Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD Peak Inspiratory Flow Rate PIFR Pulmonary Function
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 404
Healthy volunteers: no

Brief summary:
Study is a randomized, double-blind, double-dummy, parallel-group study evaluating efficacy and safety of revefenacin vs. tiotropium in adults with severe to very severe COPD and suboptimal PIFR.

Detailed description:

Arms:
arm 1: Revefenacin administered with Tiotropium Placebo arm 2: Tiotropium administered with Revefenacin Placebo

Interventions: intervention 1: Revefenacin intervention 2: Tiotropium intervention 3: Revefenacin Placebo intervention 4: Tiotropium Placebo
Intervention descriptions: intervention 1: Revefenacin 175 mcg administered once daily for 84 days via nebulization intervention 2: Tiotropium 18 mcg administered once daily for 84 days via Spiriva HandiHaler® intervention 3: Placebo for Revefenacin administered once daily for 84 days via nebulization intervention 4: Placebo for Tiotropium administered once daily for 84 days via Spiriva HandiHaler®

Protocol document:
Prot_000.pdf: 
Protocol Number: 0180 
Official Title: A Phase 4, Randomized, Double-Blind, Double-Dummy, Parallel-Group, Study Comparing Improvements in Lung Function 
in Adults With Severe to Very Severe Chronic Obstructive Pulmonary Disease and Suboptimal Inspiratory Flow Rate Following Once-
Daily Treatment Over 12 Weeks With Either Revefenacin Inhalation Solution Delivered Via Standard Jet Nebulizer or Tiotropium 
Delivered Via a Dry Powder Inhaler (Spiriva® HandiHaler®) 
NCT Number: NCT05165485 
Document Date: 27 February 2023 


Page 1 of 81 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 4, Randomized, Double-Blind, Double-Dummy, Parallel˗Group 
Study Comparing Improvements in Lung Function in Adults With 
Severe to Very Severe Chronic Obstructive Pulmonary Disease and 
Suboptimal Inspiratory Flow Rate Following Once-Daily Treatment 
Over 12 Weeks With Either Revefenacin Inhalation Solution Delivered 
via Standard Jet Nebulizer or Tiotropium Delivered via a Dry Powder 
Inhaler (Spiriva® HandiHaler®)  
Study Short Title: 
PIFR-2 Study 
Sponsor Study No.: 
0180 
Date: 
27 Feb 2023, Amendment 4 (FINAL) 
Supersedes: 09 Feb 2022, Amendment 3 
Test Product: 
Revefenacin 
US IND: 
119840 
Sponsor: 
Theravance Biopharma Ireland Limited 
Ten Earlsfort Terrace 
Dublin 2 
D02 T380 
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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Confidential – Property of Theravance Biopharma, Inc. 
PROTOCOL SYNOPSIS 
Study Number and Title: Study 0180: A Phase 4, Randomized, Double-Blind, Double-Dummy, Parallel-
Group Study Comparing Improvements in Lung Function in Adults With Severe to Very Severe Chronic 
Obstructive Pulmonary Disease and Suboptimal Inspiratory Flow Rate Following Once-Daily Treatment 
Over 12 Weeks With Either Revefenacin Inhalation Solution Delivered via Standard Jet Nebulizer or 
Tiotropium Delivered via a Dry Powder Inhaler (Spiriva® HandiHaler®) 
Study Short Title: PIFR-2 Study 
Estimated Number of Study Centers and Countries or Regions: Approximately 70 centers in the 
United States (US) 
Background and Rationale: Revefenacin is an orally inhaled muscarinic antagonist which is approved 
by the US Food and Drug Administration (FDA) for the maintenance treatment of chronic obstructive 
pulmonary disease (COPD). 
Long-acting bronchodilators can be delivered via a metered-dose inhaler (MDI), dry powder inhaler 
(DPI) or nebulizer. Successful use of a nebulizer requires the patient to breathe normally (tidal 
breathing) to successfully deliver the medicine, whereas use of MDIs and DPIs requires more complex 
coordination of actuation of the device and / or an appropriate inhalation technique (slow inhalation 
in case of MDI; forced inhalation in the case of DPI) to successfully deliver the medicine. Therefore, 
nebulized administration may have several advantages over DPI or MDI administration in some 
patients. In patients who are not able to properly engage the DPI or MDI delivery mechanism 
(Hand-Breath Coordination), patients with cognitive impairment that makes use of an MDI/DPI 
challenging, and patients with muscle weakness or manual dexterity issues, nebulized therapy may 
yield a more consistent dose due to fewer user errors and a more consistent delivery of the therapy. It 
may also be significantly easier for a care partner to administer medications via a nebulizer. 
Furthermore, several studies have suggested that adults with COPD who have more severe disease 
and limited inspiratory flow rates may receive more benefit from nebulized therapy than from therapy 
with the same mechanism of action delivered as a powder for inhalation. In a study by Mahler et al, a 
nebulized long-acting beta-2-agonist (LABA; arformoterol, BROVANA®) was more effective in 
improving forced vital capacity (FVC) than an analogous LABA delivered via a DPI (salmeterol, 
SEREVENT DISKUS®) in participants with a Peak Inspiratory Flow Rate (PIFR) of less than 60 L/min 
using an In-Check™ device set to the resistance of the DISKUS® device (approximately 23 kPa/L/min).1 
More recently, Mahler et al demonstrated in a randomized, double-blind, double-dummy study of 
revefenacin inhalation solution via a nebulizer and tiotropium powder for inhalation (Spiriva® 
HandiHaler®), that in participants with moderate to very severe COPD and suboptimal PIFR, as defined 
above, there was a trend toward greater improvement in forced expiratory volume over one second 
(FEV1) with revefenacin inhalation solution than with tiotropium powder for inhalation over 4 weeks 
of treatment.2 In the subgroup of participants with severe to very severe COPD (FEV1 < 50% of normal 
at baseline), there was a clinically important improvement of 75 mL with revefenacin compared to an 
improvement of 28 mL with tiotropium (nominal p = 0.0302), and a responder analysis of the previous 
study suggested that participants would be twice as likely to achieve an improvement from baseline of 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
100 mL with revefenacin compared with tiotropium. In a post hoc analysis, the largest differences 
were seen in those participants with a PIFR <55 L/min. The clinical significance of this magnitude of 
change is further supported by the recent FDA approval of BEVESPI® based on differences of 56 mL 
and 54 mL for the combination product over the monotherapy components. Similarly, in the ANORO® 
program, an improvement of 52 mL for the combination of umeclidinium and vilanterol was observed 
over umeclidinium. 
It is important to explore the most effective treatments for severe to very severe COPD patients with 
suboptimal PIFR, as in the more recent study participants with lower PIFR appeared to be more 
symptomatic at baseline, suggesting either that disease is worse than predicted by expiratory flow 
limitation alone, or that there may be a lack of efficacy using nonnebulized therapy at baseline, or 
both. Furthermore in another study, Loh et al showed that participants with a suboptimal PIFR (i.e., 
<60 L/min using In-Check™ at DISKUS resistance) at hospital discharge from an acute exacerbation of 
COPD had fewer days to hospital readmission and a trend toward more readmissions than those who 
had an optimal PIFR. Such participants discharged and prescribed nebulizer maintenance therapy also 
had fewer hospital readmissions compared to participants discharged on DPI/MDI maintenance 
therapy.3 
The purpose of this study is to use lung function to compare the efficacy of once-daily administration 
of nebulized revefenacin inhalation solution (YUPELRI®) with once-daily administration of tiotropium 
inhalation powder (Spiriva® HandiHaler®) over 12 weeks in adults with low PIFR measured by the In-
Check™ device, defined as < 55 L/min when the device is set to DISKUS® resistance and severe to very 
severe expiratory airflow limitation (i.e., FEV1 < 50% of normal).  
Objectives: 
The primary objectives of the study are as follows: 
• To characterize the relative efficacy on change from baseline in trough FEV1 on 
Day 85 of revefenacin inhalation solution administered once daily via nebulization 
(YUPELRI®) compared to tiotropium powder for inhalation administered once 
daily (Spiriva® HandiHaler®) in adults with severe to very severe COPD who 
have impaired expiratory flow (i.e., FEV1 < 50% of predicted normal) and 
suboptimal PIFR (i.e., PIFR < 55 L/min via In-Check™ device set to DISKUS 
resistance) following 84 days of dosing. 
• To evaluate the safety and tolerability of revefenacin inhalation solution 
administered in adults with severe to very severe COPD, impaired expiratory flow, 
and suboptimal PIFR 
The secondary objective(s) of the study are as follows: 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization 
compared to tiotropium administered once daily via HandiHaler® on average FEV1 
across Days 30, 60, and 85 


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Confidential – Property of Theravance Biopharma, Inc. 
•
To evaluate the relative efficacy of once-daily revefenacin via nebulization
compared to tiotropium administered once daily via HandiHaler® on trough FVC
on Day 85
•
To evaluate the relative efficacy of once-daily revefenacin via nebulization
compared to tiotropium administered once daily via HandiHaler® on trough FEV1
on Day 30
•
To evaluate the relative efficacy of once-daily revefenacin via nebulization
compared to tiotropium administered once daily via HandiHaler® on trough FEV1
on Day 60
•
To evaluate the relative efficacy of once-daily revefenacin via nebulization to
tiotropium administered once daily via HandiHaler® in achieving improvements in
lung function of ≥ 80 mL, as measured by trough FEV1 on Day 85
•
To evaluate time to first CompEx (composite endpoint for moderate or severe
exacerbations of COPD) event
The exploratory objective(s) of the study are as follows: 
Study Design: This is a randomized, double-blind, double-dummy, parallel-group study evaluating 
efficacy and safety of revefenacin vs. tiotropium in adults with severe to very severe COPD and 
suboptimal PIFR. Participants will visit the clinic for up to 2 screening visits and eligible participants 
will visit the clinic for a randomization visit, up to 2 intermediate on-treatment visits, and a final or 
early termination visit. Unscheduled visits may also be required. 
During screening, participants are required to “wash out” from certain medications, or to take 
a different dose. Such medications include, but are not limited to, long-acting muscarinic 
antagonists (LAMA), LABA, LAMA/LABA, LABA/inhaled corticosteroids (ICS), and 
LAMA/LABA/ICS (see complete list in Table 2). Participants will be assessed for suboptimal 
PIFR using the In-Check™ device set to DISKUS resistance in addition to other inclusion and 


Page 6 of 81 
Confidential – Property of Theravance Biopharma, Inc. 
exclusion criteria, undergo ipratropium reversibility testing, receive rescue medication, receive 
an electronic diary (eDiary) device, have their adverse events and other concomitant 
medications reviewed. Participants will also undergo physical examinations (including vital 
signs, height, and weight measurements). Participants will also undergo clinical laboratory 
testing if results from the previous 3 months are unavailable. Women of childbearing potential 
will have a urine pregnancy test. Participants who are required to wash out from medications 
will have these procedures conducted over 2 screening visits 5 to 9 days apart; participants not 
required to wash out will have these procedures conducted in a single visit. 
At the randomization visit on Day 1 (3 to 7 days after screening), eligible participants with 
PIFR < 55 L/min, post ipratropium 30% < FEV1 < 50% of predicted normal (using National 
Health and Nutrition Examination Survey-predicted equations) and absolute FEV1 > 500 mL, 
or FEV1 <30% predicted normal and absolute FEV1 > 700 mL, and who meet all other 
inclusion criteria will be randomized to revefenacin (revefenacin 175 mcg/tiotropium placebo) 
or tiotropium (tiotropium 18 mcg/revefenacin placebo) in a 1:1 ratio. Enrollment of 
participants with Global Initiative for Chronic Obstructive Lung Disease airflow category 4 
(GOLD 4; FEV1 <30% of predicted normal) will be capped at 30% to reflect what is expected 
in the population with severe to very severe COPD. Participants will be trained on the use of 
the DPI device and nebulizer prior to receiving their first dose of study medication. 
Participants will undergo baseline lung function tests, clinical outcomes assessments, and have 
their diaries, concomitant medications, and adverse events reviewed. 
 
 
Participants will return to the clinic on Days 30 and 60 ± 7 days each (Visits 3 and 4 
respectively). Diaries will be reviewed to assess compliance with regard to their completion. 
Study drug and rescue medication will be accounted for and new supplies will be dispensed. 
Adverse events and concomitant medications will be reviewed, and women of childbearing 
potential will undergo urine pregnancy testing. Clinical outcomes will be measured, and lung 
function will be assessed. 
 
 Participants will administer their study 
medication in the presence of study center personnel not involved in the measurement of 
efficacy parameters. 
Participants will self-administer study medication once daily in the morning for 84 days, 
except on Days 30 and 60, when participants will return to the study center for assessments 
prior to taking their study medication. 
Participants will return to the clinic on Day 85 ± 7 days (Visit 5) for final assessments. Study drug and 
rescue medication will be accounted for; diaries, concomitant medications, and adverse events will be 
reviewed. Participants will undergo a physical examination including vital signs. Clinical outcomes will 
be measured and lung function will be assessed. 
 
 Women of childbearing potential will undergo urine 
pregnancy testing. Participants who discontinue from the study prior to this visit will undergo the 
same procedures at an early termination visit. 
At 7 ± 2 days after the last visit, participants will be contacted by telephone for an assessment of their 
adverse events. 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
Revefenacin (or matching placebo) will be administered as a 3-mL inhalation solution using the PARI 
LC Sprint® jet nebulizer and using a mouthpiece. Tiotropium (or matching placebo) will be 
administered as a dry powder using the HandiHaler® device. Participants will take study drug via DPI 
first, and then via nebulizer. 
A supply of rescue medication (albuterol MDI) for use in the study and a supply of study medication 
will be provided for each participant at each visit, except at Visit 1B for participants requiring 2 
screening visits, and at Visit 5 or at early termination. 
The primary efficacy assessment is FEV1 as measured by spirometry. 
Secondary efficacy assessments are FVC, also measured by spirometry, and use of rescue medication 
as measured by daily participant diaries. 
Safety assessments, including collection of AEs, measurement of vital signs (heart rate and blood 
pressure), urine pregnancy testing for women of childbearing potential, and review of concomitant 
medications, will be performed at every visit. 
 
 
 
 
Duration of Study Participation: Up to 120 days including up to 10 days for washout (if necessary) and 
spirometry review prior to randomization, 84 days of dosing, a final visit after the last dose, and a 
follow-up telephone contact approximately 7 days after the last dose. The duration of study 
participation could vary based on time windows associated with each visit. 
Number of Participants per Group: Approximately 183 participants with FEV1 < 50% of normal and 
PIFR < 55 L/min will be randomized to each treatment group (366 participants total) to ensure 146 
participants per treatment group (292 participants total) are evaluable for the primary analysis at the 
end of study. 
 
 
 the 
sample size may be increased to a maximum of 488 
 
 
 
Study Population: 
Participants with diagnosed COPD, a post ipratropium 30% < FEV1 < 50% of predicted normal (using 
National Health and Nutrition Examination Survey-predicted equations) and absolute FEV1 > 500 mL, 
or FEV1 <30% predicted normal and absolute FEV1 > 700 mL, and a PIFR <55 L/min assessed using In-
Check™ device set to DISKUS resistance will be eligible for enrollment.  


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Confidential – Property of Theravance Biopharma, Inc. 
Inclusion Criteria: 
Unless otherwise noted, all participants must meet the following criteria: 
1. Participant is a male or female 40 years of age or older.
2. Participant is female and is nonpregnant and nonlactating. A woman of childbearing
potential must have a documented negative urine pregnancy test at screening.
Women are considered not to be of childbearing potential if they have had a total
hysterectomy and/or bilateral tubal ligation (documentation for either must be provided
before enrollment) or are at least 2 years postmenopausal.
3. During the study and for 30 days after receiving the last dose of study drug, women of
childbearing potential and men capable of fathering children must agree to use highly
effective birth control measures or agree to abstain from sexual intercourse.
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 as condom +
diaphragm, condom + spermicide, diaphragm + spermicide, or intrauterine device
[IUD] with documented failure rate of <1% per year, or oral/injectable/implanted
hormonal contraceptives used in combination with an additional barrier method.
4. Participant has a diagnosis of COPD, specifically, a post-ipratropium FEV1/FVC ratio
<0.7.
5. Participant has a post ipratropium 30% < FEV1 < 50% of predicted normal (using
National Health and Nutrition Examination Survey-predicted equations) and absolute
FEV1 > 500 mL, or FEV1 <30% predicted normal and absolute FEV1 > 700 mL.
6. Participant has a PIFR <60 L/min as measured by an In-Check™ device with resistance
set to DISKUS at Visit 1A (if not combined with Visit 1B) and < 55 L/min as
measured by an In-Check™ device with resistance set to DISKUS at Visit 1B and
Visit 2 prior to randomization.
7. Participant is capable of performing reproducible spirometry maneuvers 
 as described by current
American Thoracic Society (ATS) Guidelines.
8. Participant is an active or former smoker with a cigarette smoking history (or
equivalent for cigar or pipe smoking history) of at least 10 pack-years.
9. Participant or legal guardian is willing and able to provide signed and dated informed
consent to participate prior to initiation of any study related procedures.
10. Participant is willing and able to adhere to all study assessments/procedures. Care
partner assistance is acceptable.
11. Participant is willing and able to adhere to all restrictions during their study
participation as follows:
•
Use of recreational drugs


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
• Medicinal marijuana 
• Excessive alcohol during the study period 
• Participation in another investigational drug study 
• Donation of ≥500 mL blood (or equivalent) 
12. Participant (or care partner) based on the investigator’s assessment is able to properly 
prepare and administer study medication administered from both nebulizer and 
HandiHaler® according to their respective Instructions for Use. 
Exclusion Criteria: 
1. Participant has a concurrent disease or condition that, in the opinion of the investigator, 
would interfere with study participation or confound the evaluation of safety and 
tolerability of the study drug. 
2. Participant has a history of reactions or hypersensitivity to inhaled or nebulized 
anticholinergics. 
3. Participant suffers from any medical condition that would preclude the use of inhaled 
anticholinergics, including narrow-angle glaucoma, symptomatic benign prostatic 
hyperplasia, bladder neck obstruction, or urinary retention. 
4. Participant has Moderate to Severe Hepatic impairment (Child-Pugh B or C) or Severe 
Renal Insufficiency (i.e. a glomerular filtration rate <30 mL/min/1.72m2). 
5. Participant has been hospitalized for COPD or pneumonia within 8 weeks prior to 
Visit 1. 
6. Participant is receiving a LABA or LABA/inhaled corticosteroid (ICS; either QD or 
BID) at a dose that has been stable for ≤ 30 days prior to screening. 
7. Participant has used systemic corticosteroids within 8 weeks of Visit 1. 
8. Participant has used antibiotics for respiratory tract infections within 8 weeks of 
Visit 1, or is using antibiotics prophylactically. 
9. Participant received COVID-19 vaccine within 2 weeks prior to Visit 1. 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment: Revefenacin 
solution (175 mcg in 3 mL) for inhalation by jet nebulizer, administered by oral inhalation once every 
morning for up to 84 days. Revefenacin matching placebo will be administered to the participants in 
the tiotropium treatment group. 
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of Treatment: Tiotropium 
dry powder capsule (Spiriva®, 18 mcg) administered by oral inhalation once every morning using the 
HandiHaler® device for up to 84 days. Tiotropium matching placebo will be administered to the 
participants in the revefenacin treatment group. 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
Study Evaluations 
Primary and Secondary Efficacy Assessments: 
• Lung function tests (FEV1, FVC) will be measured by spirometer at the study center. 
Clinical Outcomes Assessments: 
• Efficacy 
− Daily use of rescue medication (i.e., albuterol MDI) 
− Daily nocturnal awakenings as recorded in participant diaries 
− PEF measured by participant using portable meter 
− Evaluating Respiratory Symptoms in COPD (E-RS:COPD) assessment for 
daily breathlessness, cough/sputum, and chest symptoms 
• Exploratory 
− 
 
 
 
 
 
 
 
Safety Assessments: 
Safety will be assessed via the reporting of adverse events (AEs) including exacerbations of 
COPD, physical examination findings, vital sign measurements, urine pregnancy tests 
(for women of childbearing potential), and concomitant medications.  
Statistical Methods 
Efficacy endpoints will be evaluated by comparing revefenacin to tiotropium. For each of the primary 
and secondary efficacy endpoints, the null hypothesis for the treatment comparison will be that there 
is no difference between the responses of revefenacin and tiotropium. The alternative hypothesis will 
be that there is a difference. 
Sample Size: 
 
 
 
 
 
 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
 
 
 
 
 
 
 
 The total number of subjects will be capped up to a maximum sample size of 
488 subjects.
 
 
Study Endpoints: 
The primary study endpoint is change from baseline in trough FEV1 on Day 85 following 84 days of 
dosing. 
The secondary endpoints are as follows: 
• Trough overall treatment effect (OTE) on FEV1 over 85 days 
• Change from baseline in Trough FVC on Day 85 
• Change from baseline in Trough FEV1 on Day 30 
• Change from baseline in Trough FEV1 on Day 60 
• 80-mL response, defined as at least an 80-mL improvement in trough FEV1 on Day 85 
• Time to first CompEx (composite endpoint for exacerbations of COPD) event 
A CompEx event is defined as the first occurrence of a moderate or severe 
exacerbation, or clinically relevant deteriorations based on objective measures of 
deterioration in peak expiratory flow (PEF), rescue medication use, COPD symptoms, 
and nocturnal awakening.5,6 
A moderate exacerbation is defined as an increase in symptoms that requires treatment 
with antibiotics and/or oral corticosteroids and a severe exacerbation is defined as a 
deterioration of COPD symptoms that results in hospitalization for emergency 
treatment of the COPD and the duration of the visit is ≥1 day, as recorded via CRF. 
Clinically relevant deteriorations will be defined in the statistical analysis plan (SAP). 
Exploratory endpoints are: 
 
 
 
 
 
 
 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The safety endpoints are the incidence of AEs (including exacerbations of COPD), and vital signs (heart 
rate and blood pressure). 
Analysis: 
Analysis Sets 
The full analysis set (FAS) is the primary analysis set for general and efficacy analyses and will include 
all randomized participants who: 
• Receive at least one dose of study drug (revefenacin or tiotropium) 
Participants will be analyzed according to their randomized treatment group. 
The safety analysis set is the primary analysis set for safety analyses and will include all participants 
who are randomized and receive at least one dose of study drug. Participants will be analyzed 
according to their treatment actually received. 
Analysis of Primary Efficacy Endpoint 
For the primary endpoint, a repeated measures mixed effects model (RMMM) will be used to estimate 
treatment differences. The model will include fixed class terms for randomized treatment groups, 
ipratropium reversibility (reversible/not reversible), smoking status (current/former smoker), 
concomitant LABA or ICS/LABA use (Yes/No), GOLD (3/4), sex (woman/man), age (<65/≥65), and 
continuous covariates for baseline PIFR set to DISKUS® resistance and baseline FEV1, as well as a time 
effect (visit) and its interaction terms with treatment and the baseline values of the covariates. 
Within-subject correlation will be modelled using an unstructured variance-covariance matrix. The 
Kenward and Roger method for approximating the denominator degrees of freedom will be used. 
Least-squares (LS) means and 95% confidence intervals (CIs) for LS mean differences between 
revefenacin and tiotropium will be calculated and presented in tabular and graphical format. Nominal 
p-values and CIs will be reported. 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
If the 2-sided 95% CI for the Day 85 FEV1 revefenacin vs. tiotropium treatment policy estimand 
difference lies above zero, the primary endpoint will be considered to have been met and a tipping 
point analysis systematically varying assumptions about unobserved responses. 
Analysis of Secondary
 Efficacy Endpoints 
The following endpoints can all be estimated from the same model outlined for the primary analysis: 
• Change from baseline in Trough FEV1 on Day 30 
• Change from baseline in Trough FEV1 on Day 60 
• Trough overall treatment effect (OTE) on FEV1 over 85 days 
Change from baseline in trough FVC on Day 85 will be analyzed using similar methodology as the 
primary endpoint. 
A responder analysis based on Day 85 trough FEV1 will be conducted using a logistic regression model 
with a similar set of covariates as the primary efficacy endpoint. A summary of responders will be 
presented with frequency distributions (counts and percentages), observed LS percentages, and 
revefenacin:tiotropium odds ratios. 
Cox proportional hazards model will be used to derive hazard ratios and analyze time to first event for 
CompEx COPD. 
A statistical hierarchy will be used to test the hypotheses of the primary and secondary endpoints to 
control the study-wise type 1 error rate at 5%. 
All efficacy endpoints will also be reported with nominal p-values, unless specified otherwise. 
Missing values for the primary and secondary spirometry efficacy endpoints will not be imputed 
except for the responder analysis and any additional sensitivity analyses specified in the SAP. 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
Analysis of Safety Data 
All safety data will be presented in listings. Descriptive summary tables will be provided for extent of 
exposure, treatment-emergent AEs, vital signs, and concomitant medications. Changes from baseline 
in heart rate and blood pressure measurements will be summarized. 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
SCHEDULE OF STUDY PROCEDURES 
Table 1: 
Schedule of Study Procedures 
Procedures 
Visit 
1A 
Visit 1B 
(5 ± 2 to  
7 ± 2 days 
after Visit 
1Aa) 
Day 1 
(Visit 2) 
Randomization 
(3 to 7 days after 
screening completed) 
Day 30 
(Visit 3)  
± 7 days 
Day 60 
(Visit 4)  
± 7 days 
Day 85 
(Visit 5) 
± 7 days 
Follow-Up 
Phone call 
7 days after 
last visit 
± 2 days 
Early 
Termination / 
Withdrawal 
Unscheduled 
Visit 
Informed Consentb 
X 
 
 
 
 
 
 
 
 
Medical and Medication History 
X 
 
 
 
 
 
 
 
X 
Washout of COPD Medicationsa 
X 
 
 
 
 
 
 
 
 
Physical Examination 
 
Xc 
 
 
 
X 
 
X 
X 
Height and Weight 
 
Xc 
 
 
 
 
 
 
 
Vital Signs 
 
Xc 
X 
 
 
X 
 
X 
X 
Inclusion / Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
Xd 
X 
X 
X 
 
X 
 
Ipratropium Reversibilitye 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
Xf 
 
 
 
 
 
 
Dispense eDiary 
 
X 
 
 
 
 
 
 
 
Review eDiary 
 
 
X 
X 
X 
X 
 
X 
 
Dispense Study Drug 
 
 
X 
X 
X 
 
 
 
 
Dispense Rescue Medication 
X 
 
X 
X 
X 
 
 
 
 
Study Drug/Rescue Medication 
Accountability 
 
 
X 
X 
X 
X 
 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local Lab Tests for creatinine. 
hematocrit, ALT, AST, bili, alk 
phosg 
X 
 
 
 
 
 
 
 
 
BDI 
 
 
X 
 
 
 
 
 
 
TDI 
 
 
 
X 
X 
X 
 
X 
 
PIFR 
X 
Xh 
X 
 
 
 
 
 
 
MIP 
 
 
X  
 
 
 
 
 
 
CAT 
 
 
X 
X 
X 
X 
 
X 
 
Predose Spirometry (FEV1, 
FVC) at 45 and 15 min predose 
 
Xi 
X 
X 
X 
Xj 
 
Xj 
Xj 
PEFk 
 
X 
X 
X 
X 
X 
 
X 
X 
E-RS: COPDl 
 
X 
X 
X 
X 
 
 
 
 
Nocturnal Awakenings Question 
 
X 
X 
X 
X 
X 
 
X 
X 
Plethysmography (IC, FRC, 
TLC) at 45 and 15 min predosem 
 
 
X 
 
 
Xj 
 
 
 


 
 
 
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Confidential – Property of Theravance Biopharma, Inc. 
Procedures 
Visit 
1A 
Visit 1B 
(5 ± 2 to  
7 ± 2 days 
after Visit 
1Aa) 
Day 1 
(Visit 2) 
Randomization 
(3 to 7 days after 
screening completed) 
Day 30 
(Visit 3)  
± 7 days 
Day 60 
(Visit 4)  
± 7 days 
Day 85 
(Visit 5) 
± 7 days 
Follow-Up 
Phone call 
7 days after 
last visit 
± 2 days 
Early 
Termination / 
Withdrawal 
Unscheduled 
Visit 
LABA Dosing (if applicable) 
 
 
X 
X 
X 
X 
 
 
 
Study Drug Dosingn 
 
 
X 
X 
X 
 
 
 
 
Train on HandiHaler®, 
Nebulizer  
 
 
X 
 
 
 
 
 
 
Dispense PEF Meter/Train 
Participants on Use 
 
X 
 
 
 
 
 
 
 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Alk phos, alkaline phosphatase; BDI, Baseline Dyspnea Index; bili, bilirubin; COPD, chronic 
obstructive pulmonary disease; CAT, Chronic Obstructive Pulmonary Disease Assessment Test; eDiary, electronic diary; E-RS: COPD, Evaluating Respiratory Symptoms in 
COPD assessment; FEV1, forced expiratory volume; FRC, functional residual capacity; FVC, forced vital capacity; IC, inspiratory capacity; INR; International Normalized Ratio; 
LABA, long-acting beta-2 agonist; MIP, maximal inspiratory pressure; PEF, peak expiratory flow; PIFR, peak inspiratory flow rate; TDI, Transitional Dyspnea Index; TLC, total 
lung capacity 
a For participants who require washout of certain COPD medications as specified in Table 2. For participants not requiring washout, Visit 1B can be combined with Visit 1A if 
participant does not require washout of COPD medications. 
b The research site will follow institutional and government guidelines/precautions regarding Coronavirus Disease 2019 (COVID-19) to reduce the risk of infection for study 
participants and study staff. 
c Performed/collected prior to ipratropium dosing. Vital signs (heart rate and blood pressure) will be measured after resting in a semi-recumbent position for approximately 
5 minutes. 
d Performed if visit is more than 7 days after Visit 1A. 
e Consult study manual 
f Participant eligibility must be confirmed by investigator before randomizing the participant. 
g If data from any time during the previous 3 months are not available. Collection of INR and albumin to determine Child-Pugh score for exclusion is at the discretion of the 
investigator. 
h Participants who required a washout of a LAMA must have PIFR < 55 L/min at this visit. 
i Reversibility testing pre- and postdose ipratropium after withholding bronchodilators as specified in Table 2. Spirometry will be performed predose and 45 minutes postdose 
(± 10 minutes) at this visit (whether or not it is combined with Visit 1A). 
j There is no dosing at this visit. Spirometry and plethysmography will be performed at 2 time points 30 minutes apart. 
k Performed after predose spirometry at the study center during all study visits beginning with Visit 1B. Participants will receive the portable meter and be trained on its use at 
Visit 1B for subsequent use at home between visits. 
l Before bedtime on the evening prior to the visit 
m 
Measured in participants enrolled at selected centers capable of performing these assessments. Assessments will be done immediately after PIFR assessment. 
n Between 6:00 am and 11:00 am local time 


 
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................. 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................. 22 
1. 
INTRODUCTION ....................................................................................... 24 
1.1. 
Background and Rationale .......................................................................... 24 
1.2. 
Nonclinical Profile ...................................................................................... 25 
1.2.1. 
Pharmacology .............................................................................................. 25 
1.2.2. 
Toxicology .................................................................................................. 25 
1.3. 
Clinical Experience ..................................................................................... 26 
1.4. 
Risks and Benefits ....................................................................................... 28 
2. 
OBJECTIVES ............................................................................................. 29 
3. 
STUDY DESIGN ........................................................................................ 31 
3.1. 
Overview ..................................................................................................... 31 
3.2. 
Rationale for Study Design ......................................................................... 34 
3.3. 
Selection of Doses and Duration of Treatment ........................................... 34 
3.4. 
Study Endpoints .......................................................................................... 35 
3.5. 
Minimization of Bias ................................................................................... 36 
3.5.1. 
Blinding ....................................................................................................... 36 
3.5.2. 
Treatment Assignment ................................................................................ 36 
4. 
STUDY POPULATION ............................................................................. 37 
4.1. 
Inclusion Criteria ......................................................................................... 37 
4.2. 
Exclusion Criteria ........................................................................................ 38 
5. 
STUDY DRUGS ......................................................................................... 39 
5.1. 
Description of Study Drugs ......................................................................... 39 
5.1.1. 
Revefenacin ................................................................................................. 39 
5.1.2. 
Tiotropium ................................................................................................... 39 
5.2. 
Dosage and Administration ......................................................................... 39 
5.2.1. 
Revefenacin ................................................................................................. 39 
5.2.2. 
Tiotropium ................................................................................................... 40 
5.3. 
Treatment Compliance ................................................................................ 40 
5.4. 
Drug Accountability and Reconciliation ..................................................... 41 
6. 
STUDY PROCEDURES ............................................................................ 42 


 
 
 
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6.1. 
Schedule of Study Procedures ..................................................................... 42 
6.2. 
In-Clinic Procedures by Visit ...................................................................... 42 
6.2.1. 
Screening ..................................................................................................... 42 
6.2.1.1. 
Visit 1A ....................................................................................................... 43 
6.2.1.2. 
Visit 1B ....................................................................................................... 44 
6.2.2. 
Treatment and Follow-up Period ................................................................ 45 
6.2.2.1. 
Day 1 (Visit 2) Randomization ................................................................... 45 
6.2.2.2. 
Day 30 (Visit 3) ........................................................................................... 46 
6.2.2.3. 
Day 60 (Visit 4) ........................................................................................... 47 
6.2.2.4. 
Day 85 (Visit 5) ........................................................................................... 48 
6.2.2.5. 
Follow-up Phone Call ................................................................................. 49 
6.2.3. 
Early Termination/Withdrawal Visit ........................................................... 49 
6.2.4. 
At-Home Procedures ................................................................................... 50 
6.2.5. 
Unscheduled Visits ...................................................................................... 50 
6.3. 
Description of Study Assessments .............................................................. 51 
6.3.1. 
Demographic and Baseline Assessments .................................................... 51 
6.3.2. 
Pulmonary Function Assessments ............................................................... 51 
6.3.2.1. 
Spirometry ................................................................................................... 51 
6.3.2.2. 
Peak Inspiratory Flow Rate ......................................................................... 51 
6.3.2.3. 
Maximal Inspiratory Pressure ..................................................................... 52 
6.3.2.4. 
Peak Expiratory Flow .................................................................................. 52 
6.3.3. 
Safety Assessments ..................................................................................... 52 
6.3.3.1. 
Adverse Events ............................................................................................ 52 
6.3.3.2. 
Physical Examination .................................................................................. 52 
6.3.3.3. 
Vital Signs ................................................................................................... 52 
6.3.3.4. 
Pregnancy .................................................................................................... 53 
6.3.4. 
Clinical Outcome Assessments ................................................................... 53 
6.3.4.1. 
Baseline/Transitional Dyspnea Index ......................................................... 53 
6.3.4.2. 
Chronic Obstructive Pulmonary Disease Assessment Test ........................ 53 
6.3.4.3. 
Evaluation of Respiratory Symptoms in Chronic Obstructive Pulmonary 
Disease ........................................................................................................ 53 
6.3.4.4. 
Nocturnal Awakenings ................................................................................ 54 
6.3.4.5. 
Rescue Albuterol Use .................................................................................. 54 


 
 
 
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6.3.5. 
 
6.4. 
Concomitant Medications ........................................................................... 54 
6.5. 
Restrictions .................................................................................................. 59 
6.6. 
Discontinuation ........................................................................................... 59 
6.6.1. 
Participant Discontinuation ......................................................................... 59 
6.6.2. 
Participant Replacement .............................................................................. 60 
6.6.3. 
Study Discontinuation ................................................................................. 60 
6.7. 
Pregnancy .................................................................................................... 60 
6.8. 
Exacerbation of Chronic Obstructive Pulmonary Disease .......................... 60 
7. 
ADVERSE EVENTS .................................................................................. 62 
7.1. 
Definitions ................................................................................................... 62 
7.1.1. 
Adverse Events (AEs) ................................................................................. 62 
7.1.2. 
Serious Adverse Event (SAE) ..................................................................... 63 
7.1.3. 
Additional Considerations for Serious Adverse Events .............................. 63 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ................................................ 64 
7.3. 
Assessment of Adverse Events ................................................................... 64 
7.3.1. 
Severity ....................................................................................................... 64 
7.3.2. 
Causal Relationship to Study Medication ................................................... 64 
7.4. 
AE Reporting and Recording ...................................................................... 65 
7.4.1. 
AE Reporting .............................................................................................. 65 
7.4.2. 
AE and SAE Recording .............................................................................. 65 
7.4.3. 
SAE Reporting Timeline ............................................................................. 66 
7.5. 
Adverse Event Follow-up ........................................................................... 67 
8. 
STATISTICAL CONSIDERATIONS ........................................................ 68 
8.1. 
General Considerations ............................................................................... 68 
8.2. 
Sample Size and Power ............................................................................... 68 
8.2.1. 
 ............................................................ 68 
8.3. 
Analysis Sets ............................................................................................... 68 
8.3.1. 
Examination of Subgroups .......................................................................... 69 
8.3.2. 
Major Protocol Deviations .......................................................................... 69 
8.4. 
General Analyses ........................................................................................ 69 
8.4.1. 
Demographics and Other Baseline Characteristics ..................................... 69 


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8.4.2. 
Screening and Baseline Spirometry ............................................................ 69 
8.4.3. 
COPD Clinical History and Smoking History ............................................ 69 
8.4.4. 
Medical History ........................................................................................... 70 
8.4.5. 
Reversibility ................................................................................................ 70 
8.5. 
Analysis of Efficacy .................................................................................... 70 
8.5.1. 
Efficacy Endpoints ...................................................................................... 70 
8.5.1.1. 
Primary Efficacy Evaluation ....................................................................... 71 
8.5.2. 
Secondary
 Efficacy Evaluations ....................................... 71 
8.5.3. 
Multiplicity Adjustment .............................................................................. 72 
8.6. 
Safety Analyses ........................................................................................... 72 
8.6.1. 
Extent of Exposure ...................................................................................... 72 
8.6.2. 
Adverse Event Data ..................................................................................... 73 
8.6.3. 
Concomitant Medications ........................................................................... 73 
8.6.4. 
Vital Signs Data .......................................................................................... 73 
8.7. 
Missing Data Handling ............................................................................... 73 
8.8. 
Data Monitoring Committee ....................................................................... 74 
9. 
STUDY ADMINISTRATION .................................................................... 75 
9.1. 
Principal Investigator Responsibilities ........................................................ 75 
9.2. 
Institutional Review Board/Independent Ethics Committee ....................... 76 
9.3. 
Informed Consent ........................................................................................ 76 
9.4. 
Data Recording and Quality Assurance ...................................................... 76 
9.5. 
Document Retention .................................................................................... 77 
9.6. 
Confidentiality ............................................................................................. 77 
9.7. 
Access to Data and Documents ................................................................... 78 
9.8. 
Quality Control: Study Monitoring and Auditing ....................................... 78 
9.9. 
Publication ................................................................................................... 79 
10. 
REFERENCES ............................................................................................ 80 
APPENDIX 1. PROTOCOL SIGNATURE FORM ................................................... 81 


 
 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ..................................................................... 15 
Table 2: 
List of Medications Requiring Washout (or Modification) Prior to Visit 1B 
and Prohibited During the Study ................................................................. 56 
Table 3: 
Severity Criteria for COPD Exacerbations ................................................. 61 
Table 4: 
Clinically Important Thresholds for Vital Signs ......................................... 73 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema ................................................................................. 33 
 


 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
Alk phos 
alkaline phosphatase 
BID 
twice daily 
BDI 
Baseline Dyspnea Index  
Bili 
bilirubin 
BP 
blood pressure 
CAT 
Chronic Obstructive Pulmonary Disease Assessment Test 
CFR 
(United States) Code of Federal Regulations 
CI 
confidence interval 
CompEx 
Composite endpoint for severe exacerbations of chronic obstructive 
pulmonary disease 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
Coronavirus Disease 2019 
(e)CRF 
(electronic) case report form 
DPI 
dry powder inhaler 
eDiary 
electronic diary 
EDC 
electronic data capture 
E-RS:COPD 
Evaluating Respiratory Symptoms in COPD (assessment) 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FRC 
forced residual capacity 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HR 
heart rate 


 
 
 
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Abbreviation 
Description 
IB 
Investigator’s Brochure 
IC 
inspiratory capacity 
ICF 
informed consent form 
ICH 
International Conference on Harmonization (of Technical Requirements 
for Registration of Pharmaceuticals for Human Use) 
ICS 
inhaled corticosteroid 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LABA 
long-acting beta-2 agonist 
LAMA 
Long-acting muscarinic antagonist 
MAR 
missing at random 
MDI 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
MIP 
Maximal inspiratory pressure 
OTE 
Overall treatment effect 
PEF 
peak expiratory flow 
PIFR 
peak inspiratory flow rate 
PI 
principal investigator 
PRN 
as needed 
QD 
once daily 
REB 
Research Ethics Board 
RMMM 
repeated measures mixed effects model 
RTSM 
Randomization and Trial Supply Management 
SAE 
serious adverse event 
SOP 
standard operating procedure 
TDI 
Transitional Dyspnea Index 
TLC 
total lung capacity 
US 
United States 


 
 
 
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1. 
INTRODUCTION 
1.1. 
Background and Rationale 
Revefenacin is an orally inhaled muscarinic antagonist which is approved by the US Food and 
Drug Administration (FDA) for the maintenance treatment of chronic obstructive pulmonary 
disease (COPD). 
Long-acting bronchodilators can be delivered via a metered-dose inhaler (MDI), dry powder 
inhaler (DPI) or nebulizer. Successful use of a nebulizer requires the patient to breathe normally 
(tidal breathing) to successfully deliver the medicine, whereas use of MDIs and DPIs requires 
more complex coordination of actuation of the device and / or an appropriate inhalation 
technique (slow inhalation in case of MDI; forced inhalation in the case of DPI) to successfully 
deliver the medicine. Therefore, nebulized administration may have several advantages over 
DPI or MDI administration in some patients. In patients who are not able to properly engage the 
DPI or MDI delivery mechanism (Hand-Breath Coordination), patients with cognitive 
impairment that makes use of an MDI/DPI challenging, and patients with muscle weakness or 
manual dexterity issues, nebulized therapy may yield a more consistent dose due to fewer user 
errors and a more consistent delivery of the therapy. It may also be significantly easier for a care 
partner to administer medications via a nebulizer. 
Furthermore, several studies have suggested that adults with COPD who have more severe 
disease and limited inspiratory flow rates may receive more benefit from nebulized therapy than 
from therapy with the same mechanism of action delivered as a powder for inhalation. In a 
study by Mahler et al, a nebulized long acting beta-2-agonist (LABA; arformoterol, 
BROVANA) was more effective in improving forced vital capacity (FVC) than an analogous 
LABA delivered via a DPI (salmeterol, SEREVENT DISKUS®) in participants with a Peak 
Inspiratory Flow Rate (PIFR) of less than 60 L/min using an In-Check™ device set to the 
resistance of the DISKUS® device (approximately 23 kPa/L/min).1 
More recently, Mahler et al demonstrated in a randomized, double-blind, double-dummy study 
of revefenacin inhalation solution via a nebulizer and tiotropium powder for inhalation 
(Spiriva® HandiHaler®), that in participants with moderate to very severe COPD and 
suboptimal PIFR, as defined above, there was a trend toward greater improvement in forced 
expiratory volume over one second (FEV1) with revefenacin inhalation solution than with 
tiotropium powder for inhalation over 4 weeks of treatment.2 In the subgroup of participants 
with severe to very severe COPD (FEV1 < 50% of normal at baseline), there was a clinically 
important improvement of 75 mL with revefenacin compared to an improvement of 28 mL with 
tiotropium (nominal p = 0.0302), and a responder analysis of the previous study suggested that 
participants would be twice as likely to achieve an improvement from baseline of 100 mL with 
revefenacin compared with tiotropium. In a post hoc analysis, the largest differences were seen 
in those participants with a PIFR <55 L/min. The clinical significance of this magnitude of 
change is further supported by the recent FDA approval of BEVESPI® based on differences of 
56 mL and 54 mL for the combination product over the monotherapy components. Similarly, in 
the ANORO® program, an improvement of 52 mL for the combination of umeclidinium and 
vilanterol was observed over umeclidinium. 


 
 
 
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It is important to explore the most effective treatments for severe to very severe COPD patients 
with suboptimal PIFR, as in the more recent study participants with lower PIFR appeared to be 
more symptomatic at baseline, suggesting either that disease is worse than predicted by 
expiratory flow limitation alone, or that there may be a lack of efficacy using nonnebulized 
therapy at baseline, or both. Furthermore in another study, Loh et al showed that participants 
with a suboptimal PIFR (i.e., <60 L/min using In-Check™ device at DISKUS resistance) at 
hospital discharge from an acute exacerbation of COPD had fewer days to hospital readmission 
and a trend toward more readmissions than those who had an optimal PIFR. Such participants 
discharged and prescribed nebulizer maintenance therapy also had fewer hospital readmissions 
compared to participants discharged on DPI/MDI maintenance therapy.3 
The purpose of this study is to use lung function to compare the efficacy of once-daily 
administration of nebulized revefenacin inhalation solution (YUPELRI®) with once-daily 
administration of tiotropium inhalation powder (Spiriva® HandiHaler®) over 12 weeks in 
adults with low PIFR measured by the In-Check™ device, defined as < 55 L/min when the 
device is set to DISKUS® resistance and severe expiratory airflow limitation (i.e., FEV1 < 50% 
of predicted normal). 
1.2. 
Nonclinical Profile 
A review of the nonclinical profile of revefenacin can be found in the current version of the 
revefenacin Investigator’s Brochure (IB). The following is a brief summary of the pertinent 
findings. 
1.2.1. 
Pharmacology 
Revefenacin is a potent and selective antagonist of human M1 through M5 muscarinic receptors, 
with kinetic selectivity for the M3 vs. M2 subtype. When administered by inhalation to 
conscious guinea pigs, revefenacin was an antagonist of acetylcholine-induced 
bronchoconstriction and demonstrated a duration of action comparable to that of tiotropium 
(>24 hours) at a potency equivalent- dose. In the rat, inhaled revefenacin was superior to 
tiotropium with respect to lung selectivity, which was determined by examination of the ratio of 
pilocarpine-induced antisialagogue activity and the 24-hour bronchoprotective activity of 
revefenacin. Revefenacin also demonstrated a 24-hour duration of activity in a dog model of 
methacholine-induced bronchoconstriction. Overall, the pharmacology of revefenacin, when 
administered into the lungs, is consistent with that of a long-acting muscarinic antagonist and 
demonstrates good selectivity for lung versus systemic effects. 
Safety pharmacology studies for revefenacin included assessments of potential effects on 
cardiovascular and respiratory function and for potential neurobehavioral effects. These studies 
are summarized in the IB. 
1.2.2. 
Toxicology 
The toxicology assessment of revefenacin included single-dose toxicity, repeated-dose toxicity, 
genotoxicity, reproductive and developmental toxicity, and local tolerance studies. The results 
of these studies are summarized in the IB. 


 
 
 
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1.3. 
Clinical Experience 
Revefenacin was evaluated in a single-dose first-in-human clinical study using a DPI 
formulation in 21 healthy adults. Study AC5108696 investigated the safety, tolerability, 
pharmacodynamic effect, and pharmacokinetics of single doses of revefenacin of up to 500 mcg 
DPI. Subsequently, revefenacin inhalation solution delivered using a standard jet nebulizer was 
evaluated in 3 single-dose studies in a total of 80 healthy adults (Studies 0134, 0135, and 0136), 
and in 9 repeat-dose studies in a total of 3125 adults with COPD (Studies 0059, 0091, 0116, 
0117, 0126, 0127, 0128, 0149 and 0167). An additional 9 healthy adults received a single dose 
of either an IV formulation or an oral solution formulation of [14C]-labeled revefenacin 
(Study 0130). To date, revefenacin has been evaluated in 14 clinical studies, all of which are 
described in the IB, and has been an effective bronchodilator in participants with moderate to 
very severe COPD, with a duration of action consistent with its FDA approval as a once-daily 
agent. 
Revefenacin demonstrated a consistent and favorable safety and tolerability profile during its 
development. Of the 14 completed clinical studies, the primary safety data sets that supported 
approval in the US are from the pooled double-blind, placebo-controlled replicate Phase 3 
studies (Studies 0126 and 0127) and from the long-term (52-week) active-controlled safety 
study (Study 0128). 
The safety profile for revefenacin inhalation solution in participants with moderate to very 
severe COPD was similar to placebo, and favorable when evaluated in Study 0128 with active 
control tiotropium (Spiriva® HandiHaler®). Furthermore, in the Phase 3 program, the adverse 
event (AE) profile of revefenacin inhalation solution was consistent with that of other clinical 
programs developing LABA therapies, particularly long-acting muscarinic antagonist (LAMA) 
products. 
Worsening/exacerbation of COPD (Medical Dictionary for Regulatory Activities [MedDRA] 
preferred term, chronic obstructive pulmonary disease) was the most common AE reported in 
the Phase 3 program, but the incidence of this AE was numerically lower in the revefenacin 
arms than in the placebo arm in the 12-week studies (Studies 0126 and 0127). In the long-term 
safety study (Study 0128), the incidence of this AE compared favorably to that of the clinically 
established LAMA, tiotropium, which served as the active control in the study. So, while a 
common AE in the revefenacin clinical program, chronic obstructive pulmonary disease (as the 
MedDRA preferred term) did not appear to be an adverse drug reaction. 
Other than worsening/exacerbation of COPD, the most common adverse drug reaction, defined 
as any AE where the event rate was higher than that of placebo and occurred in more than 1% of 
the population in the 12-week trials, was cough. The difference in rates between placebo and 
revefenacin, however, was very small (4.1% vs. 4.3% respectively). 
For patients who need more than 1 medication to manage their COPD, the safety profile 
supports the use of revefenacin 175 mcg. For patients taking LABA and/or inhaled 
corticosteroid (LABA or ICS/LABA), there was no apparent increase in AEs or tolerability with 
the higher dose, neither in absolute incidence nor in exposure adjusted incidence. 
Subsequent to the Phase 3 studies cited earlier, revefenacin inhalation solution (175 mcg once 
daily) was evaluated against tiotropium dry powder (18 mcg once daily) in participants with 
COPD and suboptimal PIFR (<60 L/min). Adverse events were reported less frequently during 


 
 
 
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treatment with revefenacin (11.7%) compared to tiotropium (37.5%). An AE of COPD 
(i.e., worsening of COPD) only occurred in the tiotropium group (1 participant). The most 
frequently reported AEs differed between treatment groups and are described later in this 
section. 
Safety was also evaluated when revefenacin inhalation solution (175 mcg once daily) or 
matching placebo was administered sequentially (i.e., immediately before), or in combination 
with, formoterol fumarate inhalation solution (20 mcg). The overall incidence of AEs was 
higher in the control group (placebo and formoterol; 11% to 12% depending on timing of 
administration) compared to the revefenacin and formoterol group (5% to 8%), but the 
incidence was comparable between sequential and combination administration. COPD 
(worsening) was among the most frequently reported AEs (2 participants), and occurred more 
frequently in the placebo and formoterol group compared to the revefenacin and formoterol 
group. 
In the revefenacin clinical program to date, 6 on-study deaths have been reported: 1 in the 
Phase 2 Study 0116 and 5 in the Phase 3 Studies 0126, 0127, and 0128; an additional 7 deaths 
were reported at least 7 days after the last dose in Study 0128. None of the reported on-study or 
off-study deaths were considered by the investigator to be related to the study drug, and there 
was no apparent signal related to cause of death suggesting any pattern or dose response 
relationship. 
Efficacy of revefenacin was demonstrated in the Phase 3 studies (Studies 0126 and 0127), with 
marked improvements in FEV1 (i.e., trough, peak, weighted mean, trough overall treatment 
effect) for participants treated with revefenacin when evaluated as within-group change from 
baseline measurements and as compared with placebo. Improvements in FEV1 were similar in 
subgroups of participants taking concurrent LABAs and those not taking concurrent LABAs. 
Efficacy was also characterized in the Phase 3 long-term safety study (Study 0128) through 
exploratory analyses. In Study 0128, revefenacin and tiotropium resulted in improved lung 
function (trough FEV1) throughout the study compared to baseline. 
Additional efficacy information is available from a Phase 3b study in participants with COPD 
and suboptimal PIFR comparing revefenacin to tiotropium (Study 0149). Efficacy in Study 
0149 was characterized by change from baseline in trough FEV1 as the primary endpoint, and 
changes from baseline in trough FVC and inspiratory capacity, and peak FEV1 and FVC as 
secondary endpoints. Within the ITT population, primary and secondary efficacy endpoints did 
not demonstrate statistically significant improvements in lung function relative to tiotropium. 
However for the combined GOLD 3 and GOLD 4 population, nominally statistically significant 
differences from tiotropium were observed for both trough FEV1 and FVC. 
In Study 0167, a 6-week study of revefenacin and formoterol, revefenacin administered either 
immediately before or in combination with formoterol resulted in a greater response for FEV1 
and FVC compared to formoterol alone (i.e., placebo and formoterol). 
The clinical pharmacokinetics of revefenacin inhalation solution in participants with moderate 
to severe COPD have been evaluated after single- and/or repeat-dose administration in Studies 
0059, 0091, and 0117. Plasma concentrations of revefenacin and its major metabolite, 
THRX-195518, were low after inhaled administration, declined in a bi-exponential fashion with 
an initial rapid decline and a slower terminal elimination phase, and resulted in limited 


 
 
 
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accumulation for both revefenacin and THRX-195518 in plasma after repeated administration. 
No significant renal excretion of revefenacin and THRX-195518 was observed. 
1.4. 
Risks and Benefits 
Participants in this study may be at risk of experiencing adverse events related to muscarinic 
antagonism, including headache, mouth dryness, constipation, blurred vision, dizziness and 
urinary retention. 
Participants in this study may experience discomfort due to blood draws for laboratory testing. 
Clinically significant bronchodilation has been observed in each of the COPD study 
populations. Two replicate phase 3 efficacy studies (0126 and 0127) with a 3-month treatment 
period have demonstrated that a 175-mcg dose of revefenacin was generally well tolerated, with 
comparable rates of AEs and serious adverse events for revefenacin and placebo. The most 
commonly reported AEs, across both trials were COPD exacerbation, nasopharyngitis, cough, 
dyspnea and headache. There were no reports of blurred vision, narrow-angle glaucoma or 
worsening of urinary retention, all of which are commonly reported AEs for this class of 
medication. In addition, reports of dry mouth were < 0.5% for revefenacin. A long term safety 
study (0128) with a 1-year treatment period revealed a similar safety profile to what was 
observed to the efficacy studies. 


 
 
 
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2. 
OBJECTIVES 
The primary objectives of the study are as follows: 
• To characterize the relative efficacy on change from baseline in trough FEV1 on 
Day 85 of revefenacin inhalation solution administered once daily via nebulization 
(YUPELRI ®) compared to tiotropium powder for inhalation administered once 
daily (Spiriva® HandiHaler®) in adults with severe to very severe COPD who have 
impaired expiratory flow (i.e., FEV1 < 50% of predicted normal) and suboptimal 
PIFR (i.e., PIFR < 55 L/min via In-Check™ device set to DISKUS resistance) 
following 84 days of dosing. 
• To evaluate the safety and tolerability of revefenacin inhalation solution 
administered in adults with severe to very severe COPD, impaired expiratory flow, 
and suboptimal PIFR 
The secondary objectives of the study are as follows: 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization 
compared to tiotropium administered once daily via HandiHaler® on average FEV1 
across Days 30, 60, and 85 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization 
compared to tiotropium administered once daily via HandiHaler® on trough FVC on 
Day 85 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization 
compared to tiotropium administered once daily via HandiHaler® on trough FEV1 
on Day 30 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization 
compared to tiotropium administered once daily via HandiHaler® on trough FEV1 
on Day 60 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization to 
tiotropium administered once daily via HandiHaler® in achieving improvements in 
lung function of ≥80 mL, as measured by trough FEV1 on Day 85 
• To evaluate time to first CompEx (composite endpoint for moderate or severe 
exacerbations of COPD) event 
The exploratory objectives of the study are as follows: 
 
 
 
 
 
 
 
 


 
 
 
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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a randomized, double-blind, double-dummy, parallel-group study evaluating efficacy 
and safety of revefenacin vs. tiotropium in adults with severe to very severe COPD and 
suboptimal PIFR. Participants will visit the clinic for up to 2 screening visits and eligible 
participants will visit the clinic for a randomization visit, up to 2 intermediate on-treatment 
visits, and a final or early termination visit. Unscheduled visits may also be required. 
During screening, participants are required to “wash out” from certain medications, or to take a 
different dose. Such medications include, but are not limited to, long-acting muscarinic 
antagonists (LAMA), LABA, LAMA/LABA, LABA/inhaled corticosteroids (ICS), and 
LAMA/LABA/ICS (see complete list in Table 2). Participants will be assessed for suboptimal 
PIFR using the In-Check™ device set to DISKUS resistance in addition to other inclusion and 
exclusion criteria, undergo ipratropium reversibility testing, receive rescue medication, receive 
an electronic diary (eDiary) device, receive a PEF meter and be trained on its use, have their 
adverse events and other concomitant medications reviewed. Participants will also undergo 
physical examinations (including vital signs, height, and weight measurements). Participants 
will also undergo clinical laboratory testing if results from the previous 3 months are 
unavailable. Women of childbearing potential will have a urine pregnancy test. Participants who 
are required to wash out from medications will have these procedures conducted over 
2 screening visits 5 to 9 days apart; participants not required to wash out will have these 
procedures conducted in a single visit. 
At the randomization visit on Day 1 (3 to 7 days after screening), eligible participants with 
PIFR < 55 L/min, post ipratropium 30% < FEV1 < 50% of predicted normal (using National 
Health and Nutritional Examination Survey-predicted equations) and absolute FEV1 > 500 mL, 
or FEV1 < 30% predicted normal and absolute FEV1 > 700 mL, and who meet all other 
inclusion criteria will be randomized to revefenacin (revefenacin 175mcg/tiotropium placebo) 
or tiotropium (tiotropium 18 mcg/revefenacin placebo) in a 1:1 ratio. Enrollment of participants 
with Global Initiative for the Treatment of Obstructive Lung Disease airflow category 4 (GOLD 
4; FEV1 <30% of predicted normal) will be capped at 30% to reflect what is expected in the 
population with severe to very severe COPD. Participants will be trained on the use of the DPI 
device and nebulizer prior to receiving their first dose of study medication. Participants will 
undergo baseline lung function tests, clinical outcomes assessments, and have their diaries, 
concomitant medications, and adverse events reviewed. 
 
 
Participants will return to the clinic on Days 30 and 60 ± 7 days each (Visits 3 and 4 
respectively). Diaries will be reviewed to assess compliance with regard to their completion. 
Study drug and rescue medication will be accounted for and new supplies will be dispensed. 
Adverse events and concomitant medications will be reviewed, and women of childbearing 
potential will undergo urine pregnancy testing. Clinical outcomes will be measured, and lung 
function will be assessed. 
 
 Participants will administer their study 
medication in the presence of study center personnel not involved in the measurement of 
efficacy parameters. 


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Participants will self-administer study medication once daily in the morning for 84 days, except 
on Days 30 and 60, when participants will return to the study center for assessments prior to 
taking their study medication. 
Participants will return to the clinic on Day 85 ± 7 days (Visit 5) for final assessments. Study 
drug and rescue medication will be accounted for; diaries, concomitant medications, and 
adverse events will be reviewed. Participants will undergo a physical examination including 
vital signs. Clinical outcomes will be measured, and lung function will be assessed. 
 
 
Women of childbearing potential will undergo urine pregnancy testing. Participants who 
discontinue from the study prior to this visit will undergo the same procedures at an early 
termination visit. 
At 7 ± 2 days after the last visit, participants will be contacted by telephone for an assessment of 
their adverse events. 
Revefenacin (or matching placebo) will be administered as a 3-mL inhalation solution using the 
PARI LC Sprint® jet nebulizer and using a mouthpiece. Tiotropium (or matching placebo) will 
be administered as a dry powder using the HandiHaler® device. Participants will take study 
drug via DPI first, and then via nebulizer. 
A supply of rescue medication (albuterol MDI) for use in the study and a supply of study 
medication will be provided for each participant at each visit, except at Visit 1B for participants 
requiring 2 screening visits, and at Visit 5 or at early termination. 
The primary efficacy assessment is FEV1 as measured by spirometry. 
Secondary efficacy assessments are FVC, also measured by spirometry, and use of rescue 
medication as measured by daily participant diaries. 
Safety assessments, including collection of AEs, measurement of vital signs (heart rate and 
blood pressure), urine pregnancy testing for women of childbearing potential, and review of 
concomitant medications, will be performed at every visit. 
Exploratory assessments are events associated with a composite endpoint for severe 
exacerbations of COPD (CompEx)  
 
 
. 
The study design is depicted in Figure 1. 


 
 
 
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Figure 1: 
Study Design Schema 
Visit 1A 
Visit 1B 
Visit 2 
Randomization 
Visits 3, 4, and 5 
Treatment Period 
(84 days) 
Follow-Up 
Phone Call 
Early Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs, adverse events; eDiary, electronic diary; PEF, peak expiratory flow, PIFR, peak inspiratory flow rate; 
a Measured at Visits 2 and 5 in participants enrolled at selected study centers capable of performing these assessments 
Informed 
Consent 
Determine 
eligibility, 
including 
PIFR 
Dispense 
rescue 
medication 
Safety 
Baseline 
evaluations, 
including 
ipratropium 
reversibility 
and 
spirometry 
Dispense 
eDiary and 
PEF meter 
Safety 
Confirm eligibility 
Randomization and 
first dose 
Study drug and 
rescue medication 
accountability 
 
Lung function 
Lung volumesa 
Clinical outcomes
Revefenacin 
active 
Tiotropium 
Placebo 
Revefenacin 
Placebo  
Tiotropium 
active 
Study drug and 
rescue 
medication 
accountability 
Review eDiary 
Lung function 
Clinical outcomes 
Safety 
Dispense/ account 
for study drug and 
rescue medication 
Review eDiary 
Lung function 
Lung volumesa 
Clinical outcomes 
Safety  
Washout of 
COPD 
medications 
AEs 


 
 
 
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3.2. 
Rationale for Study Design 
This is a Phase 4 study to assess revefenacin at a dose of 175 mcg administered once daily for 
84 days using the jet nebulizer that was utilized in the earlier studies of the program. This study 
is intended to provide data in patients with severe to very severe COPD who have suboptimal 
PIFR, where nebulized delivery of revefenacin could provide more benefit, as measured by 
spirometry and dyspnea symptoms, than a DPI (HandiHaler®), which would support the use in 
this demographic as a bronchodilator for the treatment of adults with COPD. The 175-mcg dose 
is approved by the US FDA for the maintenance treatment of COPD, and is considered to have 
an optimal benefit:risk ratio to further characterize its use in this population. 
The study is designed as a double-blinded, double-dummy, parallel-group study, with 
183 evaluable participants randomized to each treatment group with the intention of obtaining 
data from at least 146 evaluable participants per group on Day 85 for the primary analysis. 
Randomization allows for an unbiased assessment of treatment effects across revefenacin and 
tiotropium. The duration of treatment is limited, and all participants will have study-specific 
rescue medication (albuterol MDI) provided for the full duration of the study, including during 
the screening and follow-up periods. 
Participants will be required to meet the standard spirometry definitions for severe to very severe 
COPD (postbronchodilator FEV1/FVC ratio of <0.7 and a postbronchodilator FEV1 < 50% of 
predicted normal based on the third National Health and Nutrition Examination Survey). 
Participants should meet a PIFR of < 55 L/min as measured by In-Check™ device with 
resistance set to DISKUS® at screening. 
3.3. 
Selection of Doses and Duration of Treatment 
The selection of the 175-mcg dose of revefenacin for this study is based on approval by the US 
FDA and the results of a previous study in adults with moderate to very severe COPD and PIFR 
<60 mL/min as measured by In-Check™ device with resistance set to DISKUS. Revefenacin, 
administered once daily via a standard jet nebulizer at a dose of 175 mcg, demonstrated clinically 
important and nominally statistically significant improvements in trough FEV1 over the entire 
treatment period for participants with severe or very severe COPD (i.e., GOLD 3 and 4 airflow 
categories), which represented the majority (78%) of the ITT population. Revefenacin was well 
tolerated with rates of AEs less than those for tiotropium. The most common AEs were headache 
and dyspnea, with higher percentages of both in the tiotropium group. The AE profile did not 
differ from the expected safety/tolerability profile to date for revefenacin or other LAMAs. 


 
 
 
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3.4. 
Study Endpoints 
The primary study endpoint is change from baseline in trough FEV1 on Day 85 following 
84 days of dosing. 
The secondary endpoints are as follows: 
• Trough overall treatment effect (OTE) on FEV1 over 85 days 
• Change from baseline in Trough FVC on Day 85 
• Change from baseline in Trough FEV1 on Day 30 
• Change from baseline in Trough FEV1 on Day 60 
• 80 mL response, defined as at least an 80 mL improvement in trough FEV1 on Day 85 
• Time to first CompEx (composite endpoint for exacerbations of COPD) event 
A CompEx event is defined as the first occurrence of a moderate or severe exacerbation 
or clinically relevant deteriorations based on objective measures of deterioration in peak 
expiratory flow (PEF), rescue medication use, COPD symptoms and nocturnal 
awakening.5, 6 
A moderate exacerbation is defined as an increase in symptoms that requires treatment 
with antibiotics and/or oral corticosteroids and a severe exacerbation is defined as a 
deterioration of COPD symptoms that results in hospitalization for emergency treatment 
of the COPD and the duration of the visit is ≥1 day, as recorded via CRF. 
Clinically relevant deteriorations will be defined in the statistical analysis plan (SAP). 
Exploratory endpoints are: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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The safety endpoints are the incidence of AEs (including exacerbations of COPD), and vital 
signs (heart rate and blood pressure). 
3.5. 
Minimization of Bias 
Bias will be minimized through the use of randomization and a double-blind, double-dummy 
study design. 
3.5.1. 
Blinding 
All study participants, study investigators and their staff, and the Sponsor’s staff involved in the 
conduct of the study will be blinded to treatment assignment with regard to revefenacin and the 
tiotropium comparator arm. Participants will be assigned in random order to tiotropium or 
revefenacin according to the randomization schedule. The only personnel who will have access 
to the randomization schedule before database lock are the nominated personnel at the Contract 
Research Organization responsible for generation of the randomization schedule. 
In the event of an untoward safety observation, the investigator may unblind a participant’s 
treatment assignment using the Randomization and Trial Supply Management (RTSM) system. 
The blind should be broken only if knowledge of the participant’s study medication would affect 
subsequent treatment and such knowledge is required for the clinical management of the 
participant. Any investigator unblinding will be documented within the appropriate section of the 
participant’s case report from (CRF) and will be captured in the RTSM system. 
Unblinding of individual study participants or study center staff on the basis of results from the 
study procedures (i.e. self-unblinding) is not considered to be either an expected or likely event. 
3.5.2. 
Treatment Assignment 
After a participant is screened and the investigator determines that the participant is eligible for 
enrollment, the participant will be randomized to one of the two treatment groups using the 
RTSM system (Day 1 visit). The randomization will be stratified by ipratropium reversibility 
(reversible/not reversible) and GOLD airflow category (3/4). Enrollment of GOLD 4 
(FEV1 <30% of predicted normal) participants will be capped at 30% to reflect what is expected 
in the population with severe to very severe COPD. 


 
 
 
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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Unless otherwise noted, all participants must meet the following criteria: 
1. Participant is a male or female 40 years of age or older 
2. Participant is female and is nonpregnant and nonlactating. A woman of childbearing 
potential must have a documented negative urine pregnancy test at screening. 
Women are considered not to be of childbearing potential if they have had a total 
hysterectomy and/or bilateral tubal ligation (documentation for either must be provided 
before enrollment) or are at least 2 years postmenopausal. 
3. During the study and for 30 days after receiving the last dose of study drug, women of 
childbearing potential and men capable of fathering children must agree to use highly 
effective birth control measures or agree to abstain from sexual intercourse. 
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 as condom + 
diaphragm, condom + spermicide, diaphragm + spermicide, or intrauterine device (IUD) 
with documented failure rate of <1% per year, or oral/injectable/implanted hormonal 
contraceptives used in combination with an additional barrier method. 
4. Participant has a diagnosis of COPD, specifically, a post-ipratropium FEV1/FVC ratio 
< 0.7 
5. Participant has a post ipratropium 30% < FEV1 < 50% of predicted normal (using 
National Health and Nutrition Examination Survey-predicted equations) and absolute 
FEV1 > 500 mL, or FEV1 < 30% predicted normal and absolute FEV1 > 700 mL. 
6. Participant has a PIFR <60 L/min as measured by an In-Check™ device with resistance 
set to DISKUS at Visit 1A (if not combined with Visit 1B) and <55 L/min as measured 
by an In-Check™ device with resistance set to DISKUS at Visit 1B and Visit 2 prior to 
randomization 
7. Participant is capable of performing reproducible spirometry maneuvers
 
 as described by current 
American Thoracic Society (ATS) Guidelines. 
8. Participant is an active or former smoker with a cigarette smoking history (or equivalent 
for cigar or pipe smoking history) of at least 10 pack-years. 
9. Participant or legal guardian is willing and able to provide signed and dated informed 
consent to participate prior to initiation of any study related procedures. 
10. Participant is willing and able to adhere to all study assessments/procedures. Care partner 
assistance is acceptable. 


 
 
 
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11. Participant is willing and able to adhere to all restrictions during their study participation 
as follows: 
• Use of recreational drugs 
• Medicinal marijuana 
• Excessive alcohol during the study period 
• Participation in another investigational drug study 
• Donation of ≥500 mL blood (or equivalent) 
12. Participant (or care partner) based on the investigator’s assessment is able to properly 
prepare and administer study medication administered either from both nebulizer and 
HandiHaler® according to their respective Instructions for Use. 
4.2. 
Exclusion Criteria 
Participants who satisfy any of the following criteria are not eligible for study enrollment: 
1. Participant has a concurrent disease or condition that, in the opinion of the investigator, 
would interfere with study participation or confound the evaluation of safety and 
tolerability of the study drug. 
2. Participant has a history of reactions or hypersensitivity to inhaled or nebulized 
anticholinergics 
3. Participant suffers from any medical condition that would preclude the use of inhaled 
anticholinergics, including narrow-angle glaucoma, symptomatic benign prostatic 
hyperplasia, bladder neck obstruction, or urinary retention. 
4. Participant has Moderate to Severe Hepatic impairment (Child-Pugh B or C) or Severe 
Renal Insufficiency (i.e., a glomerular filtration rate <30 mL/min/1.72m2). 
5. Participant has been hospitalized for COPD or pneumonia within 8 weeks prior to Visit 1. 
6. Participant is receiving a LABA or LABA/inhaled corticosteroid (ICS; either QD or BID) 
at a dose that has been stable for ≤ 30 days prior to screening 
7. Participant has used systemic corticosteroids within 8 weeks of Visit 1. 
8. Participant has used antibiotics for respiratory tract infections within 8 weeks of Visit 1, 
or is using antibiotics prophylactically. 
9. Participant received COVID-19 vaccine within 2 weeks of Visit 1. 


 
 
 
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5. 
STUDY DRUGS 
All study drugs supplied by the Sponsor must be stored in a secure location accessible only to 
designated study personnel. The assignment of participants to one of the treatment groups will be 
accomplished by randomizing the participant through the RTSM system. Each drug kit will 
contain a unique kit number which will be provided by the RTSM system on Day 1 to identify 
the study drug kits to dispense to particular participants. 
More information regarding study drug dispensing, administration, handling and storage are 
provided in a separate Pharmacy Manual. 
5.1. 
Description of Study Drugs 
5.1.1. 
Revefenacin 
Revefenacin has a molecular weight of 597.76. It is a white to off-white crystalline powder and 
is slightly soluble in water. 
Revefenacin will be supplied as 3 mL of solution packaged in a unit-dose low-density 
polyethylene vial with a twist-off top overwrapped in a foil pouch. Each vial contains 175 mcg 
of revefenacin in 3 mL of isotonic, sterile aqueous solution containing sodium chloride, citric 
acid, sodium citrate, and water for injection, at pH 5.0. 
Matching placebo will be identically packaged and supplied as 3 mL of solution without the drug 
substance. 
Revefenacin and its placebo must be stored at temperatures stated in the Pharmacy Manual. 
Detailed instructions for administration will be provided separately and provided to the study 
participant. 
5.1.2. 
Tiotropium 
Tiotropium will be supplied as kits containing 1 HandiHaler® device and 4 blister cards with 
10 capsules each, containing either 18mcg Spiriva® dry powder or matching placebo. 
Tiotropium and its placebo should be stored at room temperature (68°F to 77°F [20°C to 25°C]; 
excursions permitted from 59°F to 86°F [15°C to 30°C]). 
Detailed instructions for administration will be provided in the Pharmacy Manual. 
5.2. 
Dosage and Administration 
Participant will administer tiotropium or matching placebo using a HandiHaler® device before 
administering revefenacin or matching placebo using a jet nebulizer. For participants who are 
taking a LABA, the sequence of drug administration will be LABA, followed immediately by 
tiotropium/placebo, followed by revefenacin/placebo. 
5.2.1. 
Revefenacin 
Revefenacin will be administered immediately after tiotropium placebo each day. Revefenacin 
placebo will be administered immediately after tiotropium each day. 


 
 
 
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Participant will be trained on the use of nebulizer on Day 1 after randomization during the 
administration of their first dose while at the study center. Participants will be trained to 
administer the study drug until nebulization of the study drug solution is complete, which takes 
approximately 10 minutes and is evidenced by “spluttering” of the nebulizer. Additional 
information on the training of the participant on home nebulization is contained in the Pharmacy 
Manual. 
Upon leaving the study center, the participant will take the jet nebulizer, compressor and study 
drug home. Participants will self-administer revefenacin (or placebo) every morning at 
approximately the same time within the window of 6:00 am and 11:00 am; the time will be 
chosen based on convenience for the participant and will remain the same for the duration of the 
study. Participants will record the time of administration in their eDiary. 
Participants will refrain from taking their dose at home on Days 30 and 60, when dosing will 
occur during their required visit to the study center. Participants will bring their nebulizer and 
unused revefenacin vials to the study center on these days. Prior to leaving the study center, 
participants will be dispensed sufficient revefenacin (or placebo) for home dosing until the time 
the participant returns for their next study visit. Participants may receive additional training at 
these visits at the discretion of the investigator. 
5.2.2. 
Tiotropium 
Tiotropium will be administered immediately prior to revefenacin placebo on each day. 
Tiotropium placebo will be administered immediately prior to revefenacin each day. 
Participants will be trained on the use of the HandiHaler® device on Day 1 after randomization 
during their first dose of tiotropium (or matching placebo) while at the study center. Additional 
information on the training of the participant on the use of the HandiHaler® device is contained 
in the Package Insert. 
Upon leaving the study center, the participant will take the HandiHaler® device and the 
tiotropium dry powder capsules home. Participants will self-administer tiotropium (or placebo) 
every morning at approximately the same time within the window of 6:00 am and 11:00 am; the 
time will be chosen based on convenience for the participant and will remain the same for the 
duration of the study. Participants will record the time of administration in their eDiary. 
Participants will refrain from taking their dose at home on Days 30 and 60, when dosing will 
occur during their required visit to the study center. Participants will bring their HandiHaler® 
device and unused tiotropium capsules to the study center on these days. Prior to leaving the 
study center, participants will be dispensed sufficient tiotropium (or placebo) capsules for home 
dosing until the time the participant returns for their next study visit. Participants may receive 
additional training at these visits at the discretion of the investigator. 
5.3. 
Treatment Compliance 
Compliance will be assessed in study participants when accountability is performed as described 
in the next section. Compliance will be defined as participants who are considered to have 
received 80% to 120% of the total number of doses separately for DPI and nebulizer that should 
have been administered in between study visits. 


 
 
 
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Compliance outside the 80% to 120% range for each method of administration will be 
documented in the electronic case report form (eCRF) 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 the on-site destruction or return of the material(s) as specified by the sponsor. 
Unused and expired study drugs will be disposed of in accordance with written instructions from 
Sponsor. Additional guidance may be found in the Pharmacy Manual. 
Study drug accountability will be performed at Visits 3, 4, and 5 (Days 30, 60 and 85, 
respectively) to document compliance with the dosing regimen. Participants will be instructed to 
bring back all remaining used and unused study drug at each study visit for drug accountability. 
Treatment compliance will be assessed by subtracting the number of unused returned foil 
pouches from the number of foil pouches that were supplied to the participant (for revefenacin) 
and by counting the number of used and unused blister cards (for tiotropium). If a participant 
does not return the unused foil pouches or blister cards, it will be assumed that the participant 
administered the study drug. Discrepancies between the participant’s eDiary and the count of 
returned study drug should be documented in the source documents. 
Albuterol (MDI) use will be captured from the rescue medication section of the eDiary. For 
accountability purposes, participants will be instructed to bring their albuterol inhaler to each 
study visit for drug accountability. Discrepancies between the participant’s eDiary and the count 
of returned study drug should be documented in the source documents. Additional guidance may 
be found in the Pharmacy Manual. 


 
 
 
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6. 
STUDY PROCEDURES 
6.1. 
Schedule of Study Procedures 
The schedule of study procedures is summarized in Table 1. 
Throughout the study, investigators should conduct the order of the assessments for each study 
visit as indicated in the study procedures and strive to maintain consistency in this order. All 
study procedures for a visit must be completed on the same day. Any missed visits, tests not 
done, or procedures that are not conducted must be reported as such on the eCRFs. 
The research site will follow institutional and government guidelines/precautions regarding 
Coronavirus Disease 2019 (COVID-19) to reduce the risk of infection for study participants and 
study staff. Any adaptations to study conduct will be documented appropriately and will take 
into considering the FDA Guidance on Conduct of Clinical Trials of Medical Products During 
the COVID-19 Public Health Emergency (updated January 2021) 
The scheduling of Visits 3, 4, and 5 (Day 30, Day 60, and Day 85, respectively; ± 7 days each) is 
based on the date of Visit 2 (Day 1 of the treatment period when the participant is randomized). 
The follow-up phone call should be scheduled 7 days after Visit 5, with a window of ±2 days. 
6.2. 
In-Clinic Procedures by Visit 
6.2.1. 
Screening 
Screening assessments and study procedures outlined in this section will be performed after 
obtaining informed consent. Importantly, this includes any washout of a participant’s current 
medication for the purpose of participation in the study or changing a participant’s combination 
medication containing a LAMA to LABA or ICS/LABA (see Table 2 for specific washout 
periods required). 
Prior medical history should be obtained for the previous 2 years as part of screening the 
participant for eligibility into the trial. If these records have not been obtained, then documented 
efforts to obtain these records must be present in the source documents. 
Participants in this study who, at the time of screening are taking COPD medications requiring a 
washout will have two screening visits (1A and 1B). Long acting bronchodilators requiring a 
washout include LAMAs (tiotropium (Spiriva®), glycopyrronium bromide, aclidinium 
(Tudorza®), umeclidinium (Incruze®)) or any other approved LAMA; combination 
LAMA/LABA products (ANORO®, olodaterol/tiotropium or any other approved combination 
LAMA/LABA); combination LAMA/ICS/LABA products (TRELEGY® or any other approved 
combination LAMA/ICS/LABA); and roflumilast (Table 2). The effects of the long-acting agent 
will be washed out between Visit 1A and Visit 1B and this washout period will be at least 
48 hours and no longer than 9 days. As part of the screening visit, the investigator should review 
participants’ most recent lab work (within the previous 3 months) to ensure that participants are 
stable and to confirm that creatinine, hematocrit, and liver function tests (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin [bili], alkaline phosphatase 
[alk phos]) values are normal and/or not clinically significant. If historical lab tests containing 
these tests have not been performed within 3 months, then local labs should be performed at 
Visit 1A. The local lab results (either historical or performed at Visit 1A) must be present in the 


 
 
 
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source documents. Collection of International Normalized Ratio (INR) and albumin for 
exclusion based on hepatic impairment (Section 4.2) is at the discretion of the investigator. 
Participants not taking the long-acting bronchodilators described above, and participants on 
LABAs (e.g. salmeterol, indacaterol, vilanterol, formoterol, arformoterol, olodaterol) either alone 
or in combination with an ICS (e.g. fluticasone propionate, fluticasone furoate, budesonide, 
ciclesonide, beclomethasone), will not need to undergo a washout of these medications before 
enrolling in the study; these participants can be randomized 3 to 7 days after screening. 
The first visit will be Screening Visit 1A. Informed consent will be obtained and the participant’s 
existing COPD medication will be assessed to decide whether any adjustments are required to 
comply with the requirements of the protocol. If required, participants will start a washout period 
only after signing the informed consent form. After completing the necessary washout period 
(if required) participants will return for Screening Visit 1B within the next 5 to 9 days. 
If a washout period is not required then the first two screening visits (Visit 1A and Visit 1B) may 
be conducted as one visit. The time period from the screening visit (Visit 1A if only one visit is 
required; from Visit 1B if two visits are required) to randomization at Visit 2 will be 3 to 7 days. 
Review of the spirometry results collected at the screening visit (either Visit 1A or Visit 1B) will 
take approximately 2 business days and must be completed to determine if the spirometry meets 
the eligibility criteria before the participant can be randomized. 
If a participant does not meet the eligibility criteria for reasons of a failed screening test due to a 
properly administered procedure, this test or procedure will not be allowed to be repeated and 
this should be considered screen failure. This includes spirometry such that if a participant fails 
to meet any spirometry-related criteria after the first attempt, this will be considered a screen 
failure. Repeat screening of spirometry will only be considered if there is a technical issue with 
the spirometer or with the software, or if the spirometry was not performed properly due to study 
center error. 
6.2.1.1. 
Visit 1A 
Participants should not have taken their LABA for approximately 12 hours (if on BID therapy) 
or approximately 24 hours (if on QD therapy) prior to performing the measurement for PIFR at 
Visit 1A. Additionally, participants should not have taken albuterol (MDI) or any other short 
acting bronchodilator for approximately 6 hours prior to the PIFR measurements. If participants 
have not refrained from taking these medications in the specified time windows, this visit will be 
rescheduled. 
The following procedures will be performed at this visit: 
• Informed consent after the nature of the study has been explained and before any 
study procedure is performed 
• Concomitant and previous relevant medication and medical history including an 
assessment of the participant’s COPD medication 
• If required, based on the washout periods specified in Table 2, the participant will 
begin their washout. If the participant is receiving a combination COPD medication 
containing a LAMA, this may include changing this medication to an inhaled LABA 
or ICS/LABA product. 


 
 
 
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Participants who do not require washout of their COPD medications can have all of 
these procedures combined with those for Visit 1B. 
• Review of inclusion and exclusion criteria 
• Urine pregnancy test for women of childbearing potential 
• Participant will be dispensed one albuterol MDI as a rescue bronchodilator.  
• Review of AEs 
• Local lab tests for creatinine, hematocrit, ALT, AST, bili, and alk phos, if historical 
local labs within 3 months of Visit 1A are not available; fasting values will not be 
required. Collection of INR and albumin for exclusion based on hepatic impairment 
(Section 4.2) is at the discretion of the investigator. 
• PIFR (as measured by In-Check™ device with resistance set to DISKUS®) 
− participants requiring a washout of a LAMA with PIFR ≥60 L/min will be 
considered a screen failure at Visit 1A 
− participants not requiring a washout of a LAMA with PIFR ≥55 L/min will be 
considered a screen failure at Visit 1A 
6.2.1.2. 
Visit 1B 
This visit is required for participants who began washout of their COPD medications at Visit 1A. 
Participants who did not require washout can have these procedures in combination with those 
for Visit 1A. 
Ipratropium reversibility testing will be described in the study manual. Participants should not 
have taken their LABA for approximately 12 hours (if on BID therapy) or approximately 
24 hours (if on QD therapy) prior to the dose of ipratropium at this visit. Additionally, 
participants should have refrained from taking their study supplied albuterol MDI for 6 hours 
prior to spirometry assessments. They should further refrain from using albuterol MDI 
throughout the study visit. If participants have not refrained from taking these medications in the 
specified time windows, this visit will be rescheduled. 
The following procedures will be performed at this visit: 
• Prior to administration of ipratropium 
− Complete physical examination 
− Height and weight 
− Vital signs (blood pressure [BP] and heart rate [HR]) - participants need to be 
resting in a semirecumbent position approximately 5 minutes prior to assessment 
of vital signs 
• PIFR – (before spirometry) as measured by In-Check™ device with resistance set to 
DISKUS® participants who required a washout of a LAMA with ≥55 L/min of PIFR 
will be considered a screen failure at Visit 1B 


 
 
 
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• Ipratropium Reversibility - Spirometry reversibility testing pre- and postdose 
ipratropium after withholding bronchodilators as specified in Table 2. Spirometry will 
be performed predose and 45 minutes postdose (± 10 minutes). 
• PEF (after spirometry) 
• Dispense diaries (after spirometry) and record: 
− Daily breathlessness, cough/sputum, and chest symptoms via the Evaluating 
Respiratory Symptoms in COPD (E-RS:COPD) assessment in the evening prior to 
bedtime 
− Nocturnal awakenings (after spirometry) 
− Rescue albuterol use (captured throughout the day) 
• Dispense PEF Meter for at-home collection by the participants. Training will be 
provided during the PEF collection. 
• Review of concomitant medications 
• Review of AEs 
• Review of inclusion and exclusion criteria 
6.2.2. 
Treatment and Follow-up Period 
The timing of predose procedures is relative to the start of study drug administration (using the 
HandiHaler®). 
The sequence of events for the participant to follow at home will be as follows: recording the 
start time of study drug (i.e., use of HandiHaler®) in the eDiary, then using the HandiHaler® 
first, then using the nebulizer. 
At study visits, the trough FEV1 will be assessed before administration of study drug (and before 
taking LABA if applicable). If the participant is taking a LABA this must be taken immediately 
before the study drug. For participants that are taking a LABA, the sequence will be LABA, 
followed immediately by tiotropium/placebo (HandiHaler®), and followed by nebulized 
revefenacin/placebo. 
6.2.2.1. 
Day 1 (Visit 2) Randomization 
Participants should not have taken their LABA for approximately 12 hours (if on BID therapy) 
or approximately 24 hours (if on QD therapy) prior to taking it at the study center. Additionally, 
participants will refrain from taking their short-acting bronchodilators (study-supplied albuterol 
MDI) for 6 hours prior to spirometry assessments. They will further refrain from using albuterol 
MDI throughout the study visit. If participants have not refrained from taking these medications 
in the specified time windows, this visit will be rescheduled to the following day. 
It is important at study visits that the trough FEV1 is done before receiving study drug (or and 
before taking LABA if applicable). If the participant is taking a LABA this must be taken 
immediately before the study drug. 


 
 
 
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The following procedures will be performed at this visit: 
• Vital signs (BP and HR prior to dosing and after resting in a semirecumbent position 
for approximately 5 minutes) 
• Confirm eligibility via review of inclusion and exclusion criteria 
• Randomization (participant eligibility must be confirmed by investigator before 
randomizing participant) 
• Urine pregnancy test for women of childbearing potential if visit is > 7 days after visit 
1A 
• Review eDiary 
• Dispense study drug (RTSM system will assign 1 kit of each drug) 
• Dispense/perform accountability of rescue albuterol MDI 
• Review of concomitant medications 
• Review of AEs 
• BDI assessment 
• PIFR assessment - participants will complete PIFR measured by In-Check™ device 
with resistance set to DISKUS® followed by PIFR set at the HandiHaler® resistance 
• Measure maximal inspiratory pressure 
• Completion of CAT 
• Predose FEV1, FVC via spirometry to be done 45 minutes and 15 minutes prior to the 
start of study drug dosing 
• PEF (after predose spirometry) 
• Complete nocturnal awakenings assessment 
• 
 
 
 
• If appropriate, administer LABA containing product (for those on existing 
LABA-containing therapy) 
• Study drug dosing via HandiHaler® (tiotropium or placebo) followed immediately by 
study drug dosing via nebulizer (revefenacin or placebo). Training on the specific 
devices will be performed before the first dose is administered and as part of 
receiving the first dose. 
• Complete E-RS:COPD in the evening before bedtime. 
6.2.2.2. 
Day 30 (Visit 3) 
Participants should not have taken their LABA for approximately 12 hours (if on BID therapy) 
or approximately 24 hours (if on QD therapy) prior to taking it at the study center. Additionally, 


 
 
 
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participants will refrain from taking their short-acting bronchodilators (study-supplied albuterol 
MDI) for 6 hours prior to spirometry assessments. They will further refrain from using albuterol 
MDI throughout the study visit. 
It is important at study visits that the trough FEV1 is done before receiving study drug (or and 
before taking LABA if applicable). If the participant is taking a LABA this must be taken 
immediately before the study drug. 
The following procedures will be performed at this visit: 
• Urine pregnancy test for women of childbearing potential 
• Review eDiary 
• Dispense study drug (RTSM system will assign 1 kit of each drug) 
• Dispense rescue albuterol MDI 
• Study drug/rescue medication accountability 
• Review of concomitant medications 
• Review of AEs 
• TDI assessment 
• Completion of CAT 
• Predose FEV1, FVC via spirometry to be done 45 minutes and 15 minutes prior to the 
start of study drug dosing 
• PEF (after predose spirometry) 
• Complete nocturnal awakenings assessments 
• If appropriate, administer LABA containing product (for those on existing 
LABA-containing therapy) 
• Study drug dosing via HandiHaler® (tiotropium or placebo) followed immediately by 
study drug dosing via nebulizer (revefenacin or placebo) 
• Complete E-RS:COPD in the evening before bedtime. 
6.2.2.3. 
Day 60 (Visit 4) 
Participants should not have taken their LABA for approximately 12 hours (if on BID therapy) 
or approximately 24 hours (if on QD therapy) prior to taking it at the study center. Additionally, 
participants will refrain from taking their short-acting bronchodilators (study-supplied albuterol 
MDI) for 6 hours prior to spirometry assessments. They will further refrain from using albuterol 
MDI throughout the study visit. 
It is important at study visits that the trough FEV1 is done before receiving study drug (or and 
before taking LABA if applicable). If the participant is taking a LABA this must be taken 
immediately before the study drug. 


 
 
 
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The following procedures will be performed at this visit: 
• Urine pregnancy test for women of childbearing potential 
• Review eDiary 
• Dispense study drug (RTSM system will assign 1 kit of each drug) 
• Dispense rescue albuterol MDI 
• Study drug/rescue medication accountability 
• Review of concomitant medications 
• Review of AEs 
• TDI assessment 
• Completion of CAT 
• Predose FEV1, FVC via spirometry to be done 45 minutes and 15 minutes prior to the 
start of study drug dosing 
• PEF (after predose spirometry) 
• Complete nocturnal awakenings assessments 
• If appropriate, administer LABA containing product (for those on existing 
LABA -containing therapy) 
• Study drug dosing via HandiHaler® (tiotropium or placebo) followed immediately by 
study drug dosing via nebulizer (revefenacin or placebo). 
• Complete E-RS:COPD in the evening before bedtime 
6.2.2.4. 
Day 85 (Visit 5) 
Participants should not have taken their LABA for approximately 12 hours (if on BID therapy) 
or approximately 24 hours (if on QD therapy) prior to taking it at the study center. Additionally, 
participants will refrain from taking their short-acting bronchodilators (study-supplied albuterol 
MDI) for 6 hours prior to spirometry assessments. They will further refrain from using albuterol 
MDI throughout the study visit. 
It is important at the Day 85 study visit that the trough FEV1 is done before taking COPD 
medications in the morning (e.g., LABA if applicable).  
The following procedures will be performed at this visit: 
• Physical examination 
• Vital signs (BP and HR after resting in a semi-recumbent position for approximately 
5 minutes) 
• Urine pregnancy test for women of childbearing potential 
• Review eDiary 
Participants will return the eDiary device to study staff by the conclusion of this visit. 


 
 
 
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• Study drug/rescue medication accountability 
• Review of concomitant medications 
• Review of AEs 
• TDI assessment 
• Completion of CAT 
• FEV1, FVC via spirometry at two time points 30 minutes apart 
• PEF (after spirometry) 
• Complete nocturnal awakenings assessments 
• 
 
 
 
• If appropriate, administer LABA-containing product (for those on existing 
LABA-containing therapy) 
6.2.2.5. 
Follow-up Phone Call 
The follow-up phone call is required for all randomized subjects, whether they complete or early 
terminate from the study. At 7 ± 2 days after visit 5 (or early termination), study center personnel 
will contact participants by telephone to review their AEs.  
6.2.3. 
Early Termination/Withdrawal Visit 
The following procedures will be performed at the Early Termination Visit: 
• Physical exam 
• Vital signs (BP and HR after resting in a semi-recumbent position for approximately 
5 minutes) 
• Urine pregnancy test for women of childbearing potential 
• Review of eDiary 
Participants will return the eDiary device to study staff by the conclusion of this visit. 
• Study drug/rescue medication accountability 
• Review concomitant medications 
• Review AEs 
• TDI assessment 
• Completion of CAT 
• Spirometry (FEV1, FVC) at two time points 30 minutes apart 
• PEF (after spirometry) 
• Complete nocturnal awakenings assessment 


 
 
 
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If a participant discontinues from the study prematurely due to an AE, study center personnel 
will contact the participant by telephone approximately 30 days later to review concomitant 
medications and AEs. This is in addition to the 7-day follow-up telephone call. 
Refer to the Case Report Form Completion Guidelines (CCGs) for further guidance. 
6.2.4. 
At-Home Procedures 
The following procedures will be performed by the participant prior to a scheduled visit and at 
home when not scheduled to visit the study center, unless otherwise noted: 
After completing Visit 1B: 
• PEF 
− On visit day: measurement will be performed at the study center prior to dosing 
− Other times: daily prior to dosing 
• Complete eDiary for 
− Daily breathlessness, cough/sputum, and chest symptoms via E-RS:COPD 
assessment in the evening prior to bedtime 
− Nocturnal awakenings 
− Rescue albuterol use throughout the day 
After completing Visit 2: 
• If taking a LABA containing product (for those on existing LABA-containing 
therapy), take this prior to study drug dosing. 
• Study drug dosing via HandiHaler® (tiotropium or placebo) followed immediately by 
study drug dosing via nebulizer (revefenacin or placebo). 
6.2.5. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or follow-up on AEs, at the participant’s request, or as deemed necessary by the investigator. 
The date and reason for the unscheduled visit should be recorded in the source documentation. 
The following activities may be completed at unscheduled visits as required or medically 
indicated, and results will be recorded in the appropriate CRF unless otherwise noted: 
• Medical/medication history update 
• Physical exam 
• Vital signs (BP and HR after resting in a semi-recumbent position for approximately 
5 minutes) 
• Review concomitant medications 
• Review AEs 
• PEF (before first spirometry assessment; record result in eDiary) 


 
 
 
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• Spirometry (FEV1, FVC) at two time points 30 minutes apart 
• Complete eDiary for nocturnal awakenings assessments 
6.3. 
Description of Study Assessments 
6.3.1. 
Demographic and Baseline Assessments 
After obtaining informed consent, each participant will be asked to provide a relevant medical 
history for the previous 2 years (with the aid of medical records if available) including 
medication history, concomitant medications, and demographic information including year of 
birth, sex, race, and ethnicity. The participant will also undergo a physical examination including 
vital signs, height, and weight and also will have the following assessments measured; BDI, 
PIFR, CAT, FEV1, FVC (as part of spirometry for ipratropium reversibility), and a urine 
pregnancy test for women of childbearing potential. 
Complete medical history at screening 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. Changes in medical history will be recorded at any 
unscheduled visit. 
6.3.2. 
Pulmonary Function Assessments 
6.3.2.1. 
Spirometry 
Spirometry, using a flow-volume loop for all respiratory flow measurements, will be completed 
as follows during the course of the study. Measurements will be done according to methods 
described separately in the Spirometry Manual; this Manual is based on ATS Guidelines.7 
• At Visit 1B (as part of ipratropium reversibility) 
• At Visits 2, 3, 4, prior to dosing of study drug 
• At Visit 5 prior to dosing of LABA (if applicable) 
• At early termination (if possible) 
• At any unscheduled visit (if possible) 
The time window for the 45 and 15 minute predose spirometry will be ± 10 minutes, which 
applies to the end time of the session. At Visit 5, early termination, and any unscheduled visit, 
spirometry assessments will be performed at 2 time points 30 minutes apart. 
A central spirometry reading facility will be used to provide standardized training on spirometry, 
qualification of the spirometry technician, and quality control of the spirometry throughout the 
study. 
6.3.2.2. 
Peak Inspiratory Flow Rate 
PIFR will be measured at time points shown in the schedule of study procedures (Table 1) using 
methods described in the Spirometry Manual. As PIFR will be measured with a device that 


 
 
 
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involves taking a visual reading using a graduated scale, a second person at the study center will 
be asked to verify the reading and this verification will be noted in the source documents.8 
6.3.2.3. 
Maximal Inspiratory Pressure 
Maximal inspiratory pressure will be measured at Visit 2 (randomization). 
6.3.2.4. 
Peak Expiratory Flow 
Peak expiratory flow will be measured using a portable meter that will be given to participants at 
study entry. Participants will be trained on the use of the meter at Visit 1B and will begin 
measuring PEF each day thereafter before taking COPD medications or study medication 
(beginning Day 1) in the morning. On visit days, participants will bring this meter with them to 
the study center and perform the measurements in the presence of study center personnel. 
For each study-specified assessment, participants will take 3 measurements and record the 
highest value in the eDiary. 
6.3.3. 
Safety Assessments 
6.3.3.1. 
Adverse Events 
Adverse events will be reviewed and recorded beginning at screening (i.e., after signing the 
Informed Consent Form [ICF]) up to and including the telephone contact occurring 7 days after 
the last dose of study drug; AEs will also be reviewed and recorded at the early termination visit, 
at any unscheduled visits, and, for participants who discontinue due to an AE, 30 days after the 
date of discontinuation (Section 6.2.3). Adverse events may be observed by the study center 
personnel or spontaneously reported by the participant. Participants will be reminded to call the 
study center to report AEs that occur between visits. 
6.3.3.2. 
Physical Examination 
Physical examinations will include 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. 
6.3.3.3. 
Vital Signs 
Vital signs will be collected after the participant has been resting in a semirecumbent position for 
approximately 5 minutes. 
Blood pressure (BP), and heart rate (HR), will be recorded only once in the eCRF for each 
protocol specified time point; at screening only, a second measurement may be obtained to rule 
out sustained elevation/decrease of either systolic or diastolic blood pressure. BP will be 
measured manually using a mercury sphygmomanometer or calibrated automatic blood pressure 
device. HR will be measured by palpation of the radial pulse over a 60-second period or by the 
automated blood pressure device. 


 
 
 
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6.3.3.4. 
Pregnancy 
Urine pregnancy tests will be performed per the study center’s testing procedure in women of 
childbearing potential. A positive urine pregnancy test result will be confirmed with a second 
urine test. If the second test result is positive, blood will be collected for a serum pregnancy test 
assessed by the study center’s local lab. If the participant is an early termination or withdrawal, a 
urine pregnancy test will also be performed at the early termination visit. 
Refer to Section 6.7 for additional information on reporting pregnancy during the study. 
6.3.4. 
Clinical Outcome Assessments 
All clinical outcome assessments (Section 6.3.4.1 through Section 6.3.4.5) will be collected 
electronically. Paper diaries for albuterol use data collection will be available ad hoc only in 
instances where the electronic devices are not available. 
6.3.4.1. 
Baseline/Transitional Dyspnea Index 
The BDI has a scale of 5 grades, scored 0 to 4, for each of the following categories: functional 
impairment, magnitude of task, and magnitude of effort. The ratings for each of the 3 categories 
are added to give the total score (range, 0 to 12). 
For the TDI, using the scores of the BDI as a reference point after reminding the participant 
about the comments and choices made during the initial interview, the interviewer can choose a 
score of 0 (no change), improvements (1 to 3), or worsening (-1 to -3) for each of the 
3 categories leading to a total score of between -9 and +9. 
The BDI will be completed at randomization prior to dosing (Visit 2) using the site-based eDiary 
device. The TDI will be completed prior to dosing on Day 30 and Day 60 (Visits 3 and 4), and 
on Day 85 (Visit 5, or at early termination/withdrawal) using the site-based eDiary device. 
6.3.4.2. 
Chronic Obstructive Pulmonary Disease Assessment Test 
The CAT is a participant-completed instrument that complements existing approaches to 
assessing COPD, such as FEV1 measurement. Scores on the CAT range from 0 to 40 with higher 
scores indicating worse health status. 
The CAT will be completed prior to dosing at randomization, Day 30, and Day 60 (Visits 2, 3. 
and 4), and on Day 85 (Visit 5, or at early termination/withdrawal) using the eDiary device. 
6.3.4.3. 
Evaluation of Respiratory Symptoms in Chronic Obstructive Pulmonary Disease 
The E-RS:COPD is used to assess the severity of respiratory symptoms and the effect of 
treatment in patients with stable COPD. It includes 14 items based on breathlessness, sputum and 
cough, and chest symptoms. Participants will score all 14 items, of which only the first 11 items 
will be used to calculate the overall score. Most items are scored on a 5-point scale, although 
some are based on a 4-point scale. 
Participants will complete one E-RS:COPD assessment daily in the evening prior to bedtime 
using the eDiary device, including scheduled visit days. 


 
 
 
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6.3.4.4. 
Nocturnal Awakenings 
Each day before dosing, participants will answer a single question using their eDiary device 
about the number of awakenings due to COPD symptoms during the previous night. On visit 
days, participants will answer this question using their eDiary device before visiting the study 
center. 
6.3.4.5. 
Rescue Albuterol Use 
Participants will be dispensed albuterol MDI for use as rescue medication at each study visit 
(except Visit 1B for participants requiring two screening visits, Visit 5, or early termination 
visit). Starting at Visit 1B, participants will record the use of albuterol MDI in their eDiary 
(i.e., number of inhalations, time of day) which will be reviewed at each visit. Albuterol MDI use 
will be reviewed as part of drug accountability. 
6.3.5. 
 
 
 
 
 
 
 
 
 
 
 
 
6.4. 
Concomitant Medications 
Inhaled maintenance steroid therapy will be continued at the allowed maintenance dose 
throughout the treatment and washout periods. Albuterol MDI will be allowed as required 
(or “PRN”) during the study. Albuterol MDI should be withheld for at least 6 hours before the 
first spirometry performed at each study visit until all spirometry is completed. Only study 
supplied albuterol MDI should be used during the participant’s participation in the study. 
If participants have used albuterol MDI within 6 hours of the spirometry measurement the visit 
must be rescheduled. Use of albuterol MDI as a rescue inhaler will be documented in the eDiary 
and checked in the eCRF. 
Participants who are receiving a LABA or LABA/ICS (either QD or BID) may be enrolled into 
the study provided that the dose of the LABA and/or ICS component has been stable for at least 
30 days prior to Screening and the steroid component is ≤1000 mcg/day equivalent to fluticasone 
propionate. Once enrolled it is important to standardize administration of the participant’s LABA 
or LABA/ICS together with the study drug. These participants should administer their LABA or 
LABA/ICS in the morning immediately prior to the administration of study drugs. This 
administration should be documented in the source documents on study visit days and 
participants should be instructed to follow the same procedure while at home between study 
visits. If participants have used their LABA or LABA/ICS on the morning prior to their in-clinic 


 
 
 
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visit instead of taking it immediately prior to study drug at Visit 2, this visit will be rescheduled 
and the participant will be trained on the importance of not taking this the morning of the study 
visit. 
LABA and LABA/ICS drugs include the following examples: 
• fluticasone propionate/salmeterol combination product 
• budesonide/formoterol fumarate dihydrate combination product 
• fluticasone furoate/vilanterol combination product 
• mometasone/formoterol 
The initiation of new maintenance treatment for COPD during this study is strictly prohibited; 
new treatments for the duration of COPD exacerbations are permitted. Table 2 lists the 
medications that require washout prior to Randomization. These medications are also prohibited 
throughout the study (except for exacerbations). Participants will be permitted to restart their 
routine medications after the completion of Visit 5. 
Any concomitant medication taken within 60 days prior to signing of informed consent should be 
reported on the case report form for all randomized subjects.  For subjects who sign informed 
consent but who screen fail prior to randomization, the concomitant medication case report form 
is only required for subjects who report adverse events. 


 
 
 
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Table 2: 
List of Medications Requiring Washout (or Modification) Prior to Visit 1B 
and Prohibited During the Study 
Medication 
Washout Required (or Modification) and Prohibited 
Time Period 
• 
Any ICS at a dose of >1000 mcg/day fluticasone 
propionate or equivalent 
Participants on a dose >1000 mcg/day fluticasone 
propionate or equivalent are excluded. No modification 
of ICS dose will be allowed for those participants taking 
doses above this level.  
• 
LAMA - tiotropium (Spiriva®), glycopyrronium 
bromide, aclidinium, umeclidinium, revefenacin 
• 
roflumilast 
• 
LAMA/LABA combination product 
e.g. umeclidinium/vilanterol (Anoro®) 
• 
LAMA/ICS/LABA combination products, e.g., 
umeclidinium/vilanterol/fluticasone furoate 
(Trelegy®). 
Participants on a LAMA or roflumilast need to wash out 
48 hours prior to the Ipratropium Reversibility test at 
screening and prohibited during the course of the study 
through to Day 85. 
Participants on a LAMA/LABA combination need to be 
switched to the LABA only product at least 48 hours 
prior to the Ipratropium Reversibility test at screening 
and maintained during the course of the study through 
to Day 85. 
Participants on a LAMA/ICS/LABA combination need to 
be switched to the ICS/LABA product at least 48 hours 
prior to the Ipratropium Reversibility test at screening 
and maintained during the course of the study through 
to Day 85. 
• 
LABA - salmeterol, formoterol fumarate, 
arformoterol tartrate, indacaterol, vilanterol, 
olodaterol. 
• 
LABA/ICS products 
Participants on a LABA or LABA/ICS product do not 
need to be washed out provided they have been on a 
stable dose for at least 30 days prior to the Ipratropium 
Reversibility test at screening and this is continued 
through to Day 85. The steroid component should be 
≤1000 mcg fluticasone propionate or equivalent.  
• 
Oral theophyllines 
• 
Oral leukotriene inhibitors 
• 
Other antimuscarinic medications 
(e.g. atropine, cyclopentolate, homatropine, 
hyoscine, tolterodine, oxybutynin and/or 
tropicamide) 
48 hours prior to the Ipratropium Reversibility test at 
screening and prohibited during the course of the study 
through to Day 85. 
• 
Sodium cromoglycate 
• 
Nedocromil sodium 
24 hours prior to the Ipratropium Reversibility test at 
screening and prohibited during the course of the study 
through to Day 85. 
• 
Short acting beta-agonists 
• 
Short acting anti-muscarinics (e.g. ipratropium) 
6 hours prior to the Ipratropium Reversibility test at 
screening. Participants will be provided with albuterol 
MDI to be used as rescue medication during screening 
and throughout the course of the study. Albuterol MDI 
must be withheld at least 6 hours prior to any 
spirometry performed during the study. Short acting 
antimuscarinics must be washed out prior to the 
Ipratropium Reversibility test and are prohibited during 
the course of the study through to Day 85. 
• 
Antibiotics 
Any prophylactic use of antibiotics 
• 
OATP1B1 and OATP1B3 inhibitors (e.g., 
rifampicin, cyclosporine, etc.)  
Any concomitant use of these medications is 
prohibited. 


 
 
 
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Medication 
Washout Required (or Modification) and Prohibited 
Time Period 
Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic 
antagonist 


 
 
 
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Acetaminophen is the preferred drug for pain relief or to reduce fever. 
Prophylactic use of antibiotics, and concomitant use of OATP1B1 and OATP1B3 inhibitors are 
not permitted. 
Participants on Long Term Oxygen Therapy at 2 L/min or less will be permitted to enter the 
study. 
Participants will be provided with study-specific albuterol MDI for use as rescue medication in 
the study. 
In addition to the prohibited concomitant medications listed in Table 2, participants should not 
be taking any other prescription medications that are not part of a stable regimen. Prior to 
randomization, participants should not be considered eligible for the study if they have a known 
hypersensitivity to a similar drug class as revefenacin and/or a history of hypersensitivity to 
drugs with a clinically significant reaction. Any medications including PRN medications for 
conditions other than COPD must be reviewed with the investigator. 
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 participant being discontinued from the study. 


 
 
 
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6.5. 
Restrictions 
Participants are to observe the following restrictions from Screening through Day 85: 
• Use of recreational drugs 
• Medicinal marijuana 
• Excessive alcohol during the study period 
• Participation in another investigational drug study 
• Donation of ≥500 mL blood (or equivalent) 
During study visits (i.e. when the participant is at the study center), smoking, exercise, or 
caffeine intake or large meals should be restricted (further details are provided in the study 
manual). 
6.6. 
Discontinuation 
6.6.1. 
Participant Discontinuation 
Any participant (or his or her legally authorized representative) may withdraw their consent to 
participate in the study at any time without prejudice. The investigator must withdraw from the 
study any participant who requests to be withdrawn. A participant’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 early termination 
visit should be carried out. All efforts should be made however to minimize discontinuations 
from the study. If a participant withdraws before completing the study, the reason for withdrawal 
is to be documented on the CRF and the Sponsor retains the right to use the participant’s data 
through to the date the participant withdraws consent. 
Reasons for which the investigator or the Sponsor may withdraw a participant from the study or 
a participant may choose to terminate participation before completion of the study include, but 
are not limited to, the following: 
• AE 
• Participant choice (i.e., withdrawal of consent) 
• Major deviation from the protocol 
• Lost to follow-up 
• Termination of the study by the Sponsor 
• Other 
Participants who discontinue study drug early because of an adverse reaction should be 
encouraged to continue their participation in the follow-up safety assessments. A telephone 
follow-up visit will be conducted approximately 30 days after discontinuation to review 
concomitant medications and AEs if the discontinuation was due to an AE, in addition to the 
7-day Follow-up Telephone Contact. If a participant fails to return for scheduled visits, a 


 
 
 
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documented effort must be made to determine the reason. This will consist of at least 3 telephone 
calls followed by a registered letter to the participant. 
6.6.2. 
Participant Replacement 
The assumption is that the dropout rate will be approximately 20%. The target is at least 
146 participants completing 84 days (12 weeks) of therapy in each treatment group. Participants 
who withdraw will not be replaced in this study. 
6.6.3. 
Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. 
Certain circumstances may require the premature termination of the study, if the principal 
investigator and the Sponsor feel that the type, number and/or severity of AEs justify 
discontinuation of the trial, as for example, when several cases of similar SAEs (SUSARs) 
considered related by both the investigator and the Sponsor occurs. 
6.7. 
Pregnancy 
If a female participant becomes pregnant during the study, the clinical study director 
(or designee) must be notified immediately and the participant discontinued from the study. 
The Investigator must report the pregnancy to the Sponsor within 24 hours of becoming aware 
of the pregnancy using the Pregnancy Reporting Form. 
If not all information requested on the Pregnancy Reporting Form is available at the time of 
the initial report, the Investigator is required to follow up on the pregnancy until it has 
completed. Follow-up information regarding the outcome of the pregnancy, status of the 
newborn (if applicable), and any postnatal sequelae in the newborn will be required and must be 
submitted within 24 hours of the Investigator’s becoming aware of any new information using 
the Pregnancy Reporting Form. 
6.8. 
Exacerbation of Chronic Obstructive Pulmonary Disease 
COPD exacerbation is defined as a complex of respiratory symptoms (increase or new onset) of 
more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a 
duration of at least 3 days requiring treatment with short-acting beta-agonists, antibiotics, 
systemic steroids, or hospitalization. 


 
 
 
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Table 3: 
Severity Criteria for COPD Exacerbations 
Severity of COPD exacerbation 
Criteria 
Mild 
A deterioration of COPD symptoms, in the 
judgment of the investigator, managed with an 
increased use of short-acting beta-agonists but 
not requiring the use of antibiotics or oral or 
systemic corticosteroids. 
Moderate 
A deterioration of COPD symptoms, in the 
judgment of the investigator, based on any one 
of the following criteria: 
• 
An acute change in symptoms with purulent 
sputum requiring treatment with a course of 
antibiotics for lower airway disease 
• 
An acute change in symptoms requiring 
treatment with a course of oral steroid for 
lower airway disease 
Participants meeting the above criteria may 
receive treatment in a hospital setting as long as 
the duration of the visit is <1 day 
Severe 
A deterioration of COPD symptoms that results 
in hospitalization for emergency treatment of the 
COPD and the duration of the visit is ≥1 day.  
 
Participants will be questioned regarding having experienced moderate or severe exacerbations. 
Information on all exacerbations will be collected using a separate CRF. 


 
 
 
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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”, 
and guideline E6, “Good Clinical Practice.” 
7.1.1. 
Adverse Events (AEs) 
An AE is any untoward medical occurrence in a patient or clinical trial participant 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. Adverse events 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). 
• Clinically significant changes from baseline in physical examination, laboratory tests, 
or other diagnostic investigation (e.g., laboratory results, x-ray findings). 
• The 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 informed 
consent form 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 participant is hospitalized for observation 
Any medical condition or clinically significant laboratory abnormality with an onset date prior to 
the time the participant signed the informed consent form is considered to be preexisting and 
should be documented in the medical history CRF. 
Pregnancy is not an AE; however, if a female participant 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 7.5.3. Follow-up information regarding the outcome of 
the pregnancy and any fetal or neonatal sequelae will be obtained and documented. 


 
 
 
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Exacerbations of COPD (Section 6.8) will be collected as AEs. Details of the exacerbation event 
(e.g., symptoms, concomitant medication) will be recorded on a separate CRF. 
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 
participant 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. 
• Inpatient hospitalization or prolongation of existing hospitalization 
Note: “Inpatient hospitalization” means the participant has been formally admitted to 
a hospital for medical reasons, for any length of time. This may or may not be 
overnight. It does not include presentation and care within an emergency department. 
A scheduled hospitalization for a pre-existing condition that has not worsened during 
participation in the study does not meet this criterion. Pre-planned hospitalizations for 
an elective medical/surgical procedure, scheduled treatments, or routine check-ups do 
not meet this criterion. 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 participant 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 participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such events are as follows: 
− Intensive treatment in an emergency room or at home for allergic bronchospasm 
− Blood dyscrasias or convulsions that do not result in hospitalization 
− Development of drug dependency or drug abuse 
• Severe exacerbations of COPD, as described in Section 6.8 
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 participants if the death occurs 
while the person is participating in the study. 


 
 
 
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• “Occurring at any dose” does not imply that the participant 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. 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events 
Abnormal laboratory findings (such as clinical chemistry, hematology, or urinalysis) or other 
abnormal assessments (such as electrocardiograms, X-rays, or vital signs) that are associated 
with signs and/or symptoms or are considered clinically significant in the judgment of the 
investigator must be recorded as AEs or SAEs if they meet the definition of an AE (or SAE), as 
described in Section 7.1.1 (Adverse Events) and Section 7.1.2 (Serious Adverse Events). 
If there are any AE questions, the investigator is encouraged to contact the Sponsor to discuss. 
7.3. 
Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded in the case report form, including the 
dates of onset and resolution, severity, relationship to study drug, outcome, and action taken with 
study medication. 
7.3.1. 
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 participant/event outcome or action criteria usually associated with events that pose a threat to 
a participant’s life or functioning. The severity of AEs will be assessed according to the 
following definitions: 
• Mild: the AE is noticeable to the participant 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 participant’s ability to perform routine 
activities despite symptomatic therapy. 
7.3.2. 
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, 
co-morbid 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. 


 
 
 
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• 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 participant’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 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. 
7.4. 
AE Reporting and Recording 
7.4.1. 
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 standard operating procedures 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. 
7.4.2. 
AE and SAE Recording 
All AEs, regardless of seriousness, severity, or causal relationship to study medication, will be 
recorded from signing informed consent through the last study visit (or last participant contact in 
the case of a follow-up telephone call). Adverse events will be recorded on the AE page of the 
CRF. Serious AEs, regardless of relationship to study medication will be recorded from signing 
informed consent through the last study visit (or last participant contact in the case of a follow-up 
telephone call). Additionally, investigators may report SAEs assessed as related to study 
medication through 30 days following the last study visit (or last participant 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”). 


 
 
 
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• Hospitalization or surgical procedures should not be used as AE terms (e.g., if a 
participant was hospitalized for cholecystectomy due to cholecystitis, the AE term 
should be recorded as cholecystitis, and not as the procedure, cholecystectomy). 
• “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 
participant 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 make an assessment of the causal 
relationship of the study medication to the AE using the guidelines in Section 7.3.2. 
Severity: The severity of the AE will be assessed using the guidelines in Section 7.3.1. 
Outcome: The outcome of AEs will be recorded. 
Therapeutic measures: Measures taken for the treatment or management of the AEs will be 
recorded. 
7.4.3. 
SAE Reporting Timeline 
SAEs will be reported to Clinical Safety and Pharmacovigilance 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. If the initial SAE is reported by telephone, 
a written report signed by the Investigator must 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 the Serious Adverse Event Report Form to the following: 
Theravance Biopharma Clinical 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 when requested. Additional information may be requested from the investigator 
to ensure the timely completion of accurate safety reports. 


 
 
 
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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 revefenacin Investigator’s 
Brochure. In this case, all investigators will receive notification of the event. The investigator is 
responsible for notifying the Institutional Review Board or Ethics Committee and documenting 
the notification, as required by local regulatory authorities and in accordance with the local 
institutional policy. 
7.5. 
Adverse Event Follow-up 
A participant experiencing an AE or SAE will be followed by the investigator or his/her trained 
delegate(s) through the follow-up visit or until the investigator and/or the Sponsor has 
determined that the AE or 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. 
The investigator must take all therapeutic measures necessary for resolution of an SAE. Any 
medications necessary for treatment of the SAE must be recorded in the concomitant medication 
section of the case report form. 


 
 
 
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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
General Considerations 
All individual data will be listed as measured. All statistical summaries and analyses will be 
performed using SAS software (SAS Institute, Cary, North Carolina, USA) 9.4 or higher. 
Continuous data will be summarized using n, mean, standard deviation, and other descriptive 
statistics as appropriate. 
Categorical data will be summarized using the frequency of events and percentage of total 
events. 
Any changes to the protocol-specified analyses will be pre-specified in the Statistical Analysis 
Plan (SAP) prior to data lock/unblinding. 
8.2. 
Sample Size and Power 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.1. 
 
 
 
 
 
 
 
 
 
 
 
 The total number of participants will be capped up to a maximum sample 
size of 488 participants.
 
 
8.3. 
Analysis Sets 
The full analysis set (FAS) will include all randomized participants who: 
• Receive at least one dose of study drug (revefenacin or tiotropium) 
The FAS will be the primary analysis set for general and efficacy analyses. Participants will be 
analyzed according to their randomized treatment group. 


 
 
 
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The safety analysis set is the primary analysis set for safety analyses and will include all 
participants who are randomized and receive at least one dose of study drug. Participants will be 
analyzed according to their treatment actually received. 
8.3.1. 
Examination of Subgroups 
The following subgroups are pre-defined for the purposes of analyses: 
• Baseline PIFR: [a] < 40 L/min, [b] ≥ 40 L/min 
• Baseline smoking status: [a] current smoker, [b] former smoker 
• Age: [a] < 65, [b] ≥ 65 
• Gender: [a] woman, [b] man 
• Current LABA or ICS/LABA use: [a] yes, [b] no 
• Reversibility to a short-acting bronchodilator: [a] not reversible to ipratropium, [b] 
reversible to ipratropium 
• Baseline GOLD airflow category: [a] 3 (30% to < 50% of predicted normal FEV1), 
[b] 4 (< 30% of predicted normal FEV1) 
Additional subgroups may be specified in the SAP. 
8.3.2. 
Major Protocol Deviations 
The following protocol deviations are defined as major and would be considered to have an 
impact on the analysis of efficacy data. 
• Participant did not meet efficacy-defined inclusion criteria (Inclusion criteria 4, 5, 6) 
• Participant drug compliance < 80% or > 120% separately for DPI and nebulizer 
• Participant was taking a concomitant LAMA 
Additional criteria may be specified in the SAP. Major protocol deviations will be summarized 
but will not be used to exclude subjects from analyses. 
8.4. 
General Analyses 
8.4.1. 
Demographics and Other Baseline Characteristics 
Demographics (including age, sex, race, ethnicity, height, weight, and BMI) and baseline 
characteristics (concomitant LABA use) will be summarized for the FAS. 
8.4.2. 
Screening and Baseline Spirometry 
A summary of lung function at screening, including reversibility, and at baseline using the FAS 
will be provided. 
8.4.3. 
COPD Clinical History and Smoking History 
A summary of COPD clinical characteristics/history and smoking history using the FAS will be 
provided. 


 
 
 
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8.4.4. 
Medical History 
A summary of selected medical history/characteristics using the safety analysis set will be 
provided characterizing co-morbidities and disease severity. A summary of medical history by 
system organ class and preferred term will also be provided. 
8.4.5. 
Reversibility 
Reversibility to ipratropium is defined as a postbronchodilator increase of ≥ 12% and at least a 
200-mL increase in FEV1 relative to the prebronchodilator response. A summary will be 
provided for the FAS. 
8.5. 
Analysis of Efficacy 
For efficacy analyses, the FAS will be used unless otherwise specified. For the primary efficacy 
endpoint, subgroup analyses for the subgroups listed in Section 8.3.1 will be performed. 
8.5.1. 
Efficacy Endpoints 
The primary study endpoint is change from baseline in trough FEV1 on Day 85 following 
84 days of dosing. 
The secondary endpoints are as follows: 
• Trough overall treatment effect (OTE) on FEV1 over 85 days 
• Change from baseline in Trough FVC on Day 85 
• Change from baseline in Trough FEV1 on Day 30 
• Change from baseline in Trough FEV1 on Day 60 
• 80-mL response, defined as at least an 80-mL improvement in trough FEV1 on 
Day 85 
• Time to first CompEx event 
Exploratory endpoints are: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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8.5.1.1. 
Primary Efficacy Evaluation 
The primary estimate of interest, change from baseline in trough FEV1 on Day 85 after 84 days 
of dosing, is used to evaluate the effectiveness of revefenacin therapy relative to the active 
comparator of tiotropium. 
The null hypothesis for the treatment comparison will be that there is no difference between 
revefenacin and tiotropium in change from baseline in trough FEV1 on Day 85. The alternative 
hypothesis will be that there is a difference. 
For the primary endpoint, a repeated measures mixed effects model (RMMM) model will be 
used to estimate treatment differences. The model will include fixed class terms for randomized 
treatment group, ipratropium reversibility (reversible/not reversible), smoking status 
(current/former smoker), concomitant LABA or ICS/LABA use (Yes/No), GOLD (3/4), sex 
(woman/man), age (<65/≥65), and continuous covariates for baseline PIFR set to DISKUS® 
resistance and baseline FEV1, as well as a time effect (visit) and its interaction terms with 
treatment and the baseline values of the covariates. Within-subject correlation will be modelled 
using an unstructured variance-covariance matrix. The Kenward and Roger method for 
approximating the denominator degrees of freedom will be used. Least-squares (LS) means and 
95% confidence intervals (CIs) for LS mean differences between revefenacin and tiotropium will 
be calculated and presented in tabular and graphical format. Nominal p-values and CIs will be 
reported. 
For the primary and secondary endpoints, both treatment policy and efficacy estimands will be 
estimated, as detailed in the SAP. Treatment policy analyses will not exclude data collected 
following permanent discontinuation of study drug or initiation of new maintenance treatment 
for therapy. If the 2-sided 95% CI for the Day 85 revefenacin vs. tiotropium treatment policy 
estimand difference lies above zero, the primary endpoint will be considered to have been met 
and a tipping point analysis systematically varying assumptions about unobserved responses. 
8.5.2. 
Secondary 
 Efficacy Evaluations 
The following endpoints can all be estimated from the same model outlined for the primary 
analysis: 
• Change from baseline in Trough FEV1 on Day 30 
• Change from baseline in Trough FEV1 on Day 60 
• Trough overall treatment effect (OTE) on FEV1 over 85 days 


 
 
 
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Change from baseline in trough FVC on Day 85 will be analyzed using similar methodology as 
the primary endpoint. 
A responder analysis based on Day 85 trough FEV1 will be conducted using a logistic regression 
model with a similar set of covariates as the primary efficacy endpoint. A summary of 
responders will be presented with frequency distributions (counts and percentages), observed LS 
percentages and revefenacin:tiotropium odds ratios. 
A Cox proportional hazards model with the same covariates as the primary efficacy analysis 
model will be used to derive hazard ratios and analyze time to first event for CompEx COPD. 
A statistical hierarchy will be used to test the hypotheses of the primary and secondary endpoints 
to control the family-wise type 1 error rate at 5%. Details will be provided in the SAP. 
All efficacy endpoints will also be reported with nominal p-values, unless specified otherwise. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.5.3. 
Multiplicity Adjustment 
Multiplicity adjustment of p-values for the primary and secondary hypotheses will be conducted 
in a stepwise manner; full details of the testing procedure will be provided in the SAP. 
8.6. 
Safety Analyses 
The safety endpoints are the incidence of AEs (including exacerbations of COPD), and vital 
signs. For all safety analyses, the safety analysis set will be used. 
8.6.1. 
Extent of Exposure 
A participant’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 participants will be 
listed. Using drug administration data, estimates of exposure to revefenacin and tiotropium will 


 
 
 
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be summarized. Dose discontinuations and reasons for study drug discontinuation will be listed 
and summarized. 
8.6.2. 
Adverse Event Data 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will present by system organ class, preferred term, and 
severity, along with the frequency and percentage of participants reporting each observed event. 
Adverse events observed during the period from obtaining informed consent to the start of 
administration of study drug will be regarded separately from AEs observed after study drug 
administration (i.e., treatment-emergent adverse events [TEAEs]). 
A TEAE will be defined as any AE that begins on or after the date of first dose of study drug up 
to the date of last dose of study drug plus 7 days. AEs observed during the period from obtaining 
informed consent to the start of administration of study drug will be regarded separately from 
TEAEs. 
All AEs and all TEAEs will be listed by participant. The frequency of participants who 
experience TEAEs will be summarized overall and by treatment group. AEs will also be 
summarized by relationship to treatment (study drug) and severity. 
A listing will be provided for all participants who experience an SAE. Data listings will also be 
provided for participants who discontinued the study due to any AE, as well as for an SAE. 
8.6.3. 
Concomitant Medications 
Medications will be summarized both prior to and during the treatment period. Medications will 
be summarized as COPD bronchodilator, ICS and non-COPD medications. 
8.6.4. 
Vital Signs Data 
Vital signs data (heart rate and blood pressure) will be summarized in terms of observed values 
(by time point), changes from baseline (by time point), and counts and percentages based on 
clinically important thresholds (Table 4). 
Table 4: 
Clinically Important Thresholds for Vital Signs 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
<85 
>160 
<45 
>100 
8.7. 
Missing Data Handling 
Missing values for the primary and secondary spirometry efficacy endpoints will not be imputed 
except for the responder analysis, and any additional sensitivity analyses specified in the SAP. 
The responder analysis will impute missing data with a negative outcome of non-response. 
Details on sensitivity and supplementary analyses will be outlined in the SAP. 


 
 
 
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8.8. 
Data Monitoring Committee 
No data monitoring committee is planned for this study. 
The Sponsor will monitor trial data to ensure the safety of participants via periodic review and 
discussion of safety data collected during the trial. These discussions will take place 
approximately monthly once the trial has been initiated. 


 
 
 
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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 (PI) at each study center must provide to 
the Sponsor or its designee a fully executed and signed Form FDA 1572 and, if applicable, 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 participants 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 center 
to perform critical study-related procedures and/or to make important study-related decisions 
[e.g., associates, residents, research fellows].) 
The PI 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 participants. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential participants, 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. 
• 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. 
• He or she has read and understands the information in the revefenacin Investigator’s 
Brochure, 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 adequate and accurate records in accordance with 
21 CFR Part 312.62 and to make those records available for inspection in accordance 
with 21 CFR Part 312.68. 
• He or she will ensure that the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) complies with the requirements of 21 CFR Part 56, and other 
applicable regulations, and conducts initial and ongoing reviews and approvals of the 
study. He or she will also ensure that any change in research activity and all problems 
involving risks to human participants 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 
participants. 


 
 
 
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• 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. 
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 participants 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 
participant 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 study center, 
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 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 participant 
before enrollment of the participant into the study. 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. 
The investigator will provide copies of the signed ICF to each participant (or the participant’s 
legally authorized representative) and will maintain the original in the participant’s record file. 
9.4. 
Data Recording and Quality Assurance 
As used in this protocol, the term case report form (CRF) should be understood to refer to either 
a paper or electronic form or both, depending on the data collection method used. 
Electronic data capture (EDC) technology will be used for this study. All clinical information 
requested in this protocol will be recorded on the electronic case report forms approved by the 
Sponsor, or via other data collection methods. Examples of other methods include, but are not 
limited to, eDiary, electronic clinical outcomes assessment (eCOA), eConsent, and electronic 
laboratory data transfer. Study center personnel will enter (in English) study data into the CRFs 


 
 
 
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for each participant. Training on the EDC application, as well as any other system used for the 
capture of clinical data, will be completed and documented before access 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 study center 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 participant. The investigator is also responsible for ensuring the availability of 
any original source documentation related to the study (including any films, tracings, digital 
media, and worksheets). In most cases the source is the participant’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 study center and clearly identify those data that will be 
recorded in the CRF and for which the CRF will stand as the source document. In addition, any 
data entered directly by participants (e.g., eDiary data) will be considered source documentation. 
9.5. 
Document Retention 
Until otherwise notified by the Sponsor, an investigative study center must retain in a controlled 
manner all study documents required by the Sponsor and by the applicable regulations. The 
investigative study center 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., participant 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. 
9.6. 
Confidentiality 
The investigator or designee must explain to each participant, before enrollment into the study, 
that, for evaluation of study results, the participant’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/IEC/REB. 
The investigator (or designee) is responsible for obtaining written or electronic consent to use 
confidential medical information in accordance with country-specific regulations (such as the 


 
 
 
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Health Insurance Portability and Accountability Act in the United States) from each participant 
or, if appropriate, the participant’s legally authorized representative. If permission to use 
confidential medical information is withdrawn, the investigator is responsible for documenting 
that no further data from the participant will be collected. 
Participant 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 participant information will only be identified by 
the participant identification number, year of birth, and study number, and not by the 
participant’s full name, except the participant consent form, which is archived at the study center 
only. The participant’s name will not be used in any public report of the study. 
During the course of the study, a confidential participant identification list will be maintained by 
the investigator and archived at the investigative study center. 
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 participant’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 participant 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 from 
the medical records should be attributable (signed and dated), consistent with local medical 
practice. The investigator must therefore agree to allow direct access to all source data. 
Participants (or their legally authorized representatives) must also allow access to their medical 
records, and participants will be informed of this and will confirm their agreement when giving 
informed 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 standard operating procedures (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 study center visits conducted by the Sponsor or its designees. Access to 
clinical data may occur remotely based on site and local requirements if deemed necessary. 
Members of the Sponsor’s GCP Quality Assurance Department or designees may conduct an on-
site or remote audit of a clinical study center 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 


 
 
 
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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/REB 
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 center facilities, laboratory and all data (including 
original source documentation) and all study files are available, if requested. 
Noncompliance 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 noncompliance 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. 
REFERENCES 
1. Mahler DA, Waterman LA, Ward J, Gifford AH. Comparison of Dry Powder versus 
Nebulized Beta-Agonist in Patients with COPD Who Have Suboptimal Peak Inspiratory 
Flow Rate. J Aerosol Med Pulm Drug Deliv. 2014;27:103–109. 
2. Mahler DA, Ohar JA, Barnes CN, Moran EJ, Pendyala S, Crater GD. Nebulized Versus 
Dry Powder Long-Acting Muscarinic Antagonist Bronchodilators in Patients With COPD 
and Suboptimal Peak Inspiratory Flow Rate. Chronic Obstr Pulm Dis. 2019 Oct 
23;6(4):321-31. 
3. Loh CH, Peters SP, Lovings TM, Ohar JA. Suboptimal Inspiratory Flow Rates Are 
Associated with Chronic Obstructive Pulmonary Disease and All-Cause Readmissions. 
Ann Am Thorac Soc. 2017;14:1305–1311. 
4. 
 
 
5. Fuhlbrigge AL, Bengtsson T, Peterson S, Jauhiainen A, Erickson G, Da Silva CA, et al. 
A novel endpoint for exacerbations in asthma to accelerate clinical development: a 
posthoc analysis of randomized clinical trials. Lancet Respir Med. 2017;5:577-90. 
6. Da Silva CA, Bengtsson T, Peterson S, Karlsson N, Fageras M, Jauhiainen A. 
COPDCompEx: A Novel Composite Endpoint to Accelerate Early Clinical Development 
of New Agents for Treatment of COPD. Am J Respir Crit Care Med. 2018;197:A7428. 
7. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. 
Standardization of Spirometry 2019 Update. An Official American Thoracic Society and 
European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019 
Oct 15;200(8):e70-e88. 
8. Barnes CN, Mahler DA, Ohar JA, Lombardi DA, Crater GD. Defining Repeatability 
Limits for Measuring Peak Inspiratory Flow Rates (unpublished). 


 
 
 
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APPENDIX 1. PROTOCOL SIGNATURE FORM 
 
Protocol Signature Form 
 
Protocol #:  
0180 
Protocol Title:  
A Phase 4, Randomized, Double-Blind, Double-Dummy, Parallel-Group 
Study Comparing Improvements in Lung Function in Adults With Severe 
to Very Severe Chronic Obstructive Pulmonary Disease and Suboptimal 
Inspiratory Flow Rate Following Once-Daily Treatment Over 12 Weeks 
With Either Revefenacin Inhalation Solution Delivered via Standard Jet 
Nebulizer or Tiotropium Delivered via a Dry Powder Inhaler (Spiriva® 
HandiHaler®) 
Version: 
Amendment 4 
Version Date: 
27 Feb 2023 (FINAL) 
Supersedes 9 Feb 2022 
 
 
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: 
Protocol Number: 0180 
Official Title: A Phase 4, Randomized, Double-Blind, Double-Dummy, Parallel-Group, Study Comparing Improvements in Lung Function 
in Adults With Severe to Very Severe Chronic Obstructive Pulmonary Disease and Suboptimal Inspiratory Flow Rate Following Once-
Daily Treatment Over 12 Weeks With Either Revefenacin Inhalation Solution Delivered Via Standard Jet Nebulizer or Tiotropium 
Delivered Via a Dry Powder Inhaler (Spiriva® HandiHaler®) 
NCT Number: NCT05165485 
Document Date: 10 November 2023 


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STATISTICAL ANALYSIS PLAN 
Protocol Title: 
A Phase 4, Randomized, Double-Blind, Double-Dummy, 
Parallel-Group Study Comparing Improvements in Lung 
Function in Adults With Severe to Very Severe Chronic 
Obstructive Pulmonary Disease and Suboptimal Inspiratory 
Flow Rate Following Once-Daily Treatment Over 12 Weeks 
With Either Revefenacin Yupelri® Inhalation Solution 
Delivered via Standard Jet Nebulizer or Tiotropium Delivered 
via a Dry Powder Inhaler (Spiriva® HandiHaler®) 
Protocol Number: 
0180 
Compound Number: 
Revefenacin (YUPELRI®) 
Short Title 
PIFR-2 Study 
Sponsor Name: 
Theravance Biopharma Ireland Limited 
Legal Registered Address: 
Ten Earlsfort Terrace Dublin 2 
D02 T380 
Ireland 
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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SIGNATURE PAGE 
Compound YUPELRI® (revefenacin) 
Protocol Number 0180 
Author: 
Theravance Biopharma US, Inc. 
Reviewer: 
Theravance Biopharma US, Inc. 
Reviewer: 
Theravance Biopharma US, Inc. 


 
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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................8 
VERSION HISTORY ....................................................................................................................10 
1. 
INTRODUCTION ......................................................................................................14 
1.1. 
Objectives and Endpoints ...........................................................................................14 
1.1.1. 
Primary Objectives and Endpoints .............................................................................14 
1.1.2. 
Secondary Objectives and Endpoints .........................................................................15 
1.1.3. 
 .......................................................................16 
1.2. 
Study Design ...............................................................................................................17 
1.3. 
Treatment Assignment and Blinding ..........................................................................20 
1.4. 
Schedule of Assessments ............................................................................................21 
1.5. 
 ........................................................................................23 
1.5.1. 
 ...........................................................................23 
2. 
ANALYSIS SETS ......................................................................................................24 
3. 
STATISTICAL ANALYSES .....................................................................................25 
3.1. 
General Considerations ...............................................................................................25 
3.1.1. 
Table Columns ............................................................................................................25 
3.1.2. 
Baseline .......................................................................................................................25 
3.1.3. 
Change From Baseline ................................................................................................25 
3.1.4. 
Use of the Term Trough .............................................................................................25 
3.1.5. 
Use of the Term “Evaluable N” ..................................................................................26 
3.1.6. 
Evaluable Flags for Spirometry 
 Test Results ..........................26 
3.1.6.1. 
Spirometry Quality Grades .........................................................................................26 
3.1.7. 
Screening Visit ............................................................................................................27 
3.1.8. 
Variables .....................................................................................................................27 
3.1.8.1. 
Study Day ...................................................................................................................27 
3.1.8.2. 
Age ..............................................................................................................................27 
3.1.8.3. 
Height .........................................................................................................................27 
3.1.8.4. 
LABA or LABA/ICS Use ...........................................................................................27 
3.1.8.5. 
COPD Maintenance Therapy at Baseline ...................................................................28 
3.1.8.6. 
PIFR ............................................................................................................................28 


 
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3.1.8.7. 
FEV1 (Measured and Predicted Normal) ....................................................................29 
3.1.8.8. 
FEV1 % Predicted .......................................................................................................29 
3.1.8.9. 
FVC (Measured and Predicted Normal) .....................................................................30 
3.1.8.10. 
FEV1/FVC...................................................................................................................30 
3.1.8.11. 
MIP .............................................................................................................................30 
3.1.8.12. 
PEF .............................................................................................................................31 
3.1.9. 
Analysis Windows ......................................................................................................31 
3.2. 
General Analyses ........................................................................................................32 
3.2.1. 
Enrollment and Analysis Sets .....................................................................................32 
3.2.2. 
Disposition ..................................................................................................................33 
3.2.3. 
Demographic and Baseline Characteristics ................................................................34 
3.2.4. 
COVID-19 ..................................................................................................................36 
3.2.5. 
Protocol Deviations ....................................................................................................36 
3.2.6. 
Medical History ..........................................................................................................36 
3.2.7. 
Prior and Concomitant Medications ...........................................................................36 
3.3. 
General Considerations for Efficacy Analyses ...........................................................37 
3.3.1. 
Estimand Types for Quantitative Spirometry Endpoints ............................................37 
3.3.1.1. 
Treatment Policy Estimands .......................................................................................38 
3.3.1.2. 
Hypothetical Estimands ..............................................................................................39 
3.3.1.3. 
Primary Endpoint Definitions .....................................................................................39 
3.4. 
Primary Endpoint Analyses ........................................................................................39 
3.4.1. 
Definition of Primary Endpoint ..................................................................................40 
3.4.2. 
Statistical Hypotheses .................................................................................................40 
3.4.3. 
Main Analysis Methods ..............................................................................................40 
3.4.3.1. 
Figures ........................................................................................................................41 
3.4.3.2. 
Missing Data Handling ...............................................................................................41 
3.4.4. 
Sensitivity Analysis ....................................................................................................42 
3.4.5. 
Supplementary Analysis .............................................................................................43 
3.5. 
Secondary Endpoint Analyses ....................................................................................43 
3.5.1. 
Variable Definitions ....................................................................................................43 
3.5.2. 
Main Analysis Methods ..............................................................................................44 
3.5.2.1. 
Increase From Baseline in Trough FEV1 of ≥ 80 mL on Day 85 ...............................45 


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3.5.2.2. 
Time to First CompEx Event ......................................................................................45 
3.6. 
Multiplicity Adjustment..............................................................................................45 
3.7. 
 ..................................................................................46 
3.7.1. 
 
3.7.2. 
 
3.7.3. 
COPDCompEx Events and Moderate or Severe Exacerbations .................................47 
3.7.3.1. 
Time to First Event Summaries ..................................................................................47 
3.7.3.2. 
 
3.7.4. 
Peak Expiratory Flow .................................................................................................48 
3.7.5. 
 
3.7.5.1. 
 
3.7.5.2. 
 
3.7.6. 
 
3.7.6.1. 
 
3.7.6.2. 
 
3.7.7. 
Nighttime Awakenings ...............................................................................................50 
3.7.8. 
Evaluation of Respiratory Symptoms in COPD .........................................................51 
3.7.9. 
 
3.7.10. 
 
3.8. 
Safety Analyses ..........................................................................................................52 
3.8.1. 
Extent of Exposure .....................................................................................................53 
3.8.1.1. 
Treatment Compliance ................................................................................................53 
3.8.2. 
Adverse Events ...........................................................................................................54 
3.8.2.1. 
Adverse Events of Special Interest .............................................................................57 
3.8.3. 
Additional Safety Assessments...................................................................................57 
3.8.3.1. 
Clinical Laboratory Test Results ................................................................................57 
3.8.3.2. 
Vital Signs ..................................................................................................................57 
3.9. 
Other Analyses ............................................................................................................58 
3.9.1. 
Subgroup Analyses .....................................................................................................58 
3.10. 
Interim Analyses .........................................................................................................59 
3.10.1. 
Data Monitoring Committee .......................................................................................59 
4. 
REFERENCES ...........................................................................................................60 


 
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5. 
APPENDICES ............................................................................................................61 
5.1. 
Changes to Protocol-Planned Analyses ......................................................................61 
5.1.1. 
Changes to Protocol-Planned Analyses of Primary and Secondary Efficacy 
Endpoints ....................................................................................................................61 
5.2. 
 ..........................................................61 
5.3. 
Evaluation of Respiratory Symptoms in COPD .........................................................62 
5.4. 
CompEx Events ..........................................................................................................65 
5.4.1. 
Moderate or Severe Exacerbations .............................................................................65 
5.4.2. 
Combination Rule for Exacerbations ..........................................................................65 
5.4.3. 
Clinically Relevant Deterioration ...............................................................................66 
5.5. 
Missing Data Imputation Rules ..................................................................................67 
5.5.1. 
Adverse Events Severity and Relationship .................................................................67 
5.5.2. 
Missing Start and Stop Dates and Times for Adverse Events ....................................68 
5.5.3. 
Missing Start and Stop Dates for Prior and Concomitant Medications ......................70 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................8 
Table 2: 
Version History ...........................................................................................................10 
Table 3: 
Blinded Treatment Regimens .....................................................................................17 
Table 4: 
Schedule of Study Procedures ....................................................................................21 
Table 5: 
Analysis Sets ...............................................................................................................24 
Table 6: 
Spirometry Quality Grades for FEV1 and FVC (Graded Separately) .........................26 
Table 7: 
NHANES III Normal FEV1 Prediction Equations......................................................29 
Table 8: 
NHANES III Normal FVC Prediction Equations .......................................................30 
Table 9: 
Analysis Windows for In-Clinic Visit-Based Endpoints ............................................31 
Table 10: Analysis Intervals for Diary Endpoints ......................................................................32 
Table 11: Estimand Types ..........................................................................................................38 
Table 12: Study Discontinuation Reasons Classified As Treatment Failures ............................44 
Table 13: Heart Rate and Blood Pressure Ranges ......................................................................58 
Table 14: Subgroups ...................................................................................................................58 
Table 15: E-RS: COPD Scoring .................................................................................................62 
Table 16: Threshold and Slope Criteria for Diary Variables ......................................................66 


 
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Table 17: Threshold and Slope Intervals ....................................................................................66 
Table 18: Clinical Deterioration Slope Criteria for PEF, Rescue Medication Use, and 
Symptom Score ...........................................................................................................67 
 
LIST OF FIGURES 
Figure 1. 
Study Design Schema .................................................................................................19 
 


 
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LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation Description 
ANCOVA 
analysis of covariance 
ATS 
American Thoracic Society 
BID 
twice daily 
BDI 
Baseline Dyspnea Index  
CAT 
Chronic Obstructive Pulmonary Disease Assessment Test 
CI 
confidence interval 
CompEx 
composite endpoint for severe exacerbations of chronic obstructive pulmonary disease 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
DPI 
dry powder inhaler 
eDiary 
electronic diary 
E-RS: COPD 
Evaluating Respiratory Symptoms in COPD 
EXACT 
EXAcerbations of Chronic Pulmonary Disease Tool 
FEV1 
forced expiratory volume in 1 second 
FRC 
functional residual capacity 
FVC 
forced vital capacity 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
IC 
inspiratory capacity 
ICS 
inhaled corticosteroid 
LABA 
long-acting beta-2 agonist 
LAMA 
long-acting muscarinic antagonist 
MAR 
missing at random 
MDI 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
MIP 
maximal inspiratory pressure 
PEF 
peak expiratory flow 
PIFR 
peak inspiratory flow rate 


 
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Abbreviation Description 
QD 
once daily 
RTSM 
Randomization and Trial Supply Management 
SAP 
Statistical Analysis Plan 
TDI 
Transitional Dyspnea Index 
TEAE 
treatment-emergent adverse event 
TLC 
total lung capacity 
US 
United States 


 
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Theravance Biopharma US, Inc. 
10 November 2023 
Statistical Analysis Plan – Protocol 0180 
Page 10 of 70 
 
Confidential – Property of Theravance Biopharma, Inc. 
VERSION HISTORY 
This statistical analysis plan for Study 0180 is based on protocol Amendment 4 dated 
27 February 2023. 
Table 2: 
Version History 
SAP 
Version 
and 
Approval 
Date 
Protocol 
Version and 
Approval 
Date 
Changes 
Rationale 
1.0, 14 July 
2022 
Amendment 
3, 09 
February 
2022 
Not applicable 
Original version 
2.0, 27 
March 
2023 
Amendment 
4, 27 
February 
2023 
Revise Section 1.2, Study Design: 
No. of centers changed from 
approximately 40 to approximately 
70 
Minimum postipratropium FEV1 at 
screening changed from > 700 mL 
to > 500 mL for subjects with 
postipratropium % predicted 
normal FEV1 ≥ 30% 
Reflect protocol Amendment 4 
changes 
 
 
Minor editorial changes 
Remove ambiguities, increase 
consistency of usage, omit 
unnecessary information, add 
clarifying information 
 
 
Revise Section 2, Analysis Sets, to 
add a rescue analysis set 
Because analyses of rescue 
medication use are based on 
reported uses of the 
study-supplied albuterol MDI 
inhaler, exclude subjects who are 
using non-study-supplied rescue 
medication during the treatment 
period and subjects on 
maintenance regimens that will 
limit/confound their rescue 
medication use, such as albuterol 
QID 


TD-4208 
Theravance Biopharma US, Inc. 
10 November 2023 
Statistical Analysis Plan – Protocol 0180 
Page 11 of 70 
Confidential – Property of Theravance Biopharma, Inc. 
SAP 
Version 
and 
Approval 
Date 
Protocol 
Version and 
Approval 
Date 
Changes 
Rationale 
Revise Section 3.1.3, Variables, to 
mention that not only predicted 
normal FEV1 but also predicted 
normal FVC is included in 
spirometry data transfers; same 
revision to Section 3.1.8.9, FVC, 
with addition of NHANES III 
Normal FVC Prediction Equations 
Completeness: both screening 
(pre-ipratropium) FEV1 as a 
fraction of predicted normal FEV1 
and screening (pre-ipratropium) 
FVC as a fraction of predicted 
normal FVC are included in 
summaries of baseline 
characteristics 
Add Section 3.1.8.5, COPD 
Maintenance Therapy at Baseline, 
to provide a Yes/No indicator of 
whether subjects entered the 
treatment period on COPD 
maintenance therapy 
Subjects may enter the treatment 
period on a non-LABA or 
LABA/ICS regimen, e.g., ICS 
only, albuterol QID 
Revise Section 3.2.3, Demographic 
and Baseline Characteristics, to 
add FVC summaries corresponding 
to each FEV1 summary 
Provide a fuller picture of baseline 
spirometry values, since FVC is a 
secondary endpoint 
Revise Section 3.2.7, Prior and 
Concomitant Medications, to add a 
summary of COPD maintenance 
therapy at baseline 
Subjects may enter the treatment 
period on a non-LABA or 
LABA/ICS regimen, e.g., ICS 
only, albuterol QID 
Revise Section 3.4.3, Main 
Analysis Methods, to say the 
treatment policy estimand is 
considered primary, rather than the 
hypothetical estimand as in SAP 
v1.0 
Respond to regulatory comments 
Revise Section 3.4.4 to change the 
title from “Supplementary 
Analyses” to “Sensitivity 
Analysis” and to describe the 
tipping point analysis that will be 
provided to assess the sensitivity of 
the primary analysis result to the 
assumption that missing Day 85 
FEV1 measurements are missing at 
random (in the technical sense); 
add reference 
Respond to regulatory comments 


TD-4208 
Theravance Biopharma US, Inc. 
10 November 2023 
Statistical Analysis Plan – Protocol 0180 
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Confidential – Property of Theravance Biopharma, Inc. 
SAP 
Version 
and 
Approval 
Date 
Protocol 
Version and 
Approval 
Date 
Changes 
Rationale 
Revise Section 3.7.2, Rescue-free 
Days, to change "If the eDiary was 
completed for the day" to "If there 
are eDiary data for the day" 
The original text was unclear 
because what it means to 
"complete" the eDiary for a given 
day was not defined. It is assumed 
that if the subject was able to 
report other data using the eDiary 
data, the subject could and would 
have reported any uses of rescue 
medication. 
 
 
 
 
 
 
 
 
 
 
 
Revise Section 3.8.1, Extent of 
Exposure, to add that if the date of 
last dose is not reported it will be 
imputed as the date of study 
completion or discontinuation 
Some PIs may not wish to record 
an approximate last dose date 
when the actual last dose date is 
unknown 
Revise Section 3.8.1.1, Treatment 
Compliance, to state that 
compliance will be calculated only 
for subjects who return at least 1 
study drug kit 
Blinded data reviews have 
indicated that imputing all doses 
as taken when kits are not returned 
does not give credible compliance 
estimates for subjects who 
returned no kits. 
 
 
 
 
 
Revise Appendix 5.1, Changes to 
Protocol-Planned Analyses, to list 
changes to analyses described in 
protocol Amendment 4 
SAP v2.0 is based on Amendment 
4 


 
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10 November 2023 
Statistical Analysis Plan – Protocol 0180 
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SAP 
Version 
and 
Approval 
Date 
Protocol 
Version and 
Approval 
Date 
Changes 
Rationale 
3.0, 10 
November 
2023 
Amendment 
4, 27 
February 
2023 
Correct predicted FVC units in 
Table 8 footnote from mL to L 
Correct typo; the coefficients 
given in the reference are for FVC 
in liters 
 
 
Update MedDRA and WHODrug 
coding versions 
Bring text up to date; MedDRA® 
26.1 Q3 2023 and WHODrug Q3 
2023 C3 will be the versions in 
use at database lock 
 
 
Include the pre-ipratropium value 
as an additional baseline predictor 
in the models for FEV1 and FVC 
endpoints 
Increase precision of estimation 
and power by reducing residual 
variability 
 
 
Change the description of the 
calculation of predicted normal 
FEV1 (mL) in Section 3.1.8.7 to 
state that calculated values will be 
truncated to 1 decimal place rather 
than to an integer; same change for 
predicted normal FVC, 
Section 3.1.8.9 
Bring text up to date; the 
spirometry vendor changed the 
data transfer specification to add a 
decimal place 
 
 
Revise Section 2 analysis set 
definitions for all analysis sets 
except the enrolled and 
randomized sets to exclude 
subjects from sites 
 
 
Maintain reliability of inference 
by excluding data collected at sites 
where misconduct is suspected 
 
 
Change Section 3.6 endpoint 
testing sequence; move D85 FVC 
below D30 FEV1 and D60 FEV1 
Increase expected number of 
endpoints met 
 
 
Added Section 3.4.5 
Analysis to assess the impact of 
site exclusion 


 
TD-4208 
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10 November 2023 
Statistical Analysis Plan – Protocol 0180 
Page 14 of 70 
 
Confidential – Property of Theravance Biopharma, Inc. 
1. 
INTRODUCTION 
This document presents the plan for the summarization and analysis of clinical data collected in 
Study 0180. The study purpose is to assess whether COPD patients with severe to very severe 
disease (GOLD airflow category 3 or 4) and low inspiratory flow rates have greater 
improvements in trough FEV1 over an 84-day treatment period with revefenacin administered via 
nebulizer than with tiotropium administered via dry powder inhaler. Study 0180 is the successor 
to Study 0149, a study comparing the same 2 treatments over a shorter treatment period 
(28 days) in patients with low inspiratory flow rates and moderate to very severe disease (GOLD 
airflow category 2, 3, or 4). 
1.1. 
Objectives and Endpoints 
1.1.1. 
Primary Objectives and Endpoints 
The primary objectives of the study are as follows: 
• To characterize the relative efficacy on change from baseline in trough FEV1 on 
Day 85 of revefenacin inhalation solution administered once daily via nebulization 
(YUPELRI ®) compared to tiotropium powder for inhalation administered once daily 
(Spiriva® HandiHaler®) in adults with severe to very severe COPD who have 
impaired expiratory flow (i.e., FEV1 < 50% of predicted normal) and suboptimal peak 
inspiratory flow rate (PIFR) (i.e., PIFR < 55 L/min via In-Check™ device set to 
DISKUS® resistance) following 84 days of dosing 
• To evaluate the safety and tolerability of revefenacin inhalation solution administered 
in adults with severe to very severe COPD, impaired expiratory flow, and suboptimal 
PIFR 
The primary study endpoint is change from baseline in trough FEV1 on Day 85 following 
84 days of dosing. 
The safety endpoints are the incidence of adverse events (including exacerbations of COPD), and 
vital signs (heart rate and blood pressure). 


 
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10 November 2023 
Statistical Analysis Plan – Protocol 0180 
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1.1.2. 
Secondary Objectives and Endpoints 
The secondary objectives of the study are as follows: 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization compared 
to tiotropium administered once daily via HandiHaler® on average FEV1 across Days 
30, 60, and 85 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization compared 
to tiotropium administered once daily via HandiHaler® on trough FVC on Day 85 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization compared 
to tiotropium administered once daily via HandiHaler® on trough FEV1 on Day 30 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization compared 
to tiotropium administered once daily via HandiHaler® on trough FEV1 on Day 60 
• To evaluate the relative efficacy of once-daily revefenacin via nebulization to 
tiotropium administered once daily via HandiHaler® in achieving improvements in 
lung function of ≥ 80 mL, as measured by trough FEV1 on Day 85 
• To evaluate time to first CompEx (composite endpoint for moderate or severe 
exacerbations of COPD) event 
The secondary endpoints are as follows: 
• Trough overall treatment effect (OTE) on FEV1 over 85 days 
• Change from baseline in Trough FVC on Day 85 
• Change from baseline in Trough FEV1 on Day 30 
• Change from baseline in Trough FEV1 on Day 60 
• 80 mL response, defined as at least an 80 mL improvement from baseline in trough 
FEV1 on Day 85 
• Time to first CompEx (composite endpoint for exacerbations of COPD) event 
A CompEx event is defined as the first occurrence of a moderate or severe exacerbation or 
clinically relevant deterioration based on objective measures of deterioration in peak 
expiratory flow (PEF), rescue medication use, COPD symptoms, and nocturnal awakening. 
A moderate exacerbation is defined as an increase in symptoms that requires treatment with 
antibiotics and/or corticosteroids. A severe exacerbation is defined as a deterioration of 
COPD symptoms that results in hospitalization for emergency treatment of the COPD and 
the duration of the visit is ≥ 1 day, as recorded via CRF. 
Clinically relevant deteriorations are defined in Section 5.4.3. 


 
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10 November 2023 
Statistical Analysis Plan – Protocol 0180 
Page 16 of 70 
 
Confidential – Property of Theravance Biopharma, Inc. 
1.1.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Theravance Biopharma US, Inc. 
10 November 2023 
Statistical Analysis Plan – Protocol 0180 
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1.2. 
Study Design 
This is a phase 4, randomized, double-blind, active-controlled parallel trial conducted to compare 
the effects of once daily nebulized revefenacin (Yupelri) and once daily tiotropium (Spiriva) 
delivered via the HandiHaler® on lung function in subjects with severe to very severe COPD and 
a low PIFR over an 84-day treatment period. 
The study will be conducted at approximately 70 US centers. It is expected that approximately 
366 male and female subjects 40 years of age or older will be randomized in a 1:1 ratio to one of 
the treatment regimens shown in Table 3, to be followed for up to 84 days. 
 
 the total number of subjects randomized may be 
increased to at most approximately 488 subjects. 
Table 3: 
Blinded Treatment Regimens 
Revefenacin 
Tiotropium-matching placebo dry powder capsule administered by oral 
inhalation once every morning using the HandiHaler® device, followed by 
revefenacin solution (175 mcg in 3 mL) for oral inhalation by jet nebulizer 
Tiotropium 
Tiotropium dry powder capsule (Spiriva®, 18 mcg) administered by oral 
inhalation once every morning using the HandiHaler® device, followed by 
revefenacin-matching placebo solution (3 mL) for oral inhalation by jet 
nebulizer 


 
TD-4208 
Theravance Biopharma US, Inc. 
10 November 2023 
Statistical Analysis Plan – Protocol 0180 
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During screening, subjects are required to “wash out” from certain medications or take a lower 
dose. Subjects required to wash out or take a lower dose will have their screening procedures 
conducted over 2 screening visits, 1A and 1B, where 1B is 2 to 9 days after 1A; others may 
complete all screening procedures during their first screening visit. Subjects will be assessed for 
suboptimal PIFR using the InCheck™ device set to DISKUS resistance, undergo ipratropium 
reversibility testing, receive rescue medication (albuterol MDI) for use as needed during the trial, 
receive an electronic diary (eDiary) device provided by the electronic clinical outcome 
assessment contract research organization (CRO), and have their adverse events and medications 
reviewed. Subjects will also undergo clinical laboratory testing if laboratory test results from 
within the previous 3 months are unavailable and physical examinations including vital sign, 
height, and weight measurements. Women of childbearing potential will have a local urine 
pregnancy test. 
At the randomization visit on Day 1, subjects with PIFR < 55 L/min, with postipratropium FEV1 
< 50% of predicted normal (as calculated using NHANES III equations as described in 
Section 3.1.8.7) and > 500 mL (> 700 mL when postipratropium FEV1 < 30% of predicted 
normal), and who meet all other eligibility criteria will be randomized to revefenacin 
(revefenacin 175 mcg/tiotropium placebo) or tiotropium (tiotropium 18 mcg/revefenacin 
placebo). Subjects will undergo baseline lung function tests and clinical outcome assessments 
and have their eDiaries, concomitant medications, and adverse events reviewed. 
 
 
 After in-clinic assessments are completed, subjects will take their morning long-acting 
beta-2 agonist (LABA) or LABA-combination dose if they are on LABA therapy, followed by 
their first HandiHaler® study drug dose, followed by their first nebulizer study drug dose. 
Subjects will return to the clinic on Day 30 ± 7 days and Day 60 ± 7 days (Visits 3 and 4). 
eDiaries will be reviewed. Study drug and rescue medication will be accounted for, and new 
supplies will be dispensed. Adverse events and concomitant medications will be reviewed. 
Clinical outcomes and lung function will be assessed. 
 
 
Subjects will self-administer study medication once daily in the morning for 84 days, except on 
Days 30 and 60, when subjects will return to the study center for assessments prior to taking their 
study medication, and will record their HandiHaler® and nebulizer dosing times in their eDiary. 
Subjects will return to the clinic on Day 85 ± 7 days (Visit 5) for final assessments. Study drug 
and rescue medication will be accounted for and eDiaries, concomitant medications, and adverse 
events will be reviewed. Subjects will undergo a physical examination including vital signs. 
Clinical outcomes and lung function will be assessed. 
 
 
Subjects who discontinue from the study prior to Visit 5 will undergo the same procedures at an 
early termination visit. At 7 ± 2 days after the last visit, subjects will be contacted by telephone 
for an assessment of their adverse events. 


 
 
TD-4208 
Theravance Biopharma US, Inc. 
 
10 November 2023 
Statistical Analysis Plan – Protocol 0180 
 
Page 19 of 70 
 
Confidential – Property of Theravance Biopharma, Inc. 
Figure 1. 
Study Design Schema 
Visit 1A 
Visit 1B 
Visit 2 
Randomization 
Visits 3, 4, and 5 
Treatment Period 
(84 days) 
Follow-Up 
Phone Call 
Early Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs, adverse events; eDiary, electronic diary; PEF, peak expiratory flow; PIFR, peak inspiratory flow rate 
a Measured at Visits 2 and 5 in participants enrolled at selected study centers capable of performing these assessments 
Informed 
Consent 
Determine 
eligibility, 
including 
PIFR 
Dispense 
rescue 
medication 
Safety 
Baseline 
evaluations, 
including 
ipratropium 
reversibility 
and 
spirometry 
Dispense 
eDiary and 
PEF meter 
Safety 
Confirm eligibility 
Randomization and 
first dose 
Study drug and 
rescue medication 
accountability 
 
Lung function 
Lung volumesa 
Clinical outcomes 
Safety 
Revefenacin 
active 
Tiotropium 
Placebo 
Revefenacin 
Placebo 
Tiotropium 
active 
Study drug and 
rescue 
medication 
accountability 
Review eDiary 
Lung function 
Clinical 
outcomes 
Safety 
Dispense/ account 
for study drug and 
rescue medication 
Review eDiary 
Lung function 
Lung volumesa 
Clinical outcomes 
Safety 
Washout of 
COPD 
medications 
AEs 


 
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10 November 2023 
Statistical Analysis Plan – Protocol 0180 
Page 20 of 70 
 
Confidential – Property of Theravance Biopharma, Inc. 
1.3. 
Treatment Assignment and Blinding 
During the Day 1 visit, eligible subjects will be randomized in a 1:1 ratio to receive either 
revefenacin and dummy tiotropium or dummy revefenacin and tiotropium. The randomization 
will be stratified by ipratropium reversibility status (reversible/not reversible) and GOLD airflow 
category (3/4). Subjects in each of the 4 strata will be assigned to treatments using a sequence of 
randomly permuted blocks. Enrollment of GOLD 4 (FEV1 < 30% of predicted normal) subjects 
will be capped at 30% to reflect what is expected in the population with severe to very severe 
COPD. 
Revefenacin will be supplied as 3 mL of solution packaged in a unit-dose low-density 
polyethylene vial with a twist-off top overwrapped in a foil pouch. Matching placebo will be 
identically packaged and supplied as 3 mL of solution without the drug substance. Each kit will 
contain 35 vials. At the Day 1 visit, subjects will also be provided with a PARI LC Sprint® 
nebulizer with PARI Trek S® compressor and connector tubing. 
Tiotropium will be supplied as kits containing 1 HandiHaler® device and 4 blister cards with 
10 capsules each, containing either 18 mcg Spiriva® dry powder or matching placebo. 
Subjects will administer tiotropium or matching placebo using a HandiHaler® device before 
administering revefenacin or matching placebo using the PARI LC Sprint® nebulizer. 
If they are taking a LABA, the sequence of drug administration will be LABA, followed 
immediately by tiotropium/placebo, followed by revefenacin/placebo. On in-clinic visit days, 
they will follow this sequence in the clinic; between visits, they will dose themselves every 
morning at approximately the same time within the window of 6:00 AM to 11:00 AM. The time 
will remain the same for the duration of the study. Subjects will record the time of administration 
(both HandiHaler® dosing time and nebulizer start time) in their eDiary. Only one pair of times 
can be recorded each day. 
Before database lock, access to randomized treatment assignments will be limited to certain 
randomization and trial supply management (RTSM) system personnel, investigators, and certain 
sponsor drug safety personnel. Investigators may use the RTSM system to obtain a subject’s 
randomized treatment assignment only in an emergency requiring the investigator to be 
unblinded. Drug safety personnel may use the RTSM system to obtain randomized treatment 
assignments for individual subjects only as needed to fulfill their reporting requirements. Any 
such individual-subject unblindings will be captured in the RTSM database. Any 
investigator-initiated unblindings will also be captured in the clinical database. 


 
 
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10 November 2023 
Statistical Analysis Plan – Protocol 0180 
 
Page 21 of 70 
 
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1.4. 
Schedule of Assessments 
Table 4: 
Schedule of Study Procedures 
Procedures 
Visit 
1A 
Visit 1B 
(5 ± 2 to  
7 ± 2 days 
after Visit 
1Aa) 
Day 1 
(Visit 2) 
Randomization 
(3 to 7 days after 
screening completed) 
Day 30 
(Visit 3)  
± 7 days 
Day 60 
(Visit 4)  
± 7 days 
Day 85 
(Visit 5) 
± 7 days 
Follow-Up 
Phone call 
7 days after 
last visit 
± 2 days 
Early 
Termination / 
Withdrawal 
Unscheduled 
Visit 
Informed Consentb 
X 
 
 
 
 
 
 
 
 
Medical and Medication History 
X 
 
 
 
 
 
 
 
X 
Washout of COPD Medicationsa 
X 
 
 
 
 
 
 
 
 
Physical Examination 
 
Xc 
 
 
 
X 
 
X 
X 
Height and Weight 
 
Xc 
 
 
 
 
 
 
 
Vital Signs 
 
Xc 
X 
 
 
X 
 
X 
X 
Inclusion / Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
Xd 
X 
X 
X 
 
X 
 
Ipratropium Reversibilitye 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
Xf 
 
 
 
 
 
 
Dispense eDiary 
 
X 
 
 
 
 
 
 
 
Review eDiary 
 
 
X 
X 
X 
X 
 
X 
 
Dispense Study Drug 
 
 
X 
X 
X 
 
 
 
 
Dispense Rescue Medication 
X 
 
X 
X 
X 
 
 
 
 
Study Drug/Rescue Medication 
Accountability 
 
 
X 
X 
X 
X 
 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local Lab Tests for creatinine. 
hematocrit, ALT, AST, bili, alk 
phosg 
X 
 
 
 
 
 
 
 
 
BDI 
 
 
X 
 
 
 
 
 
 
TDI 
 
 
 
X 
X 
X 
 
X 
 
PIFR 
X 
Xh 
X 
 
 
 
 
 
 
MIP 
 
 
X  
 
 
 
 
 
 
CAT 
 
 
X 
X 
X 
X 
 
X 
 
Predose Spirometry (FEV1, 
FVC) at 45 and 15 min predose 
 
Xi 
X 
X 
X 
Xj 
 
Xj 
Xj 
PEFk 
 
X 
X 
X 
X 
X 
 
X 
X 
E-RS: COPDl 
 
X 
X 
X 
X 
 
 
 
 
Nocturnal Awakenings Question 
 
X 
X 
X 
X 
X 
 
X 
X 


 
 
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Statistical Analysis Plan – Protocol 0180 
 
Page 22 of 70 
 
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Procedures 
Visit 
1A 
Visit 1B 
(5 ± 2 to  
7 ± 2 days 
after Visit 
1Aa) 
Day 1 
(Visit 2) 
Randomization 
(3 to 7 days after 
screening completed) 
Day 30 
(Visit 3)  
± 7 days 
Day 60 
(Visit 4)  
± 7 days 
Day 85 
(Visit 5) 
± 7 days 
Follow-Up 
Phone call 
7 days after 
last visit 
± 2 days 
Early 
Termination / 
Withdrawal 
Unscheduled 
Visit 
Plethysmography (IC, FRC, 
TLC) at 45 and 15 min predosem 
 
 
X 
 
 
Xj 
 
 
 
LABA Dosing (if applicable) 
 
 
X 
X 
X 
X 
 
 
 
Study Drug Dosingn 
 
 
X 
X 
X 
 
 
 
 
Train on HandiHaler®, 
Nebulizer  
 
 
X 
 
 
 
 
 
 
Dispense PEF Meter/Train 
Participants on Use 
 
X 
 
 
 
 
 
 
 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Alk phos, alkaline phosphatase; BDI, Baseline Dyspnea Index; bili, bilirubin; 
COPD, chronic obstructive pulmonary disease; CAT, Chronic Obstructive Pulmonary Disease Assessment Test; eDiary, electronic diary; E-RS: COPD, 
Evaluating Respiratory Symptoms in COPD assessment; FEV1, forced expiratory volume; FRC, functional residual capacity; FVC, forced vital capacity; IC, 
inspiratory capacity; INR; International Normalized Ratio; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; MIP, maximal 
inspiratory pressure; PEF, peak expiratory flow; PIFR, peak inspiratory flow rate; TDI, Transitional Dyspnea Index; TLC, total lung capacity 
a For participants who require washout of certain COPD medications as specified in protocol Table 2. For participants not requiring washout, Visit 1B can be 
combined with Visit 1A if participant does not require washout of COPD medications. 
b The research site will follow institutional and government guidelines/precautions regarding Coronavirus Disease 2019 (COVID-19) to reduce the risk of 
infection for study participants and study staff. 
c Performed/collected prior to ipratropium dosing. Vital signs (heart rate and blood pressure) will be measured after resting in a semi-recumbent position for 
approximately 5 minutes. 
d Performed if visit is more than 7 days after Visit 1A. 
e Consult study manual. 
f Participant eligibility must be confirmed by investigator before randomizing the participant. 
g If data from any time during the previous 3 months are not available. INR and albumin collection to determine Child-Pugh score for exclusion is at the 
investigator's discretion. 
h Participants who required a washout of a LAMA must have PIFR < 55 L/min at this visit. 
i Reversibility testing pre- and postipratropium after withholding bronchodilators as specified in protocol Table 2. Spirometry will be performed predose and 
45 minutes postdose (± 10 minutes) at this visit (whether or not it is combined with Visit 1A). 
j There is no dosing at this visit. Spirometry and plethysmography will be performed at 2 time points 30 minutes apart. 
k Performed after predose spirometry at the study center during all study visits beginning with Visit 1B. Participants will receive the portable meter and be 
trained on its use at Visit 1B for subsequent use at home between visits. 
l Before bedtime on the evening prior to the visit 
m Measured in participants enrolled at selected centers capable of performing these assessments. Assessments will be done immediately after PIFR assessment. 
n Between 6:00 am and 11:00 am local time 


 
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Statistical Analysis Plan – Protocol 0180 
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1.5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Statistical Analysis Plan – Protocol 0180 
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2. 
ANALYSIS SETS 
Table 5: 
Analysis Sets 
Analysis Set 
Definition 
Enrolled 
All enrolled subjects. Subjects enroll by consenting to participate in the study. 
Randomized 
All randomized subjects 
Interim 
The first 100 randomized subjects who receive at least 1 dose of study drug (via 
HandiHaler® or nebulizer) (Section 5.2) 
Safety* 
All randomized subjects who receive at least 1 dose of study drug (via 
HandiHaler® or nebulizer) 
Full* 
All randomized subjects who receive at least 1 dose of study drug (via 
HandiHaler® or nebulizer) (same as safety analysis set) 
Rescue* 
A subset of the full analysis set which excludes subjects who are on a SABA 
maintenance regimen at baseline (e.g., albuterol QID) and subjects who use non-
study-supplied rescue medication (e.g., nebulized albuterol) during the treatment 
period, to be used for analyses of rescue medication use and CompEx events 
 
 
 
 
*Sites 
 were excluded from analysis on the grounds of potential 
misconduct, as described in: 
PIFR-2 INDEPENDENT SPIROMETRY AND DATA ASSESSMENT FINAL 
INVESTIGATION REPORT 
Unless otherwise specified, efficacy summaries will be based on the full analysis set 
 
. SDTM and ADaM datasets will include data for site 
 and site 
 subjects and a listing of treatment-emergent adverse events 
reported for site 
 and site 
 subjects will be provided. 


 
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Statistical Analysis Plan – Protocol 0180 
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3. 
STATISTICAL ANALYSES 
3.1. 
General Considerations 
All data from both scheduled and unscheduled visits will be presented in data listings. 
However, unless noted otherwise, only data from visits (scheduled or unscheduled) that 
fall within analysis windows will be included in summaries, statistical analyses, and 
calculations of derived variables. The analysis windows are defined in Section 3.1.9. 
Analyses will be performed and tabulations will be prepared using SAS®, version 9.4. 
The SAS/STAT version will be 15.1. 
3.1.1. 
Table Columns 
Summary tables will include the following columns: 
• Tiotropium 18 mcg 
• Revefenacin 175 mcg 
• Total (required only for Section 3.2 summaries, exposure summaries, and 
compliance summaries) 
3.1.2. 
Baseline 
In general, “baseline” denotes the last measurement or assessment obtained before the 
start of study drug dosing. Both baseline and postbaseline FEV1, FVC, and lung volume 
values are calculated by averaging 2 values collected approximately 30 minutes apart. 
3.1.3. 
Change From Baseline 
Change from baseline is calculated as postbaseline value – baseline value. 
3.1.4. 
Use of the Term Trough 
For a given dosing regimen (e.g., QD, BID), trough measurements are measurements 
made when drug concentrations are at their lowest. In this study, since both dosing 
regimens are QD, trough measurements are measurements made approximately 24 hours 
after the most recent study drug dosing. The operational definition of “approximately 
24 hours” will be spirometry start time, defined as the time of the earliest 45 Minutes 
Predose/Time Point 1 effort within a testing session, within 24 ± 6 hours of HandiHaler® 
start time. If it is unclear whether this condition was met, e.g., because the subject did not 
complete the dosing diary the day before the spirometry visit, it will be assumed to have 
been met. 
 
 


 
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3.1.5. 
Use of the Term “Evaluable N” 
The term “Evaluable N” may be used in summaries presenting results of model-based 
analyses. The evaluable n is the number of subjects contributing information to the 
model-based treatment difference estimates, in the sense that excluding the subject’s data 
could alter the estimate. 
3.1.6. 
Evaluable Flags for Spirometry
 Test Results 
Spirometry 
 analysis variable values will be assigned the following 
flags as applicable (as many as apply): 
• NT for non-trough (see Section 3.1.4) 
• RM for protocol-disallowed rescue medication use (protocol definition: use of 
albuterol MDI within 6 hours of spirometry start time; operational definition: 
use of albuterol MDI within 5 hours of spirometry start time) 
• CM for confounding use of systemic corticosteroids or any medication listed 
as prohibited except during exacerbations in protocol Table 2 
• NS for evaluable but not selected for analysis, e.g., because there were 
multiple evaluable visits within the applicable analysis visit window 
Except as indicated for treatment policy analyses, flagged analysis variable values will be 
excluded from analysis. 
3.1.6.1. 
Spirometry Quality Grades 
Screening Visit 1B ipratropium reversibility spirometry must receive a grade of A or B 
for FEV1 and FVC for both pre- and postipratropium stages for the subject to be 
considered eligible for randomization. All other spirometry sessions must receive a grade 
of A, B, or C. The American Thoracic Society (ATS) quality standards (Standardization 
of Spirometry 2019 Update) applied are shown in Table 6: 
Table 6: 
Spirometry Quality Grades for FEV1 and FVC (Graded Separately) 
Quality 
Grade 
Description 
A 
2019 ATS/ERS criteria: At least 3 acceptable values with the highest 2 within 
150 mL of each other 
B 
Only 2 acceptable values and they are within 150 mL of each other 
C 
At least 2 acceptable values with the highest 2 within 200 mL of each other 
D 
At least 2 acceptable values with the highest 2 within 250 mL of each other 
E 
Only 1 acceptable value 
F 
No acceptable values 


 
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3.1.7. 
Screening Visit 
For measurements such as PIFR which are collected at both Visit 1A and Visit 1B (e.g., 
for subjects who need to complete a washout or dose-reduction period) the value selected 
for “Screening Visit” summaries will be the value from the second screening visit. 
3.1.8. 
Variables 
3.1.8.1. 
Study Day 
Study Day 1 is defined as the day of the first dose of study drug (revefenacin, revefenacin 
placebo, tiotropium, or tiotropium placebo). Study Day -1 is the day before. 
3.1.8.2. 
Age 
The subject’s full date of birth (year, month, and day) is captured in the spirometry 
database at Visit 1A and used to calculate the subject’s predicted normal FEV1 and FVC 
as a function of age, sex, height, and race/ethnicity. The subject’s birth year as integrated 
from the RTSM database is used to populate the birth year field on the Demographics 
case report form, and age in years at Visit 1A is entered at the site. This site-reported age 
will be used in listings, summaries, and analyses. 
3.1.8.3. 
Height 
The subject’s height in centimeters to 1 decimal place is captured in the spirometry 
database at Visit 1A and used in the calculation of the subject’s predicted normal FEV1 
and FVC. The subject’s height in centimeters to 1 decimal place is also captured in the 
Vital Signs - Screening eCRF at Visit 1B. For subjects whose 1A and 1B visits were not 
completed on the same day, the values may differ. The eCRF value will be used for vital 
signs listings and summaries and to calculate body mass index. 
3.1.8.4. 
LABA or LABA/ICS Use 
For summaries of LABA or LABA/ICS use at baseline, the following categories will be 
used: 
• None 
• LABA 
• LABA/ICS 
Subjects on a LABA or LABA/ICS regimen at baseline are expected to maintain their 
dosing regimen while on study drug and take their first or only LABA dose of the day 
immediately before the start of study drug dosing. 
For model-based analyses, the LABA and LABA/ICS categories will be collapsed: 
LABA or LABA/ICS use will be treated as a Yes/No variable. 


 
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3.1.8.5. 
COPD Maintenance Therapy at Baseline 
For baseline summaries and to facilitate exploratory analyses, a COPD maintenance 
therapy at baseline indicator variable (Yes/No) will be provided. Subjects will be counted 
as receiving background COPD maintenance therapy at baseline if the concomitant 
medications log has any entry with indication COPD and frequency other than PRN and a 
dosing period that includes Day 1. 
3.1.8.6. 
PIFR 
Subjects who at the time of screening are taking COPD medications requiring a washout 
or dose reduction will have 2 screening visits (1A and 1B) and will have PIFR measured 
at each visit. Subjects who do not require a washout or dose reduction may have their 
screening visits combined into one. On each screening occasion, subjects will perform 
3 maneuvers using an In-Check® device set to match the airflow resistance of a Diskus® 
inhaler. The device measures peak flow as an integer ranging from 15 to 120 L/min. All 
3 measurements will be captured and their maximum will be used for analysis. To be 
eligible, subjects requiring washout must have a maximum value of < 60 L/min at the 1A 
visit and < 55 L/min at the 1B visit; subjects who complete a single screening visit must 
have a maximum value < 55 L/min. 
At Visit 2 (Day 1), subjects will perform 3 maneuvers using an In-Check® device set to 
match the airflow resistance of a Diskus® inhaler, followed by 3 more maneuvers with 
the device set to match the airflow resistance of a Spiriva HandiHaler®. To be eligible, 
subjects must have a maximum Diskus® resistance value < 55 L/min. The maximum 
Diskus® resistance value will be summarized, used for efficacy analyses as a covariate, 
and used to define baseline PIFR subgroups. The maximum Spiriva HandiHaler® value 
will be summarized (Section 3.2.3). 


 
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3.1.8.7. 
FEV1 (Measured and Predicted Normal) 
Forced expiratory volume in 1 second (FEV1) (best effort) will be captured in mL to 
0 decimal places. The time of the maneuver will also be captured. The spirometry CRO 
will derive predicted normal FEV1 at Visit 1A using a prediction equation based on 
NHANES III survey data which is a function of sex (male or female), height in cm (136.0 
to 202.0), race/ethnicity (African American, Asian, Caucasian, Mexican American, or 
Other [Caucasian Predictor applied]), and age at visit (integer) as calculated from visit 
date and birth date (Hankinson et al. 1999, Hankinson et al. 2010). The calculated FEV1 
in mL will be truncated to 1 decimal place. The prediction equation coefficients are 
shown in Table 7. 
Table 7: 
NHANES III Normal FEV1 Prediction Equations 
Sex 
Race 
Intercept 
Age 
Age2 
Height2 
Male 
Caucasian 
553.60000 
-13.03000 
-0.17200 
0.14098 
Female 
Caucasian 
433.30000 
-3.61000 
-0.19400 
0.11496 
Male 
African 
American 
341.10000 
-23.09000 
0.00000 
0.13194 
Female 
African 
American 
343.30000 
-12.83000 
-0.09700 
0.10846 
Male 
Mexican 
American 
630.60000 
-29.28000 
0.00000 
0.15104 
Female 
Mexican 
American 
452.90000 
-11.78000 
-0.11300 
0.12154 
Age units: yr; height units: cm; predicted FEV1 units: mL. 
The prediction equations are based on samples of male subjects aged 20 to 80 and female subjects aged 18 
to 80. 
The Asian correction recommended in Hankinson et al. 2010 is applied by multiplying the Caucasian 
prediction by 0.88. 
3.1.8.8. 
FEV1 % Predicted 
FEV1 as a percentage of the predicted value will be derived by the spirometry CRO as 
FEV1 divided by the predicted normal FEV1 for the subject, converted to a percentage 
and truncated to 1 decimal place. (The calculation is performed before predicted normal 
FEV1 is truncated.) 


 
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3.1.8.9. 
FVC (Measured and Predicted Normal) 
Forced vital capacity (FVC) (best effort) will be captured in mL to 0 decimal places. The 
time of the best-effort maneuver may differ from the time of the best-effort FEV1 
maneuver. The spirometry CRO will derive predicted normal FVC at Visit 1A using a 
prediction equation based on NHANES III survey data which is a function of sex (male 
or female), height in cm (136.0 to 202.0), race/ethnicity (African American, Asian, 
Caucasian, Mexican American, or Other [Caucasian Predictor applied]), and age at visit 
(integer) as calculated from visit date and birth date (Hankinson et al. 1999, Hankinson et 
al. 2010). The calculated FVC in mL will be truncated to 1 decimal place. The prediction 
equation coefficients are shown in Table 8: 
Table 8: 
NHANES III Normal FVC Prediction Equations 
Sex 
Race 
Intercept 
Age 
Age2 
Height2 
Male 
Caucasian 
-0.1933 
0.00064 
-0.000269 
0.00018642 
Female 
Caucasian 
-0.3560 
0.01870 
-0.000382 
0.00014815 
Male 
African 
American 
-0.1517 
-0.01821 
0 
0.00016643 
Female 
African 
American 
-0.3039 
0.00536 
-0.000265 
0.00013606 
Male 
Mexican 
American 
0.2376 
-0.00891 
-0.000182 
0.00017823 
Female 
Mexican 
American 
0.1210 
0.00307 
-0.000237 
0.00014246 
Age units: yr; height units: cm; predicted FVC units: L. 
The prediction equations are based on samples of male subjects aged 20 to 80 and female subjects aged 18 
to 80. 
The Asian correction recommended in Hankinson et al. 2010 is applied by multiplying the Caucasian 
prediction by 0.88. 
3.1.8.10. FEV1/FVC 
The ratio of the best-effort FEV1 to the best-effort FVC will be derived by the spirometry 
CRO as a decimal fraction, truncated to 3 decimal places. 
3.1.8.11. MIP 
MIP, which stands for maximal (or maximum) inspiratory pressure, will be measured 
using a handheld pressure meter, the MicroRPM meter, which has a digital display 
showing results in cmH2O (water pressure units). MIP will be collected only at Visit 2 
(Day 1), after PIFR assessment and immediately after completion of 45 minutes predose 
spirometry (Spirometry Reference Manual). To perform a MIP maneuver, subjects will 
insert and position the meter’s mouthpiece, exhale completely, and then inhale as 
strongly as they can for as long as possible (a minimum of 2 seconds). Subjects will 


 
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perform 3 or more MIP maneuvers and the starting time and highest measurement (nnn) 
will be captured in the spirometry CRO database. 
For summarization, values reported as 0, if any, will be treated as missing. 
3.1.8.12. PEF 
Peak expiratory flow (PEF) will be measured using a handheld flow meter, the 
Vitalograph® asthmaPLAN meter, which has a scale ranging from 50 to 800 L/min 
marked in 10-L/min increments from 50 to 700 L/min and in 20-L/min increments up to 
800 L/min. Subjects enrolled under protocol versions earlier than Amendment 3 will be 
trained on the use of the PEF meter during the Day 1 visit, will record their highest of 
3 peak flow measurements in the eDiary before taking their first study drug dose, and will 
repeat this procedure each day through the Day 85 or early termination visit before taking 
their study medication in the morning. On visit days, subjects will bring their flow meters 
to the study center and measure their peak flow in the presence of study center personnel. 
Reported PEF values as captured by the eDiary will be integers in the range 0 to 999. 
Subjects enrolled under protocol Amendment 3 and later protocol versions will be trained 
on the use of the PEF meter at Visit 1B and will record their highest of 3 peak flow 
measurements in the eDiary during the visit and each subsequent morning through the 
Day 85 or early termination visit. Subjects will use their PEF meters following 
spirometry on spirometry visit days and before study drug dosing on study drug dosing 
days. 
For summarization and analysis, reported PEF values > 0 and < 50 will be set to 49 and 
values > 800 will be set to 801. Values reported as 0, if any, will be treated as missing. 
3.1.9. 
Analysis Windows 
Endpoints assessed at in-clinic visits will be summarized using analysis windows. Except 
as otherwise specified, only data collected within analysis windows will be included in 
summaries, statistical analyses, and calculations of derived variables. Data collected 
outside analysis windows will be listed only. 
The analysis windows shown in Table 9 will be used. The protocol windows for the 
Day 30, Day 60, and Day 85 visits are ± 7 days. The analysis windows are wider; they 
were chosen to ensure that no spirometry measurement obtained between Day 15 and 
Day 99 would be excluded from analysis as “out of window.” 
Table 9: 
Analysis Windows for In-Clinic Visit-Based Endpoints 
Nominal Visit 
Start 
Nominal Study Day 
Stop 
Visit 2 (Day 1) 
-1* 
1 
1 
Visit 3 (Day 30) 
2 
30 
45 
Visit 4 (Day 60) 
46 
60 
70 
Visit 5 (Day 85) 
71 
85 
99** 


 
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*Per protocol, subjects are randomized and begin study drug dosing during Visit 2. The analysis window is 
extended to Day -1 in case a subject cannot be randomized on the day of the visit and randomization and 
study drug dosing must be delayed until the following day. For spirometry variables, if no usable Visit 2 
data were obtained, Visit 1B pre-ipratropium data will be substituted (if usable). 
**For treatment policy analyses (Section 3.3.1.1), there is no upper limit to the Day 85 window. 
 
If more than one visit falls within a visit window, the latest visit will be selected. 
The analysis intervals shown in Table 10 will be used for endpoints collected daily, such 
as E-RS: COPD total scores and PEF measurements. 
Table 10: 
Analysis Intervals for Diary Endpoints 
Interval 
Entry Time 
First Day of Interval Last Day of Interval 
Month 1 
PM 
1 
28 
AM 
2 
29 
Month 2 
PM 
29 
56 
AM 
30 
57 
Month 3 
PM 
57 
84 
AM 
58 
85 
AM: Endpoints based on entries made in the morning before study drug dosing. 
PM: Endpoints based on entries made in the evening before going to bed. 
For instance, since PEF is measured in the morning before study drug dosing, the 
Month 1 PEF interval is Day 2 through Day 29. 
For on-treatment summaries and analyses, AM data collected > 1 day after the date of last 
dose and PM data collected after the date of last dose are not included in the interval. For 
instance, for a subject who takes the last dose on Day 80, the Month 3 PEF interval is 
Day 58 to Day 81 or the last day for which a PEF measurement was reported, whichever 
is earlier. The corresponding Month 3 E-RS total score interval is Day 57 to Day 80 or 
the last day for which E-RS total score could be calculated, whichever is earlier. 
Subjects are asked to record their study-supplied rescue medication (albuterol MDI 
inhaler) use in their eDiary device after each use. For analysis purposes, the Table 10 PM 
intervals will be used, e.g., the Month 1 rescue medication interval will be Day 1 through 
Day 28, the Month 3 interval will be Day 57 to Day 84 or the date of last dose, whichever 
is earlier. 
3.2. 
General Analyses 
3.2.1. 
Enrollment and Analysis Sets 
Enrollment will be summarized by investigator, and a summary table will be provided 
showing the number of enrolled subjects included in each analysis set and the percentage 
of randomized subjects included in each subset of the randomized set. 


 
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3.2.2. 
Disposition 
A disposition summary will be provided and will present numbers and percentages of 
subjects who: 
• Were randomized 
• Were treated with study drug 
• Completed study treatment 
• Discontinued study treatment, by reason for treatment discontinuation 
• Completed the study 
• Discontinued from the study, by reason for study discontinuation 
A disposition listing will be provided and will include the date the informed consent form 
was signed, the date of the first dose of study drug, the date of the last dose of study drug, 
the study treatment completion or discontinuation date, a column showing study 
treatment status as “Completed” or the reason for treatment discontinuation, the study 
completion or discontinuation date, and a column showing study completion status as 
“Completed” or the reason for study discontinuation. The study completion or 
discontinuation date is the date of the last visit or assessment. 


 
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3.2.3. 
Demographic and Baseline Characteristics 
The following summaries will be provided: 
• A summary of demographic and baseline characteristics, including age, age 
group (< 65, ≥ 65), sex, ethnicity (Hispanic or Latino, not Hispanic or Latino), 
race, NHANES III race (i.e., the race category used to calculate predicted 
normal FEV1 and FVC), weight (kg), height (cm), and body mass index 
(kg/m2) 
• Screening reversibility to ipratropium test results, including the following 
variables: 
− Pre-ipratropium FEV1 (mL) 
− Postipratropium FEV1 (mL) 
− Change in FEV1 [post – pre] (mL) 
− Change in FEV1 ≥ 200 mL (Yes/No) 
− FEV1 ratio (post/pre) 
− FEV1 ratio ≥ 1.12 (increase of ≥ 12%) 
− Reversibility criterion met (increase of ≥ 200 mL and ≥ 12%) (Yes/No) 
− Postipratropium FEV1 % predicted normal 
− GOLD airflow category (3 = postipratropium FEV1 % predicted 
≥ 30% to < 50%, 4 = < 30%) 
− Time between tests (elapsed time between start of pre-ipratropium 
spirometry and start of postipratropium spirometry) 
− Time from ipratropium dosing stop time to start of postipratropium 
spirometry 


 
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• Screening (pre-ipratropium) and baseline lung function test results, including 
the following variables: 
− Predicted normal FEV1 and FVC 
− Screening FEV1 and FVC 
− Screening FEV1/FVC ratio 
− Screening FEV1 and FVC % predicted normal 
− Screening PIFR (as measured by In-Check™ device with resistance set to 
DISKUS®) 
− Baseline FEV1 and FVC 
− Baseline FEV1/FVC ratio 
− Baseline FEV1 and FVC % predicted normal 
− Baseline PIFR as measured by In-Check™ device with resistance set to 
DISKUS® 
− Baseline PIFR as measured by In-Check™ device with resistance set to 
HandiHaler® 
− Baseline maximal inspiratory pressure (MIP) 
Descriptive statistics for ratio variables (FEV1/FVC ratio and FEV1 and FVC % predicted 
normal) will include geometric means, calculated as the exponentiated mean of the log 
values, and standard deviation factors, calculated as the exponentiated standard deviation 
of the log values. 
Also provided will be a summary of COPD clinical characteristics and history, including 
the following variables: 
• Time since COPD diagnosis (years) 
• Currently on supplemental oxygen (yes/no) 
• Number of exacerbations in the past 12 months 
• Number of exacerbations in the past 12 months that resulted in hospitalization 
A summary of smoking status and history will be provided and will include the following 
variables: 
• Smoking status: current, former (number, %) 
• Number of years smoked 
• Maximum number of packs per day (packs) 
• Pack years (a cigarette smoking history or equivalent of at least 10 pack years 
is an inclusion criterion) 


 
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A pack year is 20 cigarettes per day for 1 year. Pack years as a history variable is an 
estimate of the total number of cigarettes a person has smoked, expressed in pack-year 
units (ignoring leap years, 1 pack year = 20 × 365 = 7300 cigarettes). Pack years will be 
calculated by multiplying the reported maximum number of packs per day by the 
reported number of years smoked. 
3.2.4. 
COVID-19 
A by-subject listing of visits affected by the COVID-19 pandemic will be provided. The 
COVID-19 Impacts to Visits form captures whether a visit was skipped, performed onsite 
but with one or more assessments skipped, performed outside the protocol-specified 
window, or affected in any other way because of COVID-19. 
3.2.5. 
Protocol Deviations 
A summary of major protocol deviations based on the file transferred to Theravance by 
the study monitoring CRO will be provided and will include numbers and percentages of 
subjects who have any important protocol deviations and numbers and percentages of 
subjects by important protocol deviation category. A by-subject listing of all protocol 
deviations, based on the same file, will be provided. 
3.2.6. 
Medical History 
Medical history entries will be coded to preferred terms using MedDRA® version 26.1 by 
the data management CRO, with Theravance review and approval of the mappings. A by-
subject listing of medical history will be provided, and medical history entries will be 
summarized by MedDRA system organ class and preferred term. To characterize 
comorbidities, a similar summary restricted to entries mapped to system organ classes 
with an overall frequency > 5% will also be provided. 
3.2.7. 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug (WHODrug) 
Global version Q3 2023 C3 by the data management CRO with Theravance review and 
approval of the mappings. Medications entered on the Prior and Concomitant 
Medications case report form will be assigned to a WHODrug Name and a primary 
Anatomic Therapeutic Classification (ATC) drug class. Each verbatim name will be 
classified by anatomical main group (ATC level 1), therapeutic subgroup (ATC level 2), 
pharmacological subgroup (ATC level 3), and chemical subgroup (ATC level 4). 
Medication use will be summarized by ATC class and preferred name. If available, ATC 
level 4 will be used as the ATC class. If ATC level 4 is not available, the next higher 
ATC level available (i.e., level 3 if available, otherwise level 2 if available, otherwise 
level 1) will be used. Subjects reporting use of more than one medication at each level of 
summarization (any medication received, ATC class, and preferred name) will be 
counted only once. 
Prior medications are medications taken before the date of the first dose of study drug 
and concomitant medications are medications taken on or after the date of the first dose, 


 
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including ongoing prior medications. The Prior and Concomitant Medications case report 
form includes the following question: 
Did the subject take this medication at any time after first dose? 
If the answer (Yes or No) is inconsistent with the other information recorded and the 
discrepancy is not resolved by querying, the answer will be used to classify the 
medication as concomitant or not concomitant. 
The following medication summaries will be provided: 
• Prior medications 
• Baseline LABA and ICS COPD medications 
• Baseline COPD medications 
• Concomitant COPD medications 
• Concomitant non-COPD medications 
• Concomitant Corticosteroid Medications by Route of Administration 
The summary of baseline LABA and ICS medication will include frequency (QD or 
BID). Medications will be classified as COPD if “Indication: COPD” is checked Yes and 
as non-COPD otherwise. 
See Section 3.7.1 for the presentation of rescue albuterol MDI use. 
3.3. 
General Considerations for Efficacy Analyses 
All statistical tests will be tests of point null hypotheses vs. 2-sided alternatives and will 
be performed at the 0.05 significance level. P-values presented in tables will not be 
adjusted for multiple testing. 
3.3.1. 
Estimand Types for Quantitative Spirometry Endpoints 
Two estimand types are of interest: 
• Treatment Policy 
• Hypothetical 
Both will be estimated for the quantitative spirometry endpoints (FEV1 and FVC). The 
two are described in detail below. The population, analysis set, and population-level 
summary are the same: 
Population: Patients with severe to very severe COPD and suboptimal PIFR 
Analysis set: Full analysis set, i.e., subjects who are randomized and receive 
at least 1 dose of study drug 
Population-level summary: Mean revefenacin vs. tiotropium difference 


 
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Table 11 shows the clinical objective each estimand type is intended to meet. 
Table 11: 
Estimand Types 
Estimand 
Type 
Clinical Objective; Endpoints 
Treatment 
Policy 
Estimate differences in mean lung function measurements during specified 
intervals after start of dosing that would apply when patients start dosing on 
either the revefenacin or the tiotropium regimen and use albuterol MDI rescue 
medication as needed, whatever subsequent treatment changes occur. Trough 
measurements are selected if obtained; otherwise, measurements meeting ATS 
quality standards. 
Hypothetical 
Estimate revefenacin vs. tiotropium differences in mean lung function 
measurements during specified intervals after start of dosing that would apply 
when patients are on a stable background COPD regimen or taking revefenacin or 
tiotropium as monotherapy and use rescue medication as needed. It is expected 
that neither LAMA regimen is disease-modifying and consequently both can 
affect lung function only during treatment, to an extent varying with the time 
elapsed since the most recent dose; hence, trough measurements, unconfounded 
by other medication use, are selected as endpoints. 
3.3.1.1. 
Treatment Policy Estimands 
Treatments: 
• Initiation of 175 mcg revefenacin daily (in the morning) via jet nebulizer, 
added to allowed background therapy or as monotherapy, with any subsequent 
changes to background therapy or revefenacin treatment including permanent 
discontinuation 
• Initiation of 18 mcg tiotropium daily (in the morning) via DPI, with any 
subsequent changes to background therapy or tiotropium treatment including 
permanent discontinuation 
Variables: Postbaseline FEV1 and FVC: trough measurements if obtained, otherwise 
unconfounded follow-up measurements if obtained, otherwise confounded follow-up 
measurements, where “follow-up” means obtained > 1 day after study treatment 
discontinuation and “confounded” means flagged RM for use of albuterol MDI within 
5 hours of spirometry start time as described in Section 3.1.1 
Intercurrent events: 
No measurements obtained will be excluded from analysis, regardless of the occurrence 
of an intercurrent event. 
If no measurements are obtained for an analysis interval, they will be imputed, implicitly 
via MMRM modeling or explicitly via multiple imputation methods as specified in 
Section 3.4.4. 


 
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3.3.1.2. 
Hypothetical Estimands 
Treatments: 
• Administration of 175 mcg revefenacin daily (in the morning) via jet 
nebulizer, added to allowed stable background therapy or as monotherapy, 
with allowed dosing changes to background therapy as needed and with 
rescue medication (albuterol MDI) use as needed 
• Administration of 18 mcg tiotropium daily (in the morning) via DPI, under the 
same conditions 
Variables: Postbaseline trough FEV1 and FVC measurements. The operational definition 
of trough will be “obtained within 24 ± 6 hours after the last study drug dosing.” 
Intercurrent events: 
• Episodes of new COPD medication use, i.e., use of systemic corticosteroids or 
any medication listed as prohibited except during exacerbations in protocol 
Table 2. It is not expected that measurements will be obtained during such 
episodes, but if they are they will be excluded from analysis. Similarly, it is 
not expected that measurements affected by use of the study-supplied 
albuterol MDI for rescue within 5 hours of the spirometry start time 
(Section 3.1.6) will be obtained, but if they are they will be excluded from 
analysis. 
• Study treatment discontinuation. Measurements obtained more than 1 day 
after treatment discontinuation will be excluded from analysis. 
If no measurements are obtained for an analysis interval or all are excluded, they will be 
implicitly imputed via MMRM modeling. 
3.3.1.3. 
Primary Endpoint Definitions 
Because the population-level summary is the same for postbaseline values and changes 
from baseline, the Day 85 FEV1 change from baseline endpoints for the 2 estimand types 
can also be described as follows: 
• Treatment policy estimand: For subjects on study treatment, Day 85 trough 
FEV1; for subjects not on study treatment, Day 85 FEV1 at an unknown time 
relative to COPD maintenance therapy dosing 
• Hypothetical estimand: Day 85 trough FEV1 
For the sake of brevity, the term “trough” will be used in treatment policy tables and 
figures even though it may not apply to all measurements. 
3.4. 
Primary Endpoint Analyses 
For the primary endpoint and other endpoints based on spirometry measurements, the 
treatment policy estimand is considered primary. 


 
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3.4.1. 
Definition of Primary Endpoint 
At each time point (baseline, Day 30, Day 60, and Day 85), trough FEV1 will be 
calculated as the average of the first-stage and second-stage best-effort measurements, 
i.e., the 2 best-effort measurements from the stages collected approximately 30 minutes 
apart. The quality grade for each baseline and postbaseline stage must be A, B, or C 
(Section 3.1.6.1). If only 1 of the 2 stages has a quality grade of at least C, only that 
stage’s best-effort measurement will be used. 
3.4.2. 
Statistical Hypotheses 
The null hypothesis is that μR, the expected change from baseline in trough FEV1 at 
Day 85 for subjects assigned to receive revefenacin at 175 mcg, is the same as μT, as the 
expected change for subjects assigned to receive tiotropium at 18 mcg. The alternative 
hypothesis is that the expected changes differ. 
𝐻0: 𝜇𝑅= 𝜇𝑇 
𝐻1: 𝜇𝑅≠𝜇𝑇 
Because this is a randomized trial, the expected baseline FEV1 for subjects receiving 
revefenacin is identical to the expected baseline FEV1 for subjects receiving tiotropium. 
Hence, μR and μT may also be defined as expected trough FEV1 at Day 85 for subjects 
assigned to receive revefenacin and for subjects assigned to receive tiotropium. 
3.4.3. 
Main Analysis Methods 
The primary efficacy analysis is a mixed model repeated measures (MMRM) analysis of 
trough FEV1 (or equivalently change from baseline in trough FEV1) on Days 30, 60, and 
85, with the expected Day 85 revefenacin vs. tiotropium difference as the primary 
estimand. The Day 30 and Day 60 revefenacin vs. tiotropium expected differences and 
the average expected difference across the Day 30, Day 60, and Day 85 time points will 
also be estimated as secondary estimands. Point estimates, standard errors, and 95% CIs 
for the 4 revefenacin vs. tiotropium expected differences will be presented. (For this and 
all other MMRM analyses where a baseline value of the response is a covariate, 
revefenacin and tiotropium Day 30, Day 60, and Day 85 response and change from 
baseline least squares mean point estimates and standard errors will also be presented.) 
The model has terms for treatment, reversibility to ipratropium status (reversible/not 
reversible), smoking status (current/former), concomitant LABA or LABA/ICS use 
(Yes/No), GOLD airflow category (3/4, i.e., postipratropium FEV1 % predicted 
< 30%/≥ 30%), sex (woman/man), age group (< 65/≥ 65), baseline PIFR set to 
DISKUS® resistance, pre-ipratropium FEV1, and baseline FEV1. It also has terms for 
visit and its interactions with treatment and the continuous covariates, namely baseline 
PIFR, pre-ipratropium FEV1, and baseline FEV1. Within-subject correlation will be 
modelled using an unstructured variance-covariance matrix. The Kenward and Roger 
method for approximating the denominator degrees of freedom will be used. Missing 
trough FEV1 values are assumed to be missing at random (in the technical sense). 


 
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The analysis will be performed for both estimand types (treatment policy and 
hypothetical). For the treatment policy estimand analysis, postbaseline FEV1 values 
flagged as NT (non-trough), RM (confounded by recent use of rescue medication), or CM 
(confounded by use of protocol-disallowed new COPD medication) will be handled as 
follows: 
• Select the latest spirometry test within the analysis window with no 
exclusionary flags (NT, RM, or CM), if such a test was performed. 
• Otherwise, select the latest spirometry test within the analysis window. 
For the hypothetical estimand analysis, the latest spirometry test within the analysis 
window with no exclusionary flags (NT, RM, or CM) will be selected. 
The primary endpoint will be considered to have been met if the 2-sided 95% CI for the 
Day 85 revefenacin vs. tiotropium treatment policy estimand difference lies above zero 
(equivalently, if the point estimate is above zero and the 2-sided t-test p-value from the 
SAS procedure MIXED analysis is < 0.05). 
3.4.3.1. 
Figures 
Figures will be provided showing the point estimate of and 95% CI for the revefenacin 
vs. tiotropium difference in trough FEV1 (or equivalently change from baseline in trough 
FEV 1) on Days 30, 60, and 85. The figures will also show the point estimate of and 
95% CI for the revefenacin vs. tiotropium average difference in trough FEV1 across Days 
30, 60, and 85. 
Supporting figures will be provided showing model-based estimates of mean trough 
FEV1 ± 1 standard error vs. visit for each treatment, in a single panel. 
3.4.3.2. 
Missing Data Handling 
Subjects will not be excluded from spirometry analyses because they have a missing 
value for 1 or more of the baseline covariates. For all baseline covariates except smoking 
status and LABA or LABA/ICS status, missing values are not anticipated since a missing 
value would make it impossible for the IRT system to randomize the subject. Subjects 
with smoking status unclear will be assumed to be former rather than current smokers. 
LABA or LABA/ICS status at baseline, if unclear from information captured in the 
clinical database, will be confirmed prior to database lock. The information in the clinical 
database will be used for analysis purposes, if available; if not, the information in the IRT 
database will be substituted. 
Missing postbaseline data for the primary analysis is assumed missing at random (MAR) 
and imputed implicitly via the MMRM modeling outlined in Section 3.4.3. An analysis 
for assessing the sensitivity of the primary analysis result to the MAR assumption is 
outlined in Section 3.4.4. 


 
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3.4.4. 
Sensitivity Analysis 
If the primary endpoint is met, a tipping point analysis will be performed to assess the 
sensitivity of the primary analysis result to the assumption that missing Day 85 FEV1 
values are missing at random, in the technical sense that whether responses are missing 
may depend on observed responses and baseline covariates but not on unobserved 
responses. An overview is given below. SAS code adapted from a proc MIANALYZE 
example (SAS Institute Inc. 2013) will be used to perform the analysis, which will 
proceed as a sequence of multiple imputation ANCOVA analyses. In general, multiple 
imputation analysis proceeds as follows: 
Step 1. Select the model to be used to fill in the missing observations (the “imputation 
model”) and the algorithm that will be used to fill them in. Specify a random number 
seed and apply the algorithm m times to produce m randomly completed datasets. 
Step 1 will be completed using SAS proc MI with random number seed 3293. For 
each analysis, m will be set to 25. The imputation model will be the same as the final 
ANCOVA model, with the addition of Day 30 and Day 60 FEV1. 
Step 2. Fit the final model to the m randomly completed datasets and save the m estimates 
of the parameter of interest and their estimated standard errors. 
Step 2 will be carried out using SAS proc REG with a “by _imputation_ ;” 
statement. The final model will be the Day 85 FEV1 ANCOVA model corresponding 
as closely as possible to the MMRM model, i.e., with the same categorical predictors 
and the following continuous predictors: baseline PIFR as measured with the 
In-Check™ device set to DISKUS® resistance and baseline FEV1. 
Step 3. Combine the m parameter and standard error estimates to obtain a multiple 
imputation point estimate of the parameter, an interval estimate (i.e., 95% CI), and a 
p-value for testing parameter = 0 vs. ≠ 0. 
Step 3 will be carried out using SAS proc MIANALYZE. 
The parameter of interest is the Day 85 revefenacin vs. tiotropium FEV1 difference. To 
find the tipping point, the basic 3 steps are iterated as follows: 
• For a range of shift pairs (sj, tk), hypothesize that the mean of the unobserved 
revefenacin group responses is lower than the missing at random model mean 
by si and the mean of the unobserved tiotropium group responses is lower than 
the missing at random model mean by tk. For each of the shift pairs, generate 
m randomly completed datasets as in Step 1 and apply the shifts to the 
imputed responses. 
• For each of the shift pairs, follow Steps 2 and 3 as above. 
A table and figure will be provided showing, for a range of tiotropium group shifts on the 
y-axis and revefenacin group shifts on the x-axis, the difference estimates and estimated 
p-values corresponding to the shift pairs. 


 
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3.4.5. 
Supplementary Analysis 
The primary analysis will be repeated including data from site 
 and site 
 to 
assess the impact of the exclusion of both sites on the primary endpoint. 
3.5. 
Secondary Endpoint Analyses 
3.5.1. 
Variable Definitions 
The variables to be calculated for analysis are as follows: 
• Trough FEV1 on Days 30, 60, and 85 and FEV1 at baseline 
• Trough FVC on Days 30, 60, and 85 and FVC at baseline 
• Increase from baseline in FEV1 (at trough) of ≥ 80 mL on Day 85 
• Time to first CompEx event 
The baseline, Day 30, Day 60, and Day 85 FEV1 variables are defined for analysis in 
Section 3.4. The baseline, Day 30, Day 60, and Day 85 FVC variables are defined for 
analysis in the same way, as the average of the 2 best-effort measurements obtained 
approximately 30 minutes apart, with the same minimum quality grade requirements. 
Average FEV1 and average FVC across Days 30, 60, and 85 do not need to be calculated; 
an estimate of the average treatment difference across the 3 time points is obtained from 
the MMRM analysis. Time to first CompEx event is defined for analysis in 
Sections 3.7.3.1 and 5.4. 
Day 85 trough FEV1 responder/nonresponder status is a derived binary variable, scored 
as 1 (“responder”) or 0 (“nonresponder”). Response is defined as an increase of ≥ 80 mL 
over the baseline measurement: FU – BL ≥ 80 mL, where FU is a postbaseline 
measurement and BL is the baseline measurement. For subjects without a trough FEV1 
measurement obtained during the Day 85 analysis window because they discontinued 
from the study, scores will be either missing or 0 (“nonresponder”) according to the 
convention shown in Table 12: 


 
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Table 12: 
Study Discontinuation Reasons Classified As Treatment Failures 
Discontinuation Reason 
Counted As a Treatment 
Failure 
Treatment Failure Status 
Set to Missing 
(Unknown) 
Adverse Event 
  
 
Death 
  
 
Lost to Follow-up 
 
  
Physician Decision 
  
 
Pregnancy 
 
  
Protocol Violation 
 
  
Study Terminated by 
Sponsor 
 
  
Withdrawal by Subject 
  
 
Other 
 
  
The variable is a composite variable: observed changes FU – BL < 80 mL and changes 
not observed because the subject discontinued from the study, when the reported reason 
was adverse event, death, or physician or subject decision, are both assumed to be “bad” 
outcomes. 
3.5.2. 
Main Analysis Methods 
As specified in Section 3.4.3, the primary MMRM analysis of trough FEV1 will also 
provide estimates of Day 30, Day 60, and overall (i.e., averaged across Day 30, Day 60, 
and Day 85) trough FEV1 treatment differences. 
Trough FVC will be analyzed in the same way as trough FEV1, by fitting a model with 
the same terms, except that baseline FEV1 is replaced by baseline FVC and 
pre-ipratropium FEV1 is replaced by pre-ipratropium FVC. A similar summary table and 
pair of figures will be provided. The table and figure will include point and interval 
estimates of revefenacin vs. tiotropium trough FVC differences at Days 30, 60, and 85 
and the average trough FVC difference across the 3 time points. 


 
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3.5.2.1. 
Increase From Baseline in Trough FEV1 of ≥ 80 mL on Day 85 
Revefenacin and tiotropium responder probabilities will be compared by fitting a logistic 
regression model with the same predictors as the primary efficacy analysis model (but not 
including visit or associated interaction terms). The model will include terms for 
pre-ipratropium FEV1, baseline FEV1, baseline PIFR, reversibility to ipratropium status 
(reversible/not reversible), smoking status (current/former), concomitant LABA or 
LABA/ICS use (Yes/No), GOLD airflow category (3/4), sex (woman/man), age group 
(< 65/≥ 65), and treatment. A summary of responder status by treatment group will show 
counts and percentages and a point estimate of and profile likelihood 95% CI for the 
revefenacin:tiotropium odds ratio. 
As a sensitivity analysis, the analysis will be repeated for the composite variable defined 
by counting observed changes < 80 mL and changes not observed because the subject 
discontinued from the study for any reason as “bad” outcomes. 
3.5.2.2. 
Time to First CompEx Event 
A Cox proportional hazards model with the same covariates as used for the responder 
analysis will be fitted to time to first CompEx event, as described in Section 3.7.3.1. 
3.6. 
Multiplicity Adjustment 
To control the global (across families) familywise type 1 error rate at 0.05, the primary 
and secondary endpoint hypotheses will be tested in the following endpoint sequence: 
• Trough FEV1 on Day 85 
• Average FEV1 across Days 30, 60, and 85 
• Trough FEV1 on Day 30 
• Trough FEV1 on Day 60 
• Trough FVC on Day 85 
• Increase from baseline in trough FEV1 of ≥ 80 mL on Day 85 
• Time to first CompEx event 


 
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If the primary endpoint is met, i.e., the revefenacin 175 mcg vs. tiotropium 18 mcg trough 
FEV1 difference treatment policy estimand point estimate is > 0 and the 2-sided t-test 
p-value from the SAS procedure MIXED analysis is < 0.05, multiplicity-controlled 
testing will proceed to the next test in the sequence, stopping after the first failure to 
reject the null hypothesis of no treatment difference (i.e., stopping when p ≥ 0.05). 
3.7. 
Exploratory Endpoint Analyses 
3.7.1. 
Rescue Medication Use 
Daily rescue medication use (number of puffs) is a count variable which will be 
calculated for days on which the eDiary was completed. If the eDiary was completed for 
the day and no 
 uses were recorded, the count will be assumed to be 0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.7.3. 
COPDCompEx Events and Moderate or Severe Exacerbations 
COPDCompEx events are defined as any of the following events (see Appendix 5.4 for 
details). Event codes to be used in listings are shown in parentheses: 
• Severe exacerbation in COPD (S) 
• Moderate exacerbation in COPD (M) 
• Clinically relevant deterioration in COPD (D) 
• Premature termination from the study for any reason other than “Study 
Terminated by Sponsor” (T) 
This composite-event endpoint is designed as a higher-frequency surrogate for moderate 
to severe exacerbations that may enable smaller, shorter trials to be used to explore 
possible treatment differences in the rate of moderate to severe exacerbations. For 
instance, the estimated COPDCompEx hazard ratio from studies like this one might be 
used to estimate the sample size needed for a study designed to show a difference in the 
rate of moderate to severe exacerbations. It is hoped that the COPDCompEx hazard ratio 
would be a more stable estimator than the direct estimator based on the observed rates of 
moderate to severe exacerbations, which are expected to be low in this 12-week study. 
Event summaries will be summaries of treatment-emergent events as defined in 
Section 3.8.2 , i.e., events with onset on or after the date of first revefenacin/tiotropium 
dose through the date of last dose + 7 days, with the additional restriction that the date of 
onset for all clinical deterioration events must be Study Day 15 or later (see 
Appendix 5.4). 
3.7.3.1. 
Time to First Event Summaries 
For time to first event endpoints, time to first event will be calculated as follows: 
date of onset – date of first dose + 1 
For subjects without events with onset during the treatment period, censoring time will be 
calculated as follows: 
date of last dose – date of first dose + 1 
Times will be analyzed by fitting a Cox proportional hazards model with the same 
covariates as the primary efficacy analysis model. Analysis summary tables and 
Kaplan-Meier plots will be provided for the following times: 
• Time to first CompEx event 
• Time to first moderate or severe COPD exacerbation 
• Time to first severe COPD exacerbation 
The analysis summary tables will include descriptive statistics and point estimates of and 
95% CIs for revefenacin vs. tiotropium hazard ratios. 


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3.7.4. 
Peak Expiratory Flow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.7.7. 
Nighttime Awakenings 
Subjects will be given the eDiary at screening Visit 1B (which may be combined with 
Visit 1A) and will answer the following question each day thereafter through the Day 85 
or early termination visit: 
How many times did you awaken last night due to breathing problems? ________ 
(For example: wheezing, cough, shortness of breath, etc.) (If none, enter zero) 


 
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3.7.8. 
Evaluation of Respiratory Symptoms in COPD 
The Evaluation of Respiratory Symptoms in COPD (E-RS: COPD) assessment of daily 
breathlessness, cough/sputum, and chest symptoms is recorded in the eDiary. Subjects 
will complete the 14-question EXACT, which was developed to assess acute 
exacerbations of COPD, each evening just prior to bedtime, and the first 11 questions will 
be scored as shown in Appendix 5.3 (EXACT-Respiratory Symptoms [E-RS] User 
Manual). 
The response to each question is scored either from 0 (best) to 4 (worst) or from 0 to 3; 
note the special coding of questions 3, 8, 9, 10, and 11. The total score is integer-valued 
and can range from 0 to 40. Subjects will be given the eDiary at screening Visit 1B 
(which may be combined with Visit 1A) and will record their question responses each 
day thereafter through the Day 85 or early termination visit. Subjects are not expected to 
complete the E-RS daily assessment while hospitalized. 
 
 
 
 
 
 
 
 
 
 
 


 
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3.8. 
Safety Analyses 
Adverse events, vital signs (heart rate and blood pressure), and concomitant medication 
use will be summarized. Extent of study drug exposure and treatment compliance will 
also be summarized; laboratory test results will be listed. 


 
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3.8.1. 
Extent of Exposure 
Duration of study drug exposure (days) will be summarized. Duration of exposure will be 
calculated as (date of last study drug nebulizer or DPI dose – date of first study drug 
nebulizer or DPI dose + 1). The summary table will include the columns specified in 
Section 3.1.1. 
The date of last dose (Study Treatment Completion or Discontinuation Date) is collected 
on the Study Drug Discontinuation form. If no date is reported, it will be imputed for 
analysis purposes as the Study Completion or Discontinuation Date as reported on the 
End of Study form. 
3.8.1.1. 
Treatment Compliance 
Although treatment compliance for nebulizer treatment and for DPI treatment is expected 
to be identical for most subjects, it will be calculated for each route of administration. For 
subjects who return at least 1 study drug kit, treatment compliance as a percentage of the 
expected total dose will be calculated as follows from drug accountability data for 
nebulizer treatment and for DPI treatment: 
100 × (number of doses dispensed – number of doses returned)/ 
(date of last dose – date of first dose + 1), rounded to the nearest 0.1% 
Treatment compliance over the interval from first to last study drug dose will be 
summarized as a continuous variable and using the following categories: 
• > 120% 
• ≥ 105% – ≤ 120% 
• ≥ 95% — < 105% 
• ≥ 90% — < 95% 
• ≥ 80% — < 90% 
• < 80% 
The summary table will include the following columns: TIO, DPI, REV, and Nebulizer. 
Study drug accountability data will be listed, and CRF and dosing eDiary study drug 
administration data listings will be provided. An abbreviated combined listing of study 
drug administration data will also be provided and will present the following information 
for the 2 days preceding and the day of each postbaseline visit during which spirometry 
test results were obtained: 
• Spirometry Visit Date (Study Day) 
• Spirometry Start Time (Earliest) 
• Date (Study Day) 
• Was Tiotropium/Placebo Administered? (source In-Clinic Study Drug 
Administration form) 


 
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• Time of Tiotropium/Placebo Administration (source In-Clinic Study Drug 
Administration form) 
• Was Revefenacin/Placebo Administered? (source In-Clinic Study Drug 
Administration form) 
• Start Time of Revefenacin/Placebo Administration (source In-Clinic Study 
Drug Administration form) 
• End Time of Revefenacin/Placebo Administration (source In-Clinic Study 
Drug Administration form) 
• Dosing Diary Entry Start and End Date/Time 
• When did you administer 1 capsule of study drug from the HandiHaler? 
(hh:mm) (source eDiary) 
• After your HandiHaler dose, when did you nebulize your vial of study drug? 
(hh:mm) (source eDiary) 
3.8.2. 
Adverse Events 
A treatment-emergent adverse event (TEAE) will be defined as any adverse event that 
begins on or after the date of the first study drug dose up through 7 days after the date of 
the last study drug dose. COPD exacerbations are adverse events and will be included in 
all summaries of adverse events. Separate forms, “COPD Exacerbation” and “Adverse 
Event,” were developed to capture exacerbation and non-exacerbation adverse events, in 
order to collect additional information about the exacerbation events. Hence, although 
COPD exacerbations will be included in all adverse event listings except the listing of 
adverse events of special interest, a listing of COPD exacerbations based on the “COPD 
Exacerbation” form will also be provided. 


 
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Adverse events are collected from the signing of the informed consent form through the 
end of follow-up. Site personnel are to telephone subjects 7 ± 2 days after their last visit 
to review their adverse events; in addition, they are to telephone subjects who discontinue 
from the study early because of an adverse event approximately 30 days after 
discontinuation to review their adverse events and medications. Follow-up may be further 
extended as described in protocol Amendment 3 Section 7.4. 
Adverse events will be coded to the preferred terms of the Medical Dictionary for 
Regulatory Activities (MedDRA® 26.1 Q3 2023) by the data management CRO with 
Theravance review and approval of the mappings. The following adverse event 
summaries will be provided: 
• TEAE overall summary 
• TEAEs by preferred term 
• TEAEs by system organ class and preferred term 
• TEAEs by system organ class, preferred term, and LABA or LABA/ICS use 
• Severe TEAEs by system organ class and preferred term 
• TEAEs by preferred term with frequency > 3% of safety analysis set subjects 
• TEAEs by system organ class, preferred term, and severity 
• Drug-related TEAEs by system organ class and preferred term 
• Drug-related TEAEs by system organ class, preferred term, and LABA or 
LABA/ICS use 
• Drug-related TEAEs by system organ class, preferred term, and severity 
• Drug-related severe TEAEs by system organ class and preferred term 
• Serious TEAEs by system organ class and preferred term 
• Drug-related serious TEAEs by system organ class and preferred term 
• Adverse events with fatal outcome by system organ class and preferred term 
• TEAEs leading to premature study drug discontinuation by system organ class 
and preferred term 
• TEAEs of special interest by preferred term 


 
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The TEAE overall summary will show the number and percentage of subjects for whom 
at least 1 adverse event in each of the following categories was reported: 
• Any TEAE 
• Any moderate or severe TEAE 
• Any severe TEAE 
• Any drug-related TEAE 
• Any moderate or severe drug-related TEAE 
• Any severe drug-related TEAE 
• Any serious TEAE 
• Any drug-related serious TEAE 
• Any TEAE leading to permanent study drug discontinuation 
• Any TEAE leading to temporary interruption of study drug 
• Any adverse event with fatal outcome, including adverse events that were not 
treatment-emergent 
If no adverse events meeting a specific table definition are reported, the body of the table 
will contain only a statement that no adverse events met the table definition. 
The following adverse event listings will be provided: 
• TEAEs 
• COPD exacerbations 
• Adverse events leading to premature discontinuation of study drug 
• Adverse events resulting in temporary interruption of study drug 
• Serious adverse events 
• Adverse events with fatal outcome 
• Adverse events of special interest 
• Non-treatment-emergent adverse events 


 
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3.8.2.1. 
Adverse Events of Special Interest 
Since revefenacin and tiotropium are long-acting muscarinic antagonists, antimuscarinic 
TEAEs are of special interest. Any TEAE coded to one of the following preferred terms 
will be included in the summary of TEAEs of special interest: 
• Constipation 
• Dry mouth 
• Dysuria 
• Bronchospasm, paradoxical 
• Glaucoma, Angle closure glaucoma 
• Urinary retention 
3.8.3. 
Additional Safety Assessments 
3.8.3.1. 
Clinical Laboratory Test Results 
The following local laboratory test results collected at screening will be listed: 
• Creatinine 
• Hematocrit 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Bilirubin 
• Alkaline phosphatase 
• International normalized ratio (INR) 
• Albumin 
Collection of INR and albumin to calculate Child-Pugh score (since a score of B or C is 
an exclusion criterion) is at the investigator’s discretion. 
3.8.3.2. 
Vital Signs 
Blood pressure and heart rate are collected at screening, on Day 1 before dosing, and at 
the Day 85 or early termination visit. They are to be collected after the subject has been 
resting in a semi-recumbent position for approximately 5 minutes. All measurements 
obtained will be listed, and measurements outside the ranges shown in Table 13 will be 
flagged in the listing. 


 
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Table 13: 
Heart Rate and Blood Pressure Ranges 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
40–110 
85–160 
45–100 
 
Summaries of baseline measurements and of measurements and changes from baseline at 
Day 85 will be provided. Also provided will be a summary showing numbers and 
percentages of subjects with measurements outside the ranges shown in Table 13 at 
baseline and on Day 85. 
3.9. 
Other Analyses 
3.9.1. 
Subgroup Analyses 
To assess consistency of treatment differences across subgroups, the analysis of the 
primary endpoint will be repeated for each of the subgroups shown in Table 14: 
Table 14: 
Subgroups 
Subgroup Variable 
Subgroups 
Baseline PIFR* 
< 40 L/min, ≥ 40 L/min 
Baseline smoking status 
Current Smoker, Former Smoker 
Age 
< 65, ≥ 65 
Sex 
Female, Male 
Current LABA or LABA/ICS use (at 
baseline) 
Yes, No 
Baseline reversibility to ipratropium status 
(a randomization stratification variable) 
Yes, No, where reversibility to ipratropium is 
defined as a postipratropium increase of at 
least 12% and at least 200 mL in FEV1 
Baseline GOLD airflow category 
(a randomization stratification variable)** 
3, 4, where category 3 = postipratropium 
FEV1 as percentage of predicted normal 
≥ 30% to < 50% and category 4 = < 30% 
*PIFR as measured by In-Check™ device with resistance set to DISKUS®. 
**If there are any subjects with postipratropium FEV1 as percentage of predicted normal ≥ 50%, they will 
be included in the GOLD 3 subgroup for analysis purposes. 
 
The model will be adjusted as needed to remove single-valued covariates, e.g., by omitting 
sex for analyses by sex. Point estimates, standard errors, and 95% CIs for the revefenacin 
vs. tiotropium difference at each visit will be presented. For each visit (Day 30, Day 60, 


 
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and Day 85), a forest plot showing point estimates of and 95% CIs for revefenacin vs. 
tiotropium differences by subgroup will be provided. 
3.10. 
 
 
 
3.10.1. 
Data Monitoring Committee 
No independent data monitoring committee is planned for this study. 
The sponsor will monitor trial data to ensure the safety of subjects via periodic review 
and discussion of safety data collected during the trial. 


 
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4. 
REFERENCES 
1. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, 
Hallstrand TS, Kaminsky DA, McCarthy K, McCormack MC, Oropez CE, Rosenfeld 
M, Stanojevic S, Swanney MP, Thompson BR. Standardization of Spirometry 2019 
Update. An Official American Thoracic Society and European Respiratory Society 
Technical Statement. Am J Respir Crit Care Med. 2019 Oct 15;200(8):e70-e88. doi: 
10.1164/rccm.201908-1590ST. PMID: 31613151; PMCID: PMC6794117. 
2. Spirometry Reference Manual v1.0 PIFR-2 (30Nov21). 
3. Data Management Plan Revision 00: 17-Nov-2021. 
 
4. Data Management Plan Version 1.0 05-Jan-2022. 
 
5. Data Management Plan Version 2.0 15-Feb-2022. 
 
6. 
 
 
7. 
 
 
 
8. Hankinson, John L.; Odencrantz, John R.; Fedan, Kathleen B. (1999). Spirometric 
Reference Values from a Sample of the General U.S. Population. American Journal 
of Respiratory and Critical Care Medicine, 159(1), 179–187. 
9. Hankinson JL, Kawut SM, Shahar E, Smith LJ, Stukovsky KH, Barr RG. 
Performance of American Thoracic Society-recommended spirometry reference 
values in a multiethnic sample of adults: the multi-ethnic study of atherosclerosis 
(MESA) lung study. Chest. 2010 Jan;137(1):138-45. doi: 10.1378/chest.09-0919. 
Epub 2009 Sep 9. PMID: 19741060; PMCID: PMC2803123. 
10. Elmaleh-Sachs A, Balte P, Oelsner EC, Allen NB, Baugh A, Bertoni AG, Hankinson 
JL, Pankow J, Post WS, Schwartz JE, Smith BM, Watson K, Barr RG. 
Race/Ethnicity, Spirometry Reference Equations, and Prediction of Incident Clinical 
Events: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Am J Respir 
Crit Care Med. 2022 Mar 15;205(6):700-710. doi: 10.1164/rccm.202107-1612OC. 
PMID: 34913853. 
11. Vogelmeier, C. F., Fuhlbrigge, A., Jauhiainen, A., Scheepers, L., Bengtsson, T., 
Peterson, S., Karlsson, N., Sethi, T., Locantore, N., Tal-Singer, R., Rennard, S., 
Fagerås, M., & Da Silva, C. A. (2020). COPDCompEx: A novel composite endpoint 
for COPD exacerbations to enable faster clinical development. Respiratory 
medicine, 173, 106175. https://doi.org/10.1016/j.rmed.2020.106175 
12. SAS Institute Inc. 2013. SAS/STAT(R) 13.1 User's Guide. Cary, NC: SAS Institute 
Inc. The MIANALYZE Procedure, Example 62.13, Sensitivity Analysis with 
Tipping-Point Approach. Available: http://support.sas.com. 


 
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13. PIFR-2 INDEPENDENT SPIROMETRY AND DATA ASSESSMENT FINAL 
INVESTIGATION REPORT 
5. 
APPENDICES 
5.1. 
Changes to Protocol-Planned Analyses 
5.1.1. 
Changes to Protocol-Planned Analyses of Primary and Secondary 
Efficacy Endpoints 
Protocol Amendment 4 lists defines a CompEx event as the occurrence of a moderate or 
severe exacerbation or clinically relevant deterioration based on objective measures of 
deterioration in peak expiratory flow (PEF), rescue medication use, COPD symptoms, 
and nocturnal awakening. Although all 4 types of eDiary data are collected, only PEF 
measurements, rescue medication use, and E-RS: COPD total symptom scores are used to 
identify clinically relevant deterioration events. See Section 5.4.3 for details. 
5.2. 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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5.3. 
Evaluation of Respiratory Symptoms in COPD 
The scoring of EXACT questionnaire responses for the E-RS: COPD and the EXACT is 
shown below: 
Table 15: 
E-RS: COPD Scoring 
Question 
Responses 
1. Did your chest feel congested today? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
4. Extremely 
2. How often did you cough today? 
0. Not at all 
1. Rarely 
2. Occasionally 
3. Frequently 
4. Almost constantly 
3. How much mucus (phlegm) did you 
bring up when coughing today? 
0. None at all 
1. A little 
1. Some 
2. A great deal 
3. A very great deal 
“A little” and “Some” are scored the same. 
4. How difficult was it to bring up mucus 
(phlegm) today? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Quite a bit 
4. Extremely 
5. Did you have chest discomfort today? 
0. Not at all 
1. Slight 
2. Moderate 
3. Severe 
4. Extreme 
6. Did your chest feel tight today? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
4. Extremely 


 
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Question 
Responses 
7. Were you breathless today? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
4. Extremely 
8. Describe how breathless you were today: 0. Unaware of breathlessness 
1. Breathless during strenuous activity 
2. Breathless during light activity 
3. Breathless when washing or dressing 
3. Present when resting 
“Breathless when washing or dressing” and 
“Present when resting” are scored the same. 
9. Were you short of breath today while 
performing your usual personal care 
activities like washing or dressing? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
3. Extremely 
4. Too breathless to do these 
“Severely” and “Extremely” are scored the 
same. 
10. Were you short of breath today while 
performing your usual indoor activities like 
cleaning or household work? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
3. Extremely 
3. Too breathless to do these 
“Severely,” “Extremely,” and “Too breathless 
to do these” are scored the same. 
11. Were you short of breath today while 
performing your usual activities outside the 
home such as yard work or errands? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
3. Extremely 
3. Too breathless to do these 
“Severely,” “Extremely,” and “Too breathless 
to do these” are scored the same. 


 
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Question 
Responses 
Questions 12, 13, and 14 are scored for the 
EXACT but not the E-RS: COPD. 
 
12. Were you tired or weak today? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
4. Extremely 
13. Last night, was your sleep disturbed? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
4. Extremely 
14. How scared or worried were you about 
your lung problems today? 
0. Not at all 
1. Slightly 
2. Moderately 
3. Severely 
3. Extremely 
“Severely” and “Extremely” are scored the 
same. 
Source: The Exacerbations of Chronic Pulmonary Disease Tool (EXACT©) Patient-Reported Outcome 
(PRO) User Manual (Version 7.0), October 2014. EXACT© 2013, Evidera, Inc. 
 
For the E-RS: COPD, the response to each of the first 11 questions is scored either from 0 
(best) to 4 (worst) or from 0 to 3; note the special coding of questions 3, 8, 9, 10, and 11. 
The total score is integer-valued and can range from 0 to 40. The EXACT total score is 
the sum of all 14 question scores and can range from 0 to 51. EXACT total scores will be 
included in the listing of E-RS: COPD total scores but will not be summarized. 
Internally inconsistent answers, e.g., “Were you breathless today?” answered “Not at all” 
but “Describe how breathless you were today” answered “Breathless during strenuous 
activity,” will be summarized as collected. Monthly average E-RS total scores will be 
calculated only if the assessment was completed on at least 14 days during the interval. 
The eDiary does not let users skip questions; hence, it is expected that either all questions 
will be answered or none. If the questions are answered more than once during the same 
eDiary availability interval (this is not expected to occur), the latest set of answers will be 
used. 
Externally inconsistent answers, e.g., all 11 answers scored 0 but rescue medication was 
used, will also be summarized as collected. 


 
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5.4. 
CompEx Events 
5.4.1. 
Moderate or Severe Exacerbations 
A severe exacerbation is defined as a deterioration of COPD symptoms that results in 
hospitalization for emergency treatment of the COPD and the duration of the visit is 
≥ 1 day, as recorded via CRF. Criteria for classifying exacerbations of COPD as severe, 
moderate, or mild are given in protocol Section 6.8. 
A moderate exacerbation is defined as any increase in COPD symptoms that does not 
meet the criteria for a severe exacerbation but leads to treatment with antibiotics or 
systemic corticosteroids. This may include emergency treatment in a hospital setting of 
the COPD for < 1 day. 
For consistency with adverse event summaries, for CompEx analysis purposes, the date 
of onset and severity will be as captured in the COPD Exacerbation CRF. 
5.4.2. 
Combination Rule for Exacerbations 
To avoid over-counting moderate and severe exacerbations, if there are < 7 days between 
the stop date of the previous exacerbation and the start date of the next one (i.e., start date 
– stop date ≤ 7 days), they will be treated as a single exacerbation with severity moderate 
if both were moderate, and severe otherwise. This rule will be applied for CompEx 
analyses but not for adverse event summaries. 


 
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5.4.3. 
Clinically Relevant Deterioration 
A clinically relevant deterioration is defined as any increase in COPD symptoms that 
meets specified PEF, rescue medication use, and E-RS total score threshold and slope 
criteria. As shown in Table 16, either all 3 slope conditions and at least 1 of the threshold 
conditions must be met or the symptom score threshold condition and at least 1 of the 
other 2 threshold conditions must be met concurrently. 
Table 16: 
Threshold and Slope Criteria for Diary Variables 
Threshold conditions must be met concurrently on consecutive 
days 
Slope conditions 
must be met for all 3 
diary variables over 
5 consecutive days 
AM PEF: ≥ 12% 
decrease from 
baseline 
Increase in total 
albuterol MDI 
puffs/day of ≥ 1.75 × 
baseline average 
E-RS total score 
increase from 
baseline of ≥ 8 
 
  
 
 
  
 
  
 
  
 
 
  
  
  
 
  
 
 
  
  
 
A checkmark indicates that the condition is met. If there is no checkmark, the condition may or may not be 
met. 
To obtain baseline averages defined over the same interval relative to first dose for all 
subjects for testing the threshold conditions, the 10-day interval beginning on Day -3 and 
ending on Day 7 will be used, since all subjects are expected to have diary data for at 
least the 3 days preceding Day 1. If one treatment reaches its full effect on the diary 
variables more quickly than the other, this choice of interval may tend to handicap that 
treatment. 
Since at least 1 threshold condition must be met to fulfill the criteria for a clinical 
deterioration event, the date of onset will be defined as the earlier of the 2 days on which 
it was met (or they were met). Labeling the date of onset as Day 0, Table 17 shows the 
required relationship of slope and threshold intervals: 
Table 17: 
Threshold and Slope Intervals 
Condition 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0 
Day 1 
Threshold 
 
 
 
 
  
  
Slope 
  
  
  
  
  
 


 
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The slope criteria are specified in Table 18: 
Table 18: 
Clinical Deterioration Slope Criteria for PEF, Rescue Medication Use, 
and Symptom Score 
Diary Variable 
Slope Definition 
PEF 
Rate of decrease of ≥ 3%/day 
Rescue Medication Use 
Rate of increase of ≥ 0.4 puffs/day 
E-RS Total Score 
Rate of increase of ≥ 2 points/day 
 
The date of onset for all clinical deterioration events must be Study Day 15 or later and at 
least 7 days later than the onset date of any previous clinical deterioration event. It must 
also be at least 7 days later than the stop date of any previous moderate or severe 
exacerbation. For the conditions for a clinical deterioration event to be fulfilled by 
meeting all 3 slope conditions and at least 1 of the threshold conditions, data for the 
applicable slope interval must be obtained for at least 4 of the 5 days for all 3 diary 
variables. 
To determine whether the slope criterion is met for a particular diary variable, assuming 
data were obtained for at least 4 of the 5 days, fit a simple linear regression model. For 
PEF, calculate the absolute rate of change per day (L/min), R, and compare it to baseline 
PEF, B. If R < 0 and |R|/B rounded to 3 decimal places is ≥ 0.03, count the slope criterion 
as met for PEF. For rescue medication use and E-RS total score, compare the calculated 
slope to the cutpoint shown in Table 18 after rounding the slope estimate to 1 more 
decimal place than shown for the cutpoint, i.e., to 2 decimal places for rescue medication 
use and to 1 decimal place for E-RS total score. 
5.5. 
Missing Data Imputation Rules 
5.5.1. 
Adverse Events Severity and Relationship 
In adverse event summaries, adverse events with severity not reported are counted as 
“Severe” and adverse events with relationship to study drug not reported are counted as 
“Related.” 


 
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5.5.2. 
Missing Start and Stop Dates and Times for Adverse Events 
Missing start dates and times will be handled as follows: 
• Onset date completely missing: 
− If event is not ongoing and onset date missing and end date missing, then 
impute onset as date/time of first dose. 
− Else if event is not ongoing and onset date missing and end date not 
missing and date/time of first dose ≤ end date, then impute onset as 
date/time of first dose of study drug. 
− Else if event is not ongoing and onset date missing and end date not 
missing and end date is BEFORE first dose of study drug, then impute 
onset as end date YEAR and MONTH with 01 as the day and 00:00 as 
time. 
− Else if event is ongoing and onset date missing, then impute onset as 
date/time of first study drug dose. 
• Onset date has year and month only: 
− If onset date has year and month only and they are the year and month of 
first dose of study drug, then impute onset as date/time of first dose: 
− Else if onset date has year and month only and date/time of first dose is 
not missing, then impute onset as onset year and month with 01 as the date 
and 00:00 as the time. 
• Onset date has year only: 
− If onset date has year only and it is year of first dose of study drug, then 
impute onset as date/time of first dose of study drug. 
− Else if onset date has year only and date of first study drug dose is not 
missing and year of onset is NOT the year of first dose of study drug, then 
impute onset as Jan. 1 of the onset year and 00:00 as the time. 
• Onset missing (where it was not handled by the above cases): 
− If onset date is missing, then impute onset as date/time of first study drug 
dose. 
• Onset has complete date but missing time: 
− If onset date is a date only and is same as date of first study drug dose, 
then impute onset as date/time of first study drug dose. 
− Else if onset date is a date only and is NOT = date of first study drug dose, 
then impute onset as onset date with 00:00 as the time. 


 
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Missing end date and times will be handled as follows: 
• End date - completely missing: 
− If event is not ongoing and both onset and end dates are missing, then 
impute end date as date/time of last study drug dose. 
− Else if event is not ongoing and onset date not missing and end date 
missing AND onset date ≤ date/time of last dose, then impute end date as 
date/time of last study drug dose. 
− Else if event is not ongoing and onset date is not missing and end date is 
missing and date of last dose is not missing and onset is AFTER date of 
last dose, then impute end date as the last day of the month of onset date, 
with 23:59 as time. 
• End date = year and month only: 
− If event is NOT ongoing and end date consists of year and month only, 
then impute end date as the last day of the month of end date month and 
year, with 23:59 as time. 
• End date = year only: 
− If event is NOT ongoing and end date consists of a year only, and year = 
year of onset and onset date ≤ date of last study drug dose, then impute 
end date as the date of last study drug dose. 
− Else if event is NOT ongoing and end date consists of a year only, and 
year = year of onset and onset date > date of last study drug dose, then 
impute end date as the year and month of onset, with the last day of the 
month as the day, and 23:59 as the time. 
• End date = complete date but no time: 
− If event is NOT ongoing and end date consists of a complete date but no 
time, then impute end date = trim (end date) || "T23:59". 


 
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5.5.3. 
Missing Start and Stop Dates for Prior and Concomitant Medications 
To determine whether medications were used prior to initiation of dosing and whether 
they were used after initiation of dosing, missing or partial dates for medications will be 
imputed according to the following rule: 
Missing medication start date: 
• If only have a YEAR, impute as January 1 
• Else if only have YEAR and MONTH, impute as Day 1 of month 
• Else if completely missing, and (end date is present and ≥ date of first dose) or 
(end date is missing and is marked as “ONGOING”), impute as date and time 
of first dose. If missing and end date is present and prior to date of first dose, 
then leave as missing. 
Missing medication end date: 
• If only have a YEAR and it is same as year of study completion, impute as 
date of study completion 
• Else if only have a YEAR, impute as December 31 
• Else if only have YEAR and MONTH, impute as last day of the month 
• Else if end date is completely missing and not flagged as Ongoing, impute as 
date of study completion 
• Otherwise, no imputation