever is 
longer)
●  TNF inhibitors: a washout period of 2 weeks or 5 half-lives (whichever is longer), and
●  JAK inhibitor: a washout period of 1 week or 5 half-lives (whichever is longer).
See Section 6.5.1 for requirements.
[7] Have ever received convalescent plasma or intravenous immunoglobulin [IVIg]) for 
COVID-19.
[8] Have received high dose corticosteroids at doses >20 mg per day (or prednisone equivalent)
administered for >14 consecutive days in the month prior to study entry.
Note: Use of dexamethasone and/or other systemic corticosteroids that do not exceed the
above specified dose and duration in the month prior to study entry is acceptable.
[9] Strong inhibitors of OAT3 (such as probenecid) that cannot be discontinued at study entry.
[27] Have received neutralizing antibodies, such as bamlanivimab, casirivimab and imdevimab
for COVID-19.
Current or historical infections
Note: Documentation from verbal interview or available medical records is acceptable.
[10] Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less 
than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history 
only, no screening tests required).
[11] Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19)
that in the opinion of the investigator could constitute a risk when taking investigational 
product. Note: Immunocompromised patients, patients with a chronic medical condition, or 
those taking a medication that cannot be discontinued at enrollment, who, in the judgment of the 
investigator, are at increased risk for serious infections or other safety concerns given the study 
products should be excluded.
Vaccines
[12] Have received any live vaccine within 4 weeks before screening, or intend to receive a live 
vaccine during the study. 

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Note: Use of nonlive (inactivated) vaccinations is allowed for all participants.
Other medical conditions or history
[13] Require invasive mechanical ventilation, including ECMO at study entry.
[14] Current diagnosis of active malignancy that, in the opinion of the investigator, could 
constitute a risk when taking investigational product.
[15] Have a history of VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) 
within 12 weeks prior to randomization or have a history of recurrent (>1) VTE (DVT/PE).
[16] Anticipated discharge from the hospital, or transfer to another hospital (or another unit),
which is not a study site within 72 hours after study entry.
Diagnostic assessments
[17]  Have neutropenia (absolute neutrophil count <1000 cells/L) (<1.00 x 103/L or 
<1.00 GI/L)
[18] Have lymphopenia (absolute lymphocyte count <200 cells/L) (<0.20 x 103/L or 
<0.20 GI/L)
[19] Have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 times ULN
[20] eGFR (Modification of Diet in Renal Disease [MDRD]) <30 mL/min/1.73 m2.
Note: For each aforementioned diagnostic assessment (criteria 17, 18, 19, 20), 1 repeat testing is 
allowed during the screening period, and values resulting from repeat testing may be accepted 
for a participant’s enrollment eligibility if the other eligibility criteria are met. In addition, these
tests performed in the 24 hours prior to study entry will be accepted for determination of
eligibility.
Prior or concurrent clinical study experience
[21] Have a known hypersensitivity to baricitinib or any of its excipients.
[22]  Are currently enrolled in any other clinical study involving an investigation product or any 
other type of medical research judged not to be scientifically or medically compatible with 
this study.
Note: The participant should not be enrolled (started) in another clinical trial for the 
treatment of COVID-19 or SARS-CoV-2 through Day 28.
Other exclusions
[23]  Are pregnant, or intend to become pregnant or breastfeed during the study.
[24]  Are, in the opinion of the investigator or sponsor, unsuitable for inclusion in the study.
[25] Are using or will use extracorporeal blood purification (EBP) device to remove pro-
inflammatory cytokines from the blood such as a cytokine absorption or filtering device, 
for example, CytoSorb®.
[26]  Are, in the opinion of the investigator, unlikely to survive for at least 48 hours after 
screening.

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5.3.
Lifestyle Considerations
Not applicable.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event.
5.4.1.
Allowed Retesting of Screening Investigations
Repeating the screening labs associated with criteria [17], [18], [19], and [20] during the 
screening period does not constitute rescreening.
5.4.2.
Rescreening of Individuals Who Failed Screening
Individuals who do not meet the COVID-19 pulmonary infection-related criteria and other
diagnostic assessments for participation in this study (screen failures) may be rescreened.
Rescreening 1 time for any eligibility parameter that was not initially met is allowed if patient is 
expected to meet study requirements per investigator assessment. It is not necessary to repeat all 
screening requirements. Patient will not be required to reconsent due to rescreening.
Rescreened participants should be assigned a new participant number.

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6.
Study Intervention
Study intervention is defined as any investigational intervention, marketed product, placebo, or 
medical device intended to be administered to a study participant according to the study protocol.
6.1.
Study Interventions Administered
Study interventions
This study involves baricitinib and placebo, as shown below.
Treatment Name
baricitinib
placebo
Dosage Formulation
tablet 
tablet
Dosage Levels
4 mg as two 2-mg tablets*
2 placebo tablets
Routes of Administration
Oral**
Oral**
Dosing Instructions
daily
daily
* Patients with eGFR >30 mL/min/1.73 m2 to <60 mL/min/1.73 m2 at screening who 
are randomized to the baricitinib 4-mg dose will receive a 2-mg QD dose, to avoid 
exposures that exceed those of the 4-mg QD dose in patients with eGFR ≥60 
mL/min/1.73 m2. Patients on the baricitinib 2-mg QD dose will receive a single 2-mg 
tablet and will remain on this dose during the study if eGFR >30 mL/min/1.73 m2 to 
<60 mL/min/1.73 m2 at screening. Patients will remain on 2-mg dose during 
treatment.
Patients with eGFR <60 mL/min/1.73 m2 at screening who are randomized to placebo 
will receive one placebo tablet.
** Baricitinib will be administered as a 4-mg dose orally (po) (two 2-mg tablets) or 
crushed for NG tube, given daily, for the duration of the hospitalization up to a 14-day 
total course.  A placebo will be given as 2 tablets po or crushed for NG tube, daily, for 
the duration of the hospitalization up to a 14-day total course.
Investigational product will be administered to the patient at the study site. No investigational 
product will be provided to patients once discharged from the hospital.
Packaging and labeling
Study interventions (baricitinib and placebo) will be supplied by the sponsor or its designee in 
accordance with current Good Manufacturing Practice (cGMP). Clinical trial materials will be 
labeled according to the country’s regulatory requirements. All IPs will be stored, inventoried, 
reconciled, and destroyed according to applicable regulations.
6.2.
Preparation/Handling/Storage/Accountability
The Pharmacy Manual provides instructions for the preparation, handling, and storage of 
baricitinib drug product and placebo, and describes site responsibility and accountability for the 
administered products.

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Investigators should consult the information provided in the Pharmacy Manual or the label for 
specific administration information, including warnings, precautions, contraindications, adverse 
reactions, and dose modifications.
Handling and storage
Follow the storage and handling instructions on the IP packaging.
Site responsibilities and accountability
The following are responsibilities of the investigator or his or her designee:
●  The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and that any discrepancies are 
reported and resolved before use of the study intervention.
●  Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
●  The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(that is, receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
The investigator or designee is also responsible for
  explaining the correct use of the study interventions
  verifying that instructions are followed properly
  maintaining accurate records of IP dispensing and collection, and
  returning all unused medication to Lilly or its designee at the end of the study.
Note:  In some cases, sites may destroy the material if, during the investigative site 
selection, the evaluator has verified and documented that the site has appropriate 
facilities and written procedures to dispose of clinical materials.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Blinding will be maintained in the Phase 3 study.
Method of treatment assignment
Patients who meet all criteria for enrollment will be randomized in a 1:1 ratio (baricitinib 4-mg: 
placebo) at Day 1.
Randomization will be stratified by these factors:
●  disease severity:
○  hospitalized not requiring supplemental oxygen, requiring ongoing medical care

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○  hospitalized requiring supplemental oxygen by prongs or mask
○  hospitalized requiring non-invasive ventilation or high-flow oxygen
●  age (<65 years; ≥65 years)
●  region (United States, Europe, rest of world), and 
●  dexamethasone and/or other systemic corticosteroid used at baseline for primary study 
condition (Yes/No).
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).
Emergency unblinding
Emergency unblinding for adverse events may be performed through the IWRS. This option may 
be used ONLY if the participant’s well-being requires knowledge of the participant’s treatment 
assignment. All actions resulting in an unblinding event are recorded and reported by the IWRS.
If a participant’s study treatment assignment is unblinded to the investigator, to site personnel 
performing assessments, or to the participant, the participant must be discontinued from the 
study, unless the investigator obtains specific approval from the sponsor’s medical monitor for 
the participant to continue in the study (Section 7.1.1).
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participants’ intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. Where feasible and when timing of the emergent 
situation permits, the investigator should attempt to contact the Lilly medical monitor before 
unblinding a participant’s treatment assignment.
In cases where there are ethical reasons to have the participant remain in the study, the 
investigator must obtain specific approval from the sponsor for the participant to continue in the 
study.
6.4.
Study Intervention Compliance
Participants will receive study intervention directly from the investigator and/or appropriate
designee at the study site. The date and time of each dose administered will be recorded in the 
source documents and recorded in the case report form (eCRF). Deviations from the prescribed 
dosage regimen should be recorded in the eCRF.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with
●reason for use
●dates of administration including start and end dates, and
●  dosage information, including dose for concomitant therapies of special interest.

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Participants will be instructed to consult the investigator or other appropriate study site personnel 
before taking any new medications or supplements during the study.
The sponsor’s medical monitor should be contacted if there are any questions.
6.5.1.
Prior Medications
Participants must have been discontinued from following medications before enrolling in the 
study, as stated in Section 5.2:
●  Biologic therapy (such as anti-IL-1, anti-IL-6 [tocilizumab or sarilumab], T-cell targeted 
therapies, interferon) must be discontinued 4 weeks or 5 half-lives, whichever is longer,
prior to screening
●  B-cell targeted therapies (rituximab): a washout period of 24 weeks or 5 half-lives 
(whichever is longer) 
●  TNF inhibitors: a washout period of 2 weeks or 5 half-lives (whichever is longer), and
●JAK inhibitor: a washout period of 1 week or 5 half-lives (whichever is longer).
In addition, strong inhibitors of OAT3 (such as probenecid) must be discontinued at study entry.
6.5.2.
Required and Permitted Concomitant Therapy
Prophylaxis for VTE is required for all patients unless there is a major contraindication such as 
active bleeding events or history of heparin-induced thrombosis.
The following will be permitted as concomitant therapy during the study:
●  Concomitant antibiotic, antiviral, antifungal, and/or antimalarial (background therapy in 
keeping with local clinical practice for management of COVID-19). Hydroxychloroquine 
and chloroquine are only permitted as concomitant medication if these are recommended 
or required by local COVID-19 treatment guidelines.
●  Corticosteroid use should be limited unless indicated per standard of care for a concurrent 
condition such as, but not limited to, asthma, chronic obstructive pulmonary disease, 
adrenal insufficiency.
6.5.3.
Prohibited Concomitant Therapy
The following will be prohibited as concomitant therapy during the study:
●  Any biologic therapy (such as TNF inhibitors, anti- IL-1, anti-IL-6 [tocilizumab or 
sarilumab], T-cell or B-cell targeted therapies (rituximab), interferon, JAK inhibitors 
(other than baricitinib as study treatment), or immunoglobulin (IgG) for any indication.
●  Live vaccines, including herpes zoster vaccination. Nonlive seasonal vaccinations and/or 
emergency vaccination, such as rabies or tetanus vaccinations, are allowed.
●  Strong inhibitors of OAT3 (such as probenecid) that cannot be discontinued at study entry.
●  Extracorporeal blood purification device to remove pro-inflammatory cytokines from the 
blood such as a cytokine absorption or filtering device, for example, CytoSorb®.

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6.6.
Dose Modification
Patients with eGFR ≥30 mL/min/1.73 m2 to <60 mL/min/1.73 m2 at screening who are 
randomized to the baricitinib 4-mg dose will receive a 2-mg QD dose, to avoid exposures that
exceed those of the 4-mg QD dose in patients with eGFR ≥60 mL/min/1.73 m2. Patients will 
remain on this dose during the study if eGFR ≥30 mL/min/1.73 m2 to <60 mL/min/1.73 m2 at 
screening.
If after randomization eGFR decreases to less than 60 mL/min/1.73 m2 but equal to or more than 
30 mL/min/1.73 m2, patients will receive a 2-mg QD dose (one tablet) until eGFR returns to 
eGFR ≥60 mL/min/1.73 m2.
Baricitinib is not recommended for use in patients with estimated GFR of <30 mL/min/1.73 m2.
6.7.
Intervention after the End of the Study
Baricitinib will not be provided to participants following completion of the study.

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
In rare instances, it may be necessary for a participant to permanently discontinue study drug.
These sections describe reasons for a participant’s
  permanent or temporary discontinuation of study drug, or
  discontinuation (withdrawal) from the study.
Discontinuation of specific sites or of the trial as a whole are handled as part of regulatory, 
ethical, and trial oversight considerations in Appendix 10.1, Section 10.1.9.
Note: In this study, discharge from the hospital prior to Day 14 is not considered early 
discontinuation from the study drug or from the study.
7.1.
Discontinuation of Study Intervention
Study drug may be permanently discontinued or temporarily withheld during the study.
7.1.1.
Criteria for Permanent Discontinuation of Study Drug
Data collection and safety follow-up when study drug is permanently discontinued
If a patient permanently discontinues study drug early (that is, prior to hospital discharge or 
Day 14, whichever comes first), the patient should remain in the study and have the scheduled 
study assessments specified in the SoA (Section 1.3). Every effort should be made to encourage 
participants to remain in the study for the duration of their planned outcome assessments. 
Participants should be educated on the continued scientific importance of their data, even if they 
discontinue study drug.
Unless the participant withdraws consent or meets other criteria listed in Section 7.2, those who 
discontinue study drug early will remain in the study. The reason for participant discontinuation 
of study drug should be documented in the CRF.
If a patient who is not receiving study drug is unwilling or unable to continue the scheduled 
study assessments, the site personnel should attempt to collect as much follow-up information as 
possible, including, at minimum, information specified for an early termination visit (ETV) and
information for the follow-up visits, including the Study Day 60 visit.
Criteria for permanent discontinuation of study drug
Possible reasons leading to permanent discontinuation of study drug include, but are not limited 
to, the following:
Participant decision
●  The participant requests to discontinue the study drug.
Prohibited concomitant medication use
●  The participant requires treatment with a prohibited medication (Section 6.5.3).

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Pregnancy
●  The participant becomes pregnant during the study.
Safety considerations
●  The participant should be discontinued if the participant develops any of the following 
conditions during the study:
  new malignancy 
  human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) 
infection
  active TB infection or evidence of latent TB (positive QuantiFERON-TB Gold assay or 
T-SPOT.TB or greater than 1 “indeterminate” result for QuantiFERON-TB Gold assay 
or a “borderline” result T-SPOT.TB assay)
  active hepatitis B (HBV DNA) or hepatitis C (HCV RNA)
VTE (DVT/PE)
●  The investigator, after consultation with the sponsor’s designated medical monitor, 
determines that a systemic hypersensitivity reaction has occurred and is related to study 
drug administration.
●  The participant experiences any 1 of the following events on 2 consecutive samples taken 
at least 48 hours, but no more than 1 week, apart.
  Total white blood cells (WBC) <1000 cells/L
  Absolute neutrophil count (ANC) <500 cells/L
  Absolute lymphocyte count (ALC) <200 cells/L
●  The participant has an adverse event or serious adverse event or a clinically significant 
change in a laboratory value that, in the opinion of the investigator or sponsor, would 
preclude the participant from continuing to receive study drug.
Hepatic event or liver test abnormality
●  Discontinuation of study drug because of abnormal liver tests should be considered by the 
investigator when a participant meets one of the following conditions after consultation 
with the medical monitor (see Section 8.2.6)
  ALT or AST >8 times ULN or
  ALT or AST >3 times ULN and (total bilirubin >2 times ULN or PT-INR >1.5)
Other reasons
●  Unblinding: If an investigator, site personnel performing assessments, or participant is 
unblinded, the participant must be discontinued from the study drug and continue to 
post-treatment follow-up. In cases where there are ethical reasons to have the participant 
continue on study drug, the investigator must obtain specific approval from the sponsor or 
designee for the participant to continue.

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7.1.2.
Criteria for Temporary Interruption (Withholding) of Study Drug
Study drug should be interrupted for:
  Absolute neutrophil count (ANC) <500 cells/L
  Absolute lymphocyte count (ALC) <200 cells/L
  ALT or AST >5 times ULN 
  estimated GFR of <30 mL/min/1.73 m2
Study drug may be restarted when these criteria are no longer applicable, at the discretion of the 
investigator. Retest timing and frequency is at the investigator’s discretion.
Baricitinib is not recommended for use in patients with estimated GFR of <30 mL/min/1.73 m2.
7.2.
Participant Discontinuation/Withdrawal from the Study
Participant discontinuation (withdrawal from the study) is expected to be uncommon.
A participant may withdraw from the study in the following circumstances:
●  at any time at his or her own request, or at the request of his or her designee (for example, 
parents or legal guardian)
●  at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons
●  if the participant enrolls in any other clinical study involving an investigational medicinal 
product or enrollment in any other type of medical research judged not to be scientifically 
or medically compatible with this study
●  if the participant, for any reason, needs to be transferred to another hospital or another 
hospital unit
●  if the participant, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication. In this case, 
discontinuation from the study occurs prior to introduction of the new agent.
Data collection and follow-up for participants who discontinue the study
At the time of discontinuing from the study, an ETV and final follow-up visits should be 
conducted, if possible, as shown in the SoA. See the SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed.
The participant will be permanently discontinued both from the study intervention and from the 
study.
Withdrawal of consent for disclosure
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he or she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.

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7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment 
unless there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment. If the investigator and the sponsor’s clinical research physician 
agree that it is medically appropriate to continue, the investigator must obtain documented 
approval from the sponsor to allow the inadvertently enrolled participant to continue in the study 
with or without treatment with investigational medicinal product. Safety follow-up is as outlined 
in the SoA (Section 1.3), Section 8.2 (“Safety Assessments”), and Section 8.3 (“Adverse Events 
and Serious Adverse Events”).
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.

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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed. Adherence to the study design requirements, including those 
specified in the SoA, is essential and required for study conduct.
8.1.
Efficacy Assessments
8.1.1.
COVID-19 Clinical Status Assessment
The COVID-19 Clinical Status Assessment will be used to collect components needed to derive 
scores for the ordinal scales used in this study. This assessment will also collect the use of 
proning and reason for discontinuation of invasive mechanical ventilation. 
The assessment will be completed on each day of the study by entering the assessment for the 
previous day (that is, midnight to midnight; 00:00 – 23:59 [24 hour clock]). 
On Day 1, the patient’s status at randomization will be reported. 
On Day 2 the status will be reported for the period from randomization to midnight on Day 1.
The patient’s clinical status will be captured daily through Day 29. 
The hospitalization portion of the patient’s clinical status will be completed daily, regardless of 
patient’s discharge status or patient contact.
The patient’s clinical status reflecting data for Day 28 (midnight to midnight) will be recorded in 
the Day 29 eCRF.
A clinical status assessment will be conducted via telephone visit for Day 60.
Primary Endpoint Assessments
The primary endpoint will assess the proportion of patients who die or require non-invasive 
ventilation/high-flow oxygen or invasive mechanical ventilation (including extracorporeal 
membrane oxygenation [ECMO]) by Day 28. Non-invasive ventilation/high-flow oxygen 
includes administration of ventilatory support without using an invasive artificial airway 
(endotracheal tube or tracheostomy tube). High-flow oxygen consists of breathing support 
administered through a face mask, nasal mask, or a helmet (including BiPAP, CPAP). 
Patients on non-invasive ventilation/high-flow oxygen at baseline will be counted toward the 
primary endpoint if they progress to invasive mechanical ventilation.
8.1.2.
Ordinal Scale
Using data from the COVID-19 Clinical Status Assessment, results will be calculated for ordinal 
scales currently being used in other studies, and in this study, to measure clinical outcomes in 
patients treated for COVID-19, in particular the NIAID-OS.

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The NIAID-OS is as follows:
Patient State Descriptor
Not hospitalized, no limitations on activities
Not hospitalized, limitation on activities and/or requiring home oxygen
Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care:
     (This would include those kept in hospital for quarantine/infection
     control, awaiting bed in rehabilitation facility or homecare, etc).
Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care (COVID-19 related
     or otherwise)
Hospitalized, requiring supplemental oxygen
Hospitalized, on non-invasive ventilation or high-flow oxygen devices
Hospitalized, on invasive mechanical ventilation or ECMO
Death
Source: Adaptive COVID-19 Treatment Trial (ACTT) [NCT04280705].
In this study, because scores for the ordinal scales will be derived from data already entered into 
the eCRF, no additional data entry related to the ordinal scales will be required.
8.1.3.
Other Efficacy Assessments
Several secondary efficacy endpoints of this study are based on clinical assessments and 
procedures conducted in hospitalized patients with COVID-19 infection. The following table 
shows these endpoints, their definitions for this study, and measurement method.
Endpoint
Defined as
Measured by
Ventilator-free days
Patient breathing without mechanical 
ventilation assistance, if the period of 
unassisted breathing lasts at least 24 
consecutive hours and the patient does not 
die
—
Recovery
Participant satisfies one of the following 
three categories from the NIAID-OS:
●Hospitalized, not requiring supplemental 
oxygen – no longer requires ongoing 
medical care; 
●Not hospitalized, limitation on activities 
and/or requiring home oxygen; 
●Not hospitalized, no limitations on 
activities (applies to live discharge from 
hospital to home as well)
score on NIAID-OS
Duration of 
hospitalization
Period of time the patient is hospitalized
date of admission to date of 
discharge
Oxygen saturation
Measure of the oxygen level of the blood.
pulse oximetry
All-cause mortality
28-day all-cause mortality
score on NIAID-OS
Duration of stay in the 
intensive care unit (ICU)
Date of admission to ICU to date of 
discharge from ICU 
—
Clinical deterioration
One-category increase on the ordinal scale
(worsening in patient clinical status)
score on NIAID-OS

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Endpoint
Defined as
Measured by
Clinical improvement
One-category decrease on the ordinal scale
(improvement of patient clinical status)
score on NIAID-OS
Time to resolution of 
fever
Time to patients being free of fever for the 
first time for patients who had fever at 
baseline.
If temperature is assessed multiple times in 
a day, the maximum temperature will be 
used.
Fever resolution is defined by: 
≤36.6°C (axilla)
≤37.2°C (oral), or
≤37.8°C (rectal or tympanic)
This includes oral, rectal, 
tympanic (ear), axilla, forehead, 
temporal artery temperature 
measurements.
Definitive extubation
When patient is removed from mechanical 
ventilation
score on NIAID-OS
Non-invasive ventilation/ 
high-flow oxygen
Administration of ventilatory support 
without using an invasive artificial airway 
(endotracheal tube or tracheostomy tube). 
Patients requiring high-flow 
oxygen breathing support administered 
through a face mask, nasal mask, or a 
helmet (includes BiPAP, CPAP)
score on NIAID-OS
Supplemental oxygen use
Patients requiring oxygen by mask or nasal 
prongs (cannula)
score on NIAID-OS
Respiratory rate
Measure of resting respiratory rate per 
minute
—
Mechanical ventilation 
and intubation
Patient requires mechanical ventilation and 
is intubated during the study
score on NIAID-OS
Abbreviations: BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure.
8.1.3.1.
Alert Voice Pain Unresponsive (AVPU) and National Early Warning Score 
(NEWS)
Alert Voice Pain Unresponsive (AVPU)
Level of consciousness is an important parameter in assessing the severity of acute illness. The 
AVPU scale is used to measure and record a patient’s level of consciousness. The AVPU scale 
used in this study is the one recommended for use in the calculation of NEWS (Royal College of 
Physicians 2012).
The investigator and/or appropriate designee assesses the patient’s current condition in the 
following sequence, recording only one of these four possible outcomes:
Alert: The patient is fully awake, with spontaneous opening of the eyes, responsiveness 
to voice, and motor function. The patient may, or may not be, confused or 
disorientated.

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Voice: The patient makes some kind of response when spoken to. The patient’s response 
can be a response of eyes, voice, or motor function, for example, opening eyes 
when spoken to, or making a grunt or moan or moving a limb when spoken to.
Pain: The patient responds to a pain stimulus. The response may be withdrawal from pain 
or involuntary flexion or extension of limbs. 
Unresponsive: Commonly called “unconscious.” This outcome is recorded if the patient 
gives no eye, voice, or motor response to voice or pain.
National Early Warning Score (NEWS)
In this study, because the scores for the NEWS parameters will be derived from data already 
entered into the eCRF, no additional NEWS-specific data entry will be required.
The National Early Warning Score (NEWS) is used to detect and report changes in illness 
severity in patients with acute illness. The score is determined from six physiological parameters 
readily measured over time in hospitalized patients:
●  respiration rate
●  oxygen saturation
●  temperature
●  systolic blood pressure
●  heart (pulse) rate, and
●  level of consciousness, as measured by AVPU.
A score is assigned to each parameter, with the magnitude of the score representing the extremity 
of variation from the norm. A weighting score is added for patients needing supplemental 
oxygen (oxygen delivery by mask or nasal cannula). The aggregate score is reflective of the 
patient’s status (Royal College of Physicians 2012).
8.1.3.2.
Laboratory Assessments
Laboratory assessments will be collected at the times shown in the SoA (Section 1.3).
8.2.
Safety Assessments
Order of safety assessments
If multiple safety assessments are scheduled to occur during the same visit, the preferred order of 
completion is
1)  vital signs first
2)  other safety assessments, including physical examinations and nonleading (spontaneous)
adverse event collection, and finally
3) sample collection for clinical laboratory, pharmacodynamic (PD), and biomarker testing.

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Data collection and reporting
The adverse event data collection and reporting requirements are described in Section 8.3 and 
Appendix 10.3.
Any clinically significant findings that result in a diagnosis and that occur after the participant 
receives the first dose of study drug should be reported to Lilly or its designee as an adverse
event via eCRF.
Safety monitoring
The principle investigator will monitor safety and laboratory data throughout the study and 
should discuss immediate safety concerns with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue the study 
intervention.
The sponsor will monitor the safety data, including adverse events and serious adverse events 
(SAEs), discontinuations, medical history, concomitant medications, vital signs, and clinical 
laboratory results by means of periodic blinded reviews and other appropriate methods. These 
methods include reviews by a functionally independent safety physician and/or clinical research 
scientist who regularly reviews SAE reports in real time and across studies, and who reviews 
applicable clinical safety and epidemiological publications from the literature. If this safety 
monitoring uncovers an issue that needs to be addressed by unblinding at the individual or group 
level, additional analyses of the safety data can be performed (Section 9.5 and Section 9.6).
8.2.1.
Vital Signs
Vitals signs (body temperature, blood pressure, heart [pulse] rate, respiration rate, oxygen 
saturation) will be assessed and documented daily, and as clinical indicated, and entered into the 
eCRF as specified in the SoA (Section 1.3) and as clinically indicated.
These include the minimum/maximum vital signs daily (including temperature, respiratory rate, 
oxygen saturation).
The most recent measurements prior to study drug administration will be used to calculate the 
NEWS. Vital signs should be performed at approximately the same time each day.
Additional vital signs may be measured during the study visits if warranted, as determined by the 
investigator and/or appropriate designee.
8.2.2.
Physical Examinations
A complete physical examination will be performed at the screening visit if feasible. This 
examination excludes pelvic, rectal, and breast examinations unless clinically indicated. The 
screening visit should include an assessment of TB risk factors.
A symptom-directed physical examination will be performed on other days, as specified in the 
SoA (Section 1.3) and as clinically indicated.
Height will be measured or collected as reported, and weight will also be measured. Both will be 
recorded as specified in the SoA.

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8.2.3.
Electrocardiograms
For each participant, a 12-lead standard ECG will be obtained locally and read by a qualified 
physician (the investigator or qualified designee) at the site on Day 1, as specified in the SoA
(Section 1.3). ECGs obtained up to 24 hours prior to study entry are acceptable.
8.2.4.
Chest Imaging Studies
A chest x-ray or computerized tomography (CT) scan, assessed by a radiologist pulmonologist, 
or appropriate physician will be obtained and the result should be recorded in the eCRF, as 
specified in the SoA (Section 1.3).
A report on imaging (that is, documentation of hospital-based test result) available prior to study 
entry is acceptable for the Day 1 imaging (up to 24 hours prior to study entry is acceptable).
Results for imaging at other timepoints, if carried out, will be provided via the eCRF.
During screening, all participants are to be assessed for risk factors, symptoms, and signs of TB, 
including chest imaging as assessed by a radiologist or pulmonologist.
8.2.5.
Laboratory Tests
Appendix 10.2 lists the clinical laboratory tests to be performed, and the SoA (Section 1.3) 
specifies the study days at which samples are collected for clinical laboratory tests.
Laboratory tests performed in the 24 hours prior to study entry will be accepted for 
determination of eligibility (except where designated differently in the SoA).
Additional tests may be performed at any time during the study as deemed necessary by the 
investigator and/or appropriate designee, or as required by local regulations.
All protocol-required laboratory assessments, as defined in Appendix 10.2, must be conducted in 
accordance with the laboratory manual and the SoA.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator and/or appropriate designee (for example, SAE or 
adverse event or dose modification), then the results must be recorded in the eCRF.
Reviewing and recording test results
The investigator and/or appropriate designee must review the laboratory report and record any 
clinically relevant changes occurring during the study in the adverse event section of the eCRF.
Documentation of review by the investigator and/or designee may be completed according to 
institution processes or by making an entry in the patient’s progress notes (medical record) 
stating that the lab results have been reviewed.
The laboratory reports must be filed with the source documents unless a Source Document 
Agreement or comparable document cites an electronic location that accommodates the expected 
retention duration.
Clinically significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant’s condition.

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Repeat testing after clinically significant abnormal findings
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 28 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
investigator or the medical monitor during study participation. If such values do not return to 
normal/baseline within a period of time judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified.
Blinding of laboratory test results
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel (Appendix 10.2).
Sample retention
Unless otherwise specified in the subsections of Section 8 or in Appendix 10.1, Section 10.1.12
(“Long-Term Sample Retention”), all samples collected for specified laboratory tests will be 
destroyed within 60 days of receipt of confirmed test results or according to local laboratory 
procedures. Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.5.1.
Pregnancy Testing
Pregnancy testing is to be performed on women of childbearing potential (WOCBP). Participants
who are pregnant will be permanently discontinued from study drug (Section 7.1.1). A 
pregnancy test will be performed at screening only.
8.2.6.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3 times ULN, ALP ≥2 times ULN, or elevated 
TBL ≥2 times ULN, liver testing should be repeated within 2 to 3 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to appropriate levels for the patient, per investigator 
assessment.
Discontinuation criteria of investigational products, either temporary interruption or permanent 
discontinuation, due to abnormal ALT, AST, TBL, or ALP, are detailed in Section 7.1.
8.3.
Adverse Events and Serious Adverse Events
Adverse events will be reported by the participant or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative.
The investigator and any qualified designees are responsible for detecting, documenting, and
recording events that meet the definition of an adverse event or SAE and remain responsible for 
following up adverse events that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention or the study.

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Pregnancy after maternal or paternal exposure to investigational product does not meet the 
definition of an adverse event. However, to fulfill regulatory requirements, any pregnancy should 
be reported using the SAE process described in Appendix 10.3, Section 10.3.4, to collect data on 
the outcome for both mother and fetus. See also Section 8.3.5.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information
All adverse events will be collected from the time of the participant’s signing of the ICF until the 
participant’s last post-treatment follow-up visit. Adverse events will be recorded on the Adverse 
Event eCRF.
Likewise, all SAEs will be collected from the signing of the ICF until the last post-treatment 
follow-up visit.
Although all adverse events after signing the ICF are recorded by the site in the CRF/electronic 
data entry tool, SAE reporting to the sponsor begins after the participant has signed the ICF and 
has received study drug. However, if an SAE occurs after signing the ICF but prior to receiving 
study drug, the SAE needs to be reported ONLY if the SAE is considered reasonably possibly 
related to study procedures.
SAEs will be recorded and reported to the sponsor or the sponsor’s designee immediately, and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 10.3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. Serious adverse events, including death, caused by COVID-19 disease progression
should not be reported on the SAE form unless the investigator deems them to be possibly 
related to study treatment (Appendix 10.3).
Investigators are not obligated to actively seek adverse events or SAEs after the conclusion of 
study participation, that is, once the participants have discontinued and/or completed the study 
(the Participant Study Disposition eCRF has been completed). However, if the investigator learns 
of any SAE, including a death, at any time after a participant has ended his or her study
participation, and the investigator considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the sponsor.
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
The method of recording, evaluating, and assessing causality of adverse events and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.3.
Care will be taken not to introduce bias when detecting adverse events and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire about 
adverse event occurrences.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
After the initial adverse event or SAE report, the investigator is required to proactively follow 
each participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained (including death), or the participant is lost to 
follow-up (Section 7.3). Further information on follow-up procedures is provided in 
Appendix 10.3, Section 10.3.3.

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8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs), and investigators.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (for example, summary or listing of SAEs) from the sponsor will review and 
then file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5.
Pregnancy
Details about pregnancy will be collected for pregnancies occurring in female study participants 
and in female partners of male study participants.
If a pregnancy is reported as having occurred during the study or within 1 week after the last 
dose of study intervention, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 10.4, Section 10.4.3.
Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Special Assessments of Infections and Venous Thromboembolic Events
Venous Thromboembolic Events
Completion of the VTE Endpoint eCRF page is required for each VTE reported as an adverse 
event or SAE. All suspected VTE events will be independently adjudicated by a blinded Clinical 
Event Committee.
Infections
Completion of the Infection Follow-up eCRF page is required for each infection reported as an 
adverse event or SAE with site of infection and source of culture provided, if available. The 
sponsor will identify infections considered to be opportunistic based on Winthrop et al. (2015).
8.3.7.
Complaint Handling
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness or performance of a 
trial intervention. The sponsor collects product complaints on investigational products and drug 
delivery systems used in clinical studies in order to ensure the safety of study participants, 
monitor quality, and to facilitate process and product improvements.
Participants will be instructed to contact the investigator as soon as possible if they have a 
complaint or problem with the investigational product so that the situation can be assessed.

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Any adverse events/SAEs that are associated with a product complaint will also follow the 
processes outlined in Section 8.3.3 and Appendix 10.3.
Time period for detecting product complaints
Product complaints that result in an adverse event will be detected, documented, and reported to 
the sponsor during all periods of the study in which the drug/device is used. If the investigator 
learns of any product complaint at any time after a participant has ended his or her study 
participation, and such incident is considered reasonably related to a drug/device provided for the 
study, the investigator will promptly notify the sponsor.
Prompt reporting of product complaints to sponsor
Product complaints will be reported to the sponsor within 24 hours after the investigator becomes 
aware of the complaint. The Product Complaint Form will be sent to the sponsor by a method 
designated by the sponsor.
Follow-up of product complaints
Follow-up applies to all participants, including those who discontinue study intervention. The 
investigator is responsible for ensuring that follow-up includes any supplemental investigations 
as indicated to elucidate the nature and/or causality of the product complaint. New or updated 
information will be recorded on the originally completed form with all changes signed and dated 
by the investigator and submitted to the sponsor.
8.4.
Treatment of Overdose
For this study, an overdose of baricitinib is considered any dose higher than the dose assigned 
through randomization. In case of an overdose, the patient should be monitored for signs and 
symptoms of adverse reactions. Patients who develop adverse reactions should receive 
appropriate treatment. In the event of an overdose, the investigator should contact the sponsor’s 
medical monitor immediately.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the sponsor’s medical monitor based on clinical evaluation of the participant.
8.5.
Pharmacokinetics
For patients who progress to intubation in ICU, venous blood samples will be drawn on the days 
and times indicated in the SoA (Section 1.3).
These blood samples will be used to determine the plasma concentrations of baricitinib. 
Concentrations of baricitinib in human plasma will be determined by a validated liquid 
chromatography tandem mass spectrometry (LC/MS/MS) method. 
The actual date and exact timing (24-hour clock) of sample collection and the date and time of 
study drug dosing should be recorded. 
The sampling schedule should be followed as closely as possible; however, failure to take PK 
samples at the specified times will not be considered a protocol violation.
Only samples from patients receiving baricitinib will be assayed; samples from patients receiving 
placebo will not be assayed. PK samples will be kept in storage at a laboratory facility 
designated by the sponsor. PK results will not be provided to investigative sites.

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Instructions for the collection and handling of blood samples will be provided by the sponsor. 
Samples will be analyzed at a laboratory approved by the sponsor.
Sample retention
The purpose of retention, the maximum duration of retention, and facility for long-term storage
of samples is described in Appendix 10.1, Section 10.1.12.
8.6.
Pharmacodynamics
This section is not applicable.
8.7.
Genetics
This section is not applicable.
8.8.
Biomarkers
Nasopharyngeal swab (to assess viral load and other characterizations), serum, and whole blood 
for RNA, epigenetic analysis and cellular phenotyping for exploratory nonpharmacogenetic 
biomarker research will be collected on days specified in the SoA (Section 1.3), where local 
regulations allow.
The baseline exploratory sample is essential to determining progressive viral load changes in the 
exploratory analysis during participation in the study. If, due to central lab kit supply, the first 
(Study Day 1) samples are not collected, it is not necessary to collect future exploratory 
biomarker central samples (NP swabs or blood samples); this will not be considered a protocol 
deviation. If the central lab kits are available, NP swabs and whole blood samples should be 
collected on study visit days per the SOA unless a phone visit is conducted and therefore the 
samples cannot be obtained; this would not be considered a protocol deviation.
Sample use
Exploratory biomarker research is performed to address questions of relevance to drug 
disposition, target engagement, PD, mechanism of action, variability of participant response 
(including safety), and/or clinical outcome. Sample collection is incorporated into clinical studies 
to enable examination of these questions through measurement of viral load, biomolecules,
RNA, proteins, lipids, and other cellular elements.
Samples may be used for research on the drug target, disease process, variable response 
to baricitinib, pathways associated with the studied disease, mechanism of action of baricitinib, 
and/or research methods or in validating diagnostic tools or assays related to the disease or to 
baricitinib.
Confidentiality
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigative site personnel.
Sample retention
The purpose of retention, the maximum duration of retention, and facility for long-term storage
of samples is described in Appendix 10.1, Section 10.1.12.

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8.9.
Immunogenicity Assessments
Immunogenicity is not assessed in this study.
8.10.
Medical Resource Utilization and Health Economics
This section is not applicable.

C O N FI D E N TI A L
Pr ot oc ol  I 4 V-M C -K H A A( e)
5 8
9.
St atistic al C o nsi der ati o ns
9. 1.
St atistic al H y p ot heses
Pri mar y O bject i ve
T he pri mar y  o bjecti ve of t his st u d y is t o test t he h y p ot hesis t hat bariciti ni b 4-m g Q D +
bac k gr o u n d t hera p y is s u peri or t o place b o + bac k gr o u n d t hera p y i n t he treat me nt of h os pi talize d 
pati e nts wit h C O VI D - 1 9 i nfecti o n, as assesse d b y t he p r o p ortio n of  patie nts w h o die or re q uire
n o n -i n vasi ve ve ntilati on/ hi g h -fl ow o x y ge n or i n vasi ve m ec ha nical ve nt ilati on (i ncl u di n g E C M O) 
b y D a y  2 8.
T he pri mar y  o bjecti ve will be assesse d i n t he f oll owi n g p o p ulati o ns 

P o p ul at i on 1- all ra n d o mize d patie nts, a n d

P o p ul at i on 2 – pati e nts w h o, at baseli ne, re q uire o x y ge n s u p ple me ntati o n a n d are n ot 
recei vi n g de xa met has o ne or s yste mic c ortic oster oi ds f or t he pri mar y st u d y c o n ditio n
T esti n g S c he me f or t he P ri mar y A nal yses
T he 1 -side d p -val ues a n d ass ociate d test statistics are defi ne d as

  is t he 1- side d p- val ue f or P o p ulat i on 1 ;   is t he ass ociate d test statistic

  is t he1- si de d p- val ue f or P o p ulat i on 2 ;   is t he ass ociate d test statistic
T he h y p ot heses are

H 0 1 is t he n ull h y p ot hesis c orres p o n di n g t o P o p ulati o n 1

H 0 2 is t he n ull h y p ot hesis c orres p o n di n g t o P o p ulati o n 2
H 0 1 will be rejecte d if :

  < α 1 O R (   < 0. 0 2 5 A N D   < α 2)
H 0 2 will be rejecte d if :

  < α 2 O R (   < 0. 0 2 5 A N D   < α 1)
α 1 a n d α 2 are critical t hres h olds preser v i n g t he o verall 1-sid e d t y pe 1 st u d y err or at 0. 0 2 5.   
If either of t he t w o tests is si g nifica nt, t he n the st u d y will be declare d s uccessf ul.  
T he testi n g sc he me will pr o vi de a str o n g c o ntr ol of T ype -I err or f or t he st u d y at a 1-si de d 0. 0 2 5 
le vel a n d is base d o n t he cl ose d testi n g pri nci ple ( Marc us et al. 1 9 7 6).  T he testi n g sc he me is 
para m etric, w here t he k n o w n c orrelat i on is acc o u nte d f or bet wee n t he 2 test statistics   a n d   .  
T he α 1 f or P o p ulat i on 1 will be pre -s pecifie d i n t he Stati stical A nal ysis Pla n ( S A P ). T he α 2 f or 
P o p ul at i on 2 will be calc ulate d t o c o ntr ol t he st u d y T y pe I err or rate at 0. 0 2 5 , acc o u nti n g f or t he 
pres pe cifie d val ue of α 1 a n d t he c orrelat i on bet wee n t he t w o test statistics. If t he P o p ul at i on 1 test 
is rejecte d a n d t he P o p ul atio n 2 test is n ot, or vice versa, t he re mai ni n g α will be rec ycle d a n d 
use d f or s u bse q ue nt testi n g of t he p o p ulat i on t hat was n ot si gnifica nt ( Mille n a n d D mitrie n k o 
2 0 1 1). T he fi nal α le vels will be base d o n t he perce nta ge of  P o p ul at i on 2 wi t hi n P o p ul at i on 1
o bser ve d i n t he fi nal a nal ysis data set .  A d dit i onal details will be descri be d i n t he S A P .

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9.2.
Sample Size Determination
In the protocol amendment C, it was assumed that the proportion of patients progressing to death 
or non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation (including 
ECMO) by Day 28 was 28% and 18.5% for placebo and baricitinib, respectively. Accordingly, 
the sample size was increased to 600 to yield approximately 80% power to detect an absolute 
difference of 9.5% between the baricitinib treatment group and the placebo treatment group 
using a two-sided alpha of 0.05 with the provision that sample size may be updated in a blinded 
manner during the study from 600 up to approximately 1000, if warranted based on newly 
available external study data. This would include the various differing factors amongst the 
studies, including, for example, the ACTT-2 results.
In protocol amendment D, the sample size is updated based on newly available data from the 
ACTT-2 study (ACTT-2 press release 2020). Based on the emerging data and evolving 
therapeutic options for standard of care, the assumption for the proportion of patients in the 
placebo group progressing to death or non-invasive ventilation/high-flow oxygen or invasive 
mechanical ventilation (including ECMO) by Day 28 is revised to approximately 25%. The
sample size of 1000 patients will yield approximately 47% power to detect an absolute difference 
of 5% and 83% power to detect an absolute difference of 7.5% between the baricitinib treatment 
group and the placebo treatment group using a two-sided alpha of 0.05.
In protocol amendment E, the sample size is updated to approximately 1400 patients based on
blinded review of the proportion of patients requiring oxygen supplementation without the use of 
dexamethasone or systemic corticosteroids at baseline and the potential that concomitant use of 
systemic corticosteroids may reduce the magnitude of the treatment effect. 
The table below describes the power calculations for various scenarios with a total sample size of 
1400.  This assumes, for illustration, that α1 for Population 1 is 75% of the total alpha and that
60% of the patients were taking dexamethasone or other corticosteroids at baseline.
Treatment effect size in patients who are at OS 5 or 
OS 6 at baseline 
Combined Effect Size
Power for at least one of 
the two primaries to 
succeed
Patients using 
dexamethasone or a 
systemic corticosteroid
Patients not using 
dexamethasone or a 
systemic corticosteroid
0.075
0.075
0.075
81%
0.040
0.075
0.054
54%
Abbreviations: NIAID = National Institute of allergy and Infectious Diseases; OS 5 = #5 on the 8-point NIAID 
ordinal scale - Hospitalized, requiring supplemental oxygen; OS 6 = #6 on the 8-point NIAID ordinal scale –
Hospitalized, on noninvasive ventilation or high-flow oxygen devices.
Note: Power estimates were obtained from a custom simulation program.
There is still significant uncertainty with these assumptions given the limited available data.
Therefore, the sample size may be increased using an unblinded sample size re-estimation during 
an interim analysis (Gao et al. 2008).

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9.3.
Populations for Analyses
The following populations are defined for this study:
Population
Description
Entered
All participants who sign the informed consent form
Intent-to-Treat (ITT)
All participants randomly assigned to study intervention. Participants will be 
analyzed according to the intervention to which they were assigned.
Per Protocol Set (PPS)
The PPS of the ITT population analysis set will include those participants who do 
not have any identified important protocol violations considered to impact efficacy 
analyses. Qualifications for, and identification of, significant or important protocol 
violations will be determined while the study remains blinded, prior to database 
lock.
Safety
All participants randomly assigned to study intervention and who receive at least 1 
dose of study intervention and who did not discontinue from the study for the reason 
‘Lost to Follow-up’ at the first postbaseline visit. Participants will be analyzed 
according to the intervention they actually received.
Follow-up
All randomized participants who received at least 1 dose of investigational product 
and have entered the post-treatment follow-up period. Participants will be analyzed 
according to the intervention which they received in the treatment period.
A sensitivity analysis excluding patients who die within 24 hours of randomization and have Do 
Not Resuscitate (DNR) or Do Not Intubate (DNI) in ITT/PP analyses populations will be 
conducted.
9.4.
Statistical Analyses
The statistical analysis of this study will be the responsibility of the sponsor or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP and clinical study report. Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
The SAP will be finalized prior to unblinding. It will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints, including primary and key 
secondary endpoints.
9.4.1. General Considerations
Efficacy analyses will be conducted on the Intent-to-Treat (ITT) Population. Selected efficacy 
analysis may also be conducted using the Per Protocol Set. Safety analyses will be conducted on 
the Safety Population.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.
Treatment comparisons of dichotomous efficacy variables between baricitinib 4-mg QD + 
background therapy and placebo + background therapy will be made using a logistic regression 
analysis with baseline stratification factors and treatment group in the model. The percentages, 

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difference in percentages, and 95% confidence interval (CI) of the difference in percentages will 
be reported. When logistic regression sample size requirements are not met (<5 responders in 
any category for any factor), the p-value from Fisher’s exact test is produced instead of the odds 
ratio and CI.
Treatment comparisons for ordinal efficacy variables between baricitinib 4-mg QD + 
background therapy and placebo + background therapy will be made using proportional odds 
model with baseline stratification factors and treatment group in the model.
Treatment comparisons of continuous efficacy and health outcome variables will be made using 
analysis of covariance (ANCOVA) with baseline randomization factors and treatment group in 
the model, if the method is appropriate. Type III tests for least squares (LS) means will be used 
for statistical comparisons between treatment groups. The LS mean difference, standard error, 
p-value, and 95% CI may also be reported. The method used to handle missing data is described 
briefly in Section 9.4.1.3 and will be described in more detail in the SAP.
Treatment comparisons of ventilation-free days will be made using Wilcoxon rank sum test and 
will be described in more detail in the SAP.
When evaluating continuous measures over time, a restricted maximum likelihood-based mixed 
model for repeated measures (MMRM) may also be used. The model will include treatment, 
baseline randomization factors, visit, and treatment-by-visit-interaction as fixed categorical 
effects, and baseline score and baseline score-by-visit-interaction score (for endpoints other than 
baseline disease severity) as fixed continuous effects for endpoints other than baseline disease 
severity. An unstructured (co)variance structure will be used to model the between- and 
within-patient errors. If this analysis fails to converge, other structures will be tested. The 
Kenward-Roger method will be used to estimate the degrees of freedom. Type III sums of 
squares for the LS means will be used for the statistical comparison; the 95% CI will also be 
reported. Contrasts will be set up within the model to test treatment groups at specific time points 
of interest. Further details on the use of MMRM will be described in the SAP.
Log-rank test will be used as the primary analysis method for evaluating treatment effect in 
time-to-event endpoints. Kaplan-Meier curves and median survival will be estimated for each 
treatment group. Hazard ratio with 95% CI will be calculated using a Cox proportional hazards 
model with treatment as covariate and adjusted for baseline values of stratification factors. 
Diagnostic tests for checking the validity of the proportional hazards assumption may be 
performed. If the assumption of proportional hazards is not justified, a statistical model capable 
of handling nonproportional hazard will be explored to assess treatment effect, such as a max-
Combo test (Lee 1996), restricted mean survival time model (Royston and Parmar et al 2013), 
and win ratio analysis (Pocock et al. 2012). An additional analysis may be performed to treat 
death as a competing event. The competing risk survival model, such as Fine-Gray model (Fine 
and Gray 1999) and cause-specific hazard model, will be considered. Further details on these 
methods will be described in the SAP.
Subgroup analyses for the primary and selected key secondary outcomes will evaluate the 
treatment effect across the following subgroups: baseline OS (OS 4 vs. OS 5 and OS 6
combined), baseline usage of remdesivir (Y/N), baseline usage of corticosteroids (Y/N), 
geographic region, duration of symptoms prior to enrollment, age, sex, dexamethasone and/or 
other systemic corticosteroid used at baseline for primary study condition, and comorbidities (if 

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applicable). Interaction tests will be conducted to determine whether the effect of treatment 
varies by subgroup.
Fisher’s exact test will be used for TEAEs, discontinuations, and other categorical safety data for
between-treatment group comparisons. Continuous vital signs, body weight, and other
continuous safety variables, including laboratory variables, will be analyzed by an analysis of 
covariance (ANCOVA) with treatment and baseline value in the model. Shift tables for 
categorical safety analyses (for example, ‘high’ or ‘low’ laboratory results) will also be 
produced.
Adjustment for Multiple Comparisons
Multiplicity controlled analyses will be performed on the primary and key secondary endpoints 
to control the overall family-wise Type I error rate at a 2-sided α level of 0.05. The graphical 
multiple testing procedure described in Bretz et al. (2011) will be used. The graphical approach 
is a closed testing procedure; hence it strongly controls the family-wise error rate (FWER) across 
all endpoints (Alosh et al. 2014). Details of the specific graphical testing scheme (including 
testing order, interrelationships, Type I error allocation, and the associated propagation) will be 
prespecified in the SAP.
The primary and key secondary endpoints to be tested are listed in Section 9.4.2 and 
Section 9.4.3, respectively.
9.4.1.1.
Participant Disposition
A description of participant disposition will be provided, including a summary of the number and 
percentage of participants entered into the study, enrolled in the study, and treated, as well as the 
number and percentage of participants completing the study (participants who receive at least 
1 dose of study drug and have at least 1 postbaseline assessment), or discontinuing (overall and 
by reason for discontinuation). All patients who discontinue from the study or from the study 
treatment will be listed and along with their reason for discontinuation. Patients who stop taking 
study drug because they are discharged from hospital are not considered as having discontinued 
study treatment (see Section 4.1 and Section 7). Reasons for discontinuation from the study will 
be summarized by treatment group and compared between groups with Fisher’s exact test.
A summary of important protocol deviations will be provided.
9.4.1.2.
Participant Characteristics
Baseline demographic data and disease characteristics, historical diagnoses, pre-existing 
conditions, and prior therapies will be summarized descriptively by treatment group. Descriptive 
statistics including number of patients, mean, standard deviation, median, minimum, and 
maximum will be provided for continuous measures, and frequency counts and percentages will 
be tabulated for categorical measures. No formal statistical comparisons will be made among 
treatment groups unless otherwise stated in the SAP. Other participant baseline characteristics 
will be summarized by group as deemed appropriate.
9.4.1.3.
Missing Data Imputation
Multiple imputation will be performed as appropriate for the primary and key secondary 
analyses. Additional sensitivity analyses for the primary and key secondary endpoints, such as 

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tipping point analyses and reference-based multiple imputation method, may be performed. Full 
details of these analyses will be included in the SAP for this study.
9.4.2.
Primary Endpoint
The primary comparison of interest is the proportion of patients who die or require non-invasive 
ventilation/high-flow oxygen or invasive mechanical ventilation (including ECMO) by Day 28.
Patients on non-invasive ventilation/high-flow oxygen at baseline will be counted toward this 
endpoint if they progressed to invasive mechanical ventilation. Treatment comparisons between 
baricitinib 4-mg QD + background therapy and placebo + background therapy will be made 
using logistic regression with baseline stratification factors and treatment group in the model.  
The primary objective will be assessed in two populations. The primary endpoint will be met if 
either of the two tests described in Section 9.1 is statistically significant.
If the sample size is increased as a result of the interim analysis, the Cui, Hung, and Wang 
(CHW) procedure (Cui et al. 1999) will be applied to the endpoints to control the type I error at a 
one sided α=0.025 significance level. The CHW method ensures strong control of type I error 
when the sample size is increased in a data dependent manner.
If the sample size is increased as a result of the interim analysis, an unadjusted point estimate for 
the primary efficacy analysis will be calculated and reported. A median unbiased point estimate 
and a stage-wise adjusted confidence interval for the primary efficacy analysis will be calculated 
and reported based on the approach described by Brannath and colleagues (Brannath et al. 2009) 
to assess sensitivity of the point estimate.
9.4.3.
Secondary Endpoints
Secondary comparisons of interest (key secondaries) are:
●  proportion of patients with at least 1-point improvement on the NIAID-OS or live 
discharge from the hospital at Day 4, Day 7, Day 10, Day 14
●  number of ventilator-free days (Day 1 to Day 28)
●  time to recovery (NIAID-OS) (Day 1 to Day 28)
●  overall improvement on the NIAID-OS evaluated at Day 4, Day 7, Day 10, Day 14 
●  duration of hospitalization (Day 1 to Day 28)
●  proportion of patients with a change in oxygen saturation from <94% to ≥94% from 
baseline to Day 4, Day 7, Day 10, Day 14, and 
●  all-cause mortality (Day 1 to Day 28).
Analyses for these endpoints are described in Section 9.4.1.
9.4.4.
Safety Analyses
Safety analyses will include adverse events (AEs), serious adverse events (SAEs), adverse events 
of special interest (AESIs), vital signs, and laboratory analytes, using the Safety Population. 
Continuous safety measures will be summarized as mean change by visit and analyzed using
ANCOVA with treatment and baseline value in the model. For binary safety measures, Fisher’s 
exact test will be used to perform comparisons between the baricitinib 4-mg QD + background 

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therapy group and the placebo + background therapy group. Further analyses may be performed,
and details of the analyses will be included in the SAP.
Exposure to study intervention will be calculated for each participant and summarized by 
treatment group.
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by system organ class, preferred term, and severity. A treatment-
emergent adverse event (TEAE) is defined as an event that either first occurred or worsened in 
severity after the first dose of study treatment and on or prior to the last visit date during the 
analysis period. Safety analyses will be conducted separately for the double-blind treatment 
period and the post-treatment follow-up period. For events that are gender-specific, the 
denominator and computation of the percentage will include only participants from the given 
gender.
Adverse events of special interest will be identified by a standardized MedDRA query (SMQ) or 
a Lilly-defined MedDRA preferred term list. The number and percentage of participants who 
experienced TEAEs, TEAEs by maximum severity, deaths, SAEs, permanent discontinuations 
from the treatment due to an adverse event, incidence of abnormal values, and AESIs will be 
summarized. TEAEs (all, by maximum severity), SAEs including deaths, and adverse events that 
lead to treatment discontinuation will be summarized and analyzed by MedDRA system organ 
class and preferred term.
All clinical laboratory results will be descriptively summarized by treatment group. Individual 
results that are outside of normal reference ranges will be flagged in data listings. Shift tables 
will be presented for selected laboratory measures.
Post-Treatment Follow-up
Safety analyses for the post-treatment follow-up period will be conducted on the follow-up 
population. Follow-up emergent adverse events, SAEs including deaths, and adverse events that 
lead to study discontinuation will be summarized. All adverse events, including pre-existing 
conditions, will be listed by participant, visit, preferred term, treatment group, severity, and 
relationship to the treatment.
9.4.5.
Pharmacokinetic Analysis
If available, the concentration-time data for baricitinib will be evaluated via graphical 
comparison to known PK profiles at 4-mg QD dosing that have been characterized for other 
populations such as healthy subjects, patients with RA, etc. The PK data may also be analyzed 
using a population modeling approach via a nonlinear mixed-effects modeling (NONMEM) 
program, if deemed necessary. The SAP will describe the planned PK analyses in greater detail.
9.5.
Interim Analyses
The analysis for the primary database lock will be conducted when all participants have either
completed the double-blind treatment period or have discontinued.
Interim analyses at other time points, including time points prior to the primary database lock,
will be conducted using safety and/or efficacy data. These interim analyses will be used for 
safety monitoring, potentially stopping for excess mortality or futility, sample size re-estimation,

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or to implement unexpected recommendations from the DMC and to support planning activities 
associated with the development program.
Unblinding details will be specified in the unblinding plan section of the SAP, the DMC charter 
and/or in a separate unblinding plan document.
Assessments of unblinded interim data will be conducted by an external data monitor committee 
(DMC). The DMC will be authorized to evaluate unblinded interim efficacy and safety analyses, 
including evaluation of excess mortality. See also Section 9.6.
The SAP will describe the planned interim analyses in greater detail. To minimize bias, the SAP 
will be finalized and approved before any unblinding. Information that may unblind the study 
during the analyses will not be reported to study sites or the blinded study team until the study 
has been unblinded.
Study sites will receive information about interim analysis results only if the investigators need 
to know for the safety of their participants.
9.6.
Data Monitoring Committee (DMC)
An independent, external data monitoring committee (DMC) will oversee this study. The DMC 
will consist of members external to Lilly. This DMC will follow the rules defined in the DMC 
charter, focusing on potential and identified risks for this molecule and for this class of 
compounds. The DMC may recommend stopping the study for futility and sample size re-
estimation. DMC membership will include, at a minimum, a specialist with expertise in statistics 
and other appropriate specialties. Details of the DMC will be documented in a DMC charter. See 
also Appendix 10.1, Section 10.1.5.
Access to the unblinded data will be limited to the DMC and the external Statistical Analysis 
Center statisticians who are providing the analysis of the data. These statisticians will be 
independent from the study team. The study team will not have access to the unblinded data. 
Only the DMC is authorized to evaluate unblinded interim analyses. 
The study sites will receive information about interim results ONLY if they need to know for the 
safety of their patients. The DMC may request to review efficacy data to evaluate the benefit/risk 
relationship in the context of safety observations for ongoing patients in the study. In addition to 
the DMC members, a limited number of pre-identified individuals may gain access to the limited 
unblinded data, as specified in the unblinding plan, prior to the final database lock. Information 
that may unblind the study during the analyses will not be reported to study sites or blinded study 
team until the study has been unblinded.

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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
●  Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
●  Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines, and
●  Applicable laws and regulations.
The protocol, protocol amendments and addenda, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:
●  Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
●  Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, and
●  Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 United States Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other applicable 
local regulations.
After reading the protocol, each principal investigator will sign the separate protocol signature 
page and send a copy of the signed page to a Lilly representative.
Investigator sites are compensated for participation in the study as detailed in the clinical trial 
agreement.
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.

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10.1.3.
Informed Consent Process
The investigator or his or her representative will explain the nature of the study, including the 
risks and benefits, to the participant or his or her legally authorized representative and answer all
questions regarding the study.
Participants must be informed that their participation is voluntary.
Participants or their legally authorized representatives will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. The sponsor or its representatives must approve the ICFs, 
including any changes made by the ERBs, before the ICFs are used at the investigative sites.
Due to strict respiratory isolation policies, limited access to COVID-19 patient rooms, and 
SARS-CoV-2 transmissibility via droplet-contaminated paper, verbal consent and alternative 
methods of obtaining consent (for example, by phone) will be allowed if approved by the IRB. In 
addition, if a signed paper copy of the ICF is allowed by hospital policy, how it will be obtained 
and stored will need to be determined. Any variation from the standard the consent process due 
to isolation and infection control should be sent to the IRB for approval prior to enrollment. The 
site should document the process in their regulatory files and demonstrate that the process has 
IRB concurrence or approval.
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study. The statement must include the date on which the 
written consent was obtained. The authorized person obtaining the informed consent and, if 
applicable, the individual designated to witness a verbal consent, must also sign the ICFs.
Participants must be re-consented to the most current version of the ICF during their 
participation in the study.
A copy of the ICFs must be provided to the participant or the participant’s legally authorized 
representative and must be kept on file.
10.1.4.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records, datasets
or tissue samples that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred.
The participant must be informed that his or her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for his or her data to be used as 
described in the informed consent.
The participant must be informed that his or her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The sponsor has processes in place to ensure data protection, information security, and data 
integrity. These processes include appropriate contingency plans for appropriate and timely 
response in the event of a data security breach.

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10.1.5.
Committee Structure
Data Monitoring Committee (DMC)
The DMC is described in Section 9.6. Details about the DMC membership, purpose, 
responsibilities, and operation will be described in a DMC charter, which will be approved prior 
to the first unblinding.
Clinical Event Committee
A blinded Clinical Event Committee will adjudicate VTEs and deaths.
10.1.6.
Dissemination of Clinical Study Data
Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.
Data
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of pharmacokinetic (PK) or genetic data. Data are available to 
request 6 months after the indication studied has been approved in the United States and the 
European Union and after primary publication acceptance, whichever is later. No expiration date 
of data requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. Data and 
documents, including the study protocol, statistical analysis plan, clinical study report, blank or 
annotated case report forms, will be provided in a secure data sharing environment for up to 
2 years per proposal. 
For details on submitting a request, see the instructions provided at www. vivli.org.
10.1.7.
Data Quality Assurance
Investigator responsibilities
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (for example, laboratory data).
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. This documentation might include laboratory and diagnostic 
test reports, medical records, and clinical notes.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
Data monitoring and management
Monitoring details describing strategy (for example, risk-based initiatives in operations and 
quality, such as risk management and mitigation strategies and analytical risk-based monitoring), 

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methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques are provided in the Monitoring Plan.
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. The sponsor assumes accountability for actions delegated to other 
individuals (for example, contract research organizations).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF/eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
In the event that on-site monitoring activities cannot occur, alternative measures (for example, 
use of technology for off-site monitoring, providing or showing pseudonymized copies of source 
documents to the monitor electronically, etc.) will be used, as allowed by local regulations. The 
remote source data verification will be focused on critical efficacy data and important safety 
data.
Records retention and audits
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the Clinical Trial Agreement (CTA)
unless local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.
In addition, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the study site. The study may be audited by the 
sponsor or its representatives, and/or regulatory agencies at any time. Investigators will be given 
notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the eCRF.
Additionally, clinical outcome assessment (COA) data will be collected by the investigative site 
personnel, via a paper source document and will be transcribed by the investigative site 
personnel into the EDC system.
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.

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Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor’s data 
warehouse.
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system.
10.1.8.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents, or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available.
The definition of what constitutes source data can be found in Section 10.1.7.
10.1.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study is open for recruitment of participants.
The sponsor or designee reserves the right to close the study site or to terminate the study at any 
time for any reason at the sole discretion of the sponsor.
Site Closure
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The investigator may initiate study-site closure at any time, provided a reasonable cause exists 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include, but are 
not limited to, these:
●  Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines
●  Inadequate recruitment of participants by the investigator, and
●  Discontinuation of further study intervention development.
Premature Termination or Suspension of the Study 
Pending the evaluation by the Data Monitoring Committee and discussion with the sponsor, 
enrollment and/or further dosing may be stopped, or the dose and/or other study parameters may 
be modified (Section 9.5 and Section 10.1.5).
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organizations 
used in the study of the reason for termination or suspension, as specified by the applicable 

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regulatory requirements. The investigator shall promptly inform the participant and assure 
appropriate participant therapy and/or follow-up.
10.1.10.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal.
10.1.11.
Investigator Information
Physicians with expertise in the care of patients with COVID-19 infection may participate as 
investigators. This includes physicians with a specialty in infectious disease, acute or critical 
care, pulmonary disease, immunology, or other appropriate specialties when justified.
10.1.12.
Long-Term Sample Retention
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable responses that may not be observed until later in the development of 
baricitinib or after it becomes commercially available for the studied indication.
The following table lists the maximum retention period for sample types. 
The retention period begins after the last participant visit for the study.
The maximum retention times may be shorter, if specified in local regulations and/or if
ERBs/IRBs impose shorter time limits, or by decision by the sponsor.
Any samples remaining after the specified retention period will be destroyed.
The sample retention facility will be selected by the sponsor or its designee.
Sample Type
Custodian
Retention Period after Last Participant Visit
Pharmacokinetics (PK)
Sponsor or designee
1 year
Long-term storage samples
Sponsor or designee
up to 15 years

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10.2.
Appendix 2: Clinical Laboratory Tests
10.2.1.
Clinical Laboratory Tests
The clinical laboratory tests listed in the table below will be performed by a central laboratory or 
by a local laboratory as specified in the table.
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or as required by local regulations.
Protocol-specific requirements for the inclusion or exclusion of participants are specified in 
Section 5 of the protocol.
Pregnancy testing is described in the SoA, in Section 8.2.5.1, and in the table below.
Investigators must document their review of the laboratory safety report as described in Section 
8.2.5.
Laboratory test results that could unblind the study will not be reported to investigative sites or 
other blinded personnel.
Notes
Hematology
Performed locally
Hemoglobin
Hematocrit
Erythrocyte count (red blood cells [RBC])
Mean cell volume
Mean cell hemoglobin
Mean cell hemoglobin concentration
Leukocytes (white blood cells [WBC])
Absolute count of:
   Neutrophils, segmented (absolute)
    Neutrophils, juvenile (bands)
    Lymphocytes (absolute)
    Monocytes
    Eosinophils
    Basophils
Platelets
Cell morphology (RBC and WBC)
Performed if applicable and/or needed

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Notes
Clinical Chemistry
Performed locally
Sodium
Potassium
Chloride
Bicarbonate
Total bilirubin (TBL)
Direct bilirubin
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma-glutamyl transferase (GGT)
Blood urea nitrogen (BUN)
Creatinine
Total protein
Albumin
Calcium
Phosphorus
Glucose
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Notes
Hormones (females)
Performed locally
Serum pregnancy 
To be performed only on women of childbearing potential
Notes
Biomarkers
Performed locally
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)
High-sensitivity (hs-CRP) is preferred if available
Ferritin
D-dimer
Procalcitonin
Cardiac troponin
Notes
Viral Testing
Performed locally. See Section 1.3, Schedule of 
Activities, Comments column, for additional information.
SARS-CoV-2 viral infection confirmation 
Utilizing nasopharyngeal swabs

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Notes
Pharmacokinetics (PK)
Assayed by Lilly-designated laboratory.
Results will not be provided to the investigative sites.
Baricitinib
Notes
Long-Term Stored Samples:
Exploratory Biomarker Samples
Assayed by Lilly-designated laboratory.
Results will not be provided to the investigative sites.
Exploratory biomarker samples:
See Section 8.8 for instructions relating to central lab kit 
supply and tests.
     Nasopharyngeal swab
     Serum
     Whole blood RNA
     Whole blood EDTA (epigenetics)
    Whole blood for cellular phenotyping (EDTA
      plus smart reagent)
To be collected by sites with the logistic or technical 
ability
10.2.2.
Clinical Laboratory Calculations
eGFR (Modification of Diet in Renal Disease [MDRD])
●  For creatinine results reported in conventional units (mg/dL):
GFR (mL/min/1.73 m²) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American) 
●  For creatinine results reported in SI units (pmol/L):
GFR (mL/min/1.73 m²) = 175 × (Scr/88.4)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American) 

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related to 
the study intervention.
NOTE:  An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition
–  Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (for example, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (that is, not related to progression of underlying 
disease).
–  Exacerbation of a chronic or intermittent pre-existing condition, including either an increase 
in frequency and/or in intensity of the condition.
–  New conditions detected or diagnosed after study intervention administration even though 
they may have been present before the start of the study.
–  Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
–  Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming intent; 
report such overdoses regardless of sequelae.
–  “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments.
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as an AE or SAE if they fulfill the definition of an AE or SAE.
Events NOT Meeting the AE Definition
–  Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
–  The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition or results in death.

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–  Medical or surgical procedure (for example, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
–  Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
–  Anticipated day-to-day fluctuations of pre-existing diseases or conditions present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (for example, hospitalization for signs/symptoms of the disease under study).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.  Results in death
b.  Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. The term does not refer to an event 
which hypothetically might have caused death if the event were more severe.
c.  Prolongation of existing hospitalization or readmission after discharge but before 
discontinuation from study
–  In general, hospitalization signifies that the participant has been admitted to hospital for 
observation and/or treatment that would not have been appropriate in the physician’s office 
or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the AE 
should be considered serious.
–  Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.  Results in persistent disability/incapacity
–  The term ‘disability’ means a substantial disruption of a person’s ability to conduct normal 
life functions.
–  This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (for example, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.  Is a congenital anomaly/birth defect
f.  Other situations:
–  Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 

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require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.
–  Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
10.3.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.
The investigator will then record all relevant AE/SAE information in the CRF/eCRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested by the 
sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before submission to 
the sponsor or designee.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
Severe: An event that prevents normal everyday activities.
Note: An AE that is assessed as severe should not be confused with a SAE. Severe is a 
category utilized for rating the intensity of an event, and both AEs and SAEs can be assessed 
as severe. An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

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The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying diseases, concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.
The investigator will also consult the IB and/or Product Information, for marketed products, in 
his/her assessment.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the sponsor or designee.
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period,
the investigator will provide the sponsor or designee with a copy of any post-mortem findings,
including histopathology.
New or updated information will be recorded in the originally completed CRF/eCRF.
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours 
of receipt of the information.
10.3.4.
Reporting of SAEs
SAE Reporting via Paper CRF
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor.
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames.
Contacts for SAE reporting can be found in in site training documents.

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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
10.4.1.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). If fertility is unclear (for example, amenorrhea in adolescents or 
athletes) and a menstrual cycle cannot be confirmed before first dose of study intervention, 
consider additional evaluation.
Woman NOT of Childbearing Potential (not WOCBP)
Female patients of non‒child-bearing potential are defined as
●  Women who are infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation)
●  Postmenopausal, defined as a woman meeting one of the following criteria:
○  woman at least 50 years of age with an intact uterus, not on hormone therapy, who has 
either
–At least 6 months of spontaneous amenorrhea with follicle-stimulating hormone 
(FSH) of ≥40 mIU/mL, or
–  Women aged 55 years or older who are not on hormone therapy, and who have 
had at least 6 months of spontaneous amenorrhea.
○  Women aged 55 years or older who have a diagnosis of menopause.
10.4.2.
Contraception
Females
Women of childbearing potential
Female patients of child-bearing potential who are abstinent (if this is complete abstinence, as 
their preferred and usual lifestyle) or in a same-sex relationship (as part of their preferred and 
usual lifestyle) must agree to either remain abstinent or stay in a same-sex relationship without 
sexual relationships with the opposite sex.
Total abstinence is defined as refraining from intercourse during the entirety of the study and for 
at least 1 week following the last dose of investigational product. Periodic abstinence such as 
calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable 
methods of contraception.
Otherwise, female patients of childbearing potential must agree to use 1 highly effective form of 
contraception for the entirety of the study and for at least 1 week following the last dose of 
investigational product.
The following contraception methods are considered acceptable; the patient should choose one
that is highly effective, defined as less than 1% failure rate per year when used consistently and 
correctly:

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Highly effective birth control methods
○ Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: oral, intravaginal, or transdermal
○ Progestogen-only containing hormonal contraception associated with inhibition of 
ovulation: oral, intravaginal, or transdermal
○Intrauterine device (IUD)/intrauterine hormone-releasing system (IUS)
○ Vasectomized male (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate)
Effective birth control methods
○  Male or female condom with spermicide
Diaphragm with spermicide
Cervical sponge
Cervical cap with spermicide
It should be noted that the use of male and female condoms as a double barrier 
method is not considered acceptable due to the high failure rate when these methods 
are combined.
Note: When local guidelines concerning highly effective or effective methods of birth control 
differ from the above, the local guidelines must be followed.
Women not of childbearing potential (not WOCBP)
Women who are not WOCBP may participate in the study if they meet all study entry criteria. 
For such women, there are no contraception requirements.
Males
For men, there are no contraception requirements.
10.4.3.
Collection of Pregnancy Information
Male participants with partners who become pregnant
The investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive study intervention.
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the sponsor. Generally, the follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.

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Female participants who become pregnant
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a participant’s
pregnancy.
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate, and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure.
While pregnancy itself is not considered to be an adverse event (AE) or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported as an 
AE or SAE.
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring at 
>20 weeks gestational age) is always considered to be an SAE and will be reported as such.
Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the investigator will be reported to the sponsor as described in Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention.

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10.5.
Appendix 5: Abbreviations
Term
Definition
ACTT
Adaptive COVID-19 Treatment Trial
AESI
adverse event of special interest
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
AVPU
Alert Voice Pain Unresponsive
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
BiPAP
bilevel positive airway pressure
blinding
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received.
CPAP
continuous positive airway pressure
CFR
United States Code of Federal Regulations
CI
COA
confidence interval
clinical outcome assessment
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
COVID-19
coronavirus disease 2019
CRP
C reactive protein
CYP
cytochrome P 450 (CYP P)
DNA
deoxyribonucleic acid
DNI
Do Not Intubate
DNR
Do Not Resuscitate
DVT
deep vein thrombosis
EBP
extracorporeal blood purification
eCRF/CRF
electronic case report form/case report form

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ECMO
extracorporeal membrane oxygenation
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERB
Ethical Review Board (see IRB)
ETV
early termination (discontinuation) visit
GCP
good clinical practice
HBV
hepatitis B virus
HCV
hepatitis C virus
hs-CRP
C reactive protein, high-sensitivity
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICU
intensive care unit
IEC
Independent Ethics Committee (see IRB)
Ig
immunoglobulin
IL
interleukin
informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form.
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IR
incidence rate
IRB
Institutional Review Board (IRB), also called Independent Ethics Committee (IEC) or 
Ethical Review Board (ERB)

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ITT
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive web-response system
JAK
Janus kinase
LDH
lactate dehydrogenase
MDRD
Modification of Diet in Renal Disease
MERS
Middle East respiratory syndrome
NAKs
numb-associated kinases
NEWS
National Early Warning Score
NIAID
National Institute of Allergy and Infectious Diseases
NIAID-OS
NIAID ordinal scale
NIH
National Institutes of Health
NOAEL
no-observed-adverse-effect level
NONMEM
nonlinear mixed effects modeling
NP
nasopharyngeal
NRI
non-responder imputation
NSAID
nonsteroidal anti-inflammatory drug
OS
ordinal scale
PA
posterior–anterior
participant
Equivalent to Clinical Data Interchange Standards Consortium (CDISC) term “subject,” 
meaning an individual who participates in a clinical trial, either as recipient of an 
investigational medicinal product or as a control.
In this protocol, the term “participant” is used to indicate an individual who participates 
in a clinical trial, either as a recipient of an investigational medicinal product or as a 
control. This usage reflects preferences indicated by patient advocates to more 
accurately reflect the role of people who take part in clinical trials. The term “patient” is 
also used to indicate an individual who participates in this clinical trial.
PD
pharmacodynamics
PE
pulmonary embolism
PK
pharmacokinetics
PK
pharmacokinetics
QD
once daily
RA
rheumatoid arthritis

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RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SARS-CoV-2
novel SARS coronavirus 2
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SI
international system of units 
SoA
Schedule of Activities
study drug
See “study intervention”
study intervention
Any investigational intervention, marketed product, placebo, or medical device 
intended to be administered to a study participant according to the study protocol
TB
tuberculosis
TBL
total bilirubin level
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TNFi
tumor necrosis factor inhibitor
ULN
upper limit of normal
VTE
venous thromboembolism
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential

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Protocol I4V-MC-KHAA(e)
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10.6.
Appendix 6: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment D (20 October 2020):
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The main purpose of this protocol amendment is to modify the study inclusion criteria and 
provide the opportunity for the sample size to be increased (sample size re-estimation) during an 
interim analysis. These changes are based on newly available data from the ACTT-2 study and 
on evolution in clinical management of the disease. In addition, based on regulatory feedback, a 
follow-up visit is added at Day 60.
Sections # and Name
Description of Change
Brief Rationale
1.1, Synopsis: Overall Design
Added a Day 60 assessment in the 
follow-up period and increased the 
total maximum duration.
To evaluate safety and efficacy at 
Day 60 for this patient population 
based on regulatory feedback.
1.1, Synopsis: Number of 
Participants
Changed sample size to 1000 
patients. Added text for a sample size 
re-estimation to potentially increase 
the final sample size beyond 1000 
patients.
To increase sample size based on 
ACTT-2 data and modeling 
assessments. Included a sample size 
re-estimation to maintain an 
adequately powered study.
1.2, Schema
Changed figure to include a Day 60 
assessment.
To add a Day 60 assessment based 
on regulatory feedback.
1.3, Schedule of Activities
Added a column for Day 60 
assessments. 
Added text clarifying the conduct of 
various procedures. 
Added visit windows for patients 
discharged from hospital.
To add a Day 60 assessment based 
on regulatory feedback. 
To provide clarity on study visit 
procedures.
To provide greater visit window 
flexibility for patients who have 
been discharged from the hospital.
2.2, Background
Added citations for NIH and WHO 
guidelines on use of corticosteroids.
To reflect current NIH and WHO 
guidelines.
3, Objectives and Endpoints
Added an exploratory objective for 
long-term (at least Day 60) clinical 
outcomes.
To reflect addition of Day 60 
assessment based on regulatory 
feedback.
4.1, Overall Design
Added a Day 60 assessment in the 
follow-up period and increased the 
total maximum duration; changed 
description of study population.
Regulatory feedback, as stated for 
Section 1.1; see also rationale for 
Section 5.1.
4.2, Scientific Rationale for 
Study Design
Added a statement and a phrase about 
the Day 60 assessment.
Regulatory feedback, as stated for 
Section 1.1

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Sections # and Name
Description of Change
Brief Rationale
4.3, Justification for Dose
Added bold font format and 
clarifying text about patients who 
have eGFR ≥30 mL/min/1.73 m2 to 
<60 mL/min/1.73 m2 at screening.
To clarify for investigators; these 
patients will remain on blinded 2-mg 
dose (baricitinib or placebo) during 
treatment.
5.1, Inclusion Criteria
Revised protocol inclusion criterion 
#4, stating that patients must require 
oxygen supplementation at entry and 
randomization.
Changed study population based on 
ACTT-2 data availability and 
population that derived greatest 
benefit in recovery and mortality. 
6.1, Study Interventions 
Administered
Added bold font format and 
clarifying text about patients who 
have eGFR ≥30 mL/min/1.73 m2 to 
<60 mL/min/1.73 m2 at screening.
Added clarifying text about 
investigational product after patient’s 
discharge from hospital.
To clarify for investigators; these 
patients will remain on blinded 2-mg 
dose (baricitinib or placebo) during 
treatment.
To clarify for investigators: Patients
who are discharged from hospital 
will not be given investigational 
product for home use.
6.5.3, Prohibited Concomitant 
Therapy
Added a clarification in a 
parenthetical phrase about prohibited 
concomitant medication.
Baricitinib for treatment of 
COVID-19 is required for certain 
participants according to the study 
design. However, JAK inhibitors are 
prohibited as concomitant therapy 
during the study.
6.6, Dose Modification
Added words “equal to or”; corrected 
some symbols, replacing > with ≥.
To provide consistency between text 
statement and the “greater than or 
equal to” symbol (≥) in the 
preceding sentences.
7.1.1, Criteria for Permanent 
Discontinuation of Study 
Drug
Added a phrase about the Day 60 
assessment.
Regulatory feedback, as stated for 
Section 1.1
8.1.1, COVID-19 Clinical Status 
Assessment
Added a statement about a Day 60 
assessment.
Regulatory feedback, as stated for 
Section 1.1
8.3.1, Time Period and 
Frequency for Collecting 
AEs and SAEs 
Added a statement that serious 
adverse events, including death, 
caused by COVID-19 disease 
progression should not be reported 
on the SAE form unless the 
investigator deems them to be 
possibly related to study treatment.
To clarify the SAE reporting process 
and to align with language already in 
Section 10.3.
9.2, Sample Size Determination
Moved the assumptions of the sample 
size as stated in amendment C, and 
provided new assumptions for 
amendment D.
To update the assumptions used to 
calculate the new sample size. The 
assumptions use modeling inclusive 
of data available from the ACTT-2 
study.

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Sections # and Name
Description of Change
Brief Rationale
9.3, Populations for Analyses
Revised removed the phrase “within 
each study period” from the 
statement about analyzing 
participants according to the 
intervention they received.
To clarify the sentence, given that 
participants receive intervention in 
only one study period.
9.4.1, General Considerations
Added subgroups for subgroup 
analyses.
To assess subgroups of interest.
9.4.2, Primary Endpoint
Added statement about statistical 
procedure to be used to control type I
error if the sample size is increased 
as a result of interim analysis.
To control type I error in the event of 
a sample size increase.
9.4.4, Safety Analyses
Removed text about the analysis 
period being defined as the treatment 
period plus up to 30 days off-drug
follow-up time.
Removed text stating that the
treatment period will be used as the 
postbaseline period for the analysis.
Removed text about summary of 
treatment-related TEAEs.
To reflect that safety assessments 
will include safety data collected 
within the Treatment period.
To provide clarity.
To remove a nonstandard summary.
9.5, Interim Analyses
Added sample size re-estimation 
considerations of interim analyses.
Added that unblinding details may be 
specified in DMC charter or in SAP 
or separate unblinding plan 
document.
To reflect that sample size 
re-estimation may be a rationale for 
interim analyses. To provide a more 
comprehensive list of documents 
where unblinding details may be 
described.
9.6, Data Monitoring Committee 
(DMC)
Added a phrase about sample size 
re-estimation.
To maintain an adequately powered 
study; see rationale for Section 1.1.
10.2.1, Clinical Laboratory Tests
Added a note that cell morphology is 
performed “if applicable and/or 
needed.”
To clarify conduct of assessment if 
warranted.
10.3.1, Events Not Meeting AE 
Definition
Added clarifying text, stating that 
disease being studied or expected 
progression is not reported unless 
more severe than expected “or results 
in death”.
To clarify reporting of adverse 
events given death is endpoint being 
measured.
10.3.2, Definition of SAE
Clarified definition of SAE if death is 
due to progression of COVID-19
disease.
To clarify that SAE due to 
progression of COVID-19 disease is 
reported as adverse event.  
11, References
Added references and links for 
updated guidance documents from 
NIH and WHO, press release for the 
ACTT-2 study, Gao et al., Cui et al., 
and Brannath et al.
To support statement about 
corticosteroid use in the protocol’s 
background section, and to support 
statements about sample size in the 
protocol’s statistical section.
various sections
Changed singular nouns to plural (for 
example, visit to visits); changed verb 
tense from present to past.
Grammatical correctness.

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Protocol I4V-MC-KHAA(e)
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Amendment C (12 Aug 2020):
This amendment was considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The main purpose of this protocol amendment was to increase the sample size to accommodate 
evolving changes in standard-of-care therapy, especially concomitant use of dexamethasone.
Sections # and Name
Description of Change
Brief Rationale
1.1 Synopsis: Rationale
Replaced “data on file” with citations
Information has been published, 
citations added.
1.1 Synopsis: Number of 
Participants and Intervention 
Groups
Increased the total number of patients 
to be randomized from the original 
number to a range of 600 to 1000, 
keeping same randomization ratio
and same number of treatment groups
Sample size was increased to 
accommodate evolving changes in 
standard-of-care therapy, especially 
concomitant use of dexamethasone.
1.3 Schedule of Activities
Provided introductory text and 
clarifying text on the row called Site 
Visit
Provided clarification for situations 
in which patient is not able to have 
an on-site visit and what procedures 
should be done for telephone visit
1.3 Schedule of Activities
Updated Comments column for 
physical examination row
Editorial change, no intended change 
in meaning
1.3 Schedule of Activities
Updated Comments column for chest 
imaging row and ECG row
To clarify the acceptable timing of 
the procedure
1.3 Schedule of Activities
Created a separate row for Lactate 
dehydrogenase (LDH, which was 
previously written in the row for 
clinical chemistry; updated Clinical 
Chemistry row, removing LDH
To clarify that LDH is acceptable 
within 2 days of study entry
1.3 Schedule of Activities
Clarified text in Comments columns 
on rows for D-dimer, ferritin, 
C-reactive protein (CRP)
To make text about lab timing 
consistent with inclusion criteria 
requirements
1.3 Schedule of Activities
Clarified and updated text in 
Comments column about 
requirements for SARS-CoV-2 viral 
infection confirmation via 
nasopharyngeal swab
To clarify text per inclusion criteria 
requirements, if patient has 
confirmed COVID-19 infection; also 
to provide investigator judgement for 
collection of samples at other 
timepoints to reduced number of NP 
swabs, patient burden, and site 
burden
1.3 Schedule of Activities
Updated text in Comments column in 
two rows about exploratory 
biomarker samples
To reference a section describing 
collection based on lab kit 
availability
2.1 Study Rationale
Replaced “data on file” with 
citations; updated year of United 
States package insert (USPI)
Information has been published, 
citations added; UPSI was updated.
4.3 Justification for Dose
Replaced “data on file” with citation
Information has been published, 
citation added.

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Sections # and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
Added a note to exclusion criterion 
#8
To clarify corticosteroid use (dose 
and duration) for dexamethasone 
and/or other systemic corticosteroids
5.2 Exclusion Criteria
Added “or” in the phrase about deep 
vein thrombosis and pulmonary 
embolism
To clarify and support site 
understanding
5.2 Exclusion Criteria
Added a parenthetical reference to 
the aforementioned exclusion criteria 
following exclusion criterion #20
To support site understanding
6.1 Study Interventions 
Administered
Clarified dosing instructions for 
patients with eGFR >30 mL/min/1.73 
m2 to <60 mL/min/1.73 m2 at 
screening
To support site understanding
6.3 Measures to Minimize Bias: 
Randomization and Blinding
Changed one of the factors for 
stratification: removed the symptom 
onset factor, and added a factor about 
use of dexamethasone and/or other 
systemic corticosteroid use at 
baseline for primary study condition
To accommodate evolving changes 
in standard-of-care therapy
6.6 Dose Modification
Clarified dosing instructions for 
patients with eGFR >30 mL/min/1.73 
m2 to <60 mL/min/1.73 m2 at 
screening
To support site understanding
8.1.3 Other Efficacy 
Assessments
Clarified text on resolution of fever
To clarify the definitions and options 
for assessment of fever
8.2.1 Vital Signs
Revised text about body temperature, 
simplifying the text
To avoid redundancy and potential 
inconsistency. Section 8.1.3 provides 
the information about body 
temperature.
8.2.3 Electrocardiograms
Revised text about timing of ECGs 
that are acceptable, per the SOA
To keep text consistent with changes 
in the SOA, as described above
8.2.4 Chest Imaging Studies
Revised text about timing of imaging 
that is acceptable, per the SOA
To keep text consistent with changes 
in the SOA, as described above
8.8 Biomarkers
Added text about sample collection 
based on availability of centrally 
supplied lab kits 
To clarify collection based on lab kit 
availability
9.2 Sample Size Determination
Changed the number of patients to be 
randomized, changed power; changed
assumptions for the power 
calculation
To accommodate evolving changes 
in standard-of-care therapy
9.4.1 General Considerations
Changed text about subgroup 
analysis, including dexamethasone 
and/or other systemic corticosteroid 
used at baseline for primary study 
condition
To maintain consistency with other 
changes already described
9.4.1.3 Missing Data Imputation
Changed from LOCF to multiple 
imputation methods
To more accurately account for the 
variability of missing data

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Sections # and Name
Description of Change
Brief Rationale
9.5 Interim Analyses
Clarified that interim analyses may 
be used for safety monitoring
To clarify intended uses of interim 
analyses
9.6 Data Monitoring Committee
Added mention of external statistical 
analysis; removed mention of 
population PK/PD model 
development
To provide clarity and to update with 
correct information, as no PK/PD 
modeling is planned
10.2.1 Clinical Laboratory Tests
Added text and cross-references 
about SARS-CoV-2 viral infection 
confirmation and exploratory 
biomarker samples
To provide consistency and 
flexibility of investigator assessment 
for collection, consistent with 
inclusion criteria requirements and at 
other timepoints; and to clarify 
exploratory biomarker sample 
collection based on central lab kit 
availability
10.4.2 Contraception
For males and for women not of 
childbearing potential, changed 
verbiage from “there are no 
conception requirements” 
to “there are no contraception 
requirements”
To correct a typographical error
10.5 Abbreviations
Defined several terms, including but 
not limited to, ACTT, CYP, JAK, 
NP, OS, WHO
To improve ease of reading
10.6 Protocol Amendment 
History
Inserted amendment B history
To maintain the history of the 
protocol
Section 11 References
Added Beigel, Horby, Stebbing
publications; updated date of the 
USPI; updated access date of 
Summary of Product Characteristics
Information has been published, 
citations added, USPI updated.
various sections
Added punctuation marks that were 
previously missing
Editorial consistency

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Amendment B (03 Jun 2020):
This amendment was considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The main purpose of this protocol amendment was to address regulatory comments regarding the 
primary endpoint.
Sections # and Name
Description of Change
Brief Rationale
1.1 Synopsis
3.0 Objectives and Endpoints
4.1 Overall Design
4.2 Scientific Rationale
8.1.1 COVID-19 Clinical Status 
Assessment (Primary Endpoint 
Assessments)
9.1 Statistical Hypotheses
9.2 Sample Size Determination
9.4.2 Primary Endpoint
Updated primary endpoint
Response to FDA feedback. The 
updated primary endpoint is proportion 
of patients who die or require non-
invasive ventilation/high-flow oxygen 
or invasive mechanical ventilation 
(including extracorporeal membrane 
oxygenation [ECMO]) by Day 28.
1.3 Schedule of Activities
Added clarification for Vital 
Signs to be assessed and 
documented daily.
Response to FDA feedback. Added 
clarifying test that Vital Signs are
assessed and documented daily while 
hospitalized in the comment box in 
first position.
4.1 Overall Design
6.5.2 Required and Permitted 
Concomitant Therapy
11.0 References
Added statement allowing use of 
hydroxychloroquine and 
chloroquine only if 
recommended or required by 
local COVID-19 treatment 
guidelines.
Updated given updates in scientific 
literature.
5.1 Inclusion Criteria
Update to Criterion #3 to 
provide duration of time 
between confirmatory testing 
and enrollment
Response to FDA feedback. The 
updated criteria provide the duration of 
time between confirmatory testing and 
enrollment should not be more than 14 
days for SARS-CoV-2 confirmation 
>72 hours.
5.2 Exclusion Criteria
Update to Criterion #11 with 
addition of clarifying text for 
patients that may have ongoing 
infection
Response to FDA feedback. The 
updated criterion includes “Note: 
Immunocompromised patients, 
patients with a chronic medical 
condition, or those taking a medication 
that cannot be discontinued at 
enrollment, who, in the judgment of 
the investigator, are at increased risk 
for serious infections or other safety 
concerns given the study products 
should be excluded”.

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Sections # and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
Update to Criterion #22 that 
patients should not be enrolled in 
any other trials for COVID-19.
Response to FDA feedback. The 
updated criterion provides the 
participant should not be enrolled 
(start) in another clinical trial for the 
treatment of COVID-19 or SARS 
CoV-2 through Day 28.
5.2 Exclusion Criteria
6.5.3 Prohibited concomitant 
therapy
Addition of Exclusion Criterion
#25 for the use of extracorporeal 
blood purification (EBP) device 
to remove pro-inflammatory 
cytokines from the blood.
Added EBP device to remove 
pro-inflammatory cytokines 
from the blood to list of 
prohibited concomitant therapy.
The new criterion was added and the 
prohibited concomitant therapy list 
updated given recent input on current 
practices and EUA that is in place and 
use of this modality can confound 
assessments in KHAA. The new 
exclusion criterion applies if “Are 
using or will use extracorporeal blood 
purification (EBP) device to remove 
pro-inflammatory cytokines from the 
blood such as a cytokine absorption or 
filtering device, for example, CytoSorb 
®.”  
5.2 Exclusion Criteria
Addition of Exclusion Criterion
#26 to exclude patients that are 
unlikely to survive participation 
in the study
The new criterion provides exclusion if 
the patient, in the opinion of the 
investigator, unlikely to survive for at 
least 48 hours after screening.
9.3 Populations for Analyses
Addition of clarification of 
analyses population 
The new language provides that a 
sensitivity analysis excluding patients 
who die within 24 hours of 
randomization and have do not 
resuscitate (DNR) or do not intubate 
(DNI) in ITT/PP analyses populations 
will be conducted.  

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Protocol I4V-MC-KHAA(e)
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Amendment A (27 May 2020): 
Amendment A occurred before any study participant was consented or dosed at any study site.
Overall Rationale for Amendment A:
The main purpose of this protocol amendment was to address regulatory comments regarding the 
primary endpoint and regarding the role of an internal assessment committee in the review of 
unblinded data. 
Sections # and Name
Description of Change
Brief Rationale
1.1 Synopsis
3 Objectives and Endpoints
4.1 Overall Design
9.1 Statistical Hypotheses
9.4.2 Primary Endpoint
Changed primary endpoint.
Changed wording of primary 
objective.
Response to FDA feedback.
The new primary endpoint is 
proportion of patients requiring 
non-invasive ventilation/high-flow 
oxygen or invasive mechanical 
ventilation (including extracorporeal 
membrane oxygenation [ECMO]) by 
Day 28. 
A related secondary endpoint 
[“Proportion of patients requiring 
mechanical ventilation (Day 1 to Day 
28)”] has been removed; this 
secondary objective is unnecessary 
given the new primary endpoint.
The primary objective wording was 
changed (from “on clinical 
improvement of patients” to “on 
disease progression in patients”) to 
align with the primary endpoint.
1.1 Synopsis
3 Objectives and Endpoints
9.4.3 Secondary Endpoints
Added a secondary endpoint.
Response to FDA feedback.
The new secondary endpoint is overall 
improvement in NIAID ordinal scale 
evaluated at Day 10. It has been 
incorporated into the existing key 
secondary endpoint of “Overall 
improvement on the NIAID-OS 
evaluated at Day 4, Day 7, Day 10, 
Day 14.”
1.2 Schema
Removed timepoint indicator for 
the primary endpoint.
Changed to maintain consistency with 
changed primary endpoint described 
above.
2.2 Background
Replaced “creatinine kinase”
with “creatine kinase.”
Changed to fix typographical error.
4.1 Overall Design
Removed a statement about use 
of oxygen therapy at time of 
study entry.
Changed to prevent misreading.
4.2 Scientific Rationale for Study 
Design
Provided rationale for the new 
primary endpoint.
New information is included for 
consistency with the new primary 
endpoint.

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Protocol I4V-MC-KHAA(e)
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Sections # and Name
Description of Change
Brief Rationale
8.1.1 COVID-19 Clinical Status 
Assessment
Added two paragraphs defining 
terms relevant to the primary 
endpoint.
Changed for consistency with other 
listed changes and to improve clarity.
8.1.3 Other Efficacy Assessment
Added “high-flow oxygen” to 
the endpoint cell for non-
invasive ventilation.
Changed for consistency with other 
listed changes and to improve clarity.
8.2.4 Chest Imaging Studies
Added “or appropriate 
physician” to the list of 
personnel who may assess the 
chest imaging scans.
Changed to provide flexibility to sites.
8.2.5 Laboratory Tests
10.2.1 Clinical Laboratory Tests
Changed the requirements for 
documentation of reviews of 
laboratory reports.
Changed to decrease site burden, 
allowing flexibility on how the review 
is documented.
9.2 Sample Size Determination
Modified rationale for sample 
size.
Changed to align with response to 
FDA feedback, and to use more 
recently available data as part of the 
justification of sample size.
9.4.1 General Considerations
Added Wilcoxon rank sum test 
for treatment comparison of 
ventilation-free days.
Changed for consistency with changes 
in other sections.
9.4.2 Primary Endpoint
Revised primary endpoint.  
Added statement about how 
patients on non-invasive 
ventilation at baseline will be 
counted in the new endpoint.
Changed as a result of response to 
FDA feedback.
9.4.3 Secondary Endpoints
Removed secondary endpoints, 
as previously described.
See above.
9.5 Interim Analyses
9.6 Data Monitoring Committee
10.1.5 Committee Structure
10.1.9 Study and Site Start and 
Closure
Removed all references to 
Internal Assessment Committee 
(IAC).
Clarified the use of interim 
analyses.
Response to FDA feedback.
Unblinded data reviews will be carried 
out by the external Data Monitoring 
Committee (DMC), not an IAC.
10.5 Appendix 5: Abbreviations
Added and removed 
abbreviations.
Editorial. Changed for consistency 
with other changed sections.
11 References
Added and removed references.
Editorial. Changed for consistency 
with other changed sections.

C O N FI D E N TI A L
Pr ot oc ol  I 4 V-M C -K H A A( e)
9 6
1 1.
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[ A C T T-2 press release] Barici tini b has si g nifica nt effect o n rec o ver y ti me, most i m p a ctf ul i n 
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C he n N, Z h o u M, D o n g X, et al. E pi de mi ol o gical a n d cli nical  c haracteristics of 9 9 cases of 2 0 1 9 
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