Conditions: Acute Lung Injury (ALI) Associated With COVID-19 Lung Inflammation Associated With COVID-19
Keywords: Acute lung injury ALI COVID-19 Coronavirus Disease 2019 inflammatory lung conditions Inflammatory lung disease ARDS SARS-CoV-2 Pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 235
Healthy volunteers: no

Brief summary:
This Phase 2 study will evaluate the efficacy, safety, pharmacodynamics and pharmacokinetics of inhaled TD-0903 compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with confirmed COVID-19 associated acute lung injury and impaired oxygenation.

Detailed description:
Part 1 of the study includes up to 3 ascending dose cohorts, each comprised of 8 subjects (6 receiving TD-0903 and 2 receiving placebo).

Part 2 of the study will evaluate one dose of TD-0903 (selected based on the data from Part 1) as compared with placebo. Part 2 is targeting 198 subjects total.

Arms:
arm 1: 6 out of 8 subjects per cohort will be randomized to receive TD-0903 MAD Dose A arm 2: 6 out of 8 subjects per cohort will be randomized to receive TD-0903 MAD Dose B arm 3: 6 out of 8 subjects per cohort will be randomized to receive TD-0903 MAD Dose C arm 4: 2 out of 8 subjects per cohort (up to 3 cohorts) will be randomized to receive placebo arm 5: 99 subjects will be randomized to receive TD-0903 arm 6: 99 subjects will be randomized to receive Placebo

Interventions: intervention 1: TD-0903 intervention 2: Placebo
Intervention descriptions: intervention 1: Study Drug to be administered by inhalation intervention 2: Placebo to be administered by inhalation

Protocol document:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-group, Multi-center Study of an Inhaled Pan-Janus 
Kinase Inhibitor, TD-0903, to Treat Symptomatic Acute Lung 
Injury Associated with COVID-19 
Study Short Title: 
TD-0903 for ALI Associated with COVID-19 
Sponsor Study No.: 
TD-0903-0188 
Date: 
18 September 2020—
 
 
 
Test Product: 
TD-0903 
US IND: 
149220 
EudraCT No.: 
2020-001807-18 
Sponsor: 
Theravance Biopharma Ireland Limited 
Connaught House 
1 Burlington Road 
Dublin 4 
D04 C5Y6 
Ireland 
Clinical Study Director: 
 
 
Theravance Biopharma US, Inc. 
 
Telephone: 
 
 
Email: 
 
This study will be conducted according to the principles of Good Clinical Practice. 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma, Inc. It may not be 
copied or provided to any other party without the express written consent of 
Theravance Biopharma, Inc. 
© Theravance Biopharma (Unpublished Work). All rights reserved. 


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PROTOCOL SYNOPSIS 
Study Number and Title:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-group, Multi-center study of an Inhaled Pan-Janus Kinase Inhibitor, TD-0903, to 
Treat Symptomatic Acute Lung Injury Associated with COVID-19 
Study Short Title:  TD-0903 for ALI Associated with COVID-19 
Estimated Number of Study Centers and Countries or Regions:   
  
 
 
Background and Rationale:   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 


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Objectives  
Part 1: 
The objectives are: 
• Evaluate the safety and tolerability of inhaled TD-0903 in subjects with 
COVID-19 
• Assess the plasma pharmacokinetics (PK) of TD-0903 in subjects with COVID-19 
• Characterize the effect of TD-0903 on reducing the acute lung injury (as measured 
by SaO2/FiO2 ratio) associated with COVID-19  
• Explore the effect of TD-0903 on swab viral infection status, SARS-CoV-2 
antibody levels, blood cytokine levels, and biomarkers of inflammation, 
thrombosis and lung injury 
Part 2:  
The primary objective is to characterize the efficacy of TD-0903 as measured by 
respiratory failure-free days (RFDs) through Day 28. 
The secondary objectives are to evaluate the effect of TD-0903 on: 
• Reducing the acute lung injury (as measured by SaO2/FiO2 ratio) associated with 
COVID-19  
• Safety and tolerability 
• Clinical outcomes as measured by an 8-point clinical status scale   
• The proportion of subjects alive and respiratory failure-free on Day 28 
 
 
 
 
 
 
 
 
 
  
 
 


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Study Design:  This is a two-part study. 
Part 1 
Part 1 is a randomized, double-blind, placebo-controlled, multiple ascending dose study 
in hospitalized subjects with confirmed symptomatic COVID-19 who require 
supplemental oxygen. 
Up to three ascending-dose cohorts, each comprised of 8 subjects, will be dosed at 
 
 total daily dose of TD-0903 or matched placebo. Six subjects in each 
cohort will be randomized to receive TD-0903 and 2 subjects in each cohort will be 
randomized to receive placebo (3:1 randomization). Each dose level cohort will be 
initiated once the corresponding healthy volunteer cohort in Study TD-0903-0183 has 
completed dosing and the Dose Level Review Committee (DLRC) has recommended 
escalation.   Dosing will be either once or twice a day in divided doses, as informed by 
emerging data from Study TD-0903-0183 and prior cohorts in this study.   
Eligible subjects will be randomized and dosed for up to 7 days or until discharge from 
the hospital, whichever is earlier. At the end of dosing for all subjects in each cohort, the 
DLRC will review unblinded data through Day 7 and results from the same dose level 
cohort in Study TD-0903-0183 to inform progression to the next dose level and/or to 
initiate Part 2 of the study. The blinding of subjects’ treatment assignments will be 
maintained for Theravance personnel who are directly involved with the ongoing 
operational activities of the study, for all subjects, and for all site personnel until the study 
is concluded. The activities and composition of DLRC will be described in a charter. 
The DLRC will recommend the final dose to carry forward into Part 2, including the 
potential to dose twice daily. 
Part 1 will assess safety, tolerability, and PK of TD-0903.  Serial blood samples will be 
collected from all subjects for PK assessments.  Oxygenation data will be collected for all 
subjects, and the ratio of peripheral oxygen saturation to the fraction of inspired oxygen 
(SaO2/FiO2 ratio) will be measured to guide dose selection for Part 2.  
Subject follow-up after the dosing period will continue until Day 28.  
Part 2 
Part 2 is a randomized, double-blind, parallel-group study evaluating efficacy and safety 
of one dose of TD-0903 (selected based on the data from Part 1) as compared with 
placebo in hospitalized subjects with confirmed symptomatic COVID-19 who require 
supplemental oxygen.  
 
   
 
 
 
 The study drug will be 
administered once-daily or twice daily in divided doses (as determined by results from 
Study TD-0903-0183 and from Part 1 of this study) for up to 7 days or until discharge 


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from the hospital, whichever is earlier. Subjects will be followed for up to 28 days or until 
death, whichever is earlier. 
Sparse sampling for assessment of TD-0903 plasma concentrations will be collected for 
population PK analysis. 
Parts 1 and 2 
Subjects will provide informed consent upon study entry; consent can be provided by the 
subject or legally authorized representative, or as assent/proxy consent via both a clinician 
and second health professional attesting that the subject understands the risks and 
potential benefits and elects to proceed. Baseline assessments (Day 1) will include 
medical and medication history, vital signs (blood pressure, heart rate, respiratory rate 
[BP, HR, RR], and body temperature), a physical examination (including height and 
weight, and hepato- or splenomegaly at a minimum), and measures of oxygenation (pulse 
oximetry, FiO2).  Female subjects of childbearing potential will undergo a serum 
pregnancy test.  Blood samples will be collected from all subjects for hematology 
(complete blood count [CBC] with differential at a minimum), and serum chemistry 
(renal function, liver function tests, and triglycerides at a minimum).  The investigator 
will also evaluate the subject’s clinical status and review inclusion exclusion criteria.   
Oxygenation will be assessed via SaO2/FiO2 ratio.  Use of ventilatory and oxygen 
support, presence in the ICU, clinical status (including mortality), and date of discharge 
will be recorded for all subjects as appropriate.   
Clinical status will be assessed using an 8-point scale for all subjects.   
Changes in swab SARS-CoV-2 viral infection status, SARS-CoV-2 antibody levels, 
blood cytokine levels, and biomarkers of inflammation, thrombosis and lung injury will 
be explored. 
Subject safety will be assessed throughout the study using standard measures, including 
adverse event (AE) monitoring, physical examinations (including hepato- or 
splenomegaly at a minimum), vital signs (at a minimum, temperature, BP, HR and 
respiratory rate [RR]), clinical laboratory tests (at a minimum, CBC with differential, 
renal function [creatinine, blood urea nitrogen], and liver function tests [aspartate 
aminotransferase {AST}, alanine aminotransferase {ALT}, alkaline phosphatase {Alk 
Phos}, and total bilirubin {TBili}]), and concomitant medication usage.  A Safety 
Assessment Committee will meet regularly to review safety data.   
Duration of Study Participation:  28 days or until death, whichever is earlier. 
   
 
 
 
 
    


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Study Population: 
Inclusion Criteria: 
1. Willing and able to provide written informed consent on their own prior to 
performing study procedures  
In the U.K., subject assent or proxy consent as per local site procedures, may also 
be acceptable if both a clinician and second health professional attest that the 
subject understands the risks and potential benefits of the study and elects to 
proceed. 
Outside the U.K., written informed consent may only be obtained from the subject 
or legally authorized representative.  
In the event the subject loses capacity during the study, the subject consents to 
continued participation, except where this is not clinically indicated. 
2. Willing and able to comply with study-related procedures/assessments 
3. Age 18 to 80 years old 
4. Hospitalized (or documentation of a plan to admit to the hospital if the subject is 
in an emergency department) and requiring supplemental oxygen to maintain 
saturation > 90%  
5. A diagnosis of symptomatic COVID-19 defined as a positive test for SARS-CoV-
2 RNA detected by RT-PCR on a sample from the upper respiratory tract (e.g. 
nasopharyngeal, nasal, or oropharyngeal swab) collected < 72 hours prior to 
randomization 
6. Onset of COVID-19 -related symptoms > 2 days and < 14 days prior to hospital 
admission 
Exclusion Criteria: 
1. Subjects currently receiving invasive mechanical ventilation. 
2. Presence or suspicion of active malignancy with the exception of cancer in situ 
(e.g., skin cancer) 
3. Evidence of serious active infections other than COVID-19 
4. Current diagnosis of human immunodeficiency virus, hepatitis B or C 
5. In the opinion of the investigator, unlikely to survive for > 24 hours from 
enrollment 
6. Women who are pregnant or might be pregnant, or who are currently breast-
feeding 
Subjects must agree to not donate ova or sperm through 30 days after the last dose 
of study medication. 


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7. Presence of significant comorbidity that, in the opinion of the investigator, 
predisposes the subject to mortality. Such conditions might include: 
a. New York Heart Association class IV Heart Failure 
b. Hepatic dysfunction (i.e., AST or ALT >3x upper limit of normal) 
c. Renal dysfunction (i.e., estimated glomerular filtration rate (eGFR) <50 
mL/min) or receiving renal replacement therapy  
8. Presence of septic shock at time of enrollment 
9. Hemoglobin < 80 g/L 
10. Evidence of neutropenia (i.e., absolute neutrophil count < 1000 cells/μL), 
lymphopenia (i.e., absolute lymphocyte count < 200 cells/μL) or 
thrombocytopenia (i.e., platelets < 50×109/L) 
11. Hypersensitivity to TD-0903 or its components, or to other JAK inhibitors  
12. Treatment with anti-IL 6 (e.g., tocilizumab, sarilumab), anti-IL-1, anti-T cell (e.g., 
abatacept) antibodies, anti-IL-6R antagonists, JAK inhibitors (e.g., baricitinib, 
tofacitinib) supplemental interferon therapy, or tyrosine kinase inhibitors (e.g., 
erlotinib, gefinitib) in the past 30 days, or plans to receive a JAK inhibitor  during 
the study period 
13. Current treatment with conventional synthetic disease-modifying anti-rheumatic 
drugs (DMARDs)/immunosuppressive agents including: 
a. Methotrexate, cyclosporine, mycophenolate, tacrolimus, penicillamine, or 
sulfasalazine within 2 weeks prior to enrollment 
b. Azathioprine or cyclophosphamide within 12 weeks prior to enrollment 
c. Monoclonal antibodies targeting B cells (eg rituximab) within 12 weeks prior 
to enrollment 
d. Tumor necrosis factor-alpha (TNFα) inhibitors within 4 weeks prior to 
enrollment 
14. Participating in other clinical trials involving any other experimental treatment for 
COVID-19, except in the context of a single-arm antiviral or convalescent plasma 
compassionate-use protocol  
15. Subjects with active or incompletely treated pulmonary tuberculosis, or known 
history of non-tuberculosis mycobacterium over past 12 months 
16. Subject requires continuous oxygen supplementation for underlying 
cardiorespiratory history in the past 90 days 
17. Body Mass Index ≥ 40 kg/m2 
18. Receipt of any live vaccine (i.e., live attenuated) in the 4 weeks prior to visit 1 or 
plans to receive a live vaccine (or live attenuated) during the study period.  
Note: Use of non-live (inactivated) vaccinations is allowed for all subjects. 


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19. History of venous thromboembolism (VTE), deep venous thrombosis (DVT), 
Pulmonary Embolism (PE) or known hypercoagulable disorder (e.g. factor V 
Leiden, antiphospholipid antibody syndrome, protein C or S deficiency). 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:  
TD-0903 
 up to a maximum of 
 total daily dose either once or twice daily in 
divided doses for up to 7 days, will be administered via inhalation using the 
 
nebulizer system.   
For the 
 and/or
 doses, a loading dose  of 
 and/or 
 respectively, will 
be given as the total dose on Day 1 based on emerging PK and safety data from Study 
TD-0903-0183.   
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of 
Treatment:  Matching placebo will be administered once or twice daily for up to 7 days 
via inhalation using the 
 nebulizer system. 
Study Evaluations  
Subjects will be assessed daily while hospitalized, with evaluations performed according 
to the Protocol Schedule of Events. In Part 2, if subjects are discharged from the hospital 
before Days 14, 21 or 28 and are known to be alive at discharge, they will undergo a 
telephonic study visit on Days 14, 21, and/or 28 to provide data relating to clinical status, 
adverse events and concomitant medications.  
Safety Assessments: 
Subject safety will be assessed throughout the subject’s stay in hospital using standard 
measures, including clinical status, AE monitoring, physical examinations, vital signs, 
clinical laboratory tests and concomitant medication usage. 
Efficacy Assessments: 
• Pulse oximetric saturation analyses  
• Use of ventilatory and oxygen support  
• ICU days 
• Modified Borg Dyspnea Score 
• Clinical status 
• Modified HScore 
• Vital signs  
Biomarker Assessments: 
 
 
 
 
 
  


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Pharmacokinetic Assessments: 
• In Part 1, serial blood samples for assessment of TD-0903 plasma concentrations 
will be collected predose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after the dose on 
Day 1 and Day 7. If the dose on Day 1 occurs in the evening (after 1:00 pm / 
13:00), Day 1 serial PK samples may be collected on Day 2 and Day 3. 
• In Part 2, sparse sampling for assessment of TD-0903 plasma concentrations may 
be collected for population PK analysis pre-dose and within 30 to 120 minutes 
post-dose on Day 7; and additional sample on Day 5 can be taken at any time 
postdose. 
• 
 
Statistical Methods 
  
 
 
 
  
 
 
 
 
 
  
 
   
 
   
 
  
 
  
 
 
 
 
  


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Study Endpoints: 
Part 1: 
Endpoints (through Day 7) 
Safety 
• Change from baseline in vital signs and clinical laboratory results  
• Incidence and severity of treatment-emergent AEs (TEAEs) 
Pharmacokinetics 
• Plasma PK parameters on Day 1 and Day 7    
Pharmacodynamics (PD)  
• Change from baseline in SaO2/FiO2 ratio  
Additional Endpoints (through Day 28) 
Safety 
• Change from baseline in vital signs and clinical laboratory results  
• Incidence and severity of TEAEs 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Part 2:  
The primary endpoint is the number of RFDs from randomization through Day 28   
Secondary Endpoints are:  
• Change from baseline in SaO2/FiO2 ratio on Day 7 
• Proportion of subjects in each category of the 8-point clinical status scale on 
Days 7, 14, 21 and 28 
• Proportion of subjects alive and respiratory failure-free on Day 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 


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The safety endpoints are:  
• Change from baseline in vital signs and clinical laboratory results  
• Incidence and severity of TEAEs  
The PK endpoints are population PK parameters for TD-0903. 
Analysis: 
Parts 1 and 2: 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
Part 2:  
  
 
 
 
    
 


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‘


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SCHEDULE OF STUDY PROCEDURES 
Table 1: 
Schedule of Study Procedures (Part 1) 
Procedure 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 14  
Chart Review 
Day 21  
Chart 
Review 
Hospital 
Discharge 
Day 28  
Informed Consenta 
X 
X 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
Medication and Medical 
Historyb 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xd 
Xd 
Xd 
Xd 
Physical Examinatione 
 
X 
 
 
 
 
 
X 
 
 
 
 
Height and Weight 
 
Xf 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
 
X 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetryg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Modified Borg Dyspnea 
Scoreh 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
  
Hematology (CBC with 
Diff)i  
 
X 
Record results of any lab evaluations performed for 
clinical purposes. 
X 
Record results of any lab evaluations performed for 
clinical purposes. 
Serum Chemistryj 
 
X 
X 
Plasma PK samplesk 
 
X 
X 
X 
 
 
 
X 
 
 
 
  
Serum and plasma for 
biomarkers, and 
antibodies, and for 
storage for future 
analysis (if feasible)l 
 
X 
 
 
 
 
 
X 
 
 
 
  
Swab for SARS-CoV-2 
viral PCRm 
 
X 
 
 
 
 
 
X 
 
 
 
 
Clinical Status 
 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
X 
Xn 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
  
Study Drug Dosing 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
  


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Procedure 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 14  
Chart Review 
Day 21  
Chart 
Review 
Hospital 
Discharge 
Day 28  
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
X 
Xn  
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
X 
Xn  
Abbreviations: Alk Phos, alkaline phosphatase, ALT, alanine aminotransferase; AST, aspartate aminotransferase, BP, blood pressure; CBC, complete blood count; COVID-19. 
Coronavirus Disease 2019; FiO2, fraction of inspired oxygen; HR, heart rate; PCR, polymerase chain reaction; PK, pharmacokinetic; RR, respiratory rate; SARS-CoV-2; Severe 
Acute Respiratory Syndrome-associated Coronavirus-2; TBili, total bilirubin 
a Informed consent may be obtained on either Day 0 or Day 1, up to 1 week prior to study enrollment in subjects undergoing testing for COVID-19, but with milder symptoms 
that, in the investigator’s opinion, may worsen. 
b Including known immunosuppression and source of immunosuppression i.e., disease or medication) 
c Includes BP, HR, RR, and body temperature.  Measured before dosing (first daily dose if study drug given twice daily). 
d Morning vital signs 
e Including hepato-or splenomegaly at a minimum 
f If not available from subject's chart 
g Oxygen saturation via pulse oximeter is considered equivalent to arterial oxygen saturation (SaO2) for this study.  Record FiO2 at each assessment. 
h Collected while subject is at rest. 
i At a minimum.  Day 1 samples must be collected within 24 hours before dosing, inclusive of those collected prior to informed consent; Day 7 samples must be collected predose.  
Laboratory testing as per local hospital protocols will be followed. 
j Including renal function, liver function tests (AST, ALT, Alk Phos, TBili), triglycerides, ferritin, and fibrinogen.  Day 1 samples must be collected within 24 hours before dosing, 
inclusive of those collected prior to informed consent; Day 7 samples must be collected predose.  Laboratory testing as per local hospital protocols will be followed.  
k Serial blood samples for plasma PK analyses will be collected pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours (i.e., the following day) after the dose on Day 1 and Day 7. If the 
dose on Day 1 occurs in the evening (after 1 pm / 13:00), Day 1 serial PK may be collected on Day 2 and the 24-hour sample may be collected on Day 3. 
l Blood samples for biomarkers and antibodies (if feasible) will be collected predose on Day 1, and at 3 hours ± 2 hours postdose on Day 7. 
m Swab can be oropharyngeal and/or nasal (anterior nares or nasopharyngeal) consistent with site standard of care. 
n For subjects discharged prior to Day 28 and known to be alive at discharge, this information will be collected via telephone at any time between Day 25 and Day 35; other 
assessments for this day will not be performed for these subjects. 
 
 
 


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Table 2: 
Schedule of Study Procedures (Part 2) 
Procedure 
Day 
0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 
5 
Day 
6 
Day 
7 
Days 
8-13 
Day 
14 
Days 
15-20 
Day 
21 
Days 
22-27 
Hospital 
Discharge 
Day 
28 
Informed Consenta 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication and Medical 
Historyb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
 
Xd 
 
Xd 
 
Xd 
Xd 
Physical Examinatione 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Height and Weight 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetryg 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Modified Borg Dyspnea Scoreh 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Hematology (CBC with Diff)i 
 
X 
Record results of any lab evaluations 
performed for clinical purposes. 
X 
Record results of any lab evaluations performed for clinical purposes 
only on Day 14, 21, 28 (while hospitalized) and at discharge. 
Serum Chemistryj 
 
X 
X 
Plasma PK samplesk 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Serum and plasma for 
biomarkers and antibodies, and 
for storage for future analysis (if 
feasible)l 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
Swab for SARS-CoV-2 viral 
PCRm 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
Clinical Status 
 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
Xn 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
Xn 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
Xn 
Abbreviations: Alk Phos, alkaline phosphatase, ALT, alanine aminotransferase; AST, aspartate aminotransferase, BP, blood pressure; CBC, complete blood count; COVID-19. 
Coronavirus Disease 2019FiO2, fraction of inspired oxygen; HR, heart rate; PCR, polymerase chain reaction; RR, respiratory rate; SARS-CoV-2; Severe Acute Respiratory 
Syndrome-associated Coronavirus-2TBili, total bilirubin 
a Informed consent may be obtained on either Day 0 or Day 1 up to 1 week prior to study enrollment in subjects undergoing testing for COVID-19, but with milder symptoms that, 
in the investigator’s opinion, may worsen. 


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b Including known immunosuppression and source of immunosuppression i.e., disease or medication) 
c Includes BP, HR, RR, and body temperature. Measured before dosing (first daily dose if study drug given twice daily). 
d Morning vital signs 
e Including hepato-or splenomegaly at a minimum 
f If not available from subject's chart 
g Oxygen saturation via pulse oximeter is considered equivalent to arterial oxygen saturation (SaO2) for this study.  Record FiO2 at each assessment. 
h Collected while subject is at rest. 
i At a minimum.  Day 1 samples must be collected within 24 hours before dosing, inclusive of those collected prior to informed consent; Day 7 samples must be collected predose.  
Laboratory testing as per local hospital protocols will be followed.  
j Including renal function, liver function tests (AST, ALT, Alk Phos, TBili), triglycerides, ferritin, and fibrinogen.  Day 1 samples on must be collected within 24 hours before 
dosing, inclusive of those collected prior to informed consent; Day 7 samples must be collected predose.  Laboratory testing as per local hospital protocols will be followed. 
k Blood samples for plasma PK analyses will be collected predose and within 30 to 120 minutes postdose on Day 7.  Additional sample on Day 5 can be taken at any time 
postdose. 
l Blood samples for biomarkers and antibodies (if feasible) will be collected predose on Day 1, and at 3 hours ± 2 hours postdose on Day 5 and Day 7, and at hospital discharge. 
m Swab can be oropharyngeal and/or nasal (anterior nares or nasopharyngeal) consistent with site standard of care. 
n For subjects discharged prior to Day 28 inclusive and known to be alive at discharge, this information will be collected via telephone as follows: 
• 
Days 14, 21, and 28 (±3 days) for subjects discharged on Days 8 through 13 
• 
Days 21 and 28 (±3 days) for subjects discharged on Days 15 through 20 
• 
Day 28 (±3 days) for subjects discharged on Days 22 through 27 
The other assessments for these days will not be performed for these subjects. 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS............................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 25 
1. 
INTRODUCTION .................................................................................. 27 
1.1. 
Background and Rationale ...................................................................... 27 
1.2. 
Nonclinical Profile .................................................................................. 28 
1.2.1. 
Pharmacology ......................................................................................... 28 
1.2.2. 
Toxicology .............................................................................................. 29 
1.2.3. 
Pharmacokinetics .................................................................................... 29 
1.3. 
Clinical Experience ................................................................................. 29 
1.4. 
Risks and Benefits .................................................................................. 29 
2. 
OBJECTIVES ......................................................................................... 31 
3. 
STUDY DESIGN ................................................................................... 32 
3.1. 
Overview ................................................................................................. 32 
3.1.1. 
Part 1:  Multiple Ascending Dosing ....................................................... 32 
3.1.2. 
Part 2:  Parallel Group ............................................................................ 32 
3.1.3. 
Parts 1 and 2 ............................................................................................ 33 
3.2. 
Rationale for Study Design ..................................................................... 33 
3.3. 
Selection of Dose and Duration of Treatment ........................................ 34 
3.4. 
Study Endpoints ...................................................................................... 34 
3.5. 
Minimization of Bias .............................................................................. 36 
3.5.1. 
Blinding .................................................................................................. 36 
3.5.1.1. 
Part 1 ....................................................................................................... 36 
3.5.1.2. 
Part 2 ....................................................................................................... 37 
3.5.2. 
Treatment Assignment ............................................................................ 37 
3.5.2.1. 
Part 1 ....................................................................................................... 37 
3.5.2.2. 
Part 2 ....................................................................................................... 37 
4. 
STUDY POPULATION ......................................................................... 38 
4.1. 
Inclusion Criteria .................................................................................... 38 
4.2. 
Exclusion Criteria ................................................................................... 39 
5. 
STUDY DRUGS .................................................................................... 41 
5.1. 
Description of Study Drugs .................................................................... 41 


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5.1.1. 
TD-0903 .................................................................................................. 41 
5.1.2. 
TD-0903 Matching Placebo .................................................................... 41 
5.2. 
Dosage and Administration .................................................................... 41 
5.2.1. 
TD-0903 .................................................................................................. 41 
5.2.2. 
TD-0903 Matching Placebo .................................................................... 41 
5.3. 
Treatment Compliance ............................................................................ 41 
5.4. 
Drug Accountability and Reconciliation ................................................ 42 
6. 
STUDY PROCEDURES ........................................................................ 43 
6.1. 
Schedule of Study Procedures ................................................................ 43 
6.2. 
Procedures by Visit ................................................................................. 43 
6.2.1. 
Part 1 ....................................................................................................... 43 
6.2.1.1. 
Day 0 ....................................................................................................... 43 
6.2.1.2. 
Day 1 ....................................................................................................... 43 
6.2.1.3. 
Day 2 ....................................................................................................... 44 
6.2.1.4. 
Day 3 ....................................................................................................... 45 
6.2.1.5. 
Day 4 ....................................................................................................... 45 
6.2.1.6. 
Day 5 ....................................................................................................... 45 
6.2.1.7. 
Day 6 ....................................................................................................... 46 
6.2.1.8. 
Day 7 ....................................................................................................... 46 
6.2.1.9. 
Day 14 and Day 21 (Chart Review) ....................................................... 47 
6.2.1.10. 
Hospital Discharge .................................................................................. 47 
6.2.1.11. 
Day 28 (Follow-up) ................................................................................ 47 
6.2.2. 
Part 2 ....................................................................................................... 48 
6.2.2.1. 
Day 0 ....................................................................................................... 48 
6.2.2.2. 
Day 1 ....................................................................................................... 48 
6.2.2.3. 
Day 2 ....................................................................................................... 49 
6.2.2.4. 
Day 3 ....................................................................................................... 49 
6.2.2.5. 
Day 4 ....................................................................................................... 50 
6.2.2.6. 
Day 5 ....................................................................................................... 50 
6.2.2.7. 
Day 6 ....................................................................................................... 50 
6.2.2.8. 
Day 7 ....................................................................................................... 51 
6.2.2.9. 
Days 8 to 13 ............................................................................................ 51 
6.2.2.10. 
Day 14 ..................................................................................................... 52 


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6.2.2.11. 
Days 15 to 20 .......................................................................................... 52 
6.2.2.12. 
Day 21 ..................................................................................................... 52 
6.2.2.13. 
Days 22 to 27 .......................................................................................... 52 
6.2.2.14. 
Hospital Discharge .................................................................................. 53 
6.2.2.15. 
Day 28 (Follow-up) ................................................................................ 53 
6.3. 
Description of Study Assessments .......................................................... 53 
6.3.1. 
Demographic and Baseline Assessments ................................................ 53 
6.3.2. 
Efficacy Assessments ............................................................................. 54 
6.3.3. 
Pharmacokinetic Assessments ................................................................ 56 
6.3.4. 
Biomarker Assessments .......................................................................... 57 
6.3.5. 
Safety Assessments ................................................................................. 57 
6.3.5.1. 
Adverse Events ....................................................................................... 57 
6.3.5.2. 
Medical History ...................................................................................... 57 
6.3.5.3. 
Physical Examination ............................................................................. 57 
6.3.5.4. 
Vital Signs .............................................................................................. 58 
6.3.5.5. 
Laboratory Tests ..................................................................................... 58 
6.4. 
Dose Escalation Stopping Rules (Part 1 Only) ....................................... 58 
6.5. 
Concomitant Medications ....................................................................... 59 
6.6. 
Restrictions ............................................................................................. 60 
6.6.1. 
Females of Childbearing Potential .......................................................... 60 
6.6.2. 
Contraception Measures for Male and Female Subjects ........................ 60 
6.7. 
Discontinuation ....................................................................................... 61 
6.7.1. 
Subject Discontinuation .......................................................................... 61 
6.7.2. 
Subject Replacement .............................................................................. 62 
6.7.3. 
Study Discontinuation ............................................................................ 62 
6.8. 
Pregnancy ............................................................................................... 62 
6.9. 
Safety Assessment Committee ............................................................... 63 
7. 
ADVERSE EVENTS .............................................................................. 64 
7.1. 
Definitions .............................................................................................. 64 
7.1.1. 
Adverse Events (AE) .............................................................................. 64 
7.1.2. 
Serious Adverse Event (SAE) ................................................................ 65 
7.1.3. 
Additional Considerations for Serious Adverse Events ......................... 65 
7.2. 
Assessment of Adverse Events ............................................................... 66 


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7.2.1. 
Severity ................................................................................................... 66 
7.2.2. 
Causal Relationship to Study Medication ............................................... 66 
7.3. 
AE Reporting and Recording .................................................................. 67 
7.3.1. 
AE Reporting .......................................................................................... 67 
7.3.2. 
AE and SAE Recording .......................................................................... 67 
7.3.3. 
SAE Reporting Timeline ........................................................................ 68 
7.4. 
Adverse Event Follow-up ....................................................................... 68 
8. 
STATISTICAL CONSIDERATIONS ................................................... 69 
8.1. 
General Considerations ........................................................................... 69 
8.2. 
Sample Size and Power .......................................................................... 69 
8.3. 
Analysis Sets ........................................................................................... 70 
8.3.1. 
Examination of Subgroups ..................................................................... 70 
8.3.2. 
Major Protocol Analysis Deviations ....................................................... 70 
8.4. 
General Analyses .................................................................................... 70 
8.4.1. 
Demographics Characteristics ................................................................ 70 
8.4.2. 
Screening Summaries ............................................................................. 71 
8.4.3. 
Baseline Clinical Characteristics ............................................................ 71 
8.4.4. 
Analysis of Efficacy ............................................................................... 71 
8.4.4.1. 
Efficacy endpoints .................................................................................. 71 
8.4.4.2. 
Primary Efficacy Evaluation ................................................................... 72 
8.4.5. 
Secondary and Exploratory Efficacy Evaluations .................................. 73 
8.4.6. 
Multiplicity Adjustment .......................................................................... 74 
8.4.7. 
Analysis of Pharmacokinetics ................................................................. 74 
8.4.8. 
Analysis of Pharmacodynamics .............................................................. 75 
8.5. 
Safety Analyses ...................................................................................... 75 
8.5.1. 
Extent of Exposure ................................................................................. 75 
8.5.2. 
Adverse Event Data ................................................................................ 75 
8.5.3. 
Concomitant Medications ....................................................................... 75 
8.5.4. 
Laboratory Data ...................................................................................... 75 
8.5.5. 
Vital Signs Data ...................................................................................... 76 
8.6. 
Missing Data Handling ........................................................................... 76 
8.7. 
Adjudication Committee ......................................................................... 76 
8.8. 
Data Monitoring Committee ................................................................... 77 


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9. 
STUDY ADMINISTRATION ............................................................... 78 
9.1. 
Principal Investigator Responsibilities ................................................... 78 
9.2. 
Institutional Review Board/Independent Ethics Committee .................. 79 
9.3. 
Informed Consent ................................................................................... 79 
9.4. 
Data Recording and Quality Assurance .................................................. 80 
9.5. 
Document Retention ............................................................................... 80 
9.6. 
Confidentiality ........................................................................................ 81 
9.7. 
Access to Data and Documents .............................................................. 81 
9.8. 
Quality Control: Study Monitoring and Auditing .................................. 81 
9.9. 
Publication .............................................................................................. 82 
10. 
REFERENCES ....................................................................................... 83 
APPENDIX 1. PROTOCOL SIGNATURE FORM ............................................... 86 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures (Part 1) ................................................... 16 
Table 2: 
Schedule of Study Procedures (Part 2) ................................................... 18 
Table 3: 
Clinical Status Score ............................................................................... 55 
Table 4: 
Criteria for Modified HScore .................................................................. 56 
Table 5: 
Outlier Threshold for Vital Signs ........................................................... 76 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
AE 
adverse event 
ALI 
Acute lung injury 
Alk Phos 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BP 
blood pressure 
CBC 
Complete blood count 
CCL 
Chemokine (C-C motif) ligand 
CFR 
(United States) Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019 
(e)CRF(s) 
(electronic)case report form(s) 
CRP 
C-reactive protein 
DLRC 
Dose Level Review Committee 
DMARD 
Disease-modifying anti-rheumatic drug 
eGFR 
Estimated glomerular filtration rate 
ECMO 
Extracorporeal membrane oxygenation 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
HLH 
Hemophagocytic lymphohistocytosis 
HR 
Heart rate 
HScore 
Diagnostic score that generates a probability for the presence of 
secondary hemophagocytic lymphohistocytosis 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
ICU 
Intensive care unit 


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Abbreviation 
Description 
IEC 
Independent Ethics Committee 
IFN(γ) 
Interferon(-gamma) 
IL 
interleukin 
IRB 
Institutional Review Board 
JAK 
Janus kinase 
MERS-Co-V 
Middle East Respiratory Syndrome-associated coronavirus 
MMRM 
Mixed-model repeated measures 
NOAEL 
No-observed-adverse effect level 
PASS 
Power Analysis and Sample Size 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
Per-protocol 
REB 
Research Ethics Board 
RFD 
Respiratory failure-free day 
(RT-) PCR 
(Real-time) polymerase chain reaction 
RTSM 
Randomized Trial Supply Management 
SaO2 
peripheral oxygen saturation 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV(-2) 
Severe Acute Respiratory Syndrome-associated Coronavirus (-2) 
(SARS-CoV-2 is the virus attributed to COVID-19) 
SOP 
Standard operating procedure 
(p)STAT 
(phosphorylated) Signal transducers and activators of transcription 
TBili 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 


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1. 
INTRODUCTION  
1.1. 
Background and Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2. 
Nonclinical Profile 
A review of the nonclinical profile of TD-0903 can be found in the current version of the 
TD-0903 Investigator’s Brochure (IB). The following is a brief summary of the pertinent 
findings. 
1.2.1. 
Pharmacology 
 
 


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1.2.2. 
Toxicology 
 
 
 
 
 
 
 
 
 
 
1.2.3. 
Pharmacokinetics 
 
 
 
 
1.3. 
Clinical Experience 
 
 
1.4. 
Risks and Benefits 
There is a high unmet need for COVID-19 patients with ALI as there are no approved 
treatments for COVID-19.  Given the high potency of TD-0903 in inhibiting cytokine 
activation in human cells, and its formulation as an inhaled agent, TD-0903 may be a 
potentially effective treatment of inflammatory lung diseases.   
Nonclinical safety studies did not reveal any adverse safety findings
 
 


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2. 
OBJECTIVES 
The objectives are based on a subject population hospitalized with confirmed symptomatic 
COVID-19 and requiring supplemental oxygen. 
Part 1: 
The objectives are: 
• Evaluate the safety and tolerability of inhaled TD-0903 in subjects with 
COVID-19 
• Assess the plasma pharmacokinetics (PK) of TD-0903 in subjects with 
COVID-19 
• Characterize the effect of TD-0903 on reducing the acute lung injury (as 
measured by SaO2/FiO2 ratio) associated with COVID-19 
• Explore the effect of TD-0903 on swab viral infection status, SARS-CoV-2 
antibody levels, blood cytokine levels and biomarkers of inflammation, 
thrombosis and lung injury. 
Part 2:  
The primary objective is to characterize the efficacy of TD-0903 as measured by respiratory 
failure-free days (RFDs) through Day 28. 
The secondary objectives are to evaluate the effect of TD-0903 on: 
• Reducing the acute lung injury (as measured by SaO2/FiO2 ratio) associated with 
COVID-19  
• Safety and tolerability 
• Clinical outcomes as measured by an 8-point clinical status scale   
• The proportion of subjects alive and respiratory failure-free on Day 28 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a two-part study.   
3.1.1. 
Part 1:  Multiple Ascending Dosing 
Part 1 is a randomized, double-blind, placebo-controlled, multiple ascending dose study in 
hospitalized subjects with confirmed symptomatic COVID-19 who require supplemental 
oxygen. 
Up to three ascending-dose cohorts, each comprised of 8 subjects, will be dosed at 
 
total daily dose of TD-0903 or matched placebo. Six subjects in each cohort 
will be randomized to receive TD-0903 and 2 subjects in each cohort will be randomized to 
receive placebo (3:1 randomization). Each dose level cohort will be initiated once the 
corresponding healthy volunteer cohort in Study TD-0903-0183 has completed dosing and 
the Dose Level Review Committee (DLRC) has recommended escalation.   Dosing will be 
either once or twice a day in divided doses, as informed by emerging data from Study 
TD-0903-0183 and any prior cohorts in this study.   
Eligible subjects will be randomized and dosed for up to 7 days or until discharge from the 
hospital, whichever is earlier. At the end of dosing for all subjects in each cohort, the DLRC 
will review unblinded data through Day 7, and results from the same dose level cohort in 
Study TD-0903-0183 to inform progression to the next dose level and/or to initiate Part 2 of 
the study. The blinding of subjects’ treatment assignments will be maintained for Theravance 
personnel who are directly involved with the ongoing operational activities of the study, for 
all subjects, and for all site personnel until the study is concluded. The activities and 
composition of DLRC will be described in a charter. 
The DLRC will recommend the final dose to carry forward into Part 2, including the 
potential to dose twice daily. 
Part 1 will assess safety, tolerability, and PK of TD-0903.  Serial blood samples will be 
collected from all subjects for PK assessments.  Oxygenation data will be collected for all 
subjects, and the ratio of peripheral oxygen saturation to the fraction of inspired oxygen 
(SaO2/FiO2 ratio) will be measured to guide dose selection for Part 2.  
Subject follow-up after the dosing period will continue until Day 28.   
3.1.2. 
Part 2:  Parallel Group 
Part 2 is a randomized, double-blind, parallel-group study evaluating efficacy and safety of 
one dose of TD-0903 (selected based on the data from Part 1) as compared with placebo in 
hospitalized subjects with confirmed symptomatic COVID-19 who require supplemental 
oxygen.  Approximately 99 subjects per group (198 subjects total) will be enrolled in Part 2. 
 
 
 
 


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(Table 3). The study drug will be administered once-daily or twice daily in divided doses 
(as determined by results from Study TD-0903-0183 and from Part 1 of this study) for up to 
7 days or until discharge from the hospital, whichever is earlier. Subjects will be followed for 
up to 28 days or until death, whichever is earlier. 
Sparse sampling for assessment of TD-0903 plasma concentrations may be collected for 
population PK analysis. 
3.1.3. 
Parts 1 and 2 
Subjects will provide informed consent upon study entry; consent can be provided only by 
the subject or legally authorized representative outside the United Kingdom (U.K.), or, 
within the U.K., as assent/proxy consent via both a clinician and second health professional 
attesting that the subject understands the risks and potential benefits and elects to proceed. 
Baseline assessments (Day1) will include medical and medication history, vital signs (blood 
pressure, heart rate, respiratory rate [BP, HR, RR], and body temperature), a physical 
examination (including height and weight, and hepato- or splenomegaly at a minimum), and 
measures of oxygenation (pulse oximetry, FiO2).  Female subjects of childbearing potential 
will undergo a serum pregnancy test.  Blood samples will be collected from all subjects for 
hematology (complete blood count [CBC] with differential at a minimum), and serum 
chemistry (renal function, liver function tests, and triglycerides at a minimum).  The 
investigator will also evaluate the subject’s clinical status and review inclusion/exclusion 
criteria.   
Oxygenation will be assessed via SaO2/FiO2 ratio.  Use of ventilatory and oxygen support, 
presence in the ICU, clinical status (including mortality), and date of discharge will be 
recorded for all subjects as appropriate.   
Clinical status will be assessed using an 8-point scale for all subjects. 
Changes in swab SARS-CoV-2 viral infection status, SARS-CoV-2 antibody levels, blood 
cytokine levels, and biomarkers of inflammation, thrombosis, and lung injury will be 
explored. 
Subject safety will be assessed throughout the study using standard measures, including 
adverse event (AE) monitoring, physical examinations (including hepato- or splenomegaly at 
a minimum), vital signs (at a minimum, temperature, BP, HR, and respiratory rate [RR]), 
clinical laboratory tests (at a minimum, CBC with differential, renal function [creatinine, 
blood urea nitrogen], and liver function tests [aspartate aminotransferase {AST}, alanine 
aminotransferase {ALT}, alkaline phosphatase {Alk Phos}, and total bilirubin {TBili}]), and 
concomitant medication usage.  A Safety Assessment Committee will meet regularly to 
review safety data. 
3.2. 
Rationale for Study Design 
 
 
   


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3.3. 
Selection of Dose and Duration of Treatment 
 
   
 
   
 
 
 
3.4. 
Study Endpoints 
Part 1: 
Endpoints (through Day 7)  
Safety 
• Change from baseline in vital signs and clinical laboratory results  
• Incidence and severity of treatment-emergent AEs (TEAEs) 
Pharmacokinetics 
• Plasma PK parameters on Day 1 and Day 7    
Pharmacodynamics (PD) 
• Change from baseline in SaO2/FiO2 ratio  
Additional Endpoints (through Day 28) 
Safety 
• Change from baseline in vital signs, and clinical laboratory results  
• Incidence and severity of TEAEs 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 


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Part 2:  
The primary endpoint is the number of RFDs from randomization through Day 28     
Secondary Endpoints are:  
• Change from baseline in SaO2/FiO2 ratio on Day 7 
• Proportion of subjects in each category of the 8-point clinical status scale on Days 
7, 14, 21 and 28 
• Proportion of subjects alive and respiratory-failure free on Day 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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The safety endpoints are:  
• Change from baseline in vital signs and clinical laboratory results  
• Incidence and severity of TEAEs  
The PK endpoints are population PK parameters for TD-0903. 
3.5. 
Minimization of Bias 
3.5.1. 
Blinding 
Part 1 and Part 2 of this study will be conducted as a double-blind, placebo-controlled study.  
Part 1 will be unblinded to the DLRC after 7-day dosing is completed for all subjects in each 
cohort. 
3.5.1.1. 
Part 1 
For Part 1, randomization and treatment assignment will be via the Randomization Trial 
Supply Management System (RTSM). 
Subjects will be assigned in random order to TD-0903 or placebo according to the 
randomization schedule. All study subjects, study investigators and their staff, and the 
Sponsor’s staff involved in the conduct of the study will be blinded to treatment assignment 
Unblinded study staff will include dose administration staff at the research site and the site 
pharmacist and/or designee[s], neither of whom will be involved in direct subject care, or 
collection or analysis of data.  Following the final Day 7 dosing of all subjects in each cohort, 
the DLRC (as described in Section 6.4) will review the data in an unblinded manner; any 
data reviewed by Sponsor personnel before that point will be performed in a blinded manner.  
Additionally, to facilitate PK analysis, the analyst at the PK bioanalytical lab may be 
unblinded, however, any PK data provided to the Sponsor for analysis will be provided in a 
blinded fashion (i.e., PK data cannot be linked to an individual subject).   
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the subject.  If 
breaking the blind is required because of a medical emergency, the treatment identity will be 
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is one in which it appears that the other subjects may be at imminent risk, the blind may be 
broken for all subjects dosed at that dose level. The unblinding will be properly documented 
in the study file and captured in the RTSM. The responsibility to break the blind resides 
solely with the investigator (or designee), however, it is requested that the investigator or 
designee will make every effort to contact the Medical Monitor or designee to notify him/her 
of the medical emergency and the breaking of the blind as soon as it is practicable, granting 
that these efforts should not stall or delay the unblinding of trial subject treatment in 
emergency situations.  
In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed to any blinded person until all data are entered in the database, edits checks are 
performed, queries closed, electronic case report forms (eCRFs) signed by the investigator(s) 
or designee, and the database is officially locked.  
3.5.1.2. 
Part 2 
For Part 2, randomization and treatment assignment will be via the Randomization Trial 
Supply Management System. 
In the event of an untoward safety observation, the investigator may unblind a subject’s 
treatment assignment using the RTSM. The blind should be broken only if knowledge of the 
subject’s study medication would affect subsequent treatment and such knowledge is 
required for the clinical management of the subject. Any investigator unblinding will be 
documented within the appropriate section of the subject’s case report from (CRF) and will, 
for Part 2, be captured in the RTSM.  
Unblinding of individual study subjects or study center staff on the basis of results from the 
study procedures (i.e., self-unblinding) is considered to be improbable. 
3.5.2. 
Treatment Assignment 
3.5.2.1. 
Part 1 
Within each cohort, subjects will be randomized 3:1, TD-0903 to placebo. 
3.5.2.2. 
Part 2 
 
 
 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects who meet the following criteria will be eligible for study enrollment: 
1. Willing and able to provide written informed consent on their own prior to 
performing study procedures  
In the U.K., subject assent, or proxy consent as per local site procedures, may also be 
acceptable if both a clinician and second health professional attest that the subject 
understands the risks and potential benefits of the study and elects to proceed. 
Outside the U.K., written informed consent may only be obtained from the subject or 
legally authorized representative. 
In the event the subject loses capacity during the study, the subject consents to 
continued participation, except where this is not clinically indicated.  
2. Willing and able to comply with study-related procedures/assessments 
3. Age 18 to 80 years old 
4. Hospitalized (or documentation of a plan to admit to the hospital if the subject is in an 
emergency department) and requiring supplemental oxygen to maintain saturation 
> 90%  
5. A diagnosis of symptomatic COVID-19 defined as a positive test for SARS-CoV-2 
RNA detected by RT-PCR on a sample collected from the upper respiratory tract (e.g. 
nasopharyngeal, nasal, or oropharyngeal swab) collected < 72 hours prior to 
randomization 
6. Onset of COVID-19-related symptoms > 2 days and < 14 days prior to hospital 
admission 


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4.2. 
Exclusion Criteria 
Subjects who satisfy any of the following criteria are not eligible for study enrollment: 
1. Subjects currently receiving invasive mechanical ventilation  
2. Presence or suspicion of active malignancy with the exception of cancer in situ 
(e.g., skin cancer) 
3. Evidence of serious active infections other than COVID-19 
4. Current diagnosis of human immunodeficiency virus, hepatitis B or C 
5. In the opinion of the investigator, unlikely to survive for > 24 hours from enrollment 
6. Women who are pregnant or might be pregnant, or who are currently breast-feeding 
Subjects must agree to not donate ova or sperm through 30 days after the last dose of 
study medication. 
7. Presence of significant comorbidity that, in the opinion of the investigator, 
predisposes the subject to mortality. Such conditions might include: 
a. New York Heart Association class IV Heart Failure 
b. Hepatic dysfunction (i.e., AST or ALT >3x upper limit of normal) 
c. Renal dysfunction (i.e., estimated glomerular filtration rate (eGFR) <50 mL/min) 
or receiving renal replacement therapy  
8. Presence of septic shock at time of enrollment 
9. Hemoglobin < 80 g/L 
10. Evidence of neutropenia (i.e., absolute neutrophil count < 1000 cells/μL), 
lymphopenia (i.e., absolute lymphocyte count < 200 cells/μL) or thrombocytopenia 
(i.e., platelets < 50×109/L)  
11. Hypersensitivity to TD-0903 or its components, or to other JAK inhibitors  
12. Treatment with anti-IL 6, (eg tocilizumab, sarilumab), anti-IL-1, anti-T cell (e.g., 
abatacept) antibodies, anti-IL-6R antagonists, JAK inhibitors (e.g., baricitinib, 
tofacitinib), supplemental interferon therapy, or tyrosine kinase inhibitors 
(e.g.,umatibib, genfinitib) in the past 30 days, or plans to receive a JAK inhibitor 
during the study period 
13. Current treatment with conventional synthetic disease-modifying anti-rheumatic 
drugs (DMARDs)/immunosuppressive agents including: 
a. Methotrexate, cyclosporine, mycophenolate, tacrolimus, penicillamine, or 
sulfasalazine within 2 weeks prior to enrollment 
b. Azathioprine or cyclophosphamide within 12 weeks prior to enrollment 
c. Monoclonal antibodies targeting B cells (eg rituximab) within 12 weeks prior 
to enrollment 
d. Tumor Necrosis Factor-alpha (TNFα) inhibitors within 4 weeks prior to 
enrollment 


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14. Participating in other clinical trials involving any other experimental treatment related 
to COVID-19, except in the context of a single-arm antiviral or convalescent plasma 
compassionate-use protocol  
15. Subjects with active or incompletely treated pulmonary tuberculosis, or known 
history of non-tuberculosis mycobacterium over past 12 months 
16. Subject requires continuous oxygen supplementation for underlying cardiorespiratory 
history in the past 90 days 
17. Body Mass Index ≥40 kg/m2 
18. Receipt of any live vaccine (i.e., live attenuated) in the 4 weeks prior to visit 1 or 
plans to receive a live vaccine (or live attenuated) during the study period 
Note: Use of non-live (inactivated) vaccinations is allowed for all subjects. 
19. History of venous thromboembolism (VTE), deep venous thrombosis (DVT), 
Pulmonary Embolism (PE) or known hypercoagulable disorder (e.g. factor V Leiden, 
antiphospholipid antibody syndrome, protein C or S deficiency). 


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5. 
STUDY DRUGS 
All study drug supplied by the Sponsor must be stored in a secure location accessible only to 
designated study personnel. 
5.1. 
Description of Study Drugs 
5.1.1. 
TD-0903 
 
 
 
 
 
 
5.1.2. 
TD-0903 Matching Placebo 
 
 
5.2. 
Dosage and Administration 
For blinding purposes, study drug will be prepared and administered to the subject by clinical 
study staff who are designated as unblinded dosing personnel and who will not have any 
responsibilities for clinical assessment of the subject except during the dose administration 
procedure. Further details are described in the pharmacy manual. 
5.2.1. 
TD-0903 
TD-0903 
 total daily dose either once or twice daily in 
divided doses for up to 7 days, will be administered via inhalation using the 
 
nebulizer system.   
 
   
5.2.2. 
TD-0903 Matching Placebo 
Matching placebo will be administered once or twice daily for up to 7 days via inhalation 
using the 
 nebulizer system. 
5.3. 
Treatment Compliance 
Subjects will receive study drug (TD-0903 or placebo) from medical personnel as inpatients.  
Compliance will be defined as subjects who received at least 1 dose on 4 of the 7 days. 


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Receipt of less than 4 doses will be documented in the CRF as to reasons why, the number of 
doses that were outside this range, and whether any AE occurred as a result of the 
non-compliance. 
5.4. 
Drug Accountability and Reconciliation 
The investigator or designee is responsible for maintaining accountability records for all 
study drug(s) received from the Sponsor, in accordance with applicable government 
regulations and study procedures. The accountability record will include entries for receipt, 
distribution or dispensing, and destruction of the material(s). Unused and expired study drugs 
will be disposed of in accordance with written instructions from the Sponsor. 
Study drug reconciliation for each subject will not be performed because subjects will 
receive study drug as inpatients. 


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6. 
STUDY PROCEDURES 
6.1. 
Schedule of Study Procedures 
The schedule of study procedures for Part 1 and for Part 2 is summarized in Table 1 and 
Table 2, respectively.   
6.2. 
Procedures by Visit 
6.2.1. 
Part 1 
6.2.1.1. 
Day 0 
Written informed consent can be provided on Day 0 after the nature of the study has been 
explained and before any study procedure is performed.  In the U.K., subject assent, or proxy 
consent as per local site procedures, may also be acceptable if both a clinician and second 
health professional attest that the subject understands the risks and potential benefits of the 
study and elects to proceed.  Outside the U.K., written informed consent may only be 
obtained from the subject or legally authorized representative. 
Informed consent/subject assent may be obtained up to 1 week prior to study enrollment in 
subjects undergoing testing for COVID-19, but with milder symptoms that, in the 
investigator’s opinion, may worsen. 
If informed/proxy consent is obtained on Day 0, there is no need to obtain it on Day 1. 
Subjects who provide informed/proxy consent on Day 0, will be assessed for AEs. 
6.2.1.2. 
Day 1 
For purposes of this study, Day 1 is the day of enrollment.  The following procedures will be 
performed on Day 1. 
• If not provided on Day 0, written informed consent (signed and dated by the 
subject) after the nature of the study has been explained and before any study 
procedure is performed.   
Informed consent may be obtained up to 1 week prior to study enrollment in 
subjects undergoing testing for COVID-19, but with milder symptoms that, in the 
investigator’s opinion, may worsen. 
Subject assent, or proxy consent as per local site procedures, may also be 
acceptable if both a clinician and second health professional attest that the subject 
understands the risks and potential benefits of the study and elects to proceed. 
• Review of inclusion and exclusion criteria 
• Medication and medical history (including known immunosuppression and source 
of immunosuppression i.e., disease or medication) 
• Vital signs (prior to dosing; BP, HR, RR, body temperature) 


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• Complete physical examination (including height and weight, and hepato- or 
splenomegaly at a minimum) 
• Serum pregnancy test (for female subjects of childbearing potential) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Blood collection  
− CBC with differential (within 24 hours before dosing inclusive of those 
collected prior to informed consent inclusive of those collected prior to 
informed consent) 
− Serum chemistry including renal function, liver function tests, triglycerides, 
ferritin, and fibrinogen (within 24 hours before dosing inclusive of those 
collected prior to informed consent) 
− PK:  Serial blood samples for assessment of TD-0903 plasma concentrations 
will be collected pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours (i.e., on 
Day 2) after the dose. If the dose on Day 1 occurs in the evening (after 
1:00 pm / 13:00), Day 1 serial PK samples may be collected on Day 2. 
− Biomarkers, and antibodies (if feasible) at pre-dose. 
• Swab for SARS-CoV-2 viral PCR at pre-dose (oropharyngeal and/or nasal 
[anterior nares or nasopharyngeal] consistent with site standard of care) 
• Clinical status 
• Randomization 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.1.3. 
Day 2 
The following procedures will be performed on Day 2: 
• Vital signs (prior to first daily dose; BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 
• Blood sample for PK:  If feasible, the 24-hour sample following the Day 1 dose 
can be collected.  If the dose on Day 1 occurs in the evening (after 1 pm / 13:00), 
Day 1 serial PK samples may be collected on Day 2. 
• Clinical status 
• Study drug dosing 
• Adverse events 


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• Concomitant medications 
6.2.1.4. 
Day 3 
The following procedures will be performed on Day 3: 
• Vital signs (prior to first daily dose; BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 
• Blood sample for PK: If feasible, the 24-hour sample following the Day 2 dose 
can be collected if the dose on Day 1 occurs in the evening (after 1 pm / 13:00) 
and Day 1 serial PK samples are collected on Day 2. 
• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.1.5. 
Day 4 
The following procedures will be performed on Day 4: 
• Vital signs (prior to first daily dose, or morning vital signs; BP, HR, RR, body 
temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.1.6. 
Day 5 
The following procedures will be performed on Day 5: 
• Vital signs (prior to first daily dose, or morning vital signs; BP, HR, RR, body 
temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 


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• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.1.7. 
Day 6 
The following procedures will be performed on Day 6: 
• Vital signs (prior to first daily dose, or morning vital signs; BP, HR, RR, body 
temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.1.8. 
Day 7 
The following procedures will be performed on Day 7: 
• Vital signs (prior to first daily dose, or morning vital signs; BP, HR, RR, body 
temperature) 
• Physical examination (including hepato- or splenomegaly at a minimum) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Blood collection 
− CBC with differential, predose 
− Serum chemistry, including renal function, liver function tests, triglycerides, 
ferritin, and fibrinogen; predose 
− PK: Serial blood samples for assessment of TD-0903 plasma concentrations 
will be collected pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours (i.e., 
Day 8) after the dose 
− Biomarkers and antibodies (if feasible; collected at 3 hours ± 2 hours 
postdose) 
• Swab for SARS-CoV-2 viral PCR (oropharyngeal and/or nasal [anterior nares or 
nasopharyngeal] consistent with site standard of care) 


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• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.1.9. 
Day 14 and Day 21 (Chart Review) 
The following results will be recorded at Day 14 and Day 21 via chart review: 
• Vital signs (BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Adverse events 
• Concomitant medications 
. 
6.2.1.10. Hospital Discharge 
The following procedures will be performed prior to discharge from the hospital: 
• Morning vital signs (BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Adverse events 
• Concomitant medications 
6.2.1.11. Day 28 (Follow-up) 
For subjects discharged prior to Day 28 and known to be alive at time of discharge, 
information on clinical status, AEs, and concomitant medications will be collected via 
telephone at any time between Day 25 and Day 35.  No additional procedures will be 
conducted for these subjects. 
The following procedures will be performed at Day 28 for subjects who remain hospitalized: 
• Morning vital signs (BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Record results of blood work done for clinical reasons  
• Clinical status 
• Adverse events 


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• Concomitant medications 
6.2.2. 
Part 2 
6.2.2.1. 
Day 0 
Written informed consent can be provided on Day 0 after the nature of the study has been 
explained and before any study procedure is performed.  In the U.K., subject assent, or proxy 
consent as per local site procedures, may also be acceptable if both a clinician and second 
health professional attest that the subject understands the risks and potential benefits of the 
study and elects to proceed.  Outside the U.K., written informed consent may only be 
obtained from the subject or legally authorized representative. 
Informed/proxy consent may be obtained up to 1 week prior to study enrollment in subjects 
undergoing testing for COVID-19, but with milder symptoms that, in the investigator’s 
opinion, may worsen. 
If informed/proxy consent is obtained on Day 0, there is no need to obtain it on Day 1. 
Subjects who provide informed consent on Day 0, will be assessed for AEs. 
6.2.2.2. 
Day 1 
For purposes of this study, Day 1 is the day of enrollment.  The following procedures will be 
performed on Day 1. 
• If not provided on Day 0, written informed consent (signed and dated by the 
subject) after the nature of the study has been explained and before any study 
procedure is performed.   
Informed consent may be obtained up to 1 week prior to study enrollment in 
subjects undergoing testing for COVID-19, but with milder symptoms that, in the 
investigator’s opinion, may worsen. 
Subject assent, or proxy consent as per local site procedures, may also be 
acceptable if both a clinician and second health professional attest that the subject 
understands the risks and potential benefits of the study and elects to proceed. 
• Review of inclusion and exclusion criteria 
• Medication and medical history (including known immunosuppression and source 
of immunosuppression i.e., disease or medication) 
• Vital signs (prior to dosing; BP, HR, RR, body temperature 
• Complete physical examination (including height and weight, and hepato- or 
splenomegaly at a minimum) 
• Serum pregnancy test (for female subjects of childbearing potential) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Blood collection 


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− CBC with differential (within 24 hours before dosing, inclusive of those 
collected prior to informed consent) 
− Serum chemistry including renal function, liver function tests, triglycerides, 
ferritin, and fibrinogen (within 24 hours before dosing inclusive of those 
collected prior to informed consent) 
− Biomarkers and antibodies (if feasible) at pre-dose 
• Swab for SARS-CoV-2 viral PCR at pre-dose (oropharyngeal and/or nasal 
[anterior nares or nasopharyngeal] consistent with site standard of care) 
• Clinical status 
• Randomization 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.2.3. 
Day 2 
The following procedures will be performed on Day 2: 
• Vital signs (prior to first daily dose; BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.2.4. 
Day 3 
The following procedures will be performed on Day 3: 
• Vital signs (prior to first daily dose; BP, HR, RR, body temperature) 
• Oxygen saturation via pulse Oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Study drug dosing 
• Adverse events 


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• Concomitant medications 
6.2.2.5. 
Day 4 
The following procedures will be performed on Day 4: 
• Vital signs (prior to first daily dose; BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.2.6. 
Day 5 
The following procedures will be performed on Day 5: 
• Vital signs (prior to first daily dose; BP, HR, RR, body temperature) 
• Oxygen saturation via pulse Oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Record results of blood work done for clinical reasons 
• Blood collection for biomarkers and antibodies (if feasible; collected at 3 hours ± 
2 hours postdose) 
• Blood sample for PK (if feasible) postdose 
• Swab for SARS-CoV-2 viral PCR (oropharyngeal and/or nasal [anterior nares or 
nasopharyngeal] consistent with site standard of care) 
• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.2.7. 
Day 6 
The following procedures will be performed on Day 6: 
• Vital signs (prior to first daily dose; BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 


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• Record results of blood work done for clinical reasons 
• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.2.8. 
Day 7 
The following procedures will be performed on Day 7: 
• Vital signs (prior to first daily dose; BP, HR, RR, body temperature) 
• Physical examination (including hepato- or splenomegaly at a minimum) 
• Oxygen saturation via pulse Oximetry / Record FiO2 
• Modified Borg Dyspnea Score (collected while subject is at rest) 
• Blood collection  
− CBC with differential, predose  
− Serum chemistry, predose, including renal function, liver function tests, 
triglycerides, ferritin, and fibrinogen  
− PK: blood samples for plasma PK analyses may be collected pre-dose and 
within 30 to 120 minutes postdose 
− Biomarkers and antibodies (if feasible; collected at 3 hours ± 2 hours 
postdose) 
• Swab for SARS-CoV-2 viral PCR (oropharyngeal and/or nasal [anterior nares or 
nasopharyngeal] consistent with site standard of care) 
• Clinical status 
• Study drug dosing 
• Adverse events 
• Concomitant medications 
6.2.2.9. 
Days 8 to 13 
The following assessments will be performed while the subject remains hospitalized: 
• Clinical status 
• Adverse events 
• Concomitant medications 


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6.2.2.10. Day 14 
For subjects discharged prior to Day 14 and known to be alive at time of discharge, 
information on clinical status, AEs, and concomitant medications will be collected via 
telephone on this day (±3 days).  No additional procedures will be conducted for these 
subjects. 
The following procedures will be performed at Day 14 for subjects who remain hospitalized: 
• Morning vital signs (BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Adverse events 
• Concomitant medications 
6.2.2.11. Days 15 to 20 
The following assessments will be performed while the subject remains hospitalized: 
• Clinical status 
• Adverse events 
• Concomitant medications 
6.2.2.12. Day 21 
For subjects discharged prior to Day 21 and known to be alive at time of discharge, 
information on clinical status, AEs, and concomitant medications will be collected via 
telephone on this day (±3 days).  No additional procedures will be conducted for these 
subjects. 
The following procedures will be performed at Day 21 for subjects who remain hospitalized: 
• Morning vital signs (BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Adverse events 
• Concomitant medications 
6.2.2.13. Days 22 to 27 
The following assessments will be performed while the subject remains hospitalized: 
• Clinical status 
• Adverse events 


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• Concomitant medications 
 
6.2.2.14. Hospital Discharge 
The following procedures will be performed prior to discharge from the hospital: 
• Morning vital signs (BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Record results of blood work (hematology and serum chemistry) done for clinical 
reasons  
• Blood collection for biomarkers and antibodies (if feasible) 
• Swab for SARS-CoV-2 viral PCR (oropharyngeal and/or nasal [anterior nares or 
nasopharyngeal] consistent with site standard of care) 
• Clinical status 
• Adverse events 
• Concomitant medications 
6.2.2.15. Day 28 (Follow-up) 
For subjects discharged prior to Day 28 and known to be alive at time of discharge, 
information on clinical status, AEs, and concomitant medications will be collected via 
telephone on this day (±3 days).  No additional procedures will be conducted for these 
subjects. 
The following procedures will be performed at Day 28 for subjects who remain hospitalized: 
• Morning vital signs (BP, HR, RR, body temperature) 
• Oxygen saturation via pulse oximetry / Record FiO2 
• Record results of blood work done for clinical reasons 
• Clinical status 
• Adverse events 
• Concomitant medications 
6.3. 
Description of Study Assessments 
6.3.1. 
Demographic and Baseline Assessments 
Subjects will provide informed consent (or assent/proxy consent as per local site procedures 
via both a clinician and second health professional) upon admission to the hospital.  Each 
subject will be asked to provide a relevant medical history (with the aid of medical records if 
available) including review of COVID-19 symptoms that lead to hospital administration, 
medication history, concomitant medications, known immunosuppression and source of 


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immunosuppression (i.e., disease or medication) and demographic information including year 
of birth, sex, race, and ethnicity.  The subject will also undergo a physical examination 
including vital signs (BP, HR, RR, and body temperature) and height and weight, presence of 
hepato- or splenomegaly, and will also have the following assessments measured: pulse 
oximetry, FiO2, modified Borg Dyspnea Score and clinical status.  Female subjects of 
childbearing potential will have blood collected for a serum pregnancy test.  Blood will be 
collected for serial PK assessments (for subjects enrolled in Part 1), CBC with differential, 
and serum chemistry including renal function, liver function tests, triglycerides, ferritin, and 
fibrinogen. 
6.3.2. 
Efficacy Assessments 
Subjects will be evaluated for peripheral oxygen saturation on Day 1 through Day 7.  Pulse 
oximetry will be measured 3 times over 5 minutes and the average value recorded. Data will 
be used to calculate SaO2/FiO2 ratio.  
The Modified Borg Dyspnea Score is based on a 10-point scale that measures shortness of 
breath.  Scores range from 0 (nothing at all, no shortness of breath) to 10 (maximal shortness 
of breath).30  Subjects will record their resting modified Borg Dyspnea Score on Day 1 
through Day 7. 
Clinical outcomes will be assessed as follows: 
• Use of ventilatory and oxygen support 
• ICU days 
• For Part 1, clinical status assessed by the investigator on Day 1 through Day 7 
inclusive, on Day 14, Day 21, prior to hospital discharge, and on Day 28, based 
on an 8-point scale as summarized in Table 3 
• For Part 2, clinical status assessed by the investigator daily on Day 1 through Day 
28 inclusive, during hospitalization and at hospital discharge, based on an 8-point 
scale as summarized in Table 3.  If subjects are discharged from the hospital 
before Days 14, 21 or 28 and are known to be alive at discharge, they will 
undergo a telephonic study visit on Days 14, 21, and/or 28 to provide data relating 
to clinical status. 


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Table 3: 
Clinical Status Score 
Status / Criteria 
Score 
Death 
8 
Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation 
7 
Hospitalized, on non-invasive ventilation or high-flow oxygen devices  
6 
Hospitalized, requiring supplemental oxygen    
5 
Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care 
(whether or not related to COVID-19) 
4 
Hospitalized, not requiring supplemental oxygen, and no longer requiring ongoing 
medical care (including subjects hospitalized for infection control) 
3 
Not hospitalized, but with limitation on activities and/or requiring home oxygen 
2 
Not hospitalized, no limitations on activities 
1 
Note: High-flow devices include high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced 
nasal cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5). 
 
   
 
 
 


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6.3.3. 
Pharmacokinetic Assessments 
In Part 1, serial blood samples for assessment of TD-0903 plasma concentrations will be 
collected predose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after the dose on Day 1 and Day 7. 
If the dose on Day 1 occurs in the evening (after 1:00 pm / 13:00), Day 1 serial PK samples 
may be collected on Day 2 and Day 3. 
In Part 2, sparse sampling for assessment of TD-0903 plasma concentrations will be collected 
for population PK analysis pre-dose and within 30 to 120 minutes post-dose on Day 7; an 
additional sample on Day 5 can be taken at any time postdose. 


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6.3.4. 
Biomarker Assessments 
 
 
 
 
 
 
6.3.5. 
Safety Assessments 
6.3.5.1. 
Adverse Events 
Adverse events will be reviewed and recorded beginning at Day 0 or Day 1 (i.e., after signing 
the Informed Consent Form [ICF] or providing assent/proxy consent as per local site 
procedures up to and including Day 21, and prior to discharge from the hospital.  Adverse 
events will also be reviewed and recorded at the follow-up contact at Day 28.  For subjects 
who discontinue due to a nonserious AE, follow-up information on these events will be 
collected at Day 28.  For subjects who discontinue due to a serious AE, follow-up 
information will be obtained as described in Section 7.3.3.   
Adverse events may be observed by the study center personnel or spontaneously reported by 
the subject. Subjects will be reminded to call the study center to report AEs that occur 
between discharge from the hospital, and the Day 28 follow-up contact.   
6.3.5.2. 
Medical History 
To the extent possible, medical history on Day 1 will include evaluation for past and present 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, 
lymphatic, hematologic, immunologic, dermatologic, psychiatric, genitourinary, substance 
abuse, surgical history, or any other diseases or disorders, including known 
immunosuppression and source of immunosuppression (i.e., disease or medication).   
6.3.5.3. 
Physical Examination 
Physical examinations will include an assessment of hepato- or splenomegaly in order to 
obtain the subjects modified HScore (Table 4). To the extent possible, physical examinations 
at enrollment on Day 1 will include height and weight, and examination of the following:  
general appearance; head, ears, eyes, nose, and throat; neck, skin, cardiovascular system, 
respiratory system, abdominal system, lymphatic system, dermatologic system, 
musculoskeletal system, and nervous system. 
Physical examinations on subsequent days will assess changes since the previous 
examination, which may be recorded as AEs, if appropriate. 


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6.3.5.4. 
Vital Signs 
6.3.5.4.1. Part 1 
Vital signs (BP, HR, RR, and body temperature) will be collected on Day 1 through Day 7 
prior to the subject’s first dose, prior to hospital discharge (first vital signs of the morning), 
and Day 28 (for subjects still hospitalized; first vital signs of the morning).  All 
measurements will be taken after the subject has been resting in a semirecumbent position for 
approximately 5 minutes. 
On Day 14 and Day 21, this information will be collected via a review of the subject’s chart. 
6.3.5.4.2. Part 2 
Vital signs (BP, HR, RR, and body temperature) will be collected on Day 1 through Day 7, 
Day 14, Day 21, prior to hospital discharge, and Day 28 (for subjects still hospitalized).  
Measurements will be taken after the subject has been resting in a semirecumbent position 
for approximately 5 minutes. 
6.3.5.5. 
Laboratory Tests 
Blood samples for routine clinical laboratory evaluation will be collected on Day 1 and 
Day 7.  At all other times, this information will be recorded if these tests were performed for 
clinical purposes. 
6.3.5.5.1. Hematology 
Hematology assessments will include, at a minimum, a CBC with differential.   
6.3.5.5.2. Serum Chemistry 
Serum chemistry assessments will include, at a minimum, renal function (creatinine, blood 
urea nitrogen), liver function tests (AST, ALT, Alk Phos, and TBili), triglycerides, ferritin, 
and fibrinogen. 
Additional blood samples may be collected to explore PD effects by evaluating the 
biomarkers described in Section 6.3.4. 
6.3.5.5.3. Serum Pregnancy Test 
Female subjects of childbearing potential will have a serum pregnancy test performed on 
Day 1.  If the result is positive, the subject will not be enrolled into the study. 
6.4. 
Dose Escalation Stopping Rules (Part 1 Only) 
A decision to proceed to the next higher dose administration or initiate Part 2 will be made 
by the site investigator(s) and the DLRC. The DLRC will include the Sponsor’s Medical 
Monitor, Study Director, Clinical Pharmacologist, and an independent statistician; other 
representatives may be considered on a case-by-case basis if additional expertise is required.  
All pertinent safety/tolerability data (e.g., physical examinations, vital signs assessments, 
clinical laboratory tests, and AEs) and pharmacodynamic data (e.g., SaO2/FiO2 ratio) 


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through 7 days of dosing will be captured in a database snapshot and analyzed as described in 
Section 8. Results of these analyses will be reviewed to inform dose escalation decisions. In 
addition, available PK data from previous cohorts will be included in the review, for context. 
Sponsor personnel (i.e., the DLRC) will review available data in the electronic data capture 
system that has been source document verified.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Following dose escalation review, and if none of the stopping rules are met, a decision will 
be made to continue the dose escalation as planned, and/or to initiate Part 2. Dose escalation 
to a level higher than planned will not occur without a protocol amendment. 
Part 2 of the study will be initiated following the recommendation of the DLRC. The 
decision to initiate Part 2 will be based on evidence of predictable PK response, acceptable 
safety profile, and evidence of improved oxygenation at a dose lower than
  
 
 
6.5. 
Concomitant Medications 
 
   
All concomitant medications, including name of medication, date started and stopped, route 
of administration, indication, and dose will be recorded in the source documentation and on 
the CRF. The Sponsor must be notified in advance (or as soon as possible thereafter) of any 
administration of a prohibited medication. Administration of a prohibited medication may 
result in the subject being discontinued from the study. 
 
 


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6.6. 
Restrictions 
Restrictions regarding subject care will be based on hospital standards and the subject’s 
clinical course during the study.   
6.6.1. 
Females of Childbearing Potential 
Females of childbearing potential must have documentation of a negative serum pregnancy 
test prior to randomization on Day 1.  
To be considered a female of non-childbearing potential, the subject must have undergone 
one of the following sterilization procedures at least 6 months prior to dosing: 
• bilateral salpingectomy; 
• hysterectomy; 
• bilateral oophorectomy. 
A female subject will also be considered to be of non-childbearing potential if the subject is 
postmenopausal with amenorrhea for at least 12 months prior to dosing without an alternative 
medical cause. FSH levels will be measured only in cases when postmenopausal status is in 
question. 
6.6.2. 
Contraception Measures for Male and Female Subjects 
All female subjects of childbearing potential and male subjects with partners of childbearing 
potential must agree to use a highly effective method of birth control during the study and for 
at least 30 days after the last dose of study drug to prevent conception. A highly effective 
method of birth control is defined as one that results in a low failure rate (i.e., < 1% per year) 
when used consistently and correctly. Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral 
− injectable 
− implantable 
• intrauterine device 


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• intrauterine hormone-releasing system 
• bilateral tubal occlusion 
• vasectomized male partner 
Vasectomized partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the woman of childbearing potential trial 
participant and that the vasectomized partner has documented medical assessment 
of the surgical success. 
• sexual abstinence 
True abstinence is defined as refraining from heterosexual intercourse in line with 
the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, postovulation methods), declaration of abstinence for 
the duration of exposure to study drug, and withdrawal are not acceptable 
methods of contraception. 
Birth control methods which may not be considered highly effective are as follows: 
• progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
• male or female condom with or without spermicide 
• cap, diaphragm or sponge with spermicide 
Male subjects must agree to use condoms to prevent potential fetal or partner exposure 
through seminal fluid, in addition to the use of highly effective pregnancy prevention 
measures during the study and through 30 days after the last dose of study medication. 
6.7. 
Discontinuation 
6.7.1. 
Subject Discontinuation 
 
 
 
Any subject may withdraw their consent to participate in the study at any time without 
prejudice. The investigator must withdraw from the study any subject who requests to be 
withdrawn. Subjects will be asked if they can be contacted at Day 28; if they do not consent 
to this contact, tests and evaluations listed for the termination visit should be performed at the 
time of withdrawal. 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
investigator and in accordance with his or her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. If a subject withdraws 
before completing the study, the reason for withdrawal is to be documented on the CRF. 
The Sponsor will be notified of all subject withdrawals. 


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Reasons for which the investigator or the Sponsor may withdraw a subject from the study or 
a subject may choose to terminate participation before completion of the study include, but 
are not limited to, the following: 
• Adverse event 
• Subject choice 
• Major violation of the protocol 
− Did not receive a dose on at least 4 days of the treatment period 
− Received a prohibited concomitant medication 
• Termination of the study by the Sponsor 
• Other 
If a subject is discharged prior to Day 28 and there are 3 documented, unsuccessful attempts 
to reach the subject by telephone at any time between Day 25 and Day 35 (during Part 1), or 
Days 14, 21, and/or 28 (± 3 days; during Part 2), the subject will be considered lost to follow-
up. 
6.7.2. 
Subject Replacement 
 
 
6.7.3. 
Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason.   
6.8. 
Pregnancy 
Given the inpatient setting and the disease being studied, pregnancies during the study are 
not anticipated. 
However, if a female subject or a female partner of a subject discovers she is pregnant within 
30 days of dosing, the Sponsor clinical study director (or designee) must be notified 
immediately. Follow-up information regarding the outcome of the pregnancy and any 
postnatal sequelae in the infant will be required. 
Subjects must agree to not donate ova or sperm through 30 days after receiving the last dose 
of study medication (Section 4.2). 


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6.9. 
Safety Assessment Committee 
 
 
 
 
   


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7. 
ADVERSE EVENTS 
7.1. 
Definitions 
The definitions below are based on International Conference on Harmonization (ICH) 
guideline E2A, “Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting”. 
7.1.1. 
Adverse Events (AE) 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered 
a pharmaceutical product that does not necessarily have to have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product.  
• AEs may be new events 
• Preexisting events that increase in frequency, severity or change in nature or 
seriousness during or as a consequence of participation in clinical studies. 
• Pre- or post-treatment complications that occur as a result of a protocol-mandated 
procedure (such as a biopsy). 
• AEs may be clinically significant changes from baseline in physical examination, 
laboratory tests, or other diagnostic investigation (e.g., laboratory results, x-ray 
findings). 
• AEs may result from an overdose of the study medication.  
Whenever possible, the diagnosis (rather than a series of terms related to a diagnosis) should 
be recorded as the AE term. 
An AE does not include the following: 
• Medical or surgical procedures (such as surgery, endoscopy, tooth extraction, or 
transfusion); the condition that leads to the procedure is an AE. 
• Preexisting diseases or conditions present or detected before signing an ICF that 
do not worsen 
• Situations where an untoward medical occurrence has not occurred (such as 
hospitalization for elective surgery or social and/or convenience admissions) 
• Overdose of either study drug or concomitant medication without any signs or 
symptoms, unless the subject is hospitalized for observation 
Any medical condition or clinically significant laboratory abnormality with an onset date 
prior to the time the subject signed the ICF is considered to be preexisting and should be 
documented in the medical history CRF. 
Pregnancy is not an AE; however, if a female subject becomes pregnant during the conduct 
of the study, Theravance Biopharma, Inc. (TBPH) will be notified according to the 
procedures for SAE reporting as outlined in Section 7.3.3.  Follow-up information regarding 


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the outcome of the pregnancy and any fetal or neonatal sequelae will be obtained and 
documented. 
7.1.2. 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as any untoward medical occurrence occurring at 
any dose that results in any of the following outcomes: 
• Death 
• Life-threatening situation.   “Life-threatening” refers to a situation in which the 
patient was at risk of death at the time of the event; it does not refer to an event 
which might have caused death if it were more severe. 
• New Inpatient hospitalization or prolongation of existing hospitalization. 
– Note: New inpatient hospitalization refers to a subsequent hospitalization 
after the subject’s current hospitalization for COVID-19. To meet this 
criteria the subject must be formally admitted to a hospital for medical 
reasons for any length of time; it may or may not be overnight. It does not 
include presentation and care within an emergency department nor does it 
include preplanned hospitalizations. Complications that occur during 
hospitalizations are AEs. If a complication prolongs hospitalization, it is 
an SAE. 
• Disability- a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• Congenital anomaly/birth defect in the offspring of a subject who received study 
drug 
• Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization, may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition.  
7.1.3. 
Additional Considerations for Serious Adverse Events 
• Death is an outcome of an AE and not an AE in itself. Deaths of unknown cause 
for which the investigator cannot identify a cause of death will be captured as 
death of unknown cause or death not otherwise specified. 
• All deaths, regardless of cause, must be reported for subjects if the death occurs 
while the subject is participating in the study. 
• “Occurring at any dose” does not imply that the subject is receiving study drug at 
the time of the event; dosing may have been given as treatment cycles or 
interrupted temporarily before the onset of the SAE, but may have contributed to 
the event. 


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7.2. 
Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded in the CRF, including the dates of 
onset and resolution, severity, relationship to study drug, outcome, and action taken with 
study medication. 
7.2.1. 
Severity 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe nausea).  This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning.  The severity of AEs will be 
assessed according to the following definitions:   
• Mild:  the AE is noticeable to the patient and/or the investigator, but does not 
interfere with routine activity. 
• Moderate:  the AE interferes with routine activity, but responds to symptomatic 
therapy or rest. 
• Severe:  the AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy. 
7.2.2. 
Causal Relationship to Study Medication 
The investigator’s assessment of causality is based on clinical judgment regarding the 
reasonable possibility that the study medication caused the event and may include 
consideration of some or all of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, 
comorbid conditions, other drugs, and environmental factors. 
• The temporal association between drug exposure and onset of the AE.  
• Whether the clinical or laboratory manifestations of the AE are consistent with 
known actions or toxicity of the study medication. 
• Whether the AE resolved or improved with decreasing the dose or stopping the 
study medication (“dechallenge”) or recurred or worsened upon re-exposure to the 
study medication (“rechallenge”).  
The causal relationship between the study medication and the AE will be described using one 
of the following categories: 
• Not Related:  Evidence exists that the AE has an etiology other than the study 
drug (such as a preexisting condition, underlying disease, intercurrent illness, or 
concomitant medication). 
• Related: A temporal relationship exists between the event onset and 
administration of the study drug. It cannot be readily explained by the subject’s 
clinical state or concomitant therapies and appears with some degree of certainty 
to be related based on the known therapeutic and pharmacologic actions of the 


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drug. In case of cessation or reduction of the dose, the event abates or resolves 
and reappears upon rechallenge. It should be emphasized that ineffective 
treatment should not be considered as causally related in the context of AE 
reporting. 
7.3. 
AE Reporting and Recording 
7.3.1. 
AE Reporting 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
trials is crucial for the protection of patients and is mandated by regulatory agencies.  
Sponsor has established SOPs in compliance with regulatory requirements worldwide to 
ensure appropriate reporting of safety information.  All clinical trials sponsored by TBPH 
will be conducted in accordance with these procedures.  
7.3.2. 
AE and SAE Recording 
All AEs, regardless of seriousness, severity, or causal relationship to study medication, will 
be recorded from signing an ICF/providing assent through the last study visit (or last subject 
contact in the case of a follow-up telephone call).  AEs will be recorded on the AE page of 
the CRF.  SAEs, regardless of relationship to study medication will be recorded from signing 
an ICF/providing assent through the last study visit (or last subject contact in the case of a 
follow-up telephone call).   All SAEs will be recorded on both the SAE Report Form and the 
AE page of the CRF and should include the following:   
Description of event:   
• Signs and symptoms due to a common etiology should be reported as a single 
diagnosis; for example, cough, runny nose, sneezing, sore throat, and head 
congestion would be reported as “upper respiratory infection”.   
• A diagnosis or description must be as specific and as complete as possible 
(e.g., “lower extremity edema” instead of “edema”).  
• “Death” should not be used as an AE term unless the cause of death is unknown.  
For events with a fatal outcome, the cause of death should be the AE term (e.g., if 
a subject died of an acute myocardial infarction, the AE term should be recorded 
as “Myocardial Infarction” and the event outcome as fatal).     
Relationship to study medication: The investigator will assess the causal relationship of the 
study medication to the AE using the guidelines in Section 7.2.2.  
Severity: The severity of the AE will be assessed using the guidelines in Section 7.2.1. 
Outcome:  The outcome of AEs will be recorded.   
Therapeutic measures:  Measures taken for the treatment or management of the AEs will be 
recorded. 


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7.3.3. 
SAE Reporting Timeline 
SAEs will be reported to Global Safety and Pharmacovigilance or designee within 24 hours 
of the time the investigator or his/her designee becomes aware that an SAE has occurred, 
whether or not the event is considered to be related to study medication.  A written report 
signed by the investigator should be submitted within 24 hours.   
The SAE Report Form must be completed in accordance with the SAE Report Form 
Completion Guidelines.  If all information on the SAE Report Form is not available at the 
time of the initial report, follow-up SAE reports will be completed and submitted.   
To report an SAE, complete and fax or email the Serious Adverse Event Report Form to the 
following: 
Theravance Biopharma Global Safety 
Fax: 
 
Email:   
 
For medical questions regarding an SAE, contact the Sponsor medical monitor by telephone 
as follows: 
Sponsor Medical Monitor Contact Information: 
 
 
 
Telephone: 
 
Email: 
 
For fatal or life-threatening events, also fax copies of hospital case reports, autopsy reports, 
and other documents if available. Additional information may be requested from the 
investigator to ensure the timely completion of accurate safety reports. 
An SAE may qualify for reporting to regulatory authorities if the SAE is possibly attributable 
to the study drug and is unexpected/unlisted based on the current TD-0903 IB. In this case, 
all investigators will receive notification of the event. The investigator is responsible for 
notifying the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and 
documenting the notification, as required by local regulatory authorities and in accordance 
with the local institutional policy. 
7.4. 
Adverse Event Follow-up 
A subject experiencing an AE will be followed by the investigator or his/her trained 
delegate(s) through the follow-up period until Day 28.   All SAEs will be followed until the 
investigator and/or the Sponsor has determined that the SAE has resolved or a stable clinical 
endpoint is reached, whichever is longer. The Sponsor may request follow-up of certain AEs 
until resolution and documentation of assessments made during this period. 
Any medications necessary for treatment of the SAE must be recorded in the concomitant 
medication section of the CRF. 


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
General Considerations 
 
 
   
 
 
   
 
 
 
 
 
  
8.2. 
Sample Size and Power 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
   


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8.3. 
Analysis Sets 
Parts 1 and 2: 
The safety analysis set will include all subjects who receive at least one dose of study drug.  
Subjects will be analyzed according to their treatment actually received. The safety analysis 
set will be the primary analysis set for general and safety analyses.  
The Pharmacokinetic (PK) analysis set will include all randomized subjects who received at 
least one dose of active TD-0903 study drug and have at least one measurable plasma PK 
concentration. The PK analysis set will be used for PK analyses.  
The intent-to-treat (ITT) analysis set is the primary analysis set for efficacy and will include 
all subjects who are randomized into the study. Subjects will be analyzed according to their 
randomized treatment group. 
The per-protocol (PP) analysis set will include all subjects in the ITT analysis set with no 
major analysis protocol deviations. Treatment assignment will be based on actual treatment. 
All safety endpoints will be summarized descriptively using summary statistics or frequency 
distributions.  
8.3.1. 
Examination of Subgroups 
The following subgroups are pre-defined for the purposes of analyses: 
 
 
 
  
 
8.3.2. 
Major Protocol Analysis Deviations 
The following protocol deviations are defined as major and would be considered to have an 
impact on the analysis of efficacy data 
 
 
 
 
 
 
 
 
 
8.4. 
General Analyses 
8.4.1. 
Demographics Characteristics 
Demographics and baseline characteristics (including age, sex, race, ethnicity, height, weight, 
and Body Mass Index) will be summarized for the safety analysis set. 


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8.4.2. 
Screening Summaries 
Not applicable  
8.4.3. 
Baseline Clinical Characteristics  
A summary of the clinical characteristics, medical history of comorbidity as well as 
concurrent use of antiviral therapy at baseline using the safety analysis set will be provided. 
8.4.4. 
Analysis of Efficacy  
8.4.4.1. 
Efficacy endpoints 
Part 1 (Exploratory): 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
Part 2:  
The primary endpoint is the number of RFDs from randomization through Day 28   
Secondary Endpoints are:  
• Change from baseline in SaO2/FiO2 ratio on Day 7 
• Proportion of subjects in each category of the 8-point clinical status scale on Days 
7, 14, 21 and 28 
• Proportion of subjects alive and respiratory failure-free on Day 28 
 
 
 
 
 


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8.4.4.2. 
Primary Efficacy Evaluation 
  
 
 
 
  
 
 
 


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8.4.5. 
Secondary and Exploratory Efficacy Evaluations 
 
 
 
 
  
 
  
 
 
 
     
 
 
  
 
 
    
 
 
 
  
 
 
 


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8.4.6. 
Multiplicity Adjustment 
 
   
8.4.7. 
Analysis of Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.4.8. 
Analysis of Pharmacodynamics 
 
 
8.5. 
Safety Analyses  
For all safety analyses, the safety analysis population will be used. 
Safety variables to be summarized include vital signs, AEs, and clinical laboratory results 
(hematology, serum chemistry). Vital signs will be summarized in terms of observed values 
and changes from baseline.   
8.5.1. 
Extent of Exposure 
A subject’s data for the extent of exposure to study drug will be generated from the study 
drug administration page of the CRF.  Dosing information for individual subjects will be 
listed.  Using drug administration data, estimates of exposure to TD-0903 will be 
summarized.  Dose discontinuations and reasons for study drug discontinuation will be listed 
and summarized. 
8.5.2. 
Adverse Event Data 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities. Summaries will present system organ class (SOC), preferred term (PT) and 
severity, and the frequency and percentage of subjects reporting each observed event. 
Adverse events observed during the period from obtaining informed/proxy consent to the 
start of administration of study drug will be regarded separately from AEs observed after 
study drug administration (i.e., TEAEs). 
A TEAE will be defined as any AE that begins on or after the date (and time) of first dose of 
study drug up to the date/time of last dose of study drug plus up to 21 days of follow-up 
post-dose. AEs observed during the period from obtaining informed/proxy consent to the 
start of administration of study drug will be regarded separately from TEAEs. 
 
 
 
A listing will be provided for all subjects who experience an SAE.  Data listings will also be 
provided for subjects who discontinued the study due to any AE, as well as for a SAE. 
8.5.3. 
Concomitant Medications 
Medications will be summarized both prior to and during the treatment period.   
8.5.4. 
Laboratory Data 
Laboratory data will be summarized in terms of observed values, changes from baseline, 
values relative to normal ranges, and changes from baseline relative to normal ranges. 
Listings will flag laboratory values that are outside of normal range. 


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Clinical laboratory test results will be listed by subject. Reference ranges provided by the 
laboratory for each parameter will be used to evaluate the clinical significance of laboratory 
test results.  Values falling outside of the relevant reference range will be flagged, as 
appropriate, in the data listings.  Abnormalities in clinical laboratory test results will be listed 
in a separate listing.   
8.5.5. 
Vital Signs Data 
Vital signs data will be summarized in terms of observed values (by time point), changes 
from baseline (by time point), and counts and percentages within appropriately defined 
categories (Table 5). 
 
 
 
 
 
 
 
 
 
 
 
 
8.6. 
Missing Data Handling 
 
  
 
 
 
8.7. 
Adjudication Committee 
Not applicable.  


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8.8. 
Data Monitoring Committee 
   
 
 
 
 
 
 
  
  


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9. 
STUDY ADMINISTRATION 
This study will be conducted in compliance with all applicable regulations. 
9.1. 
Principal Investigator Responsibilities 
Before beginning the study, the principal investigator at each site must provide to the 
Sponsor or its designee a fully executed and signed Form FDA 1572 (or equivalent) and a 
financial disclosure form. For applicable studies, financial disclosure forms must also be 
completed for all subinvestigators who will be directly involved in the treatment or 
evaluation of research subjects in this study. (A subinvestigator is defined in ICH E6 as any 
individual member of the clinical study team designated and supervised by the investigator at 
a study site to perform critical study-related procedures and/or to make important study-
related decisions [e.g., associates, residents, research fellows].) 
The principal investigator will ensure the following: 
• He or she will conduct the study in accordance with the relevant, current protocol 
and will only make changes in a protocol after notifying the Sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential subjects, or any persons used as controls, that 
the drugs are being used for investigational purposes and he or she will ensure 
that the requirements relating to obtaining informed consent in Code of Federal 
Regulations Title 21 (21 CFR) Part 50 and institutional review board (IRB) 
review and approval in 21 CFR Part 56 are met and outside of the US, compliance 
with ICH E6 and/or local regulatory requirements is required. He or she will also 
ensure that site-specific requirements for obtaining subject assent/ proxy consent 
(per the investigative site’s procedures) are met. 
• He or she will report to the Sponsor adverse experiences that occur in the course 
of the investigation in accordance with 21 CFR 312.64 and outside of the US, 
compliance with ICH E6 and/or local regulatory requirements is required. 
• He or she has read and understands the information in the TD-0903 IB, including 
potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
• He or she will ensure that there are adequate and accurate records in accordance 
with 21 CFR 312.62 and will make those records available for inspection in 
accordance with 21 CFR 312.68 and outside of the US, compliance with ICH E6 
and/or local regulatory requirements is required. 
• He or she will ensure that the IRB/IEC complies with the with the local and 
international regulatory requirements (for example in the US, compliance with 
21 CFR 56 is required and outside of the US, compliance with ICH E6 and/or 
local regulatory requirements is required), and other applicable regulations, and 
conducts initial and ongoing reviews and approvals of the study. He or she will 


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also ensure that any change in research activity and all problems involving risks 
to human subjects or others are reported to the IRB/IEC. Additionally, he or she 
will not make any changes in the research without IRB/IEC approval, except 
where necessary to eliminate apparent immediate hazards to human subjects. 
• He or she agrees to comply with all other requirements regarding the obligations 
of clinical investigators and all other pertinent requirements in 21 CFR Part 312, 
and outside of the US, ICH E6 and/or local regulatory requirements. 
9.2. 
Institutional Review Board/Independent Ethics Committee 
Before beginning study-specific research, the investigator will obtain written confirmation 
that the IRB, IEC, or Research Ethics Board (REB) is properly constituted and compliant 
with ICH and Good Clinical Practice (GCP) requirements, applicable laws, and local 
regulations. A copy of the confirmation from the IRB/IEC/REB will be provided to the 
Sponsor or its designee. The protocol, ICF, IB, and any other appropriate written information 
provided to the subjects that the IRB/IEC/REB may require to fulfill its responsibilities will 
be submitted to the IRB/IEC/REB in advance of the study. The Sponsor or its designee must 
approve the ICF and all subject recruitment materials before they are submitted to the 
IRB/IEC/REB. The study will not proceed until appropriate documents from the 
IRB/IEC/REB confirming unconditional approval of the protocol and the ICF are obtained by 
the investigator and copies are received by the Sponsor or its designee. If possible, the 
approval document should refer to the study by study protocol title and the Sponsor study 
number, identify the documents reviewed, and include the date of the review and approval. 
The written approval of the IRB/IEC/REB will be retained as part of the study file. The study 
may proceed before approval of consent forms and other study documents translated to a 
language other than the native language of the clinical site, provided that written 
IRB/IEC/REB approval of the translated documents is obtained before they are used. Any 
amendments to the protocol should be reviewed promptly. 
The investigator must provide the appropriate periodic reports on the progress of the study to 
the IRB/IEC/REB and the Sponsor in accordance with local IRB/IEC/REB requirements and 
applicable governmental regulations, whichever is strictest. 
9.3. 
Informed Consent 
A properly written and executed ICF, in compliance with-ICH E6 (GCP Guideline, 
Section 4.8), 21 CFR Part 50, and other applicable local regulations, will be obtained for 
each subject before enrollment of the subject into the study. In the U.K, informed consent can 
be provided as proxy consent via a clinician and another health professional attesting that the 
subject understands the risks and potential benefits and elects to proceed.  Outside the U.K., 
written informed consent may only be obtained from the subject or legally authorized 
representative. 
The investigator will prepare the ICF or revise the template ICF and provide the documents 
to the Sponsor (or designee) for approval before submission to the IRB/IEC/REB. The 
Sponsor and the IRB/IEC/REB must approve the documents before they are implemented. 


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The investigator will provide copies of the signed ICF to each subject (or the subject’s LAR) 
and will maintain the original in the subject’s record file. 
9.4. 
Data Recording and Quality Assurance 
As used in this protocol, a CRF should be understood to refer to be an electronic data record. 
Electronic data capture technology will be used for this study. All clinical information 
requested in this protocol will be recorded on the eCRFs approved by the Sponsor, or via 
other data collection methods, e.g., electronic laboratory data transfer. Study site personnel 
will enter (in English) study data into the CRFs for each randomized subject. Training on the 
EDC application will be completed and documented before access to the EDC system is 
given. 
In the event of a CRF data change (e.g., correction of an error or addition of new 
information), corrections will be made to the CRF. Corrections to the CRFs, including the 
reason for change, will be automatically documented through the EDC system’s audit trail. 
The investigator is responsible for reviewing all CRFs, verifying them for accuracy, and 
approving them via an electronic signature. The investigator is designated as the signatory 
coordinating investigator. 
An electronic copy of the CRF casebooks will be sent to the site for retention with other 
study documents after full completion of the study, i.e., after database lock. 
The investigator is responsible for maintaining accurate, authentic, complete, and up-to-date 
records for each subject. The investigator is also responsible for ensuring the availability of 
any original source documentation related to the study (including any films, tracings, 
computer discs, tapes, and worksheets). In most cases the source is the subject’s medical 
record. Data collected on the CRFs must match the source documents. 
In some cases, the CRF may also serve as the source document. In these cases, a document 
should be available at the investigator’s site and clearly identify those data that will be 
recorded in the CRF and for which the CRF will stand as the source document. 
9.5. 
Document Retention 
Until otherwise notified by the Sponsor, an investigative site must retain in a controlled 
manner all study documents required by the Sponsor and by the applicable regulations. 
The investigative site must take measures to prevent accidental or premature destruction of 
essential documents, that is, documents that individually and collectively permit evaluation 
of the conduct of a study and the quality of the data produced, including paper copies of 
study records (e.g., subject charts) and any original source documents that are electronic, as 
required by applicable regulations. 
The investigator must consult the Sponsor representative before disposal of any study records 
and must notify the Sponsor of any change in the location or disposition of the study files. 
If an investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study documents, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian and must approve this transfer of responsibility. 


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9.6. 
Confidentiality 
The investigator or designee must explain to each subject, before enrollment into the study, 
that, for evaluation of study results, the subject’s confidential medical information obtained 
during the study may be shared with the study Sponsor, the study Sponsor’s affiliated 
companies, the study Sponsor’s designated service providers, regulatory agencies, and the 
IRB or IEC. The investigator (or designee) is responsible for obtaining written permission to 
use confidential medical information in accordance with country-specific regulations (such as 
the Health Insurance Portability and Accountability Act in the United States) from each 
subject. If permission to use confidential medical information is withdrawn, the investigator 
is responsible for documenting that no further data from the subject will be collected. 
Subject medical information obtained during this study is confidential, and disclosure to 
unauthorized third parties is prohibited. The pertinent sections of data protection laws will be 
complied with in full. Study records containing subject information will only be identified by 
the subject identification number, subject initials, date of birth, and study number, and not by 
the subject’s full name, except the subject consent form or documentation of subject assent, 
which is archived at the study center only. The subject’s name will not be used in any public 
report of the study. 
During the course of the study, a confidential subject identification list will be maintained by 
the investigator and archived at the investigative site. 
Before and during the conduct of the study, no study-related details may be disclosed, 
i.e., placed on the internet, published, or otherwise publicized, or provided to a third party 
without prior written permission from the Sponsor. The policy for publication of data after 
completion of the study is described in Section 9.9 (Publication). 
9.7. 
Access to Data and Documents 
Upon receipt of the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare. 
Study data recorded on the CRFs must be verifiable to the source data. All original 
recordings, laboratory reports, and subject records generated by this study must be available 
to the Sponsor, representatives of the Sponsor, the IRB/IEC/REB, and applicable regulatory 
authorities, and they may be used for submission to regulatory authorities. In addition, all 
source data should be attributable (signed and dated), consistent with local medical practice. 
The investigator must therefore agree to allow direct access to all source data. Subjects must 
also allow access to their medical records, and subjects will be informed of this and will 
confirm their agreement when giving informed/proxy consent. 
9.8. 
Quality Control: Study Monitoring and Auditing 
Qualified individuals designated by the Sponsor will monitor all aspects of the study 
according to GCP and SOPs for compliance with applicable government regulations. The 
investigator agrees to allow these monitors direct access to the clinical data and supplies, 
dispensing, and storage areas and, if requested, agrees to assist the monitors. The investigator 
and staff are responsible for being present or available for consultation during routinely 
scheduled site visits conducted by the Sponsor or its designees. 


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Members of the Sponsor’s GCP Quality Assurance Department or designees may conduct an 
audit of a clinical site at any time during or after completion of the study. The investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Inspections and audits are typically carried out during the clinical and reporting phases of this 
study to ensure that the study is conducted and data are generated, documented, and reported 
in compliance with the protocol, GCP, written SOPs and applicable laws, rules, and 
regulations. 
Representatives of the FDA or other Regulatory Agencies, including IRB/IEC 
representatives may also conduct an audit of the study. If informed of such an inspection, the 
investigator should notify the Sponsor immediately. The investigator will ensure that the 
auditors have access to the clinical supplies, study site facilities, laboratory and all data 
(including original source documentation) and all study files are available, if requested. 
Non-compliance with the protocol, ICH, GCP, or local regulatory requirements by an 
investigator, institution, institution staff, or representatives of the Sponsor will lead to prompt 
action by the Sponsor to secure compliance. Continued non-compliance may result in 
termination of the investigator’s involvement in the study. The IRB/IEC/REB and relevant 
regulatory authority will be informed. 
9.9. 
Publication 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and presentation at seminars or 
conferences. The Sponsor will retain the ownership of the data collected in this study. The 
investigator will provide any proposed manuscript or abstract to the Sponsor before 
submission for publication or presentation of any results or data obtained in this study. 
Additional details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Study 
Agreement between the Sponsor and the investigator. 


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10. 
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2. WHO | Disease Outbreak News (DONs) [Internet]. WHO. World Health 
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15. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lancet 2020;395:497-506 
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17. Chen J, Subbarao K. The Immunobiology of SARS. Annu Rev Immunol. 2007 
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18. Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, et al. 
Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses 
Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe. 2016 
Feb;19(2):181–93. 
19. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation 
and Treatment Coronavirus (COVID-19). In: StatPearls [Internet]. Treasure Island 
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20. CDC. Coronavirus Disease 2019 (COVID-19) [Internet]. Centers for Disease Control 
and Prevention. 2020 [cited 2020 Mar 16]. Available from: 
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21. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann 
E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, 
Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, 
Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, 
Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, 
Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; 
ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 - 
Preliminary Report. N Engl J Med. 2020 May 22:NEJMoa2007764. doi: 
10.1056/NEJMoa2007764. Epub ahead of print. PMID: 32445440; PMCID: 
PMC7262788. 
22. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, 
Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, 
Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, 
Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. 
Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl 
J Med. 2020 Jul 17:NEJMoa2021436. doi: 10.1056/NEJMoa2021436. Epub ahead of 
print. PMID: 32678530; PMCID: PMC7383595. 
23. Adaptive COVID-19 Treatment Trial 2 (ACTT-2) ClinicalTrials.gov [Internet]. [cited 
2020 Sept 14]. Available from https://clinicaltrials.gov/ct2/show/NCT04401579 
24. Mehta P, Ciurtin C, Scully M, Levi M, Chambers RC. JAK inhibitors in COVID-19: 
need for vigilance regarding increased inherent thrombotic risk. Eur Respir J. 2020 
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25. Theravance Biopharma Reports Positive Results from Phase 1 Clinical Trial of 
TD-8236, an Investigational, Lung-Selective, Inhaled Pan-Janus Kinase (JAK) 
Inhibitor for Inflammatory Lung Diseases [Internet]. 2019 [cited 2020 Jun 23]. 
Available from: https://investor.theravance.com/news-releases/news-release-
details/theravance-biopharma-reports-positive-results-phase-1-clinical-0 
26. Owen R, Galanter J, Zhu R, Cai F, Tom J, Wynne C, et al. A Phase 1 Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of Inhaled GDC-0214, a 
JAK1 Inhibitor, as Single- and Multiple-Ascending Doses in Healthy Volunteers. In: 
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27. A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the 
Safety, Anti-inflammatory Effect of Inhaled AZD0449 Full Text View - 
ClinicalTrials.gov [Internet]. [cited 2020 Mar 26]. Available from 
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28. Vannucchi AM, Sordi B, Morettini A, Nozzoli C, Poggesi L, Pieralli F, Bartoloni A, 
Atanasio A, Miselli F, Paoli C, Loscocco GG, Fanelli A, Para O, Berni A, Tassinari I, 
Zammarchi L, Maggi L, Mazzoni A, Scotti V, Falchetti G, Malandrino D, Luise F, 
Millotti G, Bencini S, Capone M, Piccinni MP, Annunziato F, Guglielmelli P; 
RUXO-COVID Study Group. Compassionate use of JAK1/2 inhibitor ruxolitinib for 
severe COVID-19: a prospective observational study. Leukemia. 2020 Aug 19:1–13. 
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PMC7437386. 
29. De Luca G, Cavalli G, Campochiaro C, Della-Torre E, Angelillo P, Tomelleri A, 
Boffini N, Tentori S, Mette F, Farina N, Rovere-Querini P, Ruggeri A, D'Aliberti T, 
Scarpellini P, Landoni G, De Cobelli F, Paolini JF, Zangrillo A, Tresoldi M, Trapnell 
BC, Ciceri F, Dagna L. GM-CSF blockade with mavrilimumab in severe COVID-19 
pneumonia and systemic hyperinflammation: a single-centre, prospective cohort 
study. Lancet Rheumatol. 2020 Aug;2(8):e465-e473. doi: 10.1016/S2665-
9913(20)30170-3. Epub 2020 Jun 16. PMID: 32835256; PMCID: PMC7430344. 
30. Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Campbell EJ.  The perception of 
breathlessness in asthma.  Am Rev Respir Dis. 1982 Nov;126(5):825-8 
31. Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D et al.  
Development and validation of a score for the diagnosis of reactive hemophagocytic 
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32. Evaluation of the Efficacy and Safety of Sarilumab in Hospitalized Patients with 
COVID 19.- Full Text - ClinicalTrials.gov [cited 2020 Mar 16]. Available from: 
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33. Fang Y, Zhang H, Xie J, Lin M, Ying L, Pang P, et al. Sensitivity of Chest CT for 
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APPENDIX 1. PROTOCOL SIGNATURE FORM 
 
Protocol Signature Form 
 
Protocol #:  
TD-0903-0188 
Protocol Title:   
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-group, Multi-center Study of an Inhaled Pan-Janus Kinase 
Inhibitor, TD-0903, to Treat Symptomatic Acute Lung Injury 
Associated with COVID-19 
Version: 
 
Version Date: 
18 September 2020 (FINAL) 
 
 
I have read the protocol described above and agree to conduct this study in accordance with 
procedures described therein.  I also agree to conduct the study in compliance with all 
applicable regulations. 
 
 
 
Investigator’s Name (print) 
 
 
 
Investigator’s Signature 
 
Date 
 
 
 

SAP_001.pdf: 
Theravance Biopharma 
 
22DEC2020  
Statistical Analysis Plan – Protocol 0188 (Part 1) 
 
Page 1 of 29 
 
 
Confidential – Property of Theravance Biopharma, Inc. 
STATISTICAL ANALYSIS PLAN 
PHASE 2 
(Part 1) 
Study Title:  
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-group, Multi-center Study of an Inhaled Pan-Janus 
Kinase Inhibitor, TD-0903, to Treat Symptomatic Acute Lung 
Injury Associated with COVID-19 
Short Study Title: 
TD-0903 for ALI Associated with COVID-19 
Sponsor Study Number:   
TD-0903-0188 
Test Product: 
TD-0903 
Sponsor:  
Theravance Biopharma Ireland Limited 
Legal Registered Address: 
Connaught House 
1 Burlington Road 
Dublin 4 
D04 C5Y6 
Ireland 
Regulatory Agency Identifier Number(s) 
EudraCT No.  
2020-001807-18 
US IND: 
149220 
This study will be conducted in compliance with Good Clinical Practice. 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma, Inc. It may not be copied 
or provided to any other party without the express written consent of 
Theravance Biopharma, Inc. 
 
© Theravance Biopharma (Unpublished Work). All rights reserved. 
 


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Theravance Biopharma 
 
22DEC2020  
Statistical Analysis Plan – Protocol 0188 (Part 1) 
 
Page 3 of 29 
 
 
Confidential – Property of Theravance Biopharma, Inc. 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................7 
SAP VERSION HISTORY..............................................................................................................8 
1. 
INTRODUCTION ........................................................................................................9 
1.1. 
Objectives and Endpoints .............................................................................................9 
1.1.1. 
Objective(s) and Endpoint(s) ........................................................................................9 
1.1.2. 
Secondary Objective(s) and Endpoint(s) ....................................................................10 
1.1.3. 
Exploratory Objective(s) and Endpoint(s) ..................................................................10 
1.2. 
Study Design ...............................................................................................................10 
1.3. 
Treatment Assignment ................................................................................................11 
1.4. 
Sample Size Determination ........................................................................................14 
2. 
ANALYSIS SETS ......................................................................................................15 
3. 
STATISTICAL ANALYSES .....................................................................................16 
3.1. 
General Considerations ...............................................................................................16 
3.1.1. 
Visit Windows ............................................................................................................16 
3.2. 
Study Subjects ............................................................................................................17 
3.2.1. 
Enrollment ..................................................................................................................17 
3.2.2. 
Subject Disposition and Completion Status ...............................................................17 
3.2.3. 
Demographic and Baseline Characteristics ................................................................17 
3.2.4. 
Protocol Deviations ....................................................................................................17 
3.2.5. 
Medical History ..........................................................................................................18 
3.2.6. 
Prior/Concomitant Medications ..................................................................................18 
3.3. 
Pharmacodynamic Endpoint Analysis ........................................................................19 
3.4. 
Exploratory Endpoint(s) Analyses ..............................................................................19 
3.4.1. 
Area Under the Curve (AUC) in SaO2/FiO2 Ratio from Day 1 to Day 7 ..................19 
3.4.2. 
Proportion of Subjects with an SaO2/FiO2 ratio >315 on Days 5 and 7 ....................19 
3.4.3. 
Proportion of Subjects Discharged on Days 7, 14, 21 and 28 ....................................19 
3.4.4. 
Time to Hospital Discharge ........................................................................................19 
3.4.5. 
28-day All-cause Mortality Rate ................................................................................19 
3.4.6. 
Change from Baseline in the Modified Borg Dyspnea Score on Day 7 .....................20 


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22DEC2020  
Statistical Analysis Plan – Protocol 0188 (Part 1) 
 
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3.4.7. 
Proportion of subjects in each category of the clinical status scale, as 
measured with an 8-point ordinal scale on Days 7, 14, 21 and 28 .............................20 
3.4.8. 
Proportion of Subjects Alive and Respiratory Failure-free on Day 28 ......................20 
3.4.9. 
Proportion of Subjects with an Oxygen Saturation ≥ 93% on Room Air by 
Study Day up to Day 7 ................................................................................................20 
3.4.10. 
Modified HScores .......................................................................................................20 
3.5. 
Safety Analyses ..........................................................................................................20 
3.5.1. 
Extent of Exposure .....................................................................................................21 
3.5.2. 
Treatment Compliance ................................................................................................21 
3.5.3. 
Adverse Events ...........................................................................................................21 
3.5.3.1. 
Adverse Events of Special Interest .............................................................................22 
3.5.4. 
Additional Safety Assessments...................................................................................22 
3.5.4.1. 
Clinical Laboratory Parameters ..................................................................................22 
3.5.4.2. 
Vital Signs ..................................................................................................................22 
3.6. 
Other Analyses ............................................................................................................23 
3.6.1. 
Other Variables and/or Parameters .............................................................................23 
3.6.2. 
Subgroup Analyses .....................................................................................................23 
3.7. 
Interim Analyses .........................................................................................................23 
3.7.1. 
Data Monitoring Committee .......................................................................................23 
4. 
REFERENCES ...........................................................................................................24 
5. 
SUPPORTING DOCUMENTATION ........................................................................25 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses .................................................25 
5.2. 
Appendix 2: Data Conventions and Transformations ................................................25 
5.2.1. 
Derived and Transformed Data ..................................................................................25 
5.2.1.1. 
Change from Baseline .................................................................................................25 
5.2.1.2. 
BMI .............................................................................................................................25 
5.2.1.3. 
Estimating Glomerular Filtration Rate .......................................................................25 
5.2.1.4. 
Missing/Incomplete AE/Start Date .............................................................................27 
5.2.1.5. 
Missing/Incomplete AE End Date/Time ....................................................................27 
5.2.1.6. 
Missing/Incomplete Start for Medication ...................................................................28 
5.2.1.7. 
Missing/Incomplete End Date/Time for Medication ..................................................28 
5.2.1.8. 
Laboratory Data ..........................................................................................................28 
5.2.1.9. 
AE Severity .................................................................................................................28 


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5.3. 
Calculation Using Trapezoidal Rule ...........................................................................29 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
SAP Version History Summary ....................................................................................8 
Table 3: 
Summary of Endpoints .................................................................................................9 
Table 4: 
Schedule of Study Procedures (Part 1) .......................................................................12 
Table 5:  
Analysis Sets ...............................................................................................................15 
Table 6: 
Criteria for Marked Abnormalities in Vital Signs ......................................................22 
Table 7: 
Criteria for Modified HScore ......................................................................................26 
Table 8: 
Calculation of AUC for SaO2/FiO2 Ratio ..................................................................29 
 


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LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
AUC 
Area under the curve 
BMI 
Body mass index 
COVID-19   
Coronavirus Disease 2019 
CRF 
Case Report Form 
CSR 
Clinical study report 
DLRC 
Dose Level Review Committee 
Intent-to-Treat  
Intent-to-Treat   
HLH 
Hemophagocytic lymphohistocytosis  
HR 
ITT 
LOD 
Lower limit of quantitation/limit of detection 
MedDRA 
Medical Dictionary For Regulatory Activities Terminology 
ND 
Not Detected 
PT 
Preferred Term   
SaO2/FiO2 ratio 
Ratio of peripheral oxygen saturation to the fraction of inspired oxygen 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 


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SAP VERSION HISTORY 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a detailed description of the statistical analyses 
(Part 1) of the efficacy and safety data specified in the protocol of study TD-0903-0188.   
This is a Phase 2 (2-part), randomized, double-blind, placebo-controlled, parallel-group, 
multi-center study of an inhaled pan-Janus kinase inhibitor, TD-0903, to treat symptomatic acute 
lung injury associated with Coronavirus Disease 2019 (COVID-19).  
The SAPs for 
 
will be prepared separately. 
Specifications of tables, figures, and data listings are contained in a separate document.  
1.1. 
Objectives and Endpoints 
1.1.1. 
Objective(s) and Endpoint(s) 
Based on a subject population hospitalized with confirmed COVID-19 and requiring 
supplemental oxygen, the objectives are to: 
• Evaluate the safety and tolerability of inhaled TD-0903 in subjects with COVID-19 
• Assess the plasma PK of TD-0903 in subjects with COVID19 
• Characterize the effect of TD-0903 on reducing the acute lung injury (as measured by 
ratio of peripheral oxygen saturation to the fraction of inspired oxygen [SaO2/FiO2 
ratio]) associated with COVID-19  
Endpoints are described in Table 3.  
Table 3: 
Summary of Endpoints  
Through Day 7  
Through Day 28 or Entire Study Duration  
• Change from baseline in vital signs and clinical 
laboratory results  
• Incidence and severity of treatment -emergent 
adverse events 
• Change from baseline in vital signs and clinical 
laboratory results  
• Incidence and severity of treatment-emergent 
adverse events 
• Change from baseline in SaO2/FiO2 ratio 
• Area under the curve (AUC) in SaO2/FiO2 
ratio from Day 1 to Day 7  
• Proportion of subjects with a SaO2/FiO2 ratio 
> 315 on Days 5 and 7 
• Proportion of subjects with an oxygen 
saturation > 93% on room air by study day up 
to Day 7  
• Change from baseline in the modified Borg 
Dyspnea Score on Day 7 
• Modified HScores on Day 7 
• Proportion of subjects discharged on Days 7, 
14, 21 and 28 
• Time to hospital discharge 
• 28-day all-cause mortality rate  
• Proportion of subjects in each category of the 
clinical status scale, as measured with an 
8-point ordinal scale on Days 7, 14, 21 and 28  
• Proportion of subjects alive and respiratory 
failure-free on Day 28 
Note: SaO2/FiO2, ratio of peripheral oxygen saturation to the fraction of inspired oxygen 


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1.1.2. 
Secondary Objective(s) and Endpoint(s) 
Not applicable.  
1.1.3. 
Exploratory Objective(s) and Endpoint(s) 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
1.2. 
Study Design 
This is a two-part study; this SAP applies only to Part 1. 
Part 1 is a randomized, double-blind, placebo-controlled, multiple ascending dose study in 
hospitalized subjects with confirmed symptomatic COVID-19 who require supplemental oxygen. 
Baseline assessments (Day 1) will include medical and medication history, vital signs (blood 
pressure, heart rate, respiratory rate [BP, HR, RR], and body temperature), a physical 
examination (including height and weight, and hepato- or splenomegaly at a minimum), and 
measures of oxygenation (pulse oximetry, FiO2).  Female subjects of childbearing potential will 
undergo a serum pregnancy test.  Blood samples will be collected from all subjects for 
hematology (complete blood count [CBC] with differential at a minimum), and serum chemistry 
(renal function, liver function tests, and triglycerides at a minimum).  The investigator will also 
evaluate the subject’s clinical status and review inclusion/exclusion criteria.  Subjects who meet 
all inclusion criteria except the viral testing results can be enrolled if, in the opinion of the 
investigator they have clinical evidence of COVID-19. 
Eligible subjects will be randomized and dosed for up to 7 days or until discharge from the 
hospital, whichever is earlier.  
 
 


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study for TD-0903) has completed dosing and the Dose Level Review Committee (DLRC) has 
recommended escalation.  
   
At the end of dosing for all subjects in each cohort, the DLRC will review unblinded data 
through Day 7, and results from the same dose level cohort in Study TD--0903-0183 to inform 
progression to the next dose level and/or to initiate Part 2 of the study.  
Subject follow-up after the dosing period will be via chart review for 21 days (until Day 28).   
Part 1 will assess safety, tolerability, and PK of TD-0903.  Serial blood samples will be collected 
from all subjects for PK assessments.  Oxygenation data will be collected for all subjects, and the 
SaO2/FiO2 ratio will be measured to guide dose selection for Part 2.  
Oxygenation will be assessed via SaO2/FiO2 ratio.  Use of a ventilatory support, presence in the 
ICU, clinical status (including mortality), and date of discharge will be recorded for all subjects 
as appropriate.   
Clinical status will be assessed using an 8-point scale for all subjects daily up to Day 28. 
Subject safety will be assessed throughout the study using standard measures, including adverse 
event (AE) monitoring, physical examinations (including height and weight, and hepato- or 
splenomegaly at a minimum), vital signs (at a minimum, temperature, BP, HR, and respiratory 
rate [RR]), clinical laboratory tests (at a minimum, CBC with differential, renal function 
[creatinine, blood urea nitrogen], and liver function tests [aspartate aminotransferase {AST}, 
alanine aminotransferase {ALT}, alkaline phosphatase {Alk Phos}, and total bilirubin {TBili}]), 
and concomitant medication usage.   
1.3. 
Treatment Assignment  
Study drug comprises the following:  
• Cohort 1: TD-0930 
 loading dose vs placebo on Day 1; 
 vs placebo on 
Days  
• Cohort 2: TD-0903 
 loading dose vs placebo on Day 1; 
 vs placebo on 
Days 2 through 7 
• Cohort 3: TD-0903 
 vs Placebo on Days 1 through 7 (i.e., no loading dose) 
• Schedule of Assessments 
The schedule of assessments is presented in 18T18TTable 4. 
 


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Table 4: 
Schedule of Study Procedures (Part 1) 
Procedure 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 14  
Chart 
Review 
Day 21  
Chart 
Review 
Hospital 
Discharge 
Day 28  
Informed Consenta 
X 
X 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
Medication and Medical 
Historyb 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xd 
Xd 
Xd 
Xd 
Physical Examinatione 
 
X 
 
 
 
 
 
X 
 
 
 
 
Height and Weight 
 
Xf 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
 
X 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetryg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Modified Borg Dyspnea 
Scoreh 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
  
Hematology (CBC with 
Diff)i  
 
X 
Record results of any lab evaluations performed for 
clinical purposes. 
X 
Record results of any lab evaluations performed for 
clinical purposes. 
Serum Chemistryj 
 
X 
X 
Plasma PK samplesk 
 
X 
X 
X 
 
 
 
X 
 
 
 
  
Serum and plasma for 
biomarkers, and 
antibodies, and for 
storage for future 
analysis (if feasible)l 
 
X 
 
 
 
 
 
X 
 
 
 
  
Swab for SARS-CoV-2 
viral PCRm 
 
X 
 
 
 
 
 
X 
 
 
 
 
Clinical Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
  
Study Drug Dosing 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
  
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn  
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn  


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Abbreviations: Alk Phos, alkaline phosphatase, ALT, alanine aminotransferase; AST, aspartate aminotransferase, BP, blood pressure; CBC, complete blood count; COVID-19. 
Coronavirus Disease 2019; FiO2, fraction of inspired oxygen; HR, heart rate; PCR, polymerase chain reaction; PK, pharmacokinetic; RR, respiratory rate; SARS-CoV-2; Severe 
Acute Respiratory Syndrome-associated Coronavirus-2; TBili, total bilirubin 
a Informed consent may be obtained on either Day 0 or Day 1, up to 1 week prior to study enrollment in subjects undergoing testing for COVID-19, but with milder symptoms 
that, in the investigator’s opinion, may worsen. 
b Including known immunosuppression and source of immunosuppression i.e., disease or medication) 
c Includes BP, HR, RR, and body temperature.  Measured before dosing (first daily dose if study drug given twice daily). 
d Morning vital signs 
e Including hepato-or splenomegaly at a minimum 
f If not available from subject's chart 
g Oxygen saturation via pulse oximeter is considered equivalent to arterial oxygen saturation (SaO2) for this study.  Record FiO2 at each assessment. 
h Collected while subject is at rest. 
i At a minimum.  Day 1 samples must be collected within 24 hours before dosing, inclusive of those collected prior to informed consent; Day 7 samples must be collected predose.  
Laboratory testing as per local hospital protocols will be followed. 
j Including renal function, liver function tests (AST, ALT, Alk Phos, TBili), triglycerides, ferritin, and fibrinogen.  Day 1 samples must be collected within 24 hours before dosing, 
inclusive of those collected prior to informed consent; Day 7 samples must be collected predose.  Laboratory testing as per local hospital protocols will be followed.  
k Serial blood samples for plasma PK analyses will be collected pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours (i.e., the following day) after the dose on Day 1 and Day 7. If the 
dose on Day 1 occurs in the evening (after 1 pm / 13:00), Day 1 serial PK will be collected on Day 2 and the 24-hour sample will be collected on Day 3. 
l Blood samples for biomarkers and antibodies (if feasible) will be collected predose on Day 1, and at 3 hours ± 2 hours postdose on Day 7. 
m Swab can be oropharyngeal and/or nasal (anterior nares or nasopharyngeal) consistent with site standard of care. 
n For subjects discharged prior to Day 14, 21, or 28 and known to be alive at discharge, this information will be collected via telephone on these days (± 3 days). Other 
assessments for this day will not be performed for these subjects. 
 


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1.4. 
Sample Size Determination 
 
 


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2. 
ANALYSIS SETS 
The analysis sets are defined below and the treatment assignments that will be used for each type 
of analysis are shown in Table 5. 
Table 5:  
Analysis Sets 
Analysis Set 
Definition 
Treatment 
Assignment 
Safety 
All subjects who receive at least one dose of 
study drug.  This analysis set will be used for all 
safety analyses.       
Treatment received  
Intent-to-Treat 
(ITT)  
All subjects who are randomized into the study.  
This analysis set will be used for 
pharmacodynamic and exploratory analyses.   
Randomized treatment  
 
 


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3. 
STATISTICAL ANALYSES 
3.1. 
General Considerations 
 
 
  
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
3.1.1. 
Visit Windows 
Analyses will be based on nominal CRF visits. 


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3.2. 
Study Subjects 
3.2.1. 
Enrollment 
Number and percentage of subjects enrolled in the study will be summarized by treatment group 
and total for each investigator by frequency distributions, sorted by highest enroller first. The 
ITT analysis set will be used for this summary. 
A listing of subject eligibility (inclusion or exclusion criteria exceptions) will be provided. 
3.2.2. 
Subject Disposition and Completion Status 
Subjects’ study status will be displayed in a table, including the following categories:   
• Randomized  
• Randomized and treated 
• Completed the study 
• Discontinued the study drug 
• Discontinued from the study, including reason. 
Reasons for not completing the study will be presented based on eCRF categories (adverse 
events, lost to follow-up, physician decision, pregnancy, protocol violation, study termination by 
sponsor, withdraw by subject, other).  
For all categories, the percentages will be calculated using the number of randomized patients as 
the denominator. 
A listing of subjects’ disposition and completion status will be provided. The listing of subject 
disposition will include analysis set flags (ITT, Safety (Yes/No)), date the informed consent form 
was signed, dates of first and last dose of study drug, primary reason for discontinuation of study 
treatment, study completion status, and date of last contact. 
3.2.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics (age, sex, race, ethnicity, height, weight, BMI) will be 
summarized in total and by treatment group. Age will be analyzed with descriptive statistics. 
Sex, race and ethnicity will be analyzed using frequency distributions.   
A listing of subjects’ demographic and baseline characteristics will be provided.  
3.2.4. 
Protocol Deviations 
The following protocol deviations are defined as major: 
 
 
 
 
 
 


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A summary of protocol deviations by site and treatment group based on the ITT analysis set will 
be provided. 
In addition, a summary of protocol deviations by treatment group based on the ITT analysis set 
will be provided. 
A subject listing with all protocol deviations identified prior to database lock will be provided. 
In addition, a subject listing with newly identified nonmajor protocol deviations identified during 
site closeout visits following database lock will be provided as applicable. Moreover, a listing of 
all major analysis protocol deviations will be provided. All subject listings will be based on the 
ITT analysis set. 
Subjects with major analysis protocol deviations will be identified before unblinding.     
3.2.5. 
Medical History 
Medical history is defined as conditions with onset dates prior to the first dosing of study 
medication and will be coded using the Medical Dictionary for Regulatory Activities [MedDRA] 
version 23.1 or newer. 
The number and percentage of subjects with medical history in each system organ class (SOC) 
and preferred term (PT) will be summarized by treatment group using the Safety analysis set. 
To the extent possible, medical history on Day 1 will include evaluation for past and present 
conditions, or any other disease disorders, including known immunosuppression and source of 
immunosuppression (i.e., disease or medication).  
A listing of subjects’ clinical characteristics, medical history of comorbidity as well as 
concurrent use of antiviral therapy at baseline using the Safety analysis set will be provided. 
3.2.6. 
Prior/Concomitant Medications 
Prior medications include all medications taken prior to the first dose of investigational product, 
regardless of medication end data. Concomitant medications prescribed and over-the-counter, 
encompass all non-study medicinal products that the subject was taking prior to Day 1 that are 
ongoing at the visit, in addition to all medications that have a start date on or after the first dose 
of investigational product of the treatment period. 
Recorded prior and concomitant medication names will be mapped according to the World 
Health Organization Drug Dictionary (WHODD) for this study with Theravance review and 
approval of the mappings. The 3Q2020 C3 or later version of the WHODD will be used. 
A listing of subjects’ prior and concomitant medications will be provided.   


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3.3. 
Pharmacodynamic Endpoint Analysis 
The PD endpoint is the SaO2/FiO2 ratio, calculated as SaO2 divided by FiO2. The raw values 
and change from baseline in SaO2/FiO2 will be summarized using an 8-point descriptive 
summary on ITT analysis set.    
A listing of subjects’ SaO2/FiO2 measurements will be provided.  
3.4. 
Exploratory Endpoint(s) Analyses 
 
 
 
  
 
 
 
 
 
 
  
 
   
 
   
   
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 


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3.5. 
Safety Analyses 
For all safety analyses, the Safety analysis set will be used.   


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3.5.1. 
Extent of Exposure 
A subject’s data for the extent of exposure (i.e., duration of dosing within each period) to study 
drug will be summarized by treatment using an 8-point descriptive summary. 
Dosing information for individual subjects will be listed. Discontinuation of dosing and reasons 
for discontinuation will be listed and summarized. 
3.5.2. 
Treatment Compliance 
 
 
     
   
3.5.3. 
Adverse Events 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus with Theravance review and approval of the coding. MedDRA, 
version 23.0 or later will be used. 
Summaries will present SOC, PT, and severity, and the frequency and percentage of subjects 
reporting each observed event. Adverse events observed during the period from obtaining 
informed/proxy consent to the start of administration of study drug will be regarded separately 
from AEs observed after study drug administration (i.e., TEAEs). 
A TEAE will be defined as any AE that begins on or after the date (and time) of first dose of 
study drug up to the date/time of last dose of study drug during the study period. Any AEs 
observed during the period from obtaining informed/proxy consent to the start of administration 
of study drug will be regarded separately from TEAEs. 
All AEs and all TEAEs will be listed by subject. The frequency of subjects who experience 
TEAEs will be summarized overall and by treatment group. All AEs will also be summarized by 
relationship to treatment (study drug) and severity. All SAEs will be summarized.   
The following TEAE summaries will be generated: 
• Overall Summary of Adverse Events 
• The overall summary of adverse events will include the following summary lines: 
(any AE, any AE related to Study Drug, moderate or severe AEs, moderate or severe 
AEs related to study drug, SAEs, SAEs related to study drug, AEs leading to 
discontinuation, deaths during study). 
• TEAEs by primary SOC and PT 
• Drug-related TEAEs by SOC and PT 
• TEAEs by SOC, PT, and severity 
• Drug-related TEAEs by SOC, PT, and severity  


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• Moderate or severe TEAEs by SOC and PT 
• Moderate or severe drug related TEAEs by SOC and PT 
• Serious TEAEs by SOC and PT  
• Drug-related serious TEAEs by SOC and PT  
• Adverse events leading to premature study drug discontinuation 
• TEAEs by PT with Overall Frequency > 10% of Overall Population   
Separate analyses will be performed for TEAEs occurring during the 7-day treatment period and 
the 28-day duration of Part 1.   
3.5.3.1. 
Adverse Events of Special Interest   
Not applicable. 
3.5.4. 
Additional Safety Assessments 
3.5.4.1. 
Clinical Laboratory Parameters 
Laboratory data will be summarized in terms of observed values, changes from baseline, values 
relative to normal ranges, and changes from baseline relative to normal ranges (i.e.., shifts from 
normal to abnormal high/low). Listings will flag laboratory values that are outside of normal 
range. 
Clinical laboratory test results will be listed by subject. Reference ranges for each parameter 
provided by the laboratory will be used to evaluate the clinical significance of laboratory test 
results. Values falling outside of the relevant reference range will be flagged, as appropriate, in 
the data listings. Abnormalities in clinical laboratory test results will be provided in a separate 
listing.  
3.5.4.2. 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressures, heart rate, respiratory 
rate, temperature and weight) and changes from baseline values at each visit will be presented by 
treatment group. 
Vital signs data will be summarized in terms of counts and percentages within appropriately 
defined categories (Table 6). 
A listing of subjects’ vital sign (systolic and diastolic blood pressures, heart rate, respiratory rate) 
and change from baseline at each visit will be provided.  Marked abnormalities as defined in 
18T18TTable 618T18T will be flagged in the listing. 
Table 6: 
Criteria for Marked Abnormalities in Vital Signs 
Heart Rate (bpm) 
Systolic Blood Pressure 
(mm Hg) 
Diastolic Blood Pressure 
(mm Hg) 
 
 
 
 
 
 


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3.6. 
Other Analyses 
Not applicable. 
3.6.1. 
Other Variables and/or Parameters 
Not applicable. 
3.6.2. 
Subgroup Analyses 
Not applicable.  
3.7. 
Interim Analyses 
No interim analyses are planned. 
3.7.1. 
Data Monitoring Committee  
  
 
   
 
 
 
 
 


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4. 
REFERENCES 
Not applicable  
 


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5. 
SUPPORTING DOCUMENTATION 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
 
 
 
   
 
 
 
 
 
 
 
 


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STATISTICAL ANALYSIS PLAN 
PHASE 2 
(Part 2) 
Study Title:  
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-group, Multi-center Study of an Inhaled Pan-Janus 
Kinase Inhibitor, TD-0903, to Treat Symptomatic Acute Lung 
Injury Associated with COVID-19 
Short Study Title: 
TD-0903 for ALI Associated with COVID-19 
Sponsor Study Number:   
TD-0903-0188 
Test Product: 
TD-0903 
Sponsor:  
Theravance Biopharma Ireland Limited 
Legal Registered Address: 
Connaught House 
1 Burlington Road 
Dublin 4 
D04 C5Y6 
Ireland 
Regulatory Agency Identifier Number(s) 
EudraCT No.  
2020-001807-18 
US IND: 
149220 
This study will be conducted in compliance with Good Clinical Practice. 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma, Inc. It may not be copied 
or provided to any other party without the express written consent of 
Theravance Biopharma, Inc. 
 
© Theravance Biopharma (Unpublished Work). All rights reserved. 
 


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Theravance Biopharma 
 
06MAY2021 
Statistical Analysis Plan – Protocol 0188 (Part 2) 
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Confidential – Property of Theravance Biopharma, Inc. 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
SAP VERSION HISTORY .............................................................................................................7 
1. 
INTRODUCTION ........................................................................................................8 
1.1. 
Objectives and Endpoints .............................................................................................8 
1.1.1. 
Primary Objective and Endpoint ..................................................................................8 
1.1.2. 
Secondary Objectives and Endpoints ...........................................................................8 
1.1.3. 
Exploratory Objectives and Endpoints .........................................................................9 
1.2. 
Study Design ...............................................................................................................10 
1.3. 
Treatment Assignment ................................................................................................11 
1.4. 
Sample Size Determination ........................................................................................14 
2. 
ANALYSIS SETS ......................................................................................................15 
3. 
STATISTICAL ANALYSES .....................................................................................16 
3.1. 
General Considerations ...............................................................................................16 
3.1.1. 
Visit Windows ............................................................................................................17 
3.2. 
Study Subjects ............................................................................................................18 
3.2.1. 
Enrollment ..................................................................................................................18 
3.2.2. 
Subject Disposition and Completion Status ...............................................................18 
3.2.3. 
Demographic and Baseline Characteristics ................................................................18 
3.2.4. 
Protocol Deviations ....................................................................................................18 
3.2.5. 
Medical History ..........................................................................................................19 
3.2.6. 
Prior/Concomitant Medications ..................................................................................19 
3.3. 
Primary Efficacy Endpoint Analysis ..........................................................................20 
3.3.1. 
Definition of Primary Endpoint ..................................................................................20 
3.3.2. 
Statistical Hypothesis ..................................................................................................20 
3.3.3. 
Main Analytical Method .............................................................................................20 
3.3.4. 
Missing Data Handling ...............................................................................................21 
3.3.5. 
Sensitivity Analyses ....................................................................................................21 
3.3.6. 
Supplementary Analyses ............................................................................................21 
3.4. 
Secondary Endpoint Analyses ....................................................................................22 
3.4.1. 
Change from Baseline in SaO2/FiO2 ratio on Day 7 .................................................22 


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3.4.2. 
Proportion of Subjects in Each category of the 8-point Clinical Status Scale 
on Days 7, 14, 21 and 28 ............................................................................................22 
3.4.3. 
Proportion of Subjects Alive and Respiratory-failure Free on Day 28 ......................22 
3.4.4. 
Missing Data Handling ...............................................................................................22 
3.4.4.1. 
Clinical Status Scale ...................................................................................................23 
3.4.5. 
Sensitivity Analyses ....................................................................................................23 
3.4.5.1. 
Proportion of Subjects in Each category of the 8-point Clinical Status Scale 
on Days 7, 14, 21 and 28 ............................................................................................23 
3.4.6. 
Multiple Comparisons/Multiplicity ............................................................................23 
3.5. 
Exploratory Endpoints ................................................................................................23 
3.5.1. 
Time to Recovery .......................................................................................................23 
3.5.2. 
Duration and Incidence of New Non-Invasive Ventilation or High Flow 
Oxygen Use ................................................................................................................24 
3.5.3. 
Duration and Incidence of New Use of Invasive Ventilator or Extracorporeal 
Membrane Oxygenation (ECMO) ..............................................................................24 
3.5.4. 
Area Under the Curve (AUC) in SaO2/FiO2 Ratio from Day 1 to Day 7 ..................25 
3.5.5. 
Proportion of Subjects with an SaO2/FiO2 ratio > 315 on Days 5 and 7 ...................25 
3.5.6. 
Proportion of Subjects Discharged on Days 7, 14, 21 and 28 ....................................25 
3.5.7. 
Time to Hospital Discharge ........................................................................................26 
3.5.8. 
28-day All-cause Mortality Rate ................................................................................26 
3.5.9. 
Change from Baseline in the Modified Borg Dyspnea Score on Day 7 .....................26 
3.5.10. 
Proportion of Subjects with an Oxygen Saturation ≥ 93% on Room Air by 
Study Day up to Day 7 ................................................................................................27 
3.5.11. 
Modified HScores on Day 7 .......................................................................................27 
3.5.12. 
ICU Free-Days ............................................................................................................27 
3.5.13. 
Supplementary Analyses ............................................................................................27 
3.6. 
Safety Analyses ..........................................................................................................27 
3.6.1. 
Extent of Exposure .....................................................................................................28 
3.6.2. 
Treatment Compliance ................................................................................................28 
3.6.3. 
Adverse Events ...........................................................................................................28 
3.6.3.1. 
Adverse Events of Special Interest .............................................................................29 
3.6.4. 
Additional Safety Assessments ...................................................................................29 
3.6.4.1. 
Clinical Laboratory Parameters ..................................................................................29 
3.6.4.2. 
Vital Signs ..................................................................................................................29 


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3.7. 
Other Analyses ............................................................................................................30 
3.7.1. 
Other Variables and/or Parameters .............................................................................30 
3.7.2. 
Subgroup Analyses .....................................................................................................30 
3.8. 
Interim Analyses .........................................................................................................30 
3.8.1. 
Data Monitoring Committee .......................................................................................30 
4. 
REFERENCES ...........................................................................................................31 
4.1. 
Appendix 1: Changes to Protocol-Planned Analyses .................................................32 
4.2. 
Appendix 2: Data Conventions and Transformations ................................................33 
4.2.1. 
Derived and Transformed Data ..................................................................................33 
4.2.1.1. 
Change from Baseline .................................................................................................33 
4.2.1.2. 
BMI .............................................................................................................................33 
4.2.1.3. 
Estimating Glomerular Filtration Rate .......................................................................33 
4.2.1.4. 
Modified HScore Calculation .....................................................................................33 
4.2.2. 
Missing Date Imputation ............................................................................................35 
4.2.2.1. 
Missing/Incomplete AE/Start Date .............................................................................35 
4.2.2.2. 
Missing/Incomplete AE End Date/Time ....................................................................35 
4.2.2.3. 
Missing/Incomplete Start for Medication ...................................................................35 
4.2.2.4. 
Missing/Incomplete End Date/Time for Medication ..................................................36 
4.2.2.5. 
Laboratory Data ..........................................................................................................36 
4.2.2.6. 
AE Severity .................................................................................................................36 
4.3. 
AUC Calculation Using Trapezoidal Rule .................................................................36 
4.4. 
Supplementary Support for Sample Size Estimation ..................................................38 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................6 
Table 2: 
SAP Version History Summary ....................................................................................7 
Table 3: 
Schedule of Study Procedures (Part 2) .......................................................................12 
Table 4: 
Analysis Sets ...............................................................................................................15 
Table 5: 
Analysis Windows ......................................................................................................17 
Table 6: 
Clinical Status Score ...................................................................................................20 
Table 7: 
Criteria for Marked Abnormalities in Vital Signs ......................................................30 
Table 8: 
Criteria for Modified HScore ......................................................................................34 
Table 9: 
Calculation of AUC for SaO2/FiO2 Ratio ..................................................................37 


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Statistical Analysis Plan – Protocol 0188 (Part 2) 
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LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
AUC 
Area under the curve 
BMI 
Body mass index 
COVID-19   
Coronavirus Disease 2019 
CRF 
Case Report Form 
CSR 
Clinical study report 
DLRC 
Dose Level Review Committee 
Intent-to-Treat  
Intent-to-Treat   
HLH 
Hemophagocytic lymphohistocytosis  
HR 
ITT 
LOD 
Lower limit of quantitation/limit of detection 
MedDRA 
Medical Dictionary For Regulatory Activities Terminology 
ND 
Not Detected 
PT 
Preferred Term   
SaO2/FiO2 ratio Ratio of peripheral oxygen saturation to the fraction of inspired oxygen 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 


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SAP VERSION HISTORY 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a detailed description of the statistical analyses of 
the efficacy and safety data specified in the protocol for Part 2 of study TD-0903-0188.   
This is a Phase 2 (2-part), randomized, double-blind, placebo-controlled, parallel-group, 
multi-center study of an inhaled pan-Janus kinase inhibitor, TD-0903, to treat symptomatic acute 
lung injury associated with Coronavirus Disease 2019 (COVID-19). The Phase 2 study was 
designed with separate data reporting for Parts 1 and 2.  Part 1 was completed, and Part 2 dosing 
was chosen based upon Dose Level Review Committee (DLRC) dose-escalation review of safety 
and tolerability.    
The SAPs for 
 
Specifications of tables, figures, and data listings are contained in a separate document.  
1.1. 
Objectives and Endpoints 
1.1.1. 
Primary Objective and Endpoint 
Based on a subject population hospitalized with confirmed COVID-19 and requiring 
supplemental oxygen, the primary objective is to characterize the efficacy of TD-0903 as 
measured by respiratory failure-free days (RFDs) through Day 28. 
The primary endpoint is the number of RFDs from randomization through Day 28.   
1.1.2. 
Secondary Objectives and Endpoints  
The secondary objectives are to evaluate the effect of TD-0903 on: 
• Reducing the acute lung injury (as measured by the ratio of peripheral oxygen 
saturation to the fraction of inspired oxygen [SaO2/FiO2 ratio]) associated with 
COVID-19  
• Safety and tolerability 
• Clinical outcomes as measured by an 8-point clinical status scale   
• The proportion of subjects alive and respiratory failure-free on Day 28 
Secondary Endpoints are:  
• Change from baseline in SaO2/FiO2 ratio on Day 7 
• Proportion of subjects in each category of the 8-point clinical status scale on Days 7, 
14, 21 and 28 
• Proportion of subjects alive and respiratory-failure free on Day 28 
 


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1.1.3. 
Exploratory Objectives and Endpoints  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  


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1.2. 
Study Design 
This is a two-part study; this SAP applies only to Part 2. 
Part 2 is a randomized, double-blind, parallel-group study evaluating efficacy and safety of 3 mg 
of TD-0903 (selected based on the data from Part 1) as compared with placebo in hospitalized 
subjects with confirmed symptomatic COVID-19 who require supplemental oxygen.  
 
 
 
 
 
 
 
 
Sparse sampling for assessment of TD-0903 plasma concentrations may be collected for 
population PK analysis. 
Subjects will provide informed consent upon study entry.  Baseline assessments (Day 1) will 
include medical and medication history, vital signs (blood pressure, heart rate, respiratory rate 
[BP, HR, RR], and body temperature), a physical examination (including height and weight, and 
hepato- or splenomegaly at a minimum), and measures of oxygenation (pulse oximetry, FiO2).  
Female subjects of childbearing potential will undergo a serum pregnancy test.  Blood samples 
will be collected from all subjects for hematology (complete blood count [CBC] with differential 
at a minimum), and serum chemistry (renal function [creatinine, blood urea nitrogen], liver 
function tests [aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (Alk Phos), and total bilirubin (TBili), and triglycerides, ferritin and fibrinogen.  
The investigator will also evaluate the subject’s clinical status and review inclusion/exclusion 
criteria.   
Oxygenation will be assessed via SaO2/FiO2 ratio.  Use of ventilatory and oxygen support, 
presence in the Intensive Care Unit (ICU), clinical status (including mortality), and date of 
discharge will be recorded for all subjects as appropriate.   
Clinical status will be assessed for all subjects using the 8-point scale. 
Changes in swab SARS-CoV-2 viral infection status, SARS-CoV-2 antibody levels, blood 
cytokine levels, and biomarkers of inflammation, thrombosis, and lung injury will be explored. 
Subject safety will be assessed throughout the study using standard measures, including adverse 
event (AE) monitoring, physical examinations (including hepato- or splenomegaly at a 
minimum), vital signs (at a minimum, temperature, BP, HR, and respiratory rate [RR]), clinical 
laboratory tests (at a minimum, CBC with differential, renal function, and liver function tests), 
and concomitant medication usage.  A Safety Assessment Committee (SAC) will meet regularly 
to review blinded safety data. 


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1.3. 
Treatment Assignment  
  
 
 
  
  


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Table 3: 
Schedule of Study Procedures (Part 2) 
Procedure 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 
5 
Day 
6 
Day 
7 
Days 
8-13 
Day 
14 
Days 
15-20 
Day 
21 
Days 
22-27 
Hospital 
Discharge 
Day 
28 
Informed Consenta 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication and 
Medical Historyb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
 
Xd 
 
Xd 
 
Xd 
Xd 
Physical Examinatione 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Height and Weight 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetryg 
 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
X 
 
X 
X 
Modified Borg 
Dyspnea Scoreh 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Hematology (CBC 
with Diff)i 
 
X 
Record results of any lab evaluations 
performed for clinical purposes. 
X 
Record results of any lab evaluations performed for clinical 
purposes only on Day 14, 21, 28 (while hospitalized) and at 
discharge. 
Serum Chemistryj 
 
X 
X 
Plasma PK samplesk 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Serum and plasma for 
biomarkers and 
antibodies, and for 
storage for future 
analysis (if feasible)l 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
Swab for SARS-CoV-2 
viral PCRm 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
Clinical Status 
 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
Xn 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
Xn 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
Xn 


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Abbreviations: Alk Phos, alkaline phosphatase, ALT, alanine aminotransferase; AST, aspartate aminotransferase, BP, blood pressure; CBC, complete blood 
count; COVID-19. Coronavirus Disease 2019; FiO2, fraction of inspired oxygen; HR, heart rate; PCR, polymerase chain reaction; RR, respiratory rate; 
SARS-CoV-2; Severe Acute Respiratory Syndrome-associated Coronavirus-2 TBili, total bilirubin 
a Informed consent may be obtained on either Day 0 or Day 1 up to 1 week prior to study enrollment in subjects undergoing testing for COVID-19, but with 
milder symptoms that, in the investigator’s opinion, may worsen. 
b Including known immunosuppression and source of immunosuppression i.e., disease or medication) 
c Includes BP, HR, RR, and body temperature. Measured before dosing (first daily dose if study drug given twice daily). 
d Morning vital signs 
e Including hepato-or splenomegaly at a minimum 
f If not available from subject's chart 
g Oxygen saturation via pulse oximeter is considered equivalent to arterial oxygen saturation (SaO2) for this study.  Record FiO2 at each assessment. 
h Collected while subject is at rest. 
i At a minimum.  Day 1 samples must be collected within 24 hours before dosing, inclusive of those collected prior to informed consent; Day 7 samples must be 
collected predose.  Laboratory testing as per local hospital protocols will be followed.  
j Including renal function, liver function tests (AST, ALT, Alk Phos, TBili), triglycerides, ferritin, and fibrinogen.  Day 1 samples on must be collected within 
24 hours before dosing, inclusive of those collected prior to informed consent; Day 7 samples must be collected predose.  Laboratory testing as per local 
hospital protocols will be followed. 
k Blood samples for plasma PK analyses will be collected predose and within 30 to 120 minutes postdose on Day 7.  Additional sample on Day 5 can be taken at 
any time postdose. 
l Blood samples for biomarkers and antibodies (if feasible) will be collected predose on Day 1, and at 3 hours ± 2 hours postdose on Day 5 and Day 7, and at 
hospital discharge. 
m Swab can be oropharyngeal and/or nasal (anterior nares or nasopharyngeal) consistent with site standard of care. 
n For subjects discharged prior to Day 28 inclusive and known to be alive at discharge, this information will be collected via telephone as follows: 
• 
Days 14, 21, and 28 (±3 days) for subjects discharged on Days 8 through 13 
• 
Days 21 and 28 (±3 days) for subjects discharged on Days 15 through 20 
• 
Day 28 (±3 days) for subjects discharged on Days 22 through 27 
The other assessments for these days will not be performed for these subjects. 
 


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1.4. 
Sample Size Determination 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
   
 
 
 
 


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2. 
ANALYSIS SETS 
The analysis sets are defined below and the treatment assignments that will be used for each type 
of analysis are shown in Table 4. 
Table 4: 
Analysis Sets 
Analysis Set 
Definition 
Treatment 
Assignment 
Safety 
All subjects who received at least one dose of 
study drug.  This analysis set will be used for 
all safety analyses.  
Treatment received  
Intent-to-Treat 
(ITT)  
All subjects who are randomized into the study.  
This analysis set will be used for all efficacy 
analyses.   
Randomized treatment  
Per-Protocol 
(PP; membership 
to be determined 
before unblinding) 
Intent-to-Treat subjects with no protocol 
deviations during the study that would affect 
the primary efficacy analyses.  
This analysis set will be used for primary and 
key secondary efficacy analyses.  
Treatment received 
 


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3. 
STATISTICAL ANALYSES 
3.1. 
General Considerations 
 
 
 
 
     
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.1.1. 
Visit Windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.2. 
Study Subjects 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
3.2.4. 
Protocol Deviations 
The following protocol deviations are defined as major for primary analysis: 
 
 
 
 
 
 


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A summary of protocol deviations by site and overall by treatment group based on the ITT 
analysis set will be provided. 
A subject listing with all protocol deviations identified prior to database lock will be provided. 
In addition, a subject listing with newly identified nonmajor protocol deviations identified during 
site closeout visits following database lock will be provided as applicable. Moreover, a listing of 
all major analysis protocol deviations will be provided. All subject listings will be based on the 
ITT analysis set. 
Subjects with major analysis protocol deviations will be identified before unblinding. 
3.2.5. 
Medical History 
Medical history is defined as conditions with onset dates prior to the first dose of study 
medication and will be coded using the Medical Dictionary for Regulatory Activities [MedDRA] 
version 23.1 or newer. 
The number and percentage of subjects with medical history in each system organ class (SOC) 
and for each preferred term (PT) will be summarized by treatment group using the Safety 
analysis set. 
To the extent possible, medical history on Day 1 will include evaluation for past and present 
conditions, or any other disease disorders, including known immunosuppression and source of 
immunosuppression (i.e., disease or medication). 
A listing of subjects’ clinical characteristics, medical history of comorbidity, as well as 
concurrent use of antiviral therapy at baseline using the Safety analysis set will be provided. 
3.2.6. 
Prior/Concomitant Medications 
Prior medications include all medications taken prior to the first dose of study medication, 
regardless of medication end date. Concomitant medications prescribed and over the counter, 
encompass all non-study medicinal products that the subject was taking prior to Day 1 that are 
ongoing at the visit, in addition to all medications that have a start date on or after the first dose 
of investigational product of the treatment period. 
Recorded prior and concomitant medication names will be mapped according to the World 
Health Organization Drug Dictionary (WHODD) with Theravance review and approval of the 
mappings. The 3Q2020 C3 or later version of the WHODD will be used. 
A listing of subjects’ prior and concomitant medications will be provided.   


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3.3. 
Primary Efficacy Endpoint Analysis   
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
   
 
 
   
 


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3.4. 
Secondary Endpoint Analyses 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
  
 
 


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3.5. 
Exploratory Endpoints  
 
 
 
 
 
 
 


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3.6. 
Safety Analyses 
For all safety analyses, the Safety analysis set will be used.   


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3.6.1. 
Extent of Exposure 
A subject’s data for the extent of exposure (i.e., duration of dosing) to study drug will be 
summarized for each treatment group using an 8-point descriptive summary.  
Dosing information for individual subjects will be listed. Discontinuation of dosing and reasons 
for discontinuation will be listed and summarized. 
3.6.2. 
Treatment Compliance 
 
 
   
3.6.3. 
Adverse Events 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus with Theravance clinical review and approval of the coding. 
MedDRA version 23.0 or later will be used. 
A treatment-emergent adverse event (TEAE) is defined as any AE that begins on or after the date 
(and time) of first dose of study drug up to the date/time of last dose of study drug during the 
study period. Any AEs observed during the period between obtaining informed/proxy consent 
and the start of study drug administration will be regarded separately from TEAEs. 
All AEs and all TEAEs will be listed by subject.  
Summaries will present SOC, PT, and severity, and the frequency and percentage of subjects 
within each treatment group reporting each observed event.  The frequency of subjects who 
experience TEAEs will be summarized overall and by treatment group. All AEs will also be 
summarized for each treatment group by relationship to treatment (study drug) and severity. All 
SAEs will be summarized for each treatment group.   
The following TEAE summaries will be generated: 
• Overall Summary of Adverse Events 
The overall summary of adverse events will include the following summary lines: 
(any AE, any AE related to Study Drug, moderate or severe AEs, moderate or severe 
AEs related to study drug, SAEs, SAEs related to study drug, AEs leading to 
discontinuation, deaths during study). 
• TEAEs by primary SOC and PT 
• Drug-related TEAEs by SOC and PT 
• TEAEs by SOC, PT, and severity 
• Drug-related TEAEs by SOC, PT, and severity  
• Moderate or severe TEAEs by SOC and PT 


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• Moderate or severe drug related TEAEs by SOC and PT 
• Serious TEAEs by SOC and PT 
• Drug-related serious TEAEs by SOC and PT 
• Adverse events leading to premature study drug discontinuation 
• TEAEs by PT with Overall Frequency > 10% of Overall Population   
Separate analyses will be performed for TEAEs occurring during the 7-day treatment period and 
the 28-day duration.   
Of note, SAEs include serious and life-threatening conditions such as: pulmonary embolism, 
dysrhythmia, secondary infections, stroke, hemodynamic instability requiring vasopressor 
support, acute renal failure, acute liver failure as well as other acute events, including those that 
have been associated with underlying disease.   
3.6.3.1. 
Adverse Events of Special Interest 
Not applicable. 
3.6.4. 
Additional Safety Assessments 
3.6.4.1. 
Clinical Laboratory Parameters 
Laboratory data will be summarized in terms of observed values, changes from baseline, values 
relative to normal ranges, and changes from baseline relative to normal ranges (i.e., shifts from 
normal to abnormal high/low). Listings will flag laboratory values that are outside of the normal 
range. 
Clinical laboratory test results will be listed by subject. Reference ranges for each parameter 
provided by the laboratory will be used to evaluate the clinical significance of laboratory test 
results. Values falling outside of the relevant reference range will be flagged in the data listings. 
Abnormalities in clinical laboratory test results will be provided in a separate listing.  
3.6.4.2. 
Vital Signs 
Vital signs (systolic and diastolic blood pressures, heart rate, respiratory rate, temperature and 
weight) and changes from baseline values at each visit will be summarized for each treatment 
group using descriptive statistics. 
Vital signs data will also be summarized in terms of counts and percentages within appropriately 
defined categories (Table 7). 
A listing of subjects’ vital sign measurements (systolic and diastolic blood pressures, heart rate, 
respiratory rate) and change from baseline at each visit will be provided.  Marked abnormalities 
as defined in Table 7 will be flagged in the listing. 


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Table 7: 
Criteria for Marked Abnormalities in Vital Signs 
 
 
 
 
 
 
 
 
 
 
 
 
3.7. 
Other Analyses 
Not applicable. 
3.7.1. 
Other Variables and/or Parameters 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
3.8. 
Interim Analyses 
No interim analyses are planned. 
3.8.1. 
Data Monitoring Committee  
  
 
   
 
 
 
 
 


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4. 
REFERENCES 
1. Evaluation of the Efficacy and Safety of Sarilumab in Hospitalized Patients with COVID 
19. - Full Text - ClinicalTrials.gov [cited 2020 Mar 16]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT04315298?cond=covid+19&draw=2&rank=6 
2. Fang Y, Zhang H, Xie J, Lin M, Ying L, Pang P, et al. Sensitivity of Chest CT for 
COVID-19: Comparison to RT-PCR. Radiology. 2020 Feb 19;200432. 
3. Adapted from Vannucchi AM et al (2020). Compassionate use of JAK1/2 inhibitor 
ruxolitinib for severe COVID-19: a prospective observational study. Leukemia. 2020 
Aug 19:1–13. doi: 10.1038/s41375-020-01018-y. Epub ahead of print. PMID: 32814839; 
PMCID: PMC7437386. 
4. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing 
risk. J Am Stat Assoc. 1999;94:496–509. doi: 10.1080/01621459.1999.10474144. 
SOFTWARE 
5. PASS Version 14 (NCSS, LLC, Kaysville, Utah) was used for planned sample size and 
power calculation. 
6. SAS Version 9.4 (SAS Institute Inc., Cary, NC.) or newer is to be used for all 
programming of tables, listings, and figures. 
 


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4.4. 
Supplementary Support for Sample Size Estimation