Clinical trial NCT04415151
Conditions: COVID-19 Pneumonia
Sponsor: Yale University
Start date: 2020-10-14; Completion date: 2021-02-28
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this randomized, double blinded, placebo controlled study is to assess the efficacy and safety of tofacitinib in hospitalized adult (18-99 years old) patients with SARS-CoV-2 and pneumonia who require supplemental oxygen and have serologic markers of inflammation but do not need mechanical ventilation.

Detailed description:
The purpose of this randomized, double blinded, placebo controlled Phase 2b study is to assess the efficacy and safety of tofacitinib in hospitalized adult (18-99 years old) male and female patients with SARS-CoV-2 and pneumonia who require supplemental oxygen and have serologic markers of inflammation but do not need mechanical ventilation (see Inclusion criteria). Sixty patients will be recruited to receive tofacitinib or placebo in addition to standard of care (SOC) in a 1:1 ratio.

Subjects will be screened during hospitalization. Patients with confirmed SARS-CoV-2 infection, and meeting all other Inclusion and Exclusion criteria, will be randomized to either treatment with tofacitinib or placebo in addition to SOC during hospitalization (dose adjusted, if required), with the exception of pre-specified immunomodulatory agents (as documented in the inclusion/exclusion criteria). Tofacitinib will be administered in a dose of 10 mg PO BID until return to their clinical baseline (as defined by need for supplementary oxygen), and will continue to be administered at 5 mg PO BID for a total duration of therapy of 14 days; follow-up off tofacitinib will continue up to Day 90. We anticipate completion of subject recruitment in 6 months.

Arms: arm 1: Tofacitinib will be administered in a dose of 10 mg PO BID until return to their clinical baseline (as defined by supplementary oxygen requirement), and then will continue to be administered at 5 mg PO BID for a total treatment duration of 14 days. arm 2: Matching placebo will be administered.
Interventions: intervention 1: Tofacitinib 10 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Tofacitinib will be administered in a dose of 10 mg twice daily by mouth (PO BID) until return to their clinical baseline (as defined by supplementary oxygen requirement), and then will continue to be administered at 5 mg PO BID for a total treatment duration of 14 days. intervention 2: Matching placebo tablets will be administered.

Protocol documents:
Prot_000.pdf: 
ClinicalTrials.gov ID: NCT04415151 
Brief Title: Tofacitinib for Treatment of Moderate COVID-19 (I-TOMIC) 
Date: 9/28/2020 
Document: Protocol ONLY (SAP revised 2024) 


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Investigation of Tofacitinib to Mitigate the 
Impact of COVID-19 (I-TOMIC) in Moderate 
SARS-CoV-2 (MODERATE I-TOMIC)
 Protocol Number
2000027848
Protocol Revision 5
15 SEPTEMBER 2020
PRINCIPAL INVESTIGATOR:
Hyung Chun, MD
Yale University School of Medicine
Department of Internal Medicine
Section of Cardiovascular Medicine
300 George St. 7th Floor
New Haven, CT 06511
hyung.chun@yale.edu
650-704-8383 (mobile)
203-737-6389 (office)
IND Number: PIND 149901
IND Holder: Hyung Chun, MD
NCT Number: NCT04415151
Study Phase: 2
Confidentiality Statement:
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REVISION HISTORY:
Revision #
Version Date
Original
13 April 2020
1
8 May 2020
2
18 May 2020
3
15 June 2020
4
25 June 2020
5
15 September 2020
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Synopsis
Primary Objective/Endpoint

Proportion of subjects alive and not needing any form of mechanical ventilation, high 
flow oxygen, or ECMO at day 14.
Secondary Objectives/Endpoints 

Clinical improvement as measured by NIAID 8-point ordinal scale (i.e., 1 = death and 8 
= Not hospitalized, no limitations on activities) at day 14.

Clinical status using ordinal scale (days 3 through day 14): The ordinal scale is an 
assessment of the clinical status at the first assessment of a given study day. The scale 
is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive 
ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 
5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - 
no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities 
and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.* For 
patients on chronic home O2 supplementation, supplemental O2 is defined as >= home 
O2 requirement. ** Use of NIV for chronic conditions [e.g. Obstructive sleep apnea 
(OSA)] is not applicable

Time to recovery [ Time Frame: Day 1 through Day 14] (Day of recovery is defined as 
the first day on which the subject satisfies one of the following three categories from the 
ordinal scale: 1) Hospitalized, not requiring supplemental oxygen - no longer requires 
ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home 
oxygen; 3) Not hospitalized, no limitations on activities).

Time to clinical improvement (defined as a 2-point increase on the ordinal scale)”.

Clinical status on ordinal scale at day 30, 60, and 90

Mortality rate at day 30, 60, 90

Proportion of patients requiring ICU admission and mechanical ventilatory support

Change from baseline in inflammatory parameters (e.g., hsCRP, procalcitonin, ferritin, 
D-dimers, LDH, fibrinogen, PT/PTT)

Change from baseline in cytokines (e.g. IL-1, IL-2, IL-6, IL-8, TNF-α, IL-17A, IL-17F, IP-
10, CCL5), as available

Safety as assessed by reporting of adverse events, changes in clinical laboratory 
parameters (e.g., hemoglobin, hepatic transaminases, serum creatinine, bilirubin, and 
evidence of secondary infections)

Intervention with additional immunomodulatory agent (i.e. IL-6 targeting therapy)

Change in SARS-CoV-2 viral titers during intervention
Study Duration

10 months
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Study Design 
Randomized, double-blinded, placebo-controlled phase 2B study
Number of Study Sites
1 – Yale New Haven Health System
Study Population
Male and female subjects age 18 to 99 hospitalized with moderate SARS-CoV-2 infection
Number of Participants
60
Primary Outcome Variables

Proportion of subjects alive and not needing any form of mechanical ventilation, high 
flow oxygen, or ECMO at day 14.
Secondary and Exploratory Outcome Variables (if applicable)

Clinical improvement as measured by NIAID 8-point ordinal scale (i.e., 1 = death and 8 
= Not hospitalized, no limitations on activities) at day 14.

Clinical status using ordinal scale (days 3 through day 14): The ordinal scale is an 
assessment of the clinical status at the first assessment of a given study day. The scale 
is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive 
ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 
5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - 
no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities 
and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.* For 
patients on chronic home O2 supplementation, supplemental O2 is defined as >= home 
O2 requirement. ** Use of NIV for chronic conditions [e.g. Obstructive sleep apnea 
(OSA)] is not applicable

Time to recovery [ Time Frame: Day 1 through Day 14] (Day of recovery is defined as 
the first day on which the subject satisfies one of the following three categories from the 
ordinal scale: 1) Hospitalized, not requiring supplemental oxygen - no longer requires 
ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home 
oxygen; 3) Not hospitalized, no limitations on activities).

Time to clinical improvement (defined as a 2-point increase on the ordinal scale)”.

Clinical status on ordinal scale at day 30, 60, and 90

Mortality rate at day 30, 60, 90

Proportion of patients requiring ICU admission and mechanical ventilatory support

Change from baseline in inflammatory parameters (e.g., hsCRP, procalcitonin, ferritin, 
D-dimers, LDH, fibrinogen, PT/PTT)
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
Change from baseline in cytokines (e.g. IL-1, IL-2, IL-6, IL-8, TNF-α, IL-17A, IL-17F, IP-
10, CCL5), as available

Safety as assessed by reporting of adverse events, changes in clinical laboratory 
parameters (e.g., hemoglobin, hepatic transaminases, serum creatinine, bilirubin, and 
evidence of secondary infections)

Intervention with additional immunomodulatory agent (i.e. IL-6 targeting therapy)

Change in SARS-CoV-2 viral titers during intervention
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1 Introduction
1.1
Introductory Statement
This document is a protocol for a human research study. The purpose of this protocol is to 
ensure that this study is to be conducted according to ICH GCP guidelines, and according to 
CFR 21 Part 312, other applicable government regulations and Institutional research policies 
and procedures.
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2 Background
2.1.1
Preclinical Experience
o
JAK inhibitors prevent CRS induced by CAR-T-cell therapy in mice, and JAK inhibition 
was more effective than tocilizumab1
o
JAK inhibitor ruxolitinib improves survival, decreases cardiac inflammation and fibrosis in 
an experimental myocarditis model (Hyung Chun lab, unpublished data), and improves 
Staph-induced CRS, ARDS, and MOF in mice (Jon Koff lab, unpublished data)2 
2.1.2
Clinical Experience
o
Tofacitinib improves severe myocarditis in humans with DRESS3
o
Tofacitinib improves sarcoidosis involving the skin4 and internal organs5 
o
Ruxolitinib improves CRS associated with HLH6,7 
o
Ruxolitinib improved cytokine and inflammatory profile and ventilatory requirement in one 
patient with severe SARS-CoV-2 infection at Yale New Haven Hospital (Won et.al., in 
preparation)`
2.2
Background/prevalence of research topic
Patients with SARS-CoV-2 may manifest cytokine release syndrome (CRS), associated with 
systemic inflammation, hemodynamic instability, and multiple organ failure. CRS is among 
the key reasons for SARS-CoV-2 related mortality. 
Multiple cytokines, including IL-6, are involved in CRS. Indeed, the IL-6 receptor antibody 
tocilizumab is FDA approved for the treatment of Chimeric Antigen Receptor T (CART) Cell-
Induced Severe or Life-Threatening CRS. Anti-IL-6 antibody treatment is being used in some 
cases of SARS-CoV-2, and treatment with tocilizumab is standard of care at YNHH as of 
April 4, 2020.  However, the only data to support the use of tocilizumab is a 21-patient 
retrospective case series from China.8 A therapy targeting multiple cytokines, including IL-6, 
may prove effective in SARS-CoV-2 -induced CRS.
JAK-STAT signaling is a pro-inflammatory pathway that is activated downstream of multiple 
cytokines, including IL-6. JAK inhibitors (JAKi) are small molecule inhibitors of one or more 
of the Janus kinase (JAK) family of enzymes and are used to treat hematological and 
inflammatory diseases. Over 50 cytokines signal through the JAK-STAT pathway, and hence 
JAK inhibitors have the potential to suppress the activity of multiple cytokines, including IL-2, 
IL-4, IL-6, IL-15, interferon gamma, and IL-21.  
Oral tofacitinib was approved by the FDA in 2012 for the treatment of moderately to severely 
active RA who have had an inadequate response to, or who are intolerant of, methotrexate.  
It has recently been approved for the treatment of psoriatic arthritis (PsA) and ulcerative 
colitis (UC). Its use is being studied in other inflammatory diseases, including juvenile 
idiopathic arthritis. The recommended dose of tofacitinib is 5 mg twice daily for RA and PsA 
and up to 10 mg twice daily for UC. The following table presents the risks as summarized in 
the original package insert for XELJANZ for RA. The risk profile has not changed 
significantly following studies of tofacitinib in other diseases. 
Tofacitinib is an orally administered, synthetic small molecule that selectively inhibits the JAK 
family of kinases (preferentially JAK1/JAK3) and is currently FDA-approved for the treatment 
of rheumatoid arthritis (RA), psoriatic arthritis (PsA), graft vs. host disease (GVHD) and 
ulcerative colitis (UC). Unlike targeted biologic therapies, which are directed at extracellular 
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targets such as individual soluble cytokines (e.g. TNF-), cytokine receptors (IL-1R, IL-6R) 
or other cell surface receptors (CD20, CD80, and CD86), tofacitinib works intracellularly2 and 
has been developed to target a number of cytokines known to have a role in inflammatory 
diseases (Figure 1). 
Abbreviations: IL=interleukin; IFN=interferon; EPO=erythropoietin; TPO=thrombopoietin; 
GM-CSF= granulocyte macrophage colony-stimulating factor; CSF=colony-stimulating 
factor; JAK= Janus-Kinase; TYK2= tyrosine kinase 2; Th17=T-helper phenotype.
Cytokine signaling is mediated by specific JAK and STAT combinations due to preferential 
binding to the intracellular domains of the individual cytokine receptor chains. For example, 
JAK3 only associates with the γ- common chain and therefore only mediates IL-2, -4, -7, -9, -
15, and -21 signaling, whereas JAK1 plays a broader role in cytokine signaling.
Adapted from reference10. 
Dose Rationale
The safety and clinical pharmacology of tofacitinib has been very well characterized. The 
pharmacodynamics (PD) of the tofacitinib, in terms of cytokine inhibition and biomarkers of 
pharmacologic activity, have been characterized in in vitro studies, animal models, and in 
vivo clinical studies. These data indicate rapid onset, followed by sustained pharmacologic 
activity over the dosing period. At a 10 mg BID dose, approximately 80% suppression of IL-6 
may be expected, in addition to substantial inhibition of multiple other pro-inflammatory 
cytokines, such as IFN, IL-15, IL-21, and IL-27, supporting the use of tofacitinib 10 mg BID 
for prevention of overexpression of cytokines in SARS-CoV-2 infected patients. Given the 
high mortality of COVID-19 complicated by ARDS, and the overall case mortality rate in 
COVID-19 patients, a tofacitinib dose of 10 mg immediate release formulation BID is 
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Figure 1. Tofacitinib Mechanisms of Action - Biological Significance of Signaling 
Through Different JAK Combinations 
ye Cytolcines 
(ll·2, IL_., ll• 7 
ll-9, ll-15, ll -21) 
~, 
I • 
Growth/ 
maturation 
lymphoid cells 
n/ 
• Olfferentlatlo 
homeostasis 
Tcells, NI( cell 
• Bcell clau 
swltchln1 
• Inflammation 
I 
.. 1 
Typel lFNs, 
ll•lOfamily 
ofcytolclnu 
• Antiviral 
• Inflammation 
• Antltumor 
I 
IL-6, ll •ll, ll•ll 
ll-27, ll·31, il-35 
• NaiveTcell 
different iation 
• Tcell 
homeostasis 
• lnflamrnatlon 
• Granulopoiuls 
-
IFNy 
I 
II 
• Antiviral 
• Inflammation 
• Anti-
mycobacterlal 
I 
" 
ll•U 
ll·23 
• Innate Immunity 
• Differentiation/ 
proliferation of 
Th17cells 
• Inflammation 
El'O, Tl'O 
GMCSF, 
ll-3, ll-S 
• Erythropoiuls 
• Myelopoiuls 
• Mqalcaryocyte/ 
platelet production 
• Growth 
• Mammary 
dr.,elopment 


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expected to provide maximal cytokine suppression while maintaining an overall positive 
benefit-risk profile.
If concomitant administration of a strong inhibitor of CYP3A4 (eg, ketoconazole, 
clarithromycin, ritonavir/lopinavir) or a moderate inhibitor of CYP3A4 that is also a strong 
inhibitor of CYP2C19 (eg, phenytoin, fluvoxamine, fluconazole) cannot be avoided, a 
reduced dose of tofacitinib 5 mg BID is recommended and will provide similar target 
coverage.
Because patients are likely to be discharged from the hospital soon after returning to clinical 
baseline, we will continue to administer tofacitinib 5 mg BID for a total duration of treatment 
of 14 days in order to prevent rebound of CRS that could theoretically occur with abrupt 
cessation of immunomodulatory therapy.  In these cases, patients will be discharged home 
with a pill bottle labeled as investigational drug containing the appropriate number of pills 
(either tofacitinib or placebo).
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3 Rationale/Significance
3.1
Problem Statement
Patients with SARS-CoV-2 may manifest cytokine release syndrome (CRS), associated with 
systemic inflammation, hemodynamic instability, and multiple organ failure. CRS is among 
the key reasons for SARS-CoV-2 related mortality. 
3.2
Purpose of Study/Potential Impact
The role of JAKi in the treatment of CRS and cardiac and respiratory failure in patients with 
SARS-CoV-2 is supported by both preclinical and clinical data.
Taken together, we hypothesize that JAKi treatment of patients with moderate SARS-COV-2 
and associated CRS and cardiac and respiratory complications will improve clinical 
outcomes of moderate SARS-CoV-2.
3.2.1
Potential Risks
(Please refer to tofacitinib package insert for complete risk profile)
Study Drug (Tofacitinib) Risks
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common side effects (these may affect 1 in 10 people or more, or >10%): none.
Common side effects (these may affect up to 1 in 10 people, or up to 10%): upper 
respiratory tract infection (nasopharyngitis, common cold), lung infection (pneumonia and 
bronchitis), shingles (herpes zoster), influenza (flu), sinusitis, urinary bladder infection 
(cystitis), sore throat (pharyngitis), increased muscle enzymes or cholesterol, weight gain, 
stomach (belly) pain (which may be from inflammation of the stomach lining), vomiting, 
diarrhea, nausea, indigestion, pain in the joints, low red blood cell count (anemia), fever, 
fatigue (tiredness), swelling of the feet and hands, headache, high blood pressure 
(hypertension), cough, rash.
Uncommon side effects (these may affect up to 1 in 100 people, or up to 1%): tuberculosis, 
kidney infection, viral infections, skin infection, herpes simplex or cold sores (oral herpes), 
viral infections affecting the gut, increased liver enzymes, low white blood cell count, blood 
creatinine increased (a possible sign of decreased kidney function), dehydration, pain in the 
muscles, muscle strain, tendonitis, joint swelling, ligament sprain, abnormal sensations, poor 
sleep, shortness of breath or difficulty breathing, sinus congestion, skin redness, itching, 
fatty liver, inflammation of outpouchings of your intestine (diverticulitis), tears in your 
stomach or intestines, some types of skin cancers (nonmelanoma-types), drug allergy (which 
can involve bumpy skin rash, swelling around lips and tongue, wheezing, dizziness or 
lightheadedness). 
Rare side effects (these may affect up to 1 in 1,000 people, or up to 0.1%): blood infection 
(sepsis), joint infection, tuberculosis involving the brain and spinal cord, bones and other 
organs, and other unusual infections.
EMERGING SAFETY INFORMATION - MORTALITY
In one ongoing study in rheumatoid arthritis patients who were 50 years of age or older with 
at least one risk factor for heart disease, patients treated with tofacitinib 10 mg twice a day 
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had a higher frequency of mortality (death), compared to patients treated with tofacitinib 5 
mg twice a day or a tumor necrosis factor inhibitor medication (adalimumab or etanercept). 
In patients treated with tofacitinib 10 mg twice a day in other tofacitinib studies, the 
frequency of death has not been higher than the frequency of death in patients treated with 
tofacitinib 5 mg twice a day.
Minimizing risks: Patients will be evaluated at least once daily, depending on the level of 
care required of their overall condition after treatment initiation. 
Toxicity monitoring: Patients will be monitored at least once daily after initiation of therapy, 
depending on the level of care required of their overall condition. On each day an H&P will 
be performed and the patient will undergo laboratory monitoring including hsCRP, ferritin, 
LDH, D-dimer, CBC, and CMP (SOC). If there is suspected toxicity from the therapy, the 
dose of tofacitinib may be reduced to 5 mg BID or stopped entirely, depending on the toxicity 
observed or suspected. 
Research blood samples: The results of the research testing will not appear in the subject’s 
medical file. No individual identifiers will be used for any testing. All samples and data are 
given a unique code to remove any identifying information. Any information that identifies the 
subject will be kept separate from the samples and this identified information will be kept 
until the study is complete.  
With respect to prophylactic management of VTE, we will follow the institutional standard of 
care algorithm at the time of the study (Appendix 1).
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Risk Mitigation Strategies
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention(s) Tofacitinib
Known risks associated with 
tofacitinib include the following:

Serious infections leading to 
hospitalization or death, 
including tuberculosis and 
bacterial, invasive fungal, viral, 
and other opportunistic 
infections and viral 
reactivation;

Venous thromboembolism 
(VTE), including pulmonary 
embolism and deep venous 
thrombosis;

Gastrointestinal perforations;

Interstitial lung disease;

Potential changes in 
lymphocytes, neutrophils, 
hemoglobin, liver enzymes, 
and lipids.
Other risks, which are known to 
have long latency, such as 
lymphomas and other malignancies 
and cardiovascular events, have 
also been identified with tofacitinib 
treatment.
The list of risks are based on the 
SRSD for tofacitinib.
Eligibility criteria exclude 
participants with risk factors for 
venous thromboembolism, known 
malignancies, and active infections 
other than COVID-19 pneumonia, 
and these lab abnormalities.
Thromboprophylaxis with LMWH 
is required for all participants.
Treatment with tofacitinib will be 
discontinued if the participant has 
any serious infection not considered 
related to COVID-19, VTE, or other 
safety event for which the 
investigator determines that 
continued treatment with tofacitinib 
is not in the participant’s best 
interest.
Discontinuation criteria are in place 
for these lab parameters.

Concomitant use of CYP3A4 
and CYP2C19 inhibitors and 
CYP inducers.

Participants with moderate or 
severe renal impairment.

Participants with moderate 
hepatic impairment.
Potential risks are based on the 
SRSD for tofacitinib.
Participants receiving medications 
that may interfere with tofacitinib 
metabolism (CYP inducers) within 
28 days or 5 half-lives of the 
medication are excluded from the 
study.
Dose modification instructions are 
included in the study for
co-administration of CYP inhibitors 
and tofacitinib.
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3.2.2
Potential Benefits
For study subjects, the potential benefits of this trial are halted progression of and 
improvement in their SARS-CoV-2 infection. For society at large, this study offers the 
possibility of effective therapy of moderate SARS-COV-2, an often morbid and sometimes 
fatal disease.
4 Study Objectives
4.1
Hypothesis
We hypothesize that JAKi treatment of patients with moderate SARS-COV-2 and associated 
CRS and cardiac and respiratory complications will improve clinical outcomes of moderate 
SARS-CoV-2.
4.2
Primary Objective/Endpoint
The primary objective of this study is to determine whether tofacitinib improves the clinical 
outcomes of patients with moderate SARS-CoV-2 infection as determined by the primary 
outcome measure: Proportion of subjects alive and not needing any form of mechanical 
ventilation, high flow oxygen, or ECMO by day 14.
4.3
Secondary Objectives 

Clinical improvement as measured by NIAID 8-point ordinal scale (i.e., 1 = death and 
8 = Not hospitalized, no limitations on activities) at day 14.

Clinical status using ordinal scale (days 3 through day 14): The ordinal scale is an 
assessment of the clinical status at the first assessment of a given study day. The 
scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive 
ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental 
oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing 
medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring 
supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, 
limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no 
limitations on activities.* For patients on chronic home O2 supplementation, 
supplemental O2 is defined as >= home O2 requirement. ** Use of NIV for chronic 
conditions [e.g. Obstructive sleep apnea (OSA)] is not applicable

Time to recovery [ Time Frame: Day 1 through Day 14] (Day of recovery is defined as 
the first day on which the subject satisfies one of the following three categories from 
the ordinal scale: 1) Hospitalized, not requiring supplemental oxygen - no longer 
requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or 
requiring home oxygen; 3) Not hospitalized, no limitations on activities).

Time to clinical improvement (defined as a 2-point increase on the ordinal scale)”.
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
Clinical status on ordinal scale at day 30, 60, and 90

Mortality rate at day 30, 60, 90

Proportion of patients requiring ICU admission and mechanical ventilatory support

Change from baseline in inflammatory parameters (e.g., hsCRP, procalcitonin, 
ferritin, D-dimers, LDH, fibrinogen, PT/PTT)

Change from baseline in cytokines (e.g. IL-1, IL-2, IL-6, IL-8, TNF-α, IL-17A, IL-17F, 
IP-10, CCL5), as available

Safety as assessed by reporting of adverse events, changes in clinical laboratory 
parameters (e.g., hemoglobin, hepatic transaminases, serum creatinine, bilirubin, 
and evidence of secondary infections)

Intervention with additional immunomodulatory agent (i.e. IL-6 targeting therapy)

Change in SARS-CoV-2 viral titers during intervention
5 Study Design
5.1
General Design Description
We propose a randomized, double blinded, placebo controlled Phase 2b study of the 
efficacy and safety of tofacitinib in hospitalized adult (18-99 years old) male and female 
patients with SARS-CoV-2 and pneumonia who require supplemental oxygen and have 
serologic markers of inflammation but do not need mechanical ventilation (see Inclusion 
criteria). Sixty patients will be recruited to receive tofacitinib or placebo in addition to 
standard of care (SOC) in a 1:1 ratio.
Informed Consent (Day -2)
Randomization (1:1) (Day 1)
Tofacitinib 10 mg BID + SOC
Placebo BID + SOC
Last day of treatment (Day 14)
Follow up visit 1 (Day 30)
Follow up #2 (Day 60)
Follow up visit 3/End of study
(Day 90)
Double blinded
Treatment
Period
Screening Period
Post Treatment
Period
5.1.1
Study Date Range and Duration
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Subjects will be screened during hospitalization. Patients with confirmed SARS-CoV-2 
infection, and meeting all other Inclusion and Exclusion criteria, will be randomized to either 
treatment with tofacitinib or placebo in addition to SOC during hospitalization (dose adjusted, 
if required), with the exception of any immunomodulatory agents (as documented in the 
inclusion/exclusion criteria). Tofacitinib will be administered in a dose of 10 mg PO BID until 
return to their clinical baseline (as defined by need for supplementary oxygen), and will 
continue to be administered at 5 mg PO BID for a total duration of therapy of 14 days; follow-
up off tofacitinib will continue up to Day 90.  We anticipate completion of subject recruitment 
in 6 months.
5.1.2
Number of Study Sites
1 (Yale-New Haven Health System)
5.2
Outcome Variables
5.2.1
Primary Outcome Variables

Proportion of subjects alive and not needing any form of mechanical ventilation, high 
flow oxygen, or ECMO by day 14.
5.2.2
Secondary Outcome Variables 

Clinical improvement as measured by NIAID 8-point ordinal scale (i.e., 1 = death and 
8 = Not hospitalized, no limitations on activities) at day 14.

Clinical status using ordinal scale (days 3 through day 14): The ordinal scale is an 
assessment of the clinical status at the first assessment of a given study day. The 
scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive 
ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental 
oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing 
medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring 
supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, 
limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no 
limitations on activities.* For patients on chronic home O2 supplementation, 
supplemental O2 is defined as >= home O2 requirement. ** Use of NIV for chronic 
conditions [e.g. Obstructive sleep apnea (OSA)] is not applicable

Time to recovery [ Time Frame: Day 1 through Day 14] (Day of recovery is defined as 
the first day on which the subject satisfies one of the following three categories from 
the ordinal scale: 1) Hospitalized, not requiring supplemental oxygen - no longer 
requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or 
requiring home oxygen; 3) Not hospitalized, no limitations on activities).

Time to clinical improvement (defined as a 2-point increase on the ordinal scale)”.
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
Mortality rate at day 30, 60, 90

Proportion of patients requiring ICU admission and mechanical ventilatory support

Change from baseline in inflammatory parameters (e.g., hsCRP, procalcitonin, 
ferritin, D-dimers, LDH, fibrinogen, PT/PTT)

Change from baseline in cytokines (e.g. IL-1, IL-2, IL-6, IL-8, TNF-α, IL-17A, IL-17F, 
IP-10, CCL5), as available

Safety as assessed by reporting of adverse events, changes in clinical laboratory 
parameters (e.g., hemoglobin, hepatic transaminases, serum creatinine, bilirubin, 
and evidence of secondary infections)

Intervention with additional immunomodulatory agent (i.e. IL-6 targeting therapy)

Change/clearance of SARS-CoV-2 viral titers during intervention
5.3
Study Population
Potential subjects will be identified by study coordinators in conjunction with treating 
clinicians by screening the EMR of patients with a clinical diagnosis of SARS-CoV-2. 
Patients whose providers feel they are appropriate for the study will be approached. 
Pursuant to HIPAA regulations, a log of disclosures of protected health information for 
recruitment/screening purposes will be kept. Eligibility will be determined by the PI, Dr. 
Chun, and/or co-investigators Dr. Koff or Dr. Won. To initiate the process of obtaining 
informed consent, the PI or study coordinator will first approach the patient’s treating 
clinician (ex: physician, nurse practitioner, or physician’s assistant) regarding possible 
involvement in the study. If the provider feels the patient is appropriate, they will ask if 
the patient would be interested in hearing about a research project they might be able to 
participate in. If the patient expresses interest, the PI or study coordinator will then 
approach the patient.
5.3.1
Number of Participants
A total of approximately 60 patients, both male and female, age between 18 and 99 years 
old, will be enrolled.
5.3.2
Eligibility Criteria/Vulnerable Populations
Inclusion Criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
Male or female participants between the ages of 18 and 99 years, inclusive, at screening. 
Refer to Appendix 3 for contraceptive guidance for participants.
Type of Participant and Disease Characteristics:
1.
Participants who are willing and able to comply with all scheduled visits, 
treatment plan, laboratory tests, lifestyle considerations, and other study 
procedures.
2.
Participants with laboratory-confirmed novel coronavirus (SARS-CoV-2) infection 
as determined by polymerase chain reaction (PCR) or other commercially 
available or public health assay prior to Day 1.
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3.
Participants with evidence of pneumonia assessed by radiographic imaging 
(chest x-ray or chest CT scan) AND Requiring ≥ 3L O2 OR ≥ 2L O2 and hsCRP > 
70 mg/L
4.
Participants who are hospitalized and receiving supportive care for COVID-19.
Informed Consent:
Participant (or legally authorized representative/surrogate) capable of giving signed 
informed consent.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1.
Require mechanical ventilation or ECMO on Day 1 at the time of randomization.
2.
Have current, or history of, venous thromboembolism (deep vein thrombosis or 
pulmonary embolism).
3.
Have a personal or first-degree family history of blood clotting disorders.
4.
Participants who are immunocompromised, with known immunodeficiencies, or 
taking potent immunosuppressive agents (eg, azathioprine, cyclosporine).
5.
Participants with any current malignancy or lymphoproliferative disorders that 
requires active treatment
6.
Females of child bearing potential who are pregnant or breastfeeding 
7.
Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk 
associated with study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study. 
8.
Anticipated survival < 72 hours as assessed by the Investigator.
Infection History:

Suspected or known active systemic bacterial, fungal, or viral infections (with the 
exception of COVID-19) including but not limited to:
o
Secondary bacterial pneumonia;
o
Active herpes zoster infection;
o
Known active tuberculosis or history of inadequately treated tuberculosis;
o
Known HBV, HCV, or HIV.
Prior/Concomitant Therapy:
Have received any of the following treatment regimens specified in the timeframes outlined 
below:
Within 4 weeks prior to the first dose of study intervention:
o
Prior treatment with any JAK inhibitors, potent immunosuppressants, or any 
biologic agents including IL-6 inhibitors (eg, tocilizumab) or IL-1 inhibitors (eg, 
anakinra) within the past 28 days or 5 half-lives, whichever is longer.
o
Prior treatment with any potent cytochrome P450 inducer, such as rifampin, 
within the past 28 days or 5 half-lives, whichever is longer.
Within 48 hours prior to the first dose of study intervention:
o
Treatment with herbal supplements.
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Received >/= 20 mg/day of prednisone or equivalent for >/=14 consecutive days in the 4 
weeks prior to screening
Diagnostic Assessments:

Severe hepatic impairment, defined as Child-Pugh class C.

Severe anemia (hemoglobin <8 g/dL).

ANY of the following abnormalities in clinical laboratory tests at screening, 
confirmed by a single repeat, if deemed necessary:

WBC <1000/mm3

Absolute lymphocyte count <500 cells/mm3;

Absolute neutrophil count <1000 cells/mm3.

Alanine transaminase/aspartate transaminase (ALT/AST) > 5 times the upper 
limit of normal;

Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2); 
Other Exclusions:

Known allergy to tofacitinib.

Investigator site staff or Pfizer employees directly involved in the conduct of 
the study, site staff otherwise supervised by the investigator, and their 
respective family members. 

Enrollment in another clinical trial to study COVID-19
Treatment Considerations
Guidance on the management of COVID-19 coagulopathies based on commonly available 
laboratory tests has been recently published by the ISTH. They found a high incidence of 
both severe pneumonia and lymphopenia related to COVID-19 infection in patients requiring 
hospitalization. In this setting, patients with increased D-dimers (3 to 4-fold increase) are 
more likely to die from COVID-19 infection. Subtle prolongation of prothrombin time is seen 
in these patients and may be prognostic of mortality. Thrombocytopenia is also seen in these 
patients but does not seem to be a consistent prognosticator. In addition to monitoring of D-
dimer, PT, and platelet counts, the ISTH also recommends monitoring of serum fibrinogen 
as patients with COVID -19 infection may develop DIC as early as Day 4.
ISTH recommends a prophylactic dosing of LMWH in hospitalized subjects who have 
COVID-19 infection to protect against sepsis-like coagulopathies and venous 
thromboembolism in the absence of active bleeding or a platelet count of <25,000 cells/mm3. 
Concomitant Therapy
All participants must receive pharmacologic thromboprophylaxis with LMWH and supportive 
care for COVID-19 pneumonia. Therapies currently being evaluated for treatment of COVID-
19 patients have multiple mechanisms of action and address different therapeutic targets. 
With the exception of EUAs granted by FDA, there are currently no drugs or other 
therapeutics approved by health/ regulatory authorities to prevent or treat COVID-19 or the 
severe ARDS it may cause, so it is expected that adjunctive SOC may include 
investigational and off-label treatments. Some of these therapies are prohibited concomitant 
medications with tofacitinib; others can be co- administered. Table below lists known 
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investigational products in clinical trials and drugs that might be administered off-label. In 
addition, there may be additional products that may be added to the institutional standard of 
care, for which tofacitinib dosage may need to be adjusted.  Treatments that should not be 
co-administered with tofacitinib during the conduct of this study are identified. If there is any 
uncertainty about the concomitant use of a treatment with tofacitinib, contact the sponsor. 
Investigational and Off-Label Treatments for COVID-19
Category
Treatment
Anticipated Target
Concomitant Use 
with Tofacitinib
Antiviral
Remdesivir
Stops virus from replicating; does not 
interfere with cytochrome P450 
metabolism. Approved by FDA for 
emergency use.
Not prohibited
Antimalarial
Hydroxychloroquine/ 
chloroquine
Used for the treatment of malaria; 
anecdotal data. FDA does not recommend 
use except in clinical trials.
Not prohibited
Azalide 
Antibiotic
Azithromycin
Has not been used for viral infections; 
may have some anti-inflammatory action. 
NIH advised against use of the 
combination of hydroxychloroquine and 
azithromycin.
Not prohibited
Antiviral
Combination of 
lopinavir and ritonavir 
(Kaletra)
Indicated for treatment of HIV. One study 
did not show efficacy, but other clinical 
trials are ongoing.
Requires 50% 
reduction in dose
Host Modifiers/ 
Immune-based 
Therapy
Convalescent plasma
FDA has allowed this to be used in 
patients with serious or life-threatening 
COVID-19 infections. This treatment is 
still considered experimental.
Not prohibited
Host Modifiers/ 
Immune-based 
Therapy
Hyperimmune 
immunoglobulin
Manufactured from convalescent plasma 
and is allowed to be used in the same 
population. This treatment is still 
considered experimental.
Not prohibited
IL-6 Inhibitor
Tocilizumab
Used to treat autoimmune conditions 
through inhibition of IL-6 and is in 
clinical trials for COVID to treat 
hyperinflammation.
Prohibited
IL-6 Inhibitor
Sarilumab
Similar to tocilizumab and is in clinical 
trials for COVID.
Prohibited
IL-6 Inhibitor
Siltuximab
Similar to tocilizumab and is in clinical 
trials for COVID.
Prohibited
IL-1 Inhibitor
Anakinra
Used to treat autoimmune conditions 
through inhibition of IL-1 and is in 
clinical trials for COVID to treat 
hyperinflammation.
Prohibited
Janus kinase 
Inhibitor
Baricitinib
JAK 2 selective inhibitor with ant- 
iinflammatory properties is in clinical 
trials for COVID.
Prohibited
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Janus kinase 
Inhibitor
Tofacitinib
JAK 1/ JAK 3 selective inhibitor with 
anti-inflammatory properties is in clinical 
trials for COVID.
This is the 
compound being 
studied.
Additional 
treatment is 
prohibited.
Modified from the NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines 
https://www.covid19treatmentguidelines.nih.gov/
To the extent possible, the following restrictions should be followed:

Use of strong inhibitors of cytochrome P450 3A should be avoided to the extent 
possible. Judicious use of strong inhibitors of CYP3A4 or a moderate inhibitor of 
CYP3A4 that is also a strong inhibitor of CYP2C19 is permitted, if necessary, but the 
dose of tofacitinib should be reduced to 5 mg BID PO with careful monitoring for 
adverse effects (see Tofacitinib Dose Modifications, Section Error! Reference 
source not found.). 

Concomitant use of tofacitinib with strong inducers of cytochrome P450 is not 
recommended, and tofacitinib should not be used if strong inducers have been 
discontinued less than 28 days or 5 half-lives prior to the first tofacitinib dose.

Herbal supplementation should not be administered, as many interfere with the 
cytochrome P450 pathways.

Other JAK inhibitors, biological DMARDS, or potent immunosuppressive agents, 
including IL-6 inhibitors (eg, tocilzumab) and IL-1 inhibitors (eg, anakinra) should not 
be administered during the study.

All non-pharmacologic and nutritional supportive care measures, including nutritional 
supplementation and oxygenation support are permitted. All concomitant medications 
and nondrug treatments, with dose and frequency, should be recorded.

Hormonal contraceptives are allowed to be used in participants who are WOCBP 
(Appendix 3).
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6 Methods
6.1
Treatment 
6.1.1
Identity of Investigational Product
Tofacitinib is an orally administered, synthetic small molecule that selectively inhibits the JAK 
family of kinases, and is currently FDA approved for the treatment of rheumatoid arthritis 
(RA), psoriatic arthritis (PsA), and ulcerative colitis (UC). Unlike targeted biologic therapies, 
which are directed at extracellular targets such as individual soluble cytokines (e.g. TNF-), 
cytokine receptors (IL-1R, IL-6R) or other cell surface receptors (CD20, CD80, and CD86), 
tofacitinib works intracellularly9 and has been developed to target a number of cytokines 
known to have a role in inflammatory diseases.  
SOC will be determined by YNHH SARS-CoV-2 Therapeutics Group and may 
include treatment targeting SARS-CoV-2 (e.g., anti-viral therapies).  However, those 
enrolled in our study will not receive other forms of IL-6 blocking agents (e.g. 
tocilizumab, sarilumab, or other JAKi), if these are part of the SOC algorithm (Please 
see Appendix 1 for current algorithm).
Study intervention is defined as any investigational intervention(s), marketed 
product(s), placebo, medical device(s), or study procedure(s) intended to be 
administered to a study participant according to the study protocol.
For the purposes of this protocol, study intervention refers to Tofacitinib 5 mg tablets.
All participants will receive pharmacologic thromboprophylaxis with LMWH and 
supportive care for COVID-19 pneumonia.  It is acceptable for participants to also 
receive experimental therapies for COVID-19, with the exception of prohibited 
medications listed in the eligibility criteria and concomitant medications sections of the 
protocol.
6.1.2
Dosage, Administration, Schedule 
TREATMENT DESCRIPTION
Tofacitinib or placebo will be administered.  Tofacitinib will be administered in a dose of 10 
mg PO BID until return to their clinical baseline (as defined by supplementary oxygen 
requirement), and then will continue to be administered at 5 mg PO BID for a total treatment 
duration of 14 days. Follow-up off tofacitinib will continue up to Day 90. 

Tofacitinib tablets will be sourced from Pfizer, Inc.  Matching placebo tablets will be 
provided by Pfizer, Inc..

Participants will swallow the study intervention whole and will not manipulate or 
chew the study intervention prior to swallowing.  If the participant is unable to 
swallow the study intervention whole, tofacitinib 5 mg film-coated tablets will be 
disintegrated in water (in a syringe) and administered as a liquid suspension 
through a nasal-gastric (NG) tube or percutaneous endoscopic gastrostomy 
(PEG) tube. Dosing of the suspension should occur within 4 hours from the time 
of preparation, when stored at room temperature (15-25°C), or within 24 hours, 
when at refrigerated temperature (2-8°C). Dosing verification was completed by 
Pfizer which was demonstrated through in-use stability of the prepared 
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suspension, compatibility of the suspension with common materials of 
composition for NG and PEG tubes, and accuracy of the intended dose. Since 
tofacitinib meets the Biopharmaceutics Class System (BCS) criteria for high 
solubility designation and the 5 mg IR tablet has been demonstrated to be 
bioequivalent to 5 mL of the oral solution (1 mg/mL) (Study A3921354 
conducted under IND 117,400), we expect that disintegration of the 5 mg tablet 
in the syringe will not adversely impact the bioperformance. 

Study intervention administration details will be recorded on the CRF.
REQUIRED TREATMENT MODIFICATIONS
The following dose adjustments need to be considered during the use of 10 mg BID 
in this patient population when the potential exists for differences in tofacitinib 
exposure due to DDI or changes in renal or hepatic function:

When a concomitantly used drug is a strong CYP3A4 inhibitor, OR when a 
co-administered drug is both a moderate CYP3A4 inhibitor and a strong CYP2C19 
inhibitor (eg, fluconazole), a 50% reduction in dose is recommended. Therefore, a 
5 mg BID dose should be used to achieve a similar exposure as that of 10 mg BID in 
a patient not receiving co-administered metabolic inhibitor. 

Antivirals such as lopinavir and ritonavir are examples of potent CYP3A4 
inhibitors. Cobicistat, which is used to increase concentrations of antiviral drugs, 
is also a potent CYP3A4 inhibitor. Examples of other co-administered drugs 
requiring dose reduction are ketoconazole, itraconazole, clarithromycin, 
telithromycin, and fluconazole (Appendix 2).
o
Tofacitinib dose reduction is not needed when co-administered with the 
following medication: azithromycin, hydroxychloroquine, chloroquine, 
remdesivir, favipiravir, oseltamivir, and ribavirin.

A 50% dose reduction is recommended in patients who are in moderate or severe 
renal impairment (including patients on hemodialysis) and those in moderate hepatic 
impairment. Therefore 5 mg BID should be used in these patients, which will be 
Intervention Name
Tofacitinib
ARM Name
Tofacitinib plus SoC therapy
Type
Drug
Dose Formulation
Tablet
Unit Dose Strengths
5 mg
Dosage Level
10 mg BID
Route of Administration
Oral or per nasogastric tube
Use
Experimental
IMP or NIMP
IMP
Sourcing
Provided by Pfizer
Packaging and Labeling
Study intervention will be provided in bottles with appropriate 
labeling.
Current/Former Names or Aliases
CP-690550, Xeljanz®
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changed to 5 mg PO QD upon return to their clinical baseline (as defined by 
supplementary oxygen requirement). 

Tofacitinib should not be used in patients with severe hepatic impairment 
(Participants with Child-Pugh class C are excluded). 

Tofacitinib use is not recommended in patients receiving a potent CYP3A4 inducer 
(eg, rifampin, St. John’s wort) or if they had discontinued use of a potent CYP3A4 
inducer less than 28 days or 5 half-lives prior to the first dose of tofacitinib. 
Required Tofacitinib Discontinuations:
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following. 

WBC count <1000 /mm3

Lymphocyte counts <250 cells/mm3.

Absolute neutrophil counts <500 cells/mm3. 

Hemoglobin less than 8 g/dL. 

ALT or AST ≥5 times the ULN.

Anaphylaxis or other serious allergic reaction.

Diagnosis of venous thromboembolism.

Any serious infection, including secondary bacterial pneumonia, or other safety 
event for which the investigator determines that continued treatment with 
tofacitinib is not in the participant’s best interest.

If IL-6 targeting agent or other non-FDA approved, compassionate use or 
expanded access is considered as medically necessary (AS REVIEWED BY THE 
PI)

Diagnosis of thrombosis including pulmonary embolism, deep venous 
thrombosis, and arterial thrombosis
6.1.3
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature 
conditions have been maintained during transit for all study interventions 
received and any discrepancies are reported and resolved before use of 
the study intervention.
2.
Only participants enrolled in the study may receive study intervention and 
only authorized site staff may supply or administer study intervention. All 
study interventions must be stored in a secure, environmentally 
controlled, and monitored (manual or automated recording) area in 
accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.  At a minimum, daily minimum and 
maximum temperatures for all site storage locations must be documented 
and available upon request.  Data for nonworking days must indicate the 
minimum and maximum temperatures since previously documented for all 
site storage locations upon return to business.
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3.
Any excursions from the study intervention label storage conditions should 
be reported to Pfizer upon discovery along with any actions taken. The site 
should actively pursue options for returning the study intervention to the 
storage conditions described in the labeling, as soon as possible. Once an 
excursion is identified, the study intervention must be quarantined and not 
used until Pfizer provides permission to use the study intervention.  Specific 
details regarding the definition of an excursion and information the site 
should report for each excursion will be provided to the site in the IP manual 
or other specified location.
4.
Any storage conditions stated in the SRSD will be superseded by 
the storage conditions stated on the label.
5.
Study interventions should be stored in their original containers.
6.
The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All 
study interventions will be accounted for using a study intervention 
accountability form/record.
7.
Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual or other specified location.  All 
destruction must be adequately documented.  If destruction is authorized to 
take place at the investigator site, the investigator must ensure that the 
materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by 
Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.
6.1.4
Preparation and Dispensing
A qualified staff member (investigational drug service pharmacist) will dispense the study 
intervention, in quantities appropriate according to the schedule (6.4.1).  A second staff 
member will verify the dispensing.
6.1.5
Method of Assignment/Randomization 
The Investigational Drug Service at Yale Center for Clinical Investigation will conduct the 
randomization.  Study will be double blinded.
6.1.6
Blinding and Procedures for Unblinding 
This study is blinded.  Study intervention and matching placebo tablets will be dispensed in 
appropriately marked, covered dosing cups to limit the treating physician’s knowledge of the 
treatment.
The research pharmacist will dispense the investigational product and record only the 
randomization code in the CRF and record the number of tablets each patient will receive 
independent of group assignment. As such, the research pharmacist will be unblinded.
However, as only the randomization code will be recorded in the CRF, physicians and 
caregivers will continue to be blinded. Only trained investigators and site staff as recorded on 
the delegation of authority log will have access to the CRF.
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6.1.7
Allocation to Study Intervention
This is a blinded study; potential bias will be reduced by the following steps: randomization 
provided to site. The investigator’s knowledge of the treatment should not influence the 
decision to enroll a particular participant or affect the order in which participants are 
enrolled.  The site will record the study intervention assignment on the applicable CRF, if 
required.
Study intervention will be dispensed at the study visits summarized (6.4.1).
Returned study intervention must not be re-dispensed to the participants.
The study-specific IRT reference manual and IP manual will provide the contact information.
6.1.8
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the 
CRF. The dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person administering 
the study intervention.
When compliance of less than 70% or more than 120% of the expected number of doses of 
study intervention is suspected, the reason for non-compliance with the dosing regimen 
should be documented in the dosing log of the participant’s case report form, and should 
be reported as a protocol deviation and unless there is a protocol stipulated reason for 
non-compliance with the dosing regimen, this should be recorded as a dosing error.
6.1.9
Packaging/Labeling
Clinical supply tablets and placebo will be used.
6.1.10 Storage Conditions
Tablets will be stored at and dispensed by the YNHH inpatient pharmacy or Investigational 
Drug Service. The pharmacy may convert the active ingredient into a suspension form.
6.1.11 Concomitant therapy
All participants must receive pharmacologic thromboprophylaxis with LMWH and 
supportive care for COVID-19 pneumonia. It is acceptable for participants to also 
receive experimental therapies with the exception of prohibited medications listed in 
the eligibility criteria and concomitant medications sections of the protocol. To the 
extent possible, the following restrictions should be followed:

Use of strong inhibitors of cytochrome P450 3A should be avoided to the extent 
possible. Judicious use of strong inhibitors of CYP3A4 or a moderate inhibitor of 
CYP3A4 that is also a strong inhibitor of CYP2C19 is permitted, if necessary, but the 
dose of tofacitinib should be reduced to 5 mg BID PO with careful monitoring for 
adverse effects (see Tofacitinib Dose Modifications). 

Concomitant use of tofacitinib with strong inducers of cytochrome P450 is not 
recommended, and tofacitinib should not be used if strong inducers have been 
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discontinued less than 28 days or 5 half-lives prior to the first tofacitinib dose 
(Appendix 2).

Herbal supplementation should not be administered, as many interfere with the 
cytochrome P450 pathways.

Other JAK inhibitors, biological DMARDS, or potent immunosuppressive agents, 
including IL-6 inhibitors (eg, tocilzumab) and IL-1 inhibitors (eg, anakinra) should not 
be administered during the study.

All non-pharmacologic and nutritional supportive care measures, including nutritional 
supplementation and oxygenation support are permitted. All concomitant medications 
and nondrug treatments, with dose and frequency, should be recorded.

Hormonal contraceptives that meet the requirements of this study are allowed to be 
used in participants who are WOCBP.
Tofacitinib Dose Modifications: 
The following dose adjustments need to be considered during the use of 10 mg BID 
in this patient population when the potential exists for differences in tofacitinib 
exposure due to DDI or changes in renal or hepatic function:

When a concomitantly used drug is a strong CYP3A4 inhibitor, OR when a 
co-administered drug is both a moderate CYP3A4 inhibitor and a strong CYP2C19 
inhibitor (eg, fluconazole), a 50% reduction in dose is recommended. Therefore, a 
5 mg BID dose should be used to achieve a similar exposure as that of 10 mg BID in 
a patient not receiving co-administered metabolic inhibitor. 

Antivirals such as lopinavir and ritonavir are examples of potent CYP3A4 
inhibitors. Cobicistat, which is used to increase concentrations of antiviral drugs, 
is also a potent CYP3A4 inhibitor. Examples of other co-administered drugs 
requiring dose reduction are ketoconazole, itraconazole, clarithromycin, 
telithromycin, and fluconazole (Appendix 2).
o
Tofacitinib dose reduction is not needed when co-administered with the 
following medication: azithromycin, hydroxychloroquine, chloroquine, 
remdesivir, favipiravir, oseltamivir, and ribavirin.

A 50% dose reduction is recommended in patients who are in moderate or severe 
renal impairment (including patients on hemodialysis) and those in moderate hepatic 
impairment. Therefore 5 mg BID should be used in these patients which will be 
changed to 5 mg PO QD upon return to their clinical baseline (as defined by 
supplementary oxygen requirement). 

Tofacitinib should not be used in patients with severe hepatic impairment 
(Participants with Child-Pugh class C are excluded). 

Tofacitinib use is not recommended in patients receiving a potent CYP3A4 inducer 
(eg, rifampin, St. John’s wort) or if they had discontinued use of a potent CYP3A4 
inducer less than 28 days or 5 half-lives prior to the first dose of tofacitinib. 
6.1.12 Restrictions
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None
6.2
Assessments
6.2.1
Efficacy
The primary and secondary endpoints will be assessed during the course of the study for 
each subject enrolled.  These are outlined separately.  Data will be gathered through daily 
review of the medical records, including vital signs, ventilatory requirements, laboratory 
values, and additional clinical findings.  
6.2.2
Safety and Pregnancy-related policy
Urine pregnancy testing for women of childbearing potential will be performed. Women who 
are pregnant or breast feeding will be excluded.
6.2.3
Adverse Events Definition and Reporting
Definitions
Adverse event (AE) means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
Any new infection that occurs on study, regardless of the infecting agent (i.e. viral or non-
viral) will be captured as an adverse event. Data captured will include site of infection and 
source of culture (BAL, tracheal aspirate, sputum, blood, urine etc.)
An AE or suspected adverse reaction is considered "serious" (SAE) if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 

death, 

a life-threatening adverse event, 

inpatient hospitalization or prolongation of existing hospitalization, 

a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 

a congenital anomaly/birth defect, or

An important medical event that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse.
Severity
Adverse events will be graded according to [name grading scale, e.g. CTCAE v5.0]. For AEs 
not included in the protocol defined grading system, the following guidelines will be used to 
describe severity. 

Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 

Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning.
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
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating.  Of note, the term “severe” does not necessarily equate to 
“serious”.]
Relationship to Investigational Product
All AEs must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. 
In a clinical trial, the study product must always be suspect.

Definitely Related – There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including an 
abnormal laboratory test result, occurs in a plausible time relationship to study 
intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if 
necessary.

Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.

Potentially Related – There is some evidence to suggest a causal relationship (e.g., 
the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as 
appropriate.

Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments).

Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There 
must be an alternative, definitive etiology documented by the clinician.
Expectedness
The Principal Investigator will be responsible for determining whether an AE is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study 
intervention.
Reporting
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For studies conducted under an IND, there are two types of Safety Reports submitted to 
FDA:

7-Calendar-Day FDA Telephone or Fax Report:  The sponsor-investigator will directly 
notify the FDA, within 7 calendar days after initial receipt of the information, of any 
adverse event that is fatal or life-threatening, unexpected, and considered at least 
possibly related to the investigational product. 

15-Calendar-Day FDA Written Report:  The sponsor-investigator will directly notify 
the FDA within 15 calendar days after initial receipt of the information, of any serious 
adverse event (other than those that are fatal or life-threatening) that is unexpected 
and considered at least possibly related to the investigational product.
Serious Adverse Events which do not meet the criteria for expedited reporting will be 
reported to the FDA in the IND Annual Report.
6.2.4
Biomarkers 
Research samples (3 mL of blood for exploratory analysis (including cytokine analysis), 
10 mL blood to generate plasma (for analysis of SARS-CoV-2 viral load) and 2.5 mL 
blood in Paxgene tubes (optimized for analysis of gene expression (RNA), and saliva 
samples (5mL) and/or nasopharyngeal swab for viral titer will be obtained as a part of 
this clinical trial to better understand SARS-CoV-2 pathogenesis and responses to 
tofacitinib compared to SOC. Whole blood (10 mL) may also be collected as available for 
lymphocyte subset analysis by flow cytometry. Sample collection times are specified in 
the Schedule of Activities. All research blood samples may be banked and/or used for 
exploratory analysis related to COVID-19 and/or the mechanism of action of the 
treatments administered in this study. Detailed sample collection and processing 
instructions will be provided under separate cover. Changes in research-based 
parameters will be documented. 
The results will not be relayed to the subject or the subject’s physician because they are 
for research purposes and the results may not be known for weeks after hospitalization. 
No results will be entered into the subject’s medical record. 
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6.3
Study Procedures
6.3.1
Study Schedule
Visit IdentifierError! Reference source 
not found.
.
Screening
Day 1
Daily 
assessments 
(days 2-14)c,d
Early Termination/ 
Discontinuation/ End 
of Treatment (Day 14 
or Discharge)
Follow-upErro
r! Reference source 
not found.
(Day 28)
Follow-up 
(Day 60)
Follow up 
(Day 90)
Early 
Termination/
Discontinuation
Visit Window
48 hours 
prior
to Day 1
+/-3 days
Informed consent
X
Medical history
X
Physical examinationd
X
X
X
X
X
Weightd
X
Vital signsd (pulse, blood 
pressure, respiratory ratee, 
temperaturef)
X
X
X
X
X
Laboratoryd
Hematology
X
X
X
X
X
Blood chemistry
X
X
X
X
X
Coagulationg
X
X
X
X
X
Inflammation panelh
X
X
X
X
X
Cardiac paneli
X
X
X
X
X
Pregnancy test
X
X
Oxygen saturation by pulse 
oximetry (SaO2)d
X
X
X
X
X
12 Lead ECGd
X
X
X
X
X
Record if admitted to intensive 
care unit (ICU)
X
X
X
X
X
X
Registration/randomization
X
Study drug administration
X
X
X
NIAIA Ordinal scale of 
disease severity
X
X
X
X
X
X
X
X
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Visit IdentifierError! Reference source 
not found.
.
Screening
Day 1
Daily 
assessments 
(days 2-14)c,d
Early Termination/ 
Discontinuation/ End 
of Treatment (Day 14 
or Discharge)
Follow-upErro
r! Reference source 
not found.
(Day 28)
Follow-up 
(Day 60)
Follow up 
(Day 90)
Early 
Termination/
Discontinuation
Visit Window
48 hours 
prior
to Day 1
+/-3 days
Record hospitalization 
status
X
X
X
X
X
X
X
X
Assessment signs and 
symptoms of pneumonia
X
X
X
X
X
FiO2
X
X
X
X
supplemental oxygen
X
X
X
X
Blood for exploratory 
analysisj
X
Day 7
X
X
Paxgene sample for 
exploratory biomarker 
analysisk
X
Day 7
X
Plasma, Saliva and/or nasal 
swab for SARS-CoV-2 and 
exploratory analysism
X
Day 7
X
Whole blood for FACS 
analysisn
X
Day 7
X
X
Concomitant treatment(s)
X
X
X
X
X
Adverse event monitoring
X
X
X
X
X
X
X
X
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Visit IdentifierError! Reference source 
not found.
.
Screening
Day 1
Daily 
assessments 
(days 2-14)c,d
Early Termination/ 
Discontinuation/ End 
of Treatment (Day 14 
or Discharge)
Follow-upErro
r! Reference source 
not found.
(Day 28)
Follow-up 
(Day 60)
Follow up 
(Day 90)
Early 
Termination/
Discontinuation
Visit Window
48 hours 
prior
to Day 1
+/-3 days
a.
Day relative to start of study intervention (Day 1).
b.
Contact may occur via telephone contact and will occur up to 90 days from administration of the 
final dose of study intervention. Procedures listed for Follow-up Visit 1 (with exception of ordinal 
scale of disease severity, hospitalization status, supplemental oxygen/ventilatory support status, 
contraception check, concomitant medications, and AE/SAE monitoring) will only be performed if 
the participant is hospitalized. Otherwise these visits will be remote phone or telemedicine visits.
c.
Assessments will be performed at least daily while hospitalized by the clinical service. Vital signs 
may be more frequent (eg, every 4 – 8 hours), per hospital practice.
d.
Collected as per hospital standard of care practice
e.
Note if spontaneous or mechanical ventilator setting
f.
Note if oral, rectal, or core
g.
Will include PT/PTT, fibrinogen, D-Dimers
h.
Inflammation will include as available: hsCRP, ferritin, procalcitonin, fibrinogen, LDH, etc.
i.
Cardiac panel will include as available: high sensitivity troponin, BNP, etc.
j.
Cytokine panel will include, as available: IL-1, IL-2, IL-6, IL-8, IL-17A, IL-17F, TNF-α, IP-10, IFNγ, 
CCL5, etc. Sample will be used for cytokine assessment that may include but is not limited to 
IFN, IL-1, IL-4, IL-6, IL-10, IL-12p70, TNFa, IP-10, and IL-2R. This sample may also be banked 
and/or used for additional post-hoc analyses related to COVID-19 and/or the mechanism of 
action of treatments administered in this study, including IgG and IgM antibodies to COVID-19.  
k.
Paxgene sample (optimized for RNA analysis) may be banked and/or used for exploratory 
assessments related to COVID-19 and/or the mechanism of action of treatments administered in 
this study.
l.
Physical examination by a clinician will be individualized according to participant status 
m.
Plasma, saliva and/or nasal swab will be collected and tested for SAR-CoV2 should by 
performed by polymerase chain reaction (PCR), or other commercial or public health assay in 
any specimen prior to randomization and on an ongoing basis, as needed for patient care and 
per policy at YNHH. Samples may also be used for additional analyses related to COVID-19 
and/or the mechanism of action of treatments administered in this study.
n.
Whole blood sample may be collected as available for analysis of lymphocyte subsets by flow 
cytometry.
6.3.2
Informed Consent
Potential subjects will be identified by study coordinators in conjunction with treating 
clinicians by screening the EMR of patients with a clinical diagnosis of SARS-CoV-2. 
Patients whose providers feel they are appropriate for the study will be approached. The 
PI or study coordinator will first approach the patient’s treating clinician (ex: physician, 
nurse practitioner, or physician’s assistant) regarding possible involvement in the study. 
If the provider feels the patient is appropriate, they will ask if the patient would be 
interested in hearing about a research project they might be able to participate in. If the 
patient expresses interest, the PI or study coordinator will then discuss with the patient. 
The patient or legally authorized representative/surrogate will be offered participation in 
the study during their hospitalization. Proper written, informed consent and HIPAA 
authorization will be obtained prior to patient participation in this trial. Patients will be 
provided with an unsigned consent form by a health care worker who has entered their 
room, and notified that a member of the study team will discuss the protocol with them 
over phone/video call. The overall protocol (including objectives, procedures and 
duration), potential risks and benefits, voluntary nature and ability to withdraw will be 
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discussed with each patient and/or their legally authorized representative/surrogate. The 
patient and/or their legally authorized representative/surrogate will have all questions 
answered before being asked to sign the ICF. Verification of comprehension of the 
consent will be obtained by asking the subject to describe in their words the purpose and 
risks of the study. The patient and/or their legally authorized representative/surrogate will 
be instructed that his or her care will not be affected by his or her decision to participate, 
or not. If the patient and/or their legally authorized representative/surrogate voluntarily 
agrees to participate in the trial, he or she will be asked to sign the ICF. The subject 
and/or their legally authorized representative will keep the copy of the ICF and HIPAA 
authorization form signed by them. Due to contamination of the document by infectious 
material, a photograph of the informed consent document with attestation by the person 
entering the photograph into the study record that states how that photograph was 
obtained and that it is a photograph of the informed consent signed by the patient will be 
added to the patient’s study records as documentation that the patient signed the 
informed consent document (in accordance with FDA-2020-D-1106).
6.3.3
Screening
The screening visit will include the following assessments:
-
Informed consent
-
Medical history: includes collecting the following information: age, sex, race, 
medical comorbidities, medications, smoking and alcohol history, and family 
history
-
Vital signs, weight, and pulse oximetry  
-
Targeted physical exam including an assessment of lungs, heart, 
circulation/perfusion
-
Chest X-ray (CXR)
-
Electrocardiogram (ECG) 
-
Blood and urine laboratory tests including lactate dehydrogenase (LDH), 
complete blood count with differential (CBC), comprehensive metabolic panel 
(CMP), cytokine panel, cardiac panel, coagulation, inflammation panel, viral 
serologies (including SARS-CoV-2), tuberculosis testing, and urinalysis
-
Urine pregnancy testing and contraception check for women of childbearing 
potential 
6.3.4
Enrollment 
After Screening, if the subject meets criteria, they will be enrolled. Baseline labs 
including hsCRP, ferritin, LDH, D-dimer, CBC, and CMP will be measured twice daily 
(per SOC). Research blood samples will be obtained prior to drug administration on Day 
1 and then again on Day 2 and every 48 hours thereafter. All subjects will be randomized 
to either tofacitinib 10 mg twice daily or SOC. Patients will be monitored at least once 
daily after initiation of therapy during the duration of their hospitalization, and will be 
followed up after discharge. 
6.3.5
On Study Visits
Days 1-14:
Once eligibility is confirmed, patients will be randomly assigned to receive treatment 
with either tofacitinib or placebo. Patients will receive 10 mg tofacitinib orally twice 
daily starting at the time of study enrollment until they exhibit clinical improvement, as 
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defined by need for supplemental oxygen to the baseline level. After this, patients will 
receive 5 mg tofacitinib orally twice daily. Total tofacitinib treatment duration will not 
exceed 14 days. All dosing of study drug will be in addition to current standard of 
care treatment. Research blood samples will be obtained prior to drug administration 
and again every 48 hours. Patients may undergo additional viral testing with a repeat 
nasal swab and/or blood collection at 7 and 14 days after enrollment. Standard of 
care laboratory tests will be measured twice daily. Patients will be assessed daily 
while hospitalized for the following clinical, research, and laboratory parameters:
-
Targeted physical exam
-
Electrocardiogram (ECG) 
-
Blood and urine laboratory tests including lactate dehydrogenase (LDH), 
complete blood count with differential (CBC), comprehensive metabolic panel 
(CMP), cytokine panel, cardiac panel, coagulation, inflammation panel, and 
urinalysis
-
Adverse events
-
Concomitant therapies
-
Record of ICU admission
-
Record use of supplemental oxygen
6.3.6
End of Study and Follow-up
After patients complete study treatment, they will be contacted to follow up on their 
condition. This may occur via telephone or telehealth and will occur on day 28 +/- 3 
days after the time of enrollment and then again at days 60 and 90 days. On day 28 
follow-up, blood sample for exploratory analysis may be collected.  At the time of 
follow up visits/calls, patients will be asked about:
-
Adverse events
-
Concomitant therapies
-
All efforts will be made to contact subjects for follow-up, including: telephone 
calls, texts, and emails to the subject and/or close contacts. Vital status of all 
subjects will be ascertained either by contacting the subjects and/or subjects’ 
close contacts or by a vital records search.
6.3.7
Removal of subjects
Required Tofacitinib Discontinuations:

White blood cell count < 1000 cells/mm3

Lymphocyte counts <250 cells/mm3.

Absolute neutrophil counts <500 cells/mm3. 

Hemoglobin less than 8 g/dL. 

ALT or AST ≥5 times the ULN.

Anaphylaxis or other serious allergic reaction.

Diagnosis of thrombosis including pulmonary embolism, deep venous 
thrombosis, and arterial thrombosis.

Diagnosis of venous thromboembolism.

Any serious infection, including secondary bacterial pneumonia, or other safety 
event for which the investigator determines that continued treatment with 
tofacitinib is not in the participant’s best interest.
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
If IL-6 targeting agent or other non-FDA approved, compassionate use or 
expanded access is considered as medically necessary (as reviewed by the 
investigator)
Subjects who discontinue study treatment will be followed up through Day 90 after 
discontinuation.
6.4
Statistical Method
6.4.1
Statistical Design
6.4.2
Sample Size Considerations
Assume true probability of a participant survived and not needing any form of mechanical 
ventilation, high flow oxygen, or ECMO at day 14 is 40%. Randomizing 60 participants with a 
1:1 ratio (tofacitinib+SOC: Placebo+SOC), the study will have 73% power (two-sided 
alpha=0.1) assuming an odds ratio of 3.5 for tofacitinib+SOC VS Placebo+SOC. No 
multiplicity adjustments will be performed for any secondary endpoint or exploratory endpoint 
analyses.
6.5
Planned Analyses
There will be two analyses for reporting results from this study.  The first will occur when all 
patients have completed the requirements for the day 14 efficacy endpoints, including the 
primary endpoint. This will be the primary analysis for these endpoints.  The second will be 
after all participants have completed the 90 day follow-up where mortality and final safety will 
be reported.
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
6.5.1
Primary Objective Analysis
Proportion of subjects alive, not needing any form of mechanical ventilation, high flow 
oxygen, or ECMO, and haven’t received a recue therapy at day 14, will be summarized by 
treatment arm. Treatment comparisons will be based on a logistic regression model. Odds 
ratio with 90% confidence interval will be presented. 
Full Analysis Set (FAS) is defined as all randomized participants receiving at least one dose 
of study intervention. Participants will be analyzed according to the intervention to which 
they were randomized. Efficacy analysis will be based on FAS.
For all primary analyses, data will be censored after subject received rescue therapy. 
Rescue therapy is defined as IL-6 targeting agent or other non-FDA approved, 
compassionate use or expanded access is considered as medically necessary (AS 
REVIEWED BY THE PI) (section 6.1.2). Per protocol, subjects will discontinue from study 
treatment prior to taking rescue therapy. Additional secondary analyses may be conducted 
including all the data after rescue therapy. 
6.5.2
Secondary Objectives Analyses
For the ordinal scale of disease severity, the proportion of patients in each category will be 
summarized by treatment group. A proportional odds model will be fit to compare tofacitinib 
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plus SOC versus placebo plus SOC. The odds ratio will be estimated along with its 
90% confidence interval.
Endpoints such as time to recovery and time to improvement will be summarized with 
Kaplan Meier estimation and compared used log-rank tests. Cox proportional hazard model 
will be used to estimate hazard ratios. 
For the binary outcomes, such as mortality rate at days 30, 60, and patients requiring ICU 
admission and mechanical ventilatory support, the analysis methods will be the same as for 
the primary endpoint. 
For endpoints such as duration of invasive mechanical ventilation, invasive mechanical 
ventilation free days, death is a competing event, i.e if a patient dies before invasive 
mechanical ventilation, the duration of ventilation is unknown. This will be analyzed using 
competing risk model proposed by Andersen and Gill (1982).  Generalized cox model will be 
used to estimate the hazard ratio for the treatment effect.
6.5.3
Exploratory Objectives Analyses (if applicable)
Not applicable.
6.5.4
Safety 
Included as secondary objective.
All safety analyses will be performed on the Safety Analysis Set. All safety data will be 
summarized descriptively through appropriate data tabulations, descriptive statistics, 
categorical summaries, and graphical presentations. 
Change from baseline in inflammatory parameters or cytokines will be summarized by 
descriptive statistics (N, mean, standard error of the mean, minimum, 1st, 2nd (ie, median) 
and 3rd quartiles and maximum).
Safety Analysis Set (SAF) is defined as all participants randomly assigned to study 
intervention and who take at least 1 dose of study intervention. Participants will be analyzed 
according to the intervention they actually received. All safety analysis will be based on SAF.
6.5.5
Analysis of Subject Characteristics
Demographics and medical history will be summarized by treatment group.
6.5.6
Interim Analysis (if applicable)
Safety data will be reviewed by a Yale DSMB after the first 5 patients are enrolled and again 
after every 10 patients enrolled thereafter.
6.5.7
Health economic evaluation
Not applicable
6.5.8
Other
Not applicable
6.5.9
Subsets and Covariates
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Summary statistics for the primary endpoint may be performed by subgroups below.
•
Age (years) group ((<40, ≥40);
•
Sex (Male, Female);
•
Race (White, Black or African American, Other);
6.5.10 Handling of Missing Data
For efficacy endpoints, 

Patients will be followed up after discharge via telehealth visits or other approaches. 
If a subject discontinues from study treatment early but did not withdraw consent, the 
schedule of activities will remain the same and data collection will continue. Due to 
the nature of the study, we expect that there will not be many missing data. Thus, the 
missing values for binary endpoints due to discharge or where no other information is 
available will be considered as treatment successes.

Time to event endpoint: subjects who complete the study without the event of interest 
or those who withdraw before experiencing the event of interest will have their event 
times right censored at the last available measurement time (or visit) used to define 
whether the subject experienced the associated event.

Ordinal endpoints: observed data will be analyzed. 
For safety endpoints, observed data will be analyzed.
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7  Trial Administration
7.1
 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki. All patients who are eligible to participate in this study will give 
informed consent prior to undergoing any study procedures.
7.2
Institutional Review Board (IRB) Review
The protocol, ICF, and supporting documents will be submitted to the IRB for review and 
approval. Approval of the protocol will be obtained before initiating any research activity. Any 
change to the protocol or study team will require an approved IRB amendment before 
implementation.  The IRB will determine whether informed consent and HIPAA authorization 
are required.  
The IRB will conduct continuing review at intervals appropriate to the degree of risk, but not 
less than once per year.
A study closure report will be submitted to the IRB after all research activities have been 
completed.   
Other study events (e.g. data breaches, protocol deviations) will be submitted per Yale 
University IRB's policies.
7.3
Subject Confidentiality
Subject confidentiality is held in strict trust by the research team.  Subject medical record 
review will be limited to the just the elements needed to complete the study.  Only authorized 
HIPAA and GCP trained study team members will be allowed to extract research data from 
medical records and enter it into the study’s electronic database. No direct subject identifiers 
will be entered into this database.
Each subject will be assigned a unique study number. A master list linking the unique study 
number to the human subject will be maintained in a secured spreadsheet only accessible to 
authorized study team members.  
7.4
Deviations/Unanticipated Problems
If the study team becomes aware of a problem (e.g. data breach, protocol deviation) that 
potentially affects subject safety or data integrity, the event will be reported to the IRB.
7.5
Data Collection
Research data will be collected from patients’ clinical record (paper charts and EMR, blood 
and urine samples and cardiac pressure monitoring data collected during the study). Data 
will be recorded in electronic databases (Forte & Oncore), and stored in password-protected 
software on Yale’s secure server.
7.6
Data Quality Assurance
Data collection and study documentation will be limited to the site study staff, ensuring 
consistency in data collection procedures. Yale’s core laboratory will be used exclusively for 
laboratory assessments involved in safety and efficacy analyses.
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7.7
Study Records
Study-specific documents including regulatory documents, protocols, consents forms, and 
case report forms will be stored in paper charts which will be kept in a locked office on site, 
only accessible to site study staff. 
7.8
Access to Source Documents
Source documents will consist mostly of EMR entries but may also include paper case report 
forms if study-pertinent information cannot be found in EMR. Only the study team will have 
access to both electronic and paper source documents.
7.9
Data or Specimen Storage/Security
Data will be de-identified, as described above, both during and after the study. The 
electronic data will be stored and secured on Yale computers containing encryption 
software. Paper study records will be kept in a locked office on site, only accessible to site 
study staff.
7.10 Retention of Records
Study documents will be retained for a minimum of 2 years after the last approval of a 
marketing application or until at least 2 years have elapsed since the formal discontinuation 
of clinical development of the study intervention. These documents will be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without 
the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to 
inform the investigator when these documents no longer need to be retained.
7.11 Study Monitoring
7.12 Data Safety Monitoring Plan
A data safety monitoring board will be formed, comprised of clinicians at the site who are not 
named investigators in the study, to ensure intensive safety monitoring.  
The DSMB will be responsible for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews at the specified frequency. During the review process, the 
DSMB will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment. Either the principal investigator, DSMB, 
or the IRB have the authority to stop or suspend the study or require modifications.
We do not view the risks associated with tofacitinib as minimal. Although we have 
assessed the proposed study as one of greater than minimal risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is 
not possible to predict with certainty the absolute risk in any given individual or in 
advance of first-hand experience with the proposed study methods. Therefore, we will 
monitor the data and safety of the proposed study.
Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures by the principal investigator Dr. Hyung Chun according 
to the following categories:
a.) Definite: Adverse event is clearly related to investigational agent.
b.) Probable: Adverse event is likely related to investigational agent.
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c.) Possible: Adverse event may be related to investigational agent.
d.) Unlikely: Adverse event is likely not to be related to the investigational agent.
e.) Unrelated: Adverse event is clearly not related to investigational agent.
Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during 
the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event 
meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered 
serious if it:
1. is life-threatening OR
2. results in in-patient hospitalization or prolongation of existing hospitalization OR
3. results in persistent or significant disability or incapacity OR
4. results in a congenital anomaly or birth defect OR
5. results in death OR
6. based upon appropriate medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one of the other outcomes listed 
in this definition, OR
7. adversely affects the risk/benefit ratio of the study
An adverse event may be graded as severe but still not meet the criteria for a Serious 
Adverse Event. Similarly, an adverse event may be graded as moderate but still meet the 
criteria for an SAE. It is important for the PI to consider the grade of the event as well as its 
“seriousness” when determining whether reporting to the IRB is necessary.
Plan for reporting Reportable Adverse Events and other unanticipated problems 
involving risks to subjects or others to the IRB:
The principal investigator will report the following types of events to the IRB: a) adverse 
events that are serious or life-threatening AND unanticipated (or anticipated but occurring 
with a greater frequency than expected) AND possibly, probably or definitely related to the 
drug; and b) other unanticipated problems involving risks to subjects or others. These 
adverse events or unanticipated problems involving risks to subjects or others will be 
reported to the IRB in accordance with IRB Policy 710, using the appropriate forms found on 
the website.
The principal investigator will conduct a review of all adverse events upon completion of 
every study subject. The principal investigator will evaluate the frequency and severity of the 
adverse events and determine if modifications to the protocol or consent form are required.
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7.13 Study Modification
If the protocol, ICF, or any supporting document needs to be amended, modifications will be 
submitted to the IRB and FDA as needed, prior to implementing changes (unless changes 
pertain to the safety of participants, in which case a deviation would be reported). 
7.14 Study Discontinuation
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
7.15 Study Completion
The IRB and FDA will be notified upon completion of this study.
7.16 Conflict of Interest Policy
Yale policies require investigators engaged in human subjects research to disclose annually. 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership in conjunction with the appropriate conflict of interest review 
committee has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. All investigators will follow the applicable conflict of interest policies.
7.17 Funding Source
The study will be funded by Pfizer.
7.18 Publication Plan
Results of the study will be published by the investigators.
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8 Appendices
Appendix 1. Current YNHH COVID-19 treatment algorithm (please see attached)
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Appendix 2. Table of Potent Inhibitors of CYP3A4, Moderate Inhibitors of CYP3A4 and 
Potent Inhibitors of CYP2C19, and Potent CYP Inducers*
Potent Inhibitors 
CYP3A4
Moderate 
Inhibitors of 
CYP3A4 and 
Potent Inhibitors 
of CYP2C19
Potent CYP 
Inducers
Antibiotics
Clarithromycin
Telithromycin
Rifampin
Anticonvulsant
Phenytoin
Barbiturates
Fosphenytoin
Phenobarbital
Primidone
Carbamazepine
Antidepressants
Nefazodone
Fluvoxamine
St. John’s Wort
Antifungals
Itraconazole
Ketoconazole
Fluconazole
Antihyperglycemic
Troglitazone 
(withdrawn in US)
Narcotic
Suboxone
Protease Inhibitors
Atazanavir
Darunavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
Cobicistat
Stimulants
Modafinil
*This is not a complete list of all CYP inhibitors and inducers with potential DDI with 
tofacitinib.
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Appendix 3. Contraceptive Considerations 
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100 fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:
•
Is not a WOCBP (see definitions below in Section 10.4.3).
OR
•
WOCBP should consider pregnancy planning and prevention during the treatment 
period and for up to 28 days after the last dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before the first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP:
1.
Premenopausal female with 1 of the following:
•
Documented hysterectomy;
•
Documented bilateral salpingectomy;
•
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2.
Postmenopausal female:
•
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition, a:
•
High FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 
•
Female on HRT and whose menopausal status is in doubt will be required to use one 
of the nonestrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraception Methods
Contraceptive use by women should be consistent with local availability/regulations 
regarding the use of contraception.
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Appendix 4. Tofacitinib 10 mg BID, Relative to 5 mg BID, in COVID-19
COVID-19 and hyperinflammation
Coronavirus disease – 2019 (COVID-19) is a viral disease caused by a novel coronavirus, 
SARS-CoV-2 that can cause a severe acute respiratory syndrome (ARDS). While several 
types of cytokine storm syndromes are recognized (Behrens 2017), a cytokine profile 
resembling secondary haemophagocytic lymphohistiocytosis is associated with COVID-19 
disease severity. Predictors of fatality from a recent retrospective, multicenter study of 150 
confirmed COVID-19 cases in Wuhan, China, included elevated ferritin and IL-6, suggesting 
that mortality might be due to virally driven hyperinflammation (Ruan 2020). The 
management of the cytokine storm is one of the major unmet medical needs in the treatment 
of COVID-19. 
Efficacy of tofacitinib 10 mg BID, relative to 5 mg BID, on inflammatory response
Tofacitinib has not been evaluated previously for short-term treatment of airway 
inflammatory response related to COVID-19 or other diseases. In COVID-19 patients with 
pneumonitis who are at risk for progression to ARDS, rapid onset of anti-inflammatory 
effects, followed by sustained inhibition of inflammatory mediators over the dosing period is 
desirable.
Therefore, potential benefits of tofacitinib were assessed based on expected modulation of 
inflammatory mediators in COVID-19 patients, based on in vitro studies and in vivo 
characterization of anti-inflammatory effects in RA patients. These data indicate:
(1) Based on in vitro IC50 values for suppression of inflammatory mediators, the higher 
systemic exposure of tofacitinib at 10 mg BID, compared to 5 mg BID, is expected to result 
in greater suppression of inflammatory mediators in vivo.
(2) Dose-response of tofacitinib on markers of systemic inflammation in vivo in RA patients 
(IP-10, CRP) indicates that 10 mg BID provides substantially higher suppression of these 
inflammatory markers, and may also provide a faster onset of effect, compared to 5 mg BID.
(1) In vitro studies
Potency of tofacitinib binding to JAK subtypes and cytokine inhibition were determined in 
vitro in cell based and whole blood assays (Dowty et al 2019).  The expected percent 
inhibition of various cytokines in humans, at the average plasma tofacitinib concentrations 
expected at the 5 mg and 10 mg BID dose levels, are shown in the spider plot in Figure 1. At 
the 10 mg BID dose, approximately 80% suppression of IL-6 may be expected, in addition to 
substantial inhibition of multiple other cytokines such as IFN, IL-15, IL-21, and IL-27. The 
expected magnitude of cytokine suppression is lower at the 5 mg BID dose, with 
approximately 60% predicted suppression of IL-6. 
Figure 1. Predicted percent inhibition of cytokines in humans by tofacitinib 5 mg BID 
(blue line) and 10 mg BID (red line) based on in vitro whole blood potency assay and 
predicted average plasma tofacitinib concentrations 
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The time course of predicted IL-6 inhibition over a steady-state dosing interval is shown in 
Figure 2 for tofacitinib IR 10 mg BID, the equivalent MR dose of 22 mg QD, and baricitinib 4 
mg QD. The y-axis (ICxx) represents the inhibitory concentration (IC) for a given % inhibition 
of IL-6 activity as shown on the axis. Tofacitinib IR 10 mg BID is expected to provide 
concentrations above the IC50 value throughout the dosing interval and up to IC85 at peak 
concentration, indicating sustained pharmacologic activity. Tofacitinib IR 5 mg BID is not 
expected to provide sustained exposure above the IC50 of IL-6 inhibition over a 24-hour 
period, as shown in Figure 3.
Figure 2. Inhibitory tofacitinib concentration for a given % inhibition of IL-6 activity 
(ICxx) over a steady-state dosing interval. Left Panel: tofacitinib IR 10 mg BID (black 
line), tofacitinib MR 22 mg QD (blue line), and baricitinib 4 mg QD (red line); Right 
Panel: tofacitinib IR 5 mg BID (black line), tofacitinib MR 11 mg QD (blue line), and 
baricitinib 4 mg QD (red line). The light blue horizontal line represents the IC50 value.
(2) Clinical studies
Biomarkers in the JAK signaling pathway, such as interferon gamma-induced protein 10 (IP-
10) and CRP, were measured in multiple clinical studies in RA patients treated with 
APPROVED BY THE YALE UNIVERSITY IRB 9/28/2020
IL-10 
100 
100 
80 
80 
)( 
)( 
60 
60 
... 
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40 
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Time hr 


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tofacitinib. Both these markers are known to be elevated in COVID-19 patients with 
inflammatory response. 
In Study A3921073 in RA patients, serial IP-10 and CRP measurements were performed 
early after initiation of treatment and following the end of the treatment phase, to 
characterize onset and offset of pharmacologic activity of tofacitinib. The effect of 10 mg BID 
tofacitinib treatment, relative to placebo, on IP-10 concentration is shown in Figure 3.  Onset 
of pharmacologic activity within the 4 hours after the first dose is suggested by the significant 
difference from placebo at this time point. This indicates that 10 mg BID may be beneficial in 
terms of rapid onset of effect.
Figure 3. IP-10 Serum Levels in RA Patients Receiving Tofacitinib 10 mg BID 
(A3921073)
In clinical studies in RA patients, CRP suppression was generally higher at 10 mg BID, 
compared to 5 mg BID. In Study A3921019, median CRP (% of baseline) was suppressed in 
a dose-dependent manner, with approximately 50% suppression at 5 mg BID by Day 14, 
and >75% suppression at higher doses. In Study A3921073, >75% median CRP 
suppression was observed by Day 10 following tofacitinib 10 mg BID dosing (Figure 4). 
Figure 4. Median CRP (% change from baseline) in Studies A3921019 and A3921073 in 
RA patients
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0.15 
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0.10 
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On drug (Day 1-28) 
-- Placebo 
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·p< 0.05, ··p< 0.005 Change trom Day 1 pre-dose relative to p1aceoo. Milo:ed effect moc1e1 with treatment visit, and treatment by visit rltet'&ction as factor, Md baSeline (Oay 1) as a covariate, subject as 
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BIO, twiee daily; IP, Interferon-inducible protein; RA, lfleo.matold artl'Witl$ 


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Short-term safety of tofacitinib 10 mg BID, relative to 5 mg BID
In the context of understanding benefit-risk, there are known risks that need to be 
considered for JAK inhibitors, both as a class and for selective JAK subtypes. The 
contribution of secondary bacterial infection to COVID-19 related mortality is unknown, and 
immunomodulation with biologic or targeted synthetic disease-modifying anti-rheumatic 
drugs (DMARDs) may increase the risk of secondary infections in COVID-19 patients. JAK 
inhibitors are also known to increase the risk of thromboembolism, therefore use of 
tofacitinib in this population should be managed in the context of the higher background risk 
of thromboembolism in COVID-19 disease.
Therefore, thrombosis risk of tofacitinib was assessed in the context of short-term treatment 
in COVID-19 patients, based on large clinical studies in RA and UC patients. These data 
indicate:
(1) Short-term exposure to tofacitinib 10 mg BID has not been associated with an increased 
risk of thrombosis (either arterial or venous) when compared to 5 mg BID.
(2) In pooled RA month 0-3 data, there were no events reported among tofacitinib 5 mg BID 
or 10 mg BID treated patients who did not have baseline VTE risk factors such as previous 
VTE, previous heart failure, or age ≥60 years.  
 (2) No thrombosis events were reported for 10 mg BID patients during the first 14 days of 
treatment and time to first reported thrombotic event was 72 days and 216 days in RA and 
UC patients, respectively, treated with 10 mg BID.
Venous or arterial thrombosis
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--25 
CD 
LL 
(.) 
a.. 
0:: -50 
(.) 
-75 
Rheumatoid Arthritis 
10 
20 
Time Post First Dose (days) 
Randonized Dose (mg) 
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Short-term exposure to tofacitinib 10 mg BID has not been associated with an increased risk 
of thrombosis (either arterial or venous) when compared to 5 mg BID (Pfizer Data on File, 
Sandborn et al 2019). In pooled data from tofacitinib Phase 2 and Phase 3 RA studies, 3 
thrombotic events were reported during month 0-3, all events occurring at day 45 (patient 
receiving tofacitinib 5 mg BID) or later, and no events were reported among tofacitinib 5 mg 
BID or 10 mg BID treated patients who did not have baseline venous thromboembolic event 
(VTE) risk factors such as previous VTE, previous heart failure, or ≥60 years of age (Figure 
5).  
Figure 5. Proportions of subjects without embolic and thrombotic events by baseline 
VTE risk factors in RA Phase 2 Phase 3 studies (Month 0-3)
Total follow up time calculated up to the day of the first event, subject to a risk period of 28 
days beyond the last dose or to the data cutoff date. VTE risk factor is defined for a subject 
meeting any of the following criteria: Day 1 use of oral contraceptives or hormone 
replacement therapy, previous heart failure, previous VTE, age ≥60 years, BMI ≥30 kg/m2, 
smoking, Day 1 antidepressant use, or Day 1 aspirin use. Data cutoff date Feb 2017. DVT, 
deep vein thrombosis; PE, (PE); ATE, arterial thromboembolic event.
In the clinical development program for UC, no thrombotic events were reported in patients 
receiving 8 weeks of tofacitinib 10 mg BID induction therapy (Sandborn et al). In completed 
studies in RA and UC patients treated with tofacitinib 10 mg BID, there were no events 
during the first 14 days of treatment and time to first reported thrombotic event was 72 days 
and 216 days in RA and UC patients, respectively (Table 1).
Table 1. Days of treatment prior to first reported thrombotic event in completed 
studies in RA and UC patients
5 mg 
10 mg
Pbo
MTX
ADA
RA
45
72
31
25
57
UC
N/A
216
3
N/A
N/A
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Event Subcategory: DVI or PE or A IT (IE) 
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---0- · Placebo - Yes 
-
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-...=- -
2 
Time (Months, 28 days) from fo,-i Dose 
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Benefit/risk assessment and dose recommendation
Based on the above discussion, there appears to be a meaningful dose-dependent 
difference in effect on inflammation favoring the higher dose whereas there is no apparent 
short-term, dose-dependent risk increase for thrombosis.  Taken together, in combination 
with the appropriate risk minimization measures, the benefit/risk is considered more 
favorable with tofacitinib 10 mg BID relative to 5 mg BID and the higher dose is therefore 
suggested as appropriate for evaluation in COVID-19 patients. Specifically, the following 
rationale supports evaluation of 10 mg BID:

At the 10 mg BID dose, plasma tofacitinib concentrations are maintained above the 
IC50 for IL-6 inhibition throughout a 24-hour dosing interval at steady-state, unlike 
the lower dose of 5 mg BID. Along with other PD data discussed, the 10 mg BID 
dose provides better anti-inflammatory effects, than 5 mg BID, for controlling 
potential increase in cytokines and progression to ARDS.

Tofacitinib 5 and 10 mg BID have been extensively studied in RA, PsA and UC 
clinical development programs and the short-term and long-term safety profile of 
tofacitinib 10 mg BID is well characterized.

Tofacitinib 10 mg BID is the approved dose - in the EU and globally - for induction 
therapy up to 16 weeks in UC patients with potential for longer term use if needed for 
maintenance of treatment benefit. 

Short-term exposure to tofacitinib 10 mg BID has not been associated with an 
increased risk of thrombosis (either arterial or venous) when compared to 5 mg BID 
and time to first reported thrombotic event in patients treated with tofacitinib 10 mg 
BID was 72 days and 216 days in RA and UC patients, respectively.
o
Protocol risk minimization measures include:

Patients with severe hearth failure (NYHA 3 or 4), history of recurrent 
DVT or PE are excluded per protocol.

In pooled RA studies, there were no events reported during the 
first 3 months of tofacitinib 5 mg BID or 10 mg BID treatment in 
patients who did not have baseline VTE risk factors such as 
previous VTE, previous heart failure, or age ≥60 years.  

All patients will receive Low Molecular Weight Heparin subcutaneously 
at prophylactic dosage.

Therefore, the benefit/risk of short duration treatment appears more favorable with 
tofacitinib 10 mg BID relative to 5 mg BID for the control of potential 
hyperinflammation in COVID-19 and the use of 10 mg BID appears to be justified 
based on currently available information.
9 References
1.
Huarte E, O'Connor RS, Parker M, Huang T, Milone MC, Smith P. Prophylactic Itacitinib 
(INCB039110) for the Prevention of Cytokine Release Syndrome Induced By Chimeric Antigen 
Receptor T-Cells (CAR-T-cells) Therapy. Blood 2019;134:1934-.
2.
Das R, Guan P, Sprague L, et al. Janus kinase inhibition lessens inflammation and 
ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood 
2016;127:1666-75.
APPROVED BY THE YALE UNIVERSITY IRB 9/28/2020


APPROVED BY THE YALE UNIVERSITY IRB 9/28/2020
Protocol 2000027848
Version R5; 15 SEPTEMBER 2020
51
3.
Damsky WE, Vesely MD, Lee AI, et al. Drug-induced hypersensitivity syndrome with 
myocardial involvement treated with tofacitinib. JAAD Case Rep 2019;5:1018-26.
4.
Damsky W, Thakral D, Emeagwali N, Galan A, King B. Tofacitinib Treatment and 
Molecular Analysis of Cutaneous Sarcoidosis. New England Journal of Medicine 2018;379:2540-
6.
5.
Damsky W, Young BD, Sloan B, Miller EJ, Obando JA, King B. Treatment of Multiorgan 
Sarcoidosis With Tofacitinib. ACR Open Rheumatology 2020;2:106-9.
6.
Ahmed A, Merrill SA, Alsawah F, et al. Ruxolitinib in adult patients with secondary 
haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. Lancet Haematol 
2019;6:e630-e7.
7.
Sin JH, Zangardi ML. Ruxolitinib for secondary hemophagocytic lymphohistiocytosis: First 
case report. Hematol Oncol Stem Cell Ther 2019;12:166-70.
8.
Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with 
Tocilizumab. ChinaXiv preprint 2020.
9.
Hodge J, Kawabata T, Krishnaswami S, et al. The mechanism of action of tofacitinib-an 
oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 
2016;34:318-28.
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Clark JD, Flanagan ME, Telliez J-B. Discovery and development of Janus Kinase (JAK) 
inhibitors for inflammatory diseases: Miniperspective. Journal of medicinal chemistry 
2014;57:5023-38.
APPROVED BY THE YALE UNIVERSITY IRB 9/28/2020

SAP_001.pdf: 
ClinicalTrials.gov ID: NCT04415151 
Brief Title: Tofacitinib for Treatment of Moderate COVID-19 (I-TOMIC) 
Date: 3/18/2024 
Document: Amended SAP due to Study Termination 


Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
 
Protocol 2000027848 / WI256061 
 
 
 
 
INVESTIGATION OF TOFACITINIB TO MITIGATE THE IMPACT OF COVID-19 (I-TOMIC) 
IN MODERATE SARS-COV-2 (MODERATE I-TOMIC) 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
2.0  
Date:  
18 Mar 2024 
 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................... 4 
LIST OF FIGURES .................................................................................................................. 4 
APPENDICES ......................................................................................................................... 4 
1. VERSION HISTORY ........................................................................................................... 5 
SUMMARY OF CHANGES ..................................................................................................... 5 
2. INTRODUCTION ................................................................................................................. 5 
2.1. Modifications to the Analysis Plan Described in the Protocol ................................. 5 
2.2. Study Objectives, Endpoints, and Estimands ......................................................... 5 
2.2.1. Estimands .................................................................................................. 7 
2.3. Study Design .......................................................................................................... 7 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS .......... 9 
3.1. Primary Efficacy Endpoint(s) .................................................................................. 9 
3.2. Secondary Efficacy Endpoint(s) .............................................................................. 9 
3.3. Other Efficacy Endpoint(s) ...................................................................................... 9 
3.4. Baseline Variables .................................................................................................. 9 
3.5. Safety Endpoints ................................................................................................... 10 
3.5.1. Adverse Events ........................................................................................ 10 
3.5.2. Laboratory data ........................................................................................ 10 
3.5.3. Vital signs ................................................................................................. 10 
3.5.4. Electrocardiogram (ECG) ......................................................................... 10 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ...................................................... 10 
5. GENERAL METHODOLOGY AND CONVENTIONS ........................................................ 11 
5.1. Hypotheses and Decision Rules ........................................................................... 11 
5.2. General Methods .................................................................................................. 11 
5.2.1. Analyses for Categorical (including Binary) Endpoints ............................. 11 
5.2.2. Analyses for Continuous Endpoints ......................................................... 11 
5.2.3. Analyses for Time-to-Event Endpoints ..................................................... 12 
5.3. Methods to Manage Missing Data ........................................................................ 12 
6. ANALYSES AND SUMMARIES ........................................................................................ 12 
6.1. Primary Endpoint(s) .............................................................................................. 12 
6.2. Secondary Efficacy Endpoint(s) ............................................................................ 12 
6.3. Subset Analyses ................................................................................................... 13 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
6.4. Baseline and Other Summaries and Analyses .....................................................13
6.4.1. Baseline Summaries ................................................................................ 13 
6.4.2. Study Conduct and Participant Disposition ..............................................13
6.4.3. Study Intervention Compliance ................................................................ 13 
6.4.4. Concomitant Medications and Nondrug Treatments ................................ 14 
6.5. Safety Summaries and Analyses .......................................................................... 14 
7. INTERIM ANALYSIS ......................................................................................................... 14 
8. REFERENCE .................................................................................................................... 14 
APPENDICES ....................................................................................................................... 15 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
LIST OF TABLES
No table of figures entries found. 
LIST OF FIGURES
Figure 1. 
Study Schema .......................................................................................... 8 
APPENDICES 
Appendix 1. Definition and Use of Visit Windows in Reporting ............................................. 15 
Appendix 2. List of Abbreviations .......................................................................................... 15 
 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
1. VERSION HISTORY
SUMMARY OF CHANGES  
SAP Version
Change
Rationale
2.0 
Hypothesis testing for 
treatment comparison 
will not be conducted. 
Only descriptive 
analyses will be 
generated. 
The study concluded prematurely 
with a smaller-than-anticipated 
participant cohort, attributed to the 
return to pre-pandemic conditions as 
COVID-related restrictions eased 
during the recruitment phase. The 
abbreviated CSR is intended to be 
reported for this study (as per 
DMB10-GSOP), the changes in 
statistical reporting modification have 
been implemented. 
1.0 
Not Applicable 
Not Applicable 
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the 
data collected in Study 2000027848.  
Statistical Analysis Plan (SAP) has been developed in response to the challenges posed by 
the COVID-19 pandemic, which led to a lower-than-anticipated recruitment of patients and 
the premature conclusion of the study. As a result, the estimands outlined in this version 
primarily focus on descriptive methods rather than comparative analysis between treatment 
groups. This document provides a comprehensive overview of the updated methodology for 
summarizing and analyzing the data collected in Study 2000027848, considering the 
modifications necessitated by the unique circumstances of the pandemic. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
As rationalized above, no hypotheses testing for treatment comparison will be done, only 
descriptive analysis will be done by the treatment groups.  
2.2. Study Objectives, Endpoints, and Estimands 
Objectives/ 
Endpoints 
Type of Endpoints 
[categorical (including 
binary), continuous, or 
time to endpoints] 
Primary 
The primary objective of this study is to determine whether 
tofacitinib improves the clinical outcomes of patients with 
moderate SARS-CoV-2 infection as determined by the 
Primary outcome measure. 
 
Binary endpoint 
 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
Endpoint: Proportion of subjects alive and not needing 
any form of mechanical ventilation, high flow oxygen, 
or ECMO by day 14 and day 30. 
Secondary 
Clinical improvement (defined as a 2-point increase) as 
measured by NIAID 8-point ordinal scale (i.e., 1 = death 
and 8 = Not hospitalized, no limitations on activities) at day 
14. 
Categorical endpoint 
Clinical status using ordinal scale (days 3 through day 14): 
The ordinal scale is an assessment of the clinical status at 
the first assessment of a given study day. The scale is as 
follows: 1) Death; 2) Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane oxygenation 
(ECMO); 3) Hospitalized, on non-invasive ventilation or 
high flow oxygen devices; 4) Hospitalized, requiring 
supplemental oxygen; 5) Hospitalized, not requiring 
supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 6) Hospitalized, not 
requiring supplemental oxygen - no longer requires 
ongoing medical care; 7) Not hospitalized, limitation on 
activities and/or requiring home oxygen; 8) Not 
hospitalized, no limitations on activities. 
Categorical endpoint 
Time to recovery (Day of recovery is defined as the first 
day on which the subject satisfies one of the following 
three categories from the clinical status of ordinal scale: 6) 
Hospitalized, not requiring supplemental oxygen - no 
longer requires ongoing medical care; 7) Not hospitalized, 
limitation on activities and/or requiring home oxygen; 8) 
Not hospitalized, no limitations on activities) through day 
14 and day 30 from day 1. 
Time to endpoint. 
Time to clinical improvement (defined as a 2-point 
increase on the ordinal scale). 
Time to endpoint 
Clinical status on ordinal scale at day 30, 60, and 90. 
Categorical endpoint 
Mortality rate at day 30, 60 and 90. 
Binary endpoint 
Proportion of patients requiring ICU admission and 
mechanical ventilatory support (defined as clinical status 
of 2 and hospitalization status = ICU) at 14 and 30 days. 
Binary endpoint 
Change from Baseline in inflammatory parameters (eg. 
hsCRP, procalcitonin, ferritin, D-dimers, LDH, fibrinogen, 
PT/PTT). 
Continuous endpoint 
Change from baseline in cytokines (e.g. IL-1, IL-2, IL-6, IL-
8, TNF-
-17A, IL-17F, IP-10, CCL5), as available 
Continuous endpoint 
Safety as assessed by reporting of adverse events, 
changes in clinical laboratory parameters (e.g., 
hemoglobin, hepatic transaminases, serum creatinine, 
bilirubin, and evidence of secondary infections) 
 
Safety Endpoints:  
Adverse events:  
 
 
 
 
 
 
 
 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
Incidence of treatment emergent adverse events
(TEAE), serious adverse events, AEs leading to 
discontinuation.
 
Laboratory data 
Change from baseline clinical laboratory parameters. 
Incidence of clinically significant abnormalities in 
laboratory parameters. 
 
Vital signs 
incidence of clinically significant abnormalities in vital 
signs 
 
Electrocardiogram  
 
Changes from baseline for the ECG parameters 
 
Incidence of clinically significant abnormalities in 
ECG results 
Binary endpoint 
 
 
 
 
Continuous endpoint 
Binary endpoint 
 
 
 
Binary endpoint 
 
 
 
Continuous endpoint 
Binary endpoint 
 
Intervention with additional immunomodulatory agent (i.e. 
IL-6 targeting therapy) 
Binary endpoint 
Change in SARS-CoV-2 viral titers during intervention 
Continuous endpoint 
2.2.1. Estimands 
The estimand with treatment policy strategy will be utilized. All observed data (regardless of 
whether an intercurrent event occurs) will be included in the analysis. It includes the 
following 4 attributes: 
 
Population: Participants with COVID-19 pneumonia who meet all inclusion/exclusion 
criteria. The analysis will consider all observed data without employing any 
imputation for missing data;    
 
Variable: Yes or No for the occurrence of the event for categorical endpoints 
(including Binary endpoints), change from baseline for continuous endpoints and 
time to event for time to event endpoints. 
 
Intercurrent event(s): discontinuation of study intervention due to any reason or 
receiving rescue therapy. 
 
Population level summary: Proportion for categorical endpoints (including binary 
endpoints), mean for continuous endpoints and median time to event for time to 
event endpoints.  
2.3. Study Design 
The study concluded prematurely with a smaller-than-anticipated participant cohort, 
attributed to the return to pre-pandemic conditions as COVID-related restrictions eased 
during the recruitment phase. The situation warranted early termination of the study.  
The study is a randomized, double blinded, placebo-controlled Phase 2b study of the 
efficacy and safety of tofacitinib in hospitalized adult (18-65 years old) male and female 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
patients with SARS-CoV-2 and pneumonia who require supplemental oxygen and have 
serologic markers of inflammation but do not need mechanical ventilation (see Inclusion 
criteria). Sixty patients will be recruited to receive tofacitinib or placebo in addition to 
standard of care (SOC) in a 2:1 ratio. Subjects will be screened during hospitalization. 
Patients with confirmed SARS-CoV-2 infection, and meeting all other Inclusion and 
Exclusion criteria, will be randomized to either treatment with tofacitinib or placebo in 
addition to SOC during hospitalization (dose adjusted, if required), with the exception of any 
immunomodulatory agents (as documented in the inclusion/exclusion criteria). Tofacitinib 
will be administered in a dose of 10 mg PO BID until return to their clinical baseline (as 
defined by need for supplementary oxygen) and will continue to be administered at 5 mg PO 
BID for a total duration of therapy of 14 days; follow-up off tofacitinib will continue up to Day 
90. Because patients are likely to be discharged from the hospital soon after returning to 
clinical baseline, patients will continue to be administered tofacitinib 5 mg BID for a total 
duration of treatment of 14 days in order to prevent rebound of CRS that could theoretically 
occur with abrupt cessation of immunomodulatory therapy. In these cases, patients will be 
discharged home with a pill bottle labeled as investigational drug containing the appropriate 
number of pills (either tofacitinib or placebo). Rescue therapy is defined as IL-6 targeting 
agent or other non-FDA approved, compassionate use or expanded access when 
considered as medically necessary (AS REVIEWED BY THE PI) (Protocol section 6.1.2). 
Per protocol, subjects will discontinue from study treatment prior to taking rescue therapy.  
Figure 1. Study Schema 
 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS
3.1. Primary Efficacy Endpoint(s) 
The primary objective is to determine whether tofacitinib improves the clinical outcomes of 
patients with moderate SARS-CoV-2 infection as determined by the primary outcome 
measure.  The primary endpoint is proportion of subjects alive and not needing any form of 
mechanical ventilation, high flow oxygen, or ECMO by day 14. 
3.2. Secondary Efficacy Endpoint(s) 
 
Clinical improvement (defined as a 2-point increase) as measured by NIAID 8-point 
ordinal scale (i.e., 1 = death and 8 = Not hospitalized, no limitations on activities) at 
day 14. 
 
Clinical status using ordinal scale (days 3 through day 14): The ordinal scale is an 
assessment of the clinical status at the first assessment of a given study day.  
 
Time to recovery [ Time Frame: Day 1 through Day 14] (Day of recovery is defined 
as the first day on which the subject satisfies one of the following three categories 
from the clinical status of ordinal scale: 6) Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on 
activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on 
activities.  
 
Time to clinical improvement (defined as a 2-point increase on the ordinal scale).  
 
Clinical status on ordinal scale at day 30, 60, and 90  
 
Mortality rate at day 30, 60, 90  
 
Proportion of patients requiring ICU admission and mechanical ventilatory support 
 
Change from baseline in inflammatory parameters hsCRP, procalcitonin, ferritin, D-
dimers, LDH, fibrinogen, PT/PTT 
 
Change from baseline in cytokines IL-1, IL-2, IL-6, IL-8, TNF-
-17A, IL-17F, IP-
10, CCL5 as available. 
 
Intervention with additional immunomodulatory agent (i.e. IL-6 targeting therapy) 
 
Change in SARS-CoV-2 viral titers during intervention. 
3.3. Other Efficacy Endpoint(s) 
N/A 
3.4. Baseline Variables 
Unless specifically stated otherwise, the Baseline value is defined as the last non-missing 
measurement prior to the first administration of study drug at Day 1. As per protocol, it is 
intended all Day 1 assessments will be performed prior to dosing. 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
3.5. Safety Endpoints
3.5.1. Adverse Events 
An adverse event is considered a TEAE to a given treatment (for a participant who received 
at least of one dose of study intervention) if the event start date is on or after the treatment 
period start date and within 28 days of the treatment end date. The safety endpoints will be 
as follows.   
 
Incidence of TEAEs.  
 
Incidence of SAEs, and AEs leading to discontinuation.  
3.5.2. Laboratory data 
The following laboratory tests will be performed at time points identified in the Schedule of 
Activities.  Unscheduled clinical labs may be obtained at any time during the study to assess 
 
. 
 
Blood and urine laboratory tests including lactate dehydrogenase (LDH), complete 
blood count with differential (CBC), comprehensive metabolic panel (CMP), cytokine 
panel, cardiac panel, coagulation, inflammation panel, and urinalysis. 
The following endpoints for laboratory data will be analyzed.  
 
Incidence of clinically significant abnormalities in laboratory parameters 
 
Changes in Clinical laboratory parameters from the baseline (hemoglobin, hepatic 
transaminases, serum creatinine, bilirubin, and evidence of secondary infections). 
3.5.3. Vital signs 
Vital signs (pulse, blood pressure, respiratory rate, temperature) will be measured as 
indicated in the Schedule of Activities of the protocol.  The following endpoint will be 
analyzed: incidence of clinically significant abnormalities in vital signs.   
3.5.4. Electrocardiogram (ECG) 
ECGs should be collected at times specified in the Schedule of Activities of the protocol.  
The following endpoints will be analyzed: 
 
Changes from baseline for the ECG parameters 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Population 
Description 
Applicable Analysis 
Full analysis 
set (FAS) 
All participants randomly assigned 
to study intervention. Participants 
will be analyzed according to the 
All efficacy endpoints 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
intervention to which they were 
randomized. 
Safety analysis 
set (SAS) 
All participants randomly assigned 
to study intervention and who take 
at least 1 dose of study 
intervention. Participants will be 
analyzed according to the 
intervention to which they 
received. 
All safety endpoints 
If a participant is randomized but receives the incorrect treatment, then the participant will be 
reported under the randomized treatment group for all efficacy analyses.  If a participant is 
randomized but receives partially incorrect treatment, then the participant will be 
summarized under the treatment received for most of the time during the study, for all safety 
analyses.  
5. GENERAL METHODOLOGY AND CONVENTIONS 
Final analyses will occur after database lock after LSLV.  
5.1. Hypotheses and Decision Rules 
No Hypotheses testing. 
5.2. General Methods 
5.2.1. Analyses for Categorical (including Binary) Endpoints 
Categorical (including binary) data will be analyzed using the Estimand with treatment policy 
strategy specified in Section 2.2.1. All summary statistics are based on each treatment 
group. 
 
The number of participants, number, and percent of participant with event along with 
the 95% confidence interval by Clopper-Pearson exact method (see reference in 
Section 8) will be presented for observed data. 
 
For Binary data over time, line plot for the event rate and 95% CI will be presented. 
5.2.2. Analyses for Continuous Endpoints 
Continuous endpoints will be analyzed using the Estimand with treatment policy strategy 
specified in Section 2.2.1.   
The data for each continuous endpoint will be summarized by treatment group and by time 
point in tables containing descriptive statistics (N [which is the number of participants 
evaluable for the endpoint at the time point], mean, standard deviation, standard error of the 
mean, minimum, 1st, 2nd (i.e., median) and 3rd quartiles and maximum) for actual and change 
from baseline values for those endpoints measured at baseline.  In case when N=1 (i.e., 
only one participant is available/evaluable for summary), standard deviation and standard 
error will be reported as 
 while the remaining statistical parameters will 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
have the same value as the mean. For selected endpoints, mean (+/-SD) over time by 
treatment group will be plotted. 
5.2.3. Analyses for Time-to-Event Endpoints
For time to recovery and time to clinical improvement 
 
If subject died prior to or on the specified time point (Day 14 or Day 30), the result for 
time to event will be censored on the date of death regardless of if subjects have 
experienced recovery or clinical improvement prior to Death.  
 
If no death is recorded through the specified time point (Day 14 or Day 30):  For a 
participant who experiences the event of recovery/clinical improvement through Day 
14 or Day 30, the time to event will be the study day corresponding to the earliest 
visit date at which the participant has already experienced the event.  
 
For all participants who have not experienced the event, their time to event will be 
right censored at the last available measurement time of the clinical status through 
Day 14 or Day 30. 
Time to event endpoints will be analyzed using the Estimand with treatment policy strategy 
specified in Section 2.2.1.  
The number of participants, number and percent of participants censored, and participants 
with recovery or clinical response will be provided for each treatment group.  The median 
and quartiles time to event will be estimated by the Kaplan-Meier method.   
5.3. Methods to Manage Missing Data 
All data will be evaluated as observed, and no imputation method for missing values will be 
used. 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoint(s) 
The primary endpoint of proportion of subjects alive and not needing any form of mechanical 
ventilation, high flow oxygen, or ECMO by day 14, will be analyzed as described in Section 
5.2.1 by treatment group based on FAS defined in Section 4.  
6.2. Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints are listed in Section 3.2.   
For the categorical (including binary) endpoints, results will be analyzed as described in 
Section 5.2.1 by treatment group based on FAS defined in Section 4. 
For continuous endpoints, results will be analyzed as described in Section 5.2.2 by 
treatment group based on FAS defined in Section 4.  
For time to endpoints, results will be analyzed as described in Section 5.2.3 by treatment 
group based on FAS defined in Section 4.  
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
6.3. Subset Analyses
N/A 
6.4. Baseline and Other Summaries and Analyses
6.4.1. Baseline Summaries 
The following demographics and Baseline characteristics will be summarized by treatment 
group and for total. 
 
Gender (female, male) 
 
Race (American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black or African American, White, more than one race and not reported) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino and unknown or not reported) 
 
NIAID ordinal scale of disease severity scores (i.e., 1 = death and 8 = Not 
hospitalized, no limitations on activities) 
 
Prothrombin time/partial prothrombin time (PT/PTT) 
 
Days since onset of symptoms 
 
Days since diagnosis 
 
Fibrinogen 
 
D-dimer 
 
Hs-CRP 
 
Ferritin 
 
Procalcitonin 
 
LDH 
 
Tobacco history (type of substance, Usage (Never, current and former) 
 
Height  
 
Weight 
 
6.4.2. Study Conduct and Participant Disposition 
Participants evaluation for FAS and SAS, disposition, and discontinuation will be 
summarized by treatment group and for total. 
6.4.3. Study Intervention Compliance 
 
 Actual Dosing Days (ADY) is defined as the total number of dosing days on which 
study drug was administered. 
 
Exposure Time is defined as the total number of days from first to and including last 
day of study dosing (Last Oral Dosing Date - First Oral Dosing Date + 1);  
 
Dose Compliance is defined as the number of doses of study drug the subject took 
out of the expected total number of doses of study drug 
o ADY1 = Date of returning to clinical baseline  Date of first dosing (Day 1) + 1  
o Expected Doses (by mg):  
 Doses = 14 * 20 mg = 280 mg; 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
(b) ADY1 < 14, Expected Doses = ADY1 * 20 mg + (14 
ADY1) * 10 
mg = (140 + 10 * ADY1) mg; 
o
Dose Compliance = (Total Actual Doses/ Expected Doses) * 100% 
The continuous endpoints of actual Dosing Days, exposure Time, total actual doses and 
dose Compliance will be summarized as described in Section 5.2.2 by treatment group 
based on SAS as defined in Section 4.  
8 ~ 13 days, 14 days), and Dose Compliance categories (< 70%, 70% ~ 130%, > 130%). 
6.4.4. Concomitant Medications and Nondrug Treatments 
Prior treatment are the ones stopped prior to Day 1 of study treatment.  Concomitant 
treatments are the ones taken on Day 1 or after. Prior drug and non-drug treatment, 
concomitant drug (including SoC) and non-drug treatment will be summarized by treatment 
group. Number and percent of subjects used additional immunomodulatory agent (i.e., IL-6 
targeting therapy), or other non-FDA approved, compassionate use or expanded access 
treatment will be reported by treatment group. 
6.5. Safety Summaries and Analyses 
The safety endpoints are listed in Section 3.5.  All safety analyses will be performed on the 
SAS (Section 4). 
For the categorical (including binary) endpoints, results will be analyzed as described in 
Section 5.2.1 by treatment group. 
For continuous endpoints, results will be analyzed as described in Section 5.2.2 by 
treatment group.  
7. INTERIM ANALYSIS 
No interim analysis will be performed.  Safety data will be reviewed by a Yale DSMB.  
The first safety review was conducted after randomization of 24 subjects and there was no 
further review as additional patients were not enrolled. 
8. REFERENCE 
C. J. Clopper; E. S. Pearson. The Use of Confidence or Fiducial Limits Illustrated in the case 
of the Binomial. Biometrika, Vol. 26, No. 4. (Dec. 1934), pp. 404-413. 
 
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
APPENDICES
Appendix 1. Definition and Use of Visit Windows in Reporting 
The data will be analyzed at each scheduled visit per defined in section 6.3.1 of the study 
protocol. 
Appendix 2. List of Abbreviations 
Abbreviation Term 
AE 
adverse event 
BID 
twice daily
CCL5 
C-C motif chemokine ligand 5
CI 
confidence interval 
COVID-19
Corona Virus Infectious Disease-19
CRF 
Case Report Form 
ECG 
electrocardiogram 
ECMO 
extra-corporeal membrane oxygenation 
FAS 
full analysis set 
FDA 
Food and Drug Administration (United States) 
hs-CRP
high-sensitivity-C-reactive protein
ICU 
Intensive Care Unit 
IL 
interleukin 
IP-10
interferon gamma-induced protein-10 
LDH 
lactate dehydrogenase
MAX 
Maximum 
MIN 
Minimum 
N/A 
Not Applicable 
NIAID 
National Institute of Allergy and Infectious Diseases
PT/PTT 
prothrombin time/partial prothrombin time
SAE 
serious adverse event
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome-Coronavirus-2
SAS 
safety analysis set
SD 
standard deviation 
SoC 
standard-of-care
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor
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Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
 
 
Signature/Approval Page 
 
  
 
 
Reviewed/Approved by: 
 
 
 
 
 
 
_____________________________________ DATE: _____________  
R. Balasubramaniam  
Clinical Statistician 
Pfizer, Inc. 
 
 
 
 
 
 
_____________________________________ DATE: _____________  
Kenneth Kwok 
I&I Rheumatology Statistical Group Lead 
Pfizer, Inc. 
 
 
 
 
 
  
_____________________________________ DATE: _____________  
Anthony J. Zygmunt, Pharm.D 
Vice-President 
US Medical Affairs Lead 
Pfizer, Inc. 
 
 
 
 
 
  
_____________________________________ DATE: _____________  
Hyung Chun, MD 
Principal Investigator 
Yale University School of Medicine 
 
 
 
03/21/2024
3/24/2024


Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan 
 
 
Signature/Approval Page 
 
  
 
 
Reviewed/Approved by: 
 
 
 
 
 
 
_____________________________________ DATE: _____________  
R. Balasubramaniam  
Clinical Statistician 
Pfizer, Inc. 
 
 
 
 
 
 
_____________________________________ DATE: _____________  
Kenneth Kwok 
I&I Rheumatology Statistical Group Lead 
Pfizer, Inc. 
 
 
 
 
 
  
_____________________________________ DATE: _____________  
Anthony J. Zygmunt, Pharm.D 
Vice-President 
US Medical Affairs Lead 
Pfizer, Inc. 
 
 
 
 
 
  
_____________________________________ DATE: _____________  
Hyung Chun, MD 
Principal Investigator 
Yale University School of Medicine 
 
 
 
March 21, 2024


Protocol 2000027848 / WI256061 (Tofacitinib) Statistical Analysis Plan
Signature/Approval Page
Reviewed/Approved by:
_____________________________________ DATE: _____________
R. Balasubramaniam
Clinical Statistician
Pfizer, Inc.
_____________________________________ DATE: _____________
Kenneth Kwok
I&I Rheumatology Statistical Group Lead
Pfizer, Inc.
_____________________________________ DATE: _____________
Anthony J. Zygmunt, Pharm.D
Vice-President
US Medical Affairs Lead
Pfizer, Inc.
_____________________________________ DATE: _____________
Hyung Chun, MD
Principal Investigator
Yale University School of Medicine
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