Clinical trial NCT05046795
Conditions: COPD
Keywords: Revefenacin Long-acting muscarinic receptor antagonist(LAMA)
Sponsor: Mylan Pharma UK Ltd.
Start date: 2021-11-10; Completion date: 2023-07-26
Enrollment: 258 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a phase III clinical study to assess the efficacy and safety of Revefenacin inhalation solution 175 mcg administered once daily via nebulization for 12 weeks compared to placebo in a population of Chinese subjects with moderate to very severe COPD.

Detailed description:
This will be a multi-center, randomized, double blind, placebo-controlled, parallel group study, randomizing approximately 320 male or female moderate-very severe COPD subjects. Subjects will receive study drug for 12 weeks. Treatments to be received during the study will include one of the following, administered using a centrally-provided, standard jet nebulizer and compressor via a mouthpiece: A. Revefenacin inhalation solution 175 mcg Quaque die (QD). B. Placebo inhalation solution QD. Subjects will have approximately 6 clinic visits (encompassing a screening period of up to 30 days and a treatment period of 12 weeks), and a follow-up telephone call 1-2 weeks after the End of Treatment (EoT) visit.

Arms: arm 1: Revefenacin inhalation solution 175 mcg QD. arm 2: Placebo inhalation solution QD.
Interventions: intervention 1: Revefenacin 175 mcg in 3 ML Inhalation Solution intervention 2: Placebo inhalation solution QD
Intervention descriptions: intervention 1: Revefenacin intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
 
REV-3001 Final Protocol Version 2.0, 15 JUL 2020 
Confidential 
 
REV-3001  CLINICAL STUDY PROTOCOL 
Protocol Title 
A Randomized, Double Blind, Placebo-Controlled, Parallel Group Study of 
Nebulized Revefenacin Inhalation Solution in Chinese Subjects with Moderate 
to Very Severe Chronic Obstructive Pulmonary Disease (COPD). 
Product 
Revefenacin Inhalation Solution  
Study Type 
Phase 3 
Version 
2.0 (Global Protocol Amendment 1) 
Protocol Date 
03 December 2019 
Revision Date 
15 July 2020 
EudraCT no. 
Not applicable 
IND no. 
Not applicable 
Legal/Filing 
Sponsor 
Mylan Pharma UK Ltd. 
Registered office: 
20 Station Close, Potters Bar, Hertfordshire, EN6 1TL, UK. 
UK Business address: 
Mylan Global Respiratory Group, Ramsgate Road, Sandwich, Kent, CT13 9ND, 
UK. 
Background 
and Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
COPD is a respiratory disease characterized by airflow obstruction that is not 
fully reversible. The airflow limitation is usually both progressive and associated 
with an abnormal inflammatory response in the airways and the lung to noxious 
particles or gases (Global Initiative for Chronic Obstructive Lung Disease 
[GOLD], 2019 [1]). In 2012, it was estimated that more than 3 million people 
died prematurely due to COPD and it is projected to be the third leading cause of 
death worldwide by 2020 (GOLD 2019 [1]). 
In the People's Republic of China, the prevalence rate of COPD was reported to 
be between 1.20% and 8.87% depending on the provinces/cities surveyed (Zhu 
et al., 2018 [2]), and in 2013 there were 910,809 deaths due to COPD, which 
represented 31% of total deaths due to COPD in the world (Yin et al., 2016 [3]). 
In addition to the high prevalence of COPD in China, a separate survey across 7 
provinces found that only 7.9% of patients had regular medical treatment for 
COPD, highlighting the need, in some regions of China at least, for 
improvement in the management of COPD (Zhu et al., 2018 [2]).  
Pharmacologic treatment of COPD with bronchodilators is central to the 
management of both the symptoms and the long-term risks of the condition. 
Long-acting inhaled bronchodilators are convenient and are more effective for 
long-term symptom relief than short-acting bronchodilators; accordingly, widely 
accepted treatment guidelines such as those produced by GOLD recommend the 
use of a long-acting muscarinic antagonist (LAMA) bronchodilator as first-line 
therapy for patients with persistent COPD symptoms (GOLD 2019 [1]).  
 
 
 
NCT05046795


 
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For some COPD patients, nebulization may be the optimal method for delivering 
bronchodilator therapy.  
Revefenacin is a potent LAMA that was designed as a lung selective, once-daily 
agent and formulated as an inhalation solution to be administered using a 
standard jet nebulizer via a mouthpiece. Revefenacin inhalation solution 
(175 mcg in 3 mL) was approved by the United States Food and Drug 
Administration (US FDA) in November 2018 with the tradename Yupelri® for 
the maintenance treatment of patients with COPD [4].  
In support of the US FDA approval, the efficacy and safety of revefenacin 
inhalation solution were evaluated in two replicate 12-week, Phase 3 clinical 
trials examining efficacy and safety (studies 0126 and 0127), and a 52-week 
long-term safety trial (study 0128), in moderate to very severe COPD patients. 
Although the data from studies 0126, 0127 and 0128 were derived from clinical 
trials with patients of predominantly Caucasian ethnicity, based on metabolism 
of the drug, it is unlikely to exhibit different exposure in Chinese patients, 
making these studies highly relevant for extrapolating safety and efficacy.  
Clinical trials on other LAMAs conducted in East Asian COPD patients have 
demonstrated comparable efficacy and safety compared to large global 
registration trials conducted primarily in Caucasian patients. For example, Wang 
et al. (2015) [5] reported that the efficacy and safety results of the GLOW7 trial 
on glycopyrronium in predominantly East Asian patients with moderate to 
severe COPD were similar to previous trials conducted in predominantly 
Caucasian patients. Likewise, a comparison of the efficacy data for East Asian 
patients compared to the overall study population of the TONADO trial on 
tiotropium/olodaterol versus its mono-components concluded that the lung 
function responses were consistent and there were no significant differences in 
safety outcomes between the two populations (Bai et al., 2017 [6]).  
The objectives of this study are therefore to confirm the efficacy and safety of 
revefenacin inhalation solution (175 mcg once daily) for the treatment of 
Chinese patients with moderate to very severe COPD, in order to provide a 
bridge for this population to the existing body of data derived from clinical trials 
with patients of predominantly Caucasian ethnicity. 
Primary 
Objective 
To confirm the efficacy of revefenacin inhalation solution 175 mcg administered 
once daily via nebulization for 12 weeks compared to placebo in a population of 
Chinese subjects with moderate to very severe COPD. 
Study 
Endpoints 
The primary endpoint is: 
• 
Trough Forced Expiratory Volume in 1 second (FEV1) on Day 85 (mean 
of measurements at -45 and -15 minutes pre-dose)  
The secondary efficacy endpoints are: 
• 
Peak FEV1 (0-2h) on Day 1 
• 
St. George’s Respiratory Questionnaire (SGRQ) responders (total score 
4 units) on Day 85 
• 
Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
on Day 85 
• 
Average count of salbutamol puffs per day (Days 1-85) 
• 
Percentage of salbutamol rescue free 24h periods (Days 1-85) 


 
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• 
Trough FEV1 on Days 29 and 57 
• 
BDI/TDI on Day 29 and 57 
• 
Weighted Mean FEV1 (0-2h) on Day 1 and Day 85 
• 
Peak FEV1 (0-2h) on Day 85 
• 
Trough forced vital capacity (FVC) on Days 29, 57 and 85 
• 
SGRQ on Day 85 (continuous endpoint) 
• 
TDI responders (focal score 1) on Days 29, 57 and 85  
The secondary safety endpoints are:  
• 
Adverse Events (AE) 
• 
Acute Exacerbations of COPD (AECOPD) 
• 
Laboratory Tests 
• 
Vital Signs (blood pressure and pulse rate) 
• 
12-lead ECG 
Pharmacokinetic (PK) endpoints are: 
• 
Population PK parameters for revefenacin inhalation solution (Cmax, 
Ctrough) 
 
Methodology 
and 
Treatments 
This will be a multi-center, randomized, double blind, placebo-controlled, 
parallel group study, randomizing approximately 320 male or female 
moderate-very severe COPD subjects. Subjects will receive study drug for 
12 weeks. 
Treatments to be received during the study will include one of the following, 
administered using a centrally-provided, standard jet nebulizer and compressor 
via a mouthpiece: 
 
A.  Revefenacin inhalation solution 175 mcg QD. 
 
B.  Placebo inhalation solution QD. 
Subjects will be randomly assigned via Interactive Voice/Web Response System 
(IVRS/IWRS) to receive either revefenacin or placebo in a 1:1 ratio stratified by 
concomitant long-acting β2 agonists (LABA) use and reversibility to 
ipratropium. They will be permitted to remain on stable doses of LABA, inhaled 
corticosteroids (ICS), or combinations containing LABA/ICS provided the ICS 
component is equivalent to fluticasone propionate ≤1000 mcg/day. Rescue 
medication (salbutamol) will be provided to all subjects. 
Subjects will have approximately 6 clinic visits (encompassing a screening 
period of up to 30 days and a treatment period of 12 weeks), and a follow-up 
telephone call 1-2 weeks after the End of Treatment (EoT) visit: 
V1: Screening Visit 1 (14 days prior to V3 [permitted window: 30-4 days 
prior to V3]) 
V2: Screening Visit 2 (7 (± 3) days prior to V3) 
V3: Day 1, Randomization 
V4: Day 29 (±7 days) 
V5: Day 57 (±7 days) 
V6: Day 85 (±7 days), EoT  
Follow-up (7-14 days after V6; by telephone) 


 
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Subjects will commence screening procedures within 30 days prior to 
randomization to confirm that they meet the selection criteria for the study.  
At Screening V1, assessments will include informed consent, a review of 
demography, medical history (including COPD, smoking, and COPD 
exacerbation history) and concomitant medication, a physical examination, 
supine or semi-recumbent vital signs, supine or semi-recumbent 12-lead ECG, 
laboratory safety tests, pregnancy test (if required), and a chest X-ray (unless 
obtained within the previous 12 months). Subjects who are on a LAMA-
containing treatment for their COPD will be required to have a washout of at 
least 7 days prior to undergoing an ipratropium reversibility test at Visit 2. 
However, for subjects who are not on LAMAs and who have observed the 
appropriate washout for other concomitant medications (e.g., 48 hours for oral 
leukotriene antagonists and systemic anti-muscarinics, 6 hours for short-acting 
beta-agonists and anti-muscarinics), V2 procedures (i.e., pre- and post-
bronchodilator spirometry for FEV1/FVC measured as part of an ipratropium 
reversibility test) may be conducted on the same day as Visit 1.  
After completion of V2 procedures, subjects will be discharged from the clinic 
with salbutamol as rescue medication and a diary card to record rescue 
medication use and return 7 (± 3) days later for V3. 
Subjects who are eligible to be randomized to the study will undergo the 
procedures below during the 12-week treatment period (V3-V6). 
Admission procedures for each visit: 
On admission at V3 to V6 the Investigator should check if the appropriate 
washout period has been met for use of rescue medication or other restricted 
concomitant medications. If not, then the visit should be rescheduled within the 
protocol-specified timeframe.  
Subjects should first complete the patient reported outcomes questionnaires 
(PRO) - BDI/TDI, Modified Medical Research Council Dyspnea Scale 
(mMRC), SGRQ (in that order) - at the following visits: 
BDI/TDI: BDI at V3 and TDI at V4, V5, and V6 
mMRC: at V3 
SGRQ: at V3 and V6 
After completion of PROs, AEs, concomitant medication use, and rescue 
medication use since the previous visit should be reviewed. 
Rescue medication: 
Salbutamol (100 mcg) pressurized metered dose inhalers (pMDI) will be 
provided as rescue medication to all subjects. Subjects will record the use of 
salbutamol rescue medication (number of puffs daily) in a diary card which will 
be reviewed by the Investigator and recorded in the CRF. If a subject has used 
rescue medication on the same day as the clinic visit, prior to spirometry 
assessments, then both the number of puffs and the time of administration will 
be documented to allow evaluation of impact, if any, on spirometry 
measurements. Please note that if subjects have used rescue medication within 
6 hours prior to spirometry, then the visit should be rescheduled. 
Vital signs and 12-lead ECG: 
Supine or semi-recumbent blood pressure, pulse rate, and 12-lead ECG (single 
measurement) will be measured pre-dose and approximately 1 hour post-dose at 


 
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V3-V6. Where ECG and spirometry are scheduled at the same timepoint, ECG 
must be performed before spirometry. 
PK sampling: 
Pre- and post-dose PK samples will be collected at all visits between V3 and V6. 
A pre-dose PK sample will be collected within 30 minutes prior to dosing and a 
post-dose PK sample will be collected at any time between 1 to 30 minutes post-
dose. At V6 only, an additional PK sample will be collected at any time between 
1-4 hours post-dose. Care will be taken to ensure that PK samples are not 
contaminated by the study drug dosing procedure (i.e., by performing PK 
sampling and sample processing in a different room to study drug 
administration). 
Safety laboratory tests:  
Urine or serum pregnancy tests will be performed at all visits between V3 and 
V6 for female subjects of child-bearing potential. At V6 only, blood and urine 
samples will be taken for routine laboratory safety tests (hematology, clinical 
chemistry, urinalysis). 
Spirometry: 
Spirometry measurements of FEV1 and FVC will be performed in accordance 
with the American Thoracic Society/European Respiratory Society (ATS/ERS) 
guidelines (Graham et al., 2019 [7]) using standardized, centralized spirometry 
equipment that have been calibrated according to manufacturer’s guidelines. 
Investigators must check that subjects have not taken salbutamol rescue 
medication within 6 hours prior to spirometry. If the washout period for rescue 
medication or other restricted medications have not been met, the visit should be 
rescheduled within the visit window. Pre-dose measurements will be performed 
at -45 and -15 minutes pre-dose at all visits between V3 and V6. Post-dose 
measurements will be performed at V3 and V6 only at the following timepoints 
after dosing: 5, 15, and 30 minutes, and 1, 1.5, and 2 hours.  
Study drug administration: 
Study drug will be administered using a centrally-provided, standard jet 
nebulizer (PARI LC Sprint) and compressor (PARI TurboBOY) via a 
mouthpiece. Prior to the first dose on Day 1, subjects (and their caregiver, if 
applicable) will be trained on the use and maintenance of the nebulizer and 
compressor. Study drug administration will be performed at the Investigator site 
at V3, V4, V5 and V6. It will take up to approximately 10 minutes and 
completion will be evidenced by spluttering of the nebulizer. Dosing time will 
be recorded in date, hours, and minutes corresponding to the start and 
completion of nebulization. Pre-dose assessment time is defined relative to the 
start of nebulization. Post-dose assessment time is defined relative to the 
completion of nebulization. Subjects who are on concomitant LABA or 
ICS/LABA should take their regular morning dose after pre-dose spirometry and 
immediately prior to study drug administration (if a subject takes their LABA or 
ICS/LABA prior to the pre-dose spirometry, the visit should be rescheduled). 
Between visits, study drug will be self-administered at home every morning at 
approximately the same time within the window of 06:00 and 11:00. The time of 
home administration will be recorded by the subjects in their diary. Study drug 
compliance will be checked by counting used and unused vials returned to the 
site at each visit to ensure that it is within 80-120%. Study drug administration 
must be performed in a different room from that used for PK blood sampling and 
processing to avoid contamination of PK samples. 


 
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Discharge procedures for each visit: 
Prior to discharge from the clinic at V3 to V5, subjects will be dispensed 
sufficient rescue medication, study drug supplies, and diary cards (for recording 
rescue medication and study drug administration). 
At V6 only, a general physical examination will be performed prior to discharge. 
Follow-up: 
A follow-up telephone call will be conducted 7-14 days after V6 to review 
adverse events and concomitant medication. 
Inclusion/ 
Exclusion 
Criteria 
Inclusion criteria 
1. Males and females of Chinese ethnicity, at least 40 years of age. 
Females may be of either childbearing or non-childbearing potential. All 
females of childbearing potential must be using an acceptable, highly 
effective method of contraception and have a negative pregnancy test at 
screening.   
2. A clinical diagnosis for at least 6 months prior to screening of COPD 
according to GOLD guidelines (GOLD, 2019 [1]).  
3. Subject is capable of performing reproducible spirometry maneuvers as 
described by current American Thoracic Society/European Respiratory 
Society (ATS/ERS) Guidelines (Graham et al., 2019 [7]) and has a post-
ipratropium (500 mcg nebulized) FEV1/FVC ratio <0.7 at Visit 2. 
4. Subject has moderate to very severe COPD with a post-ipratropium 
(500 mcg nebulized) FEV1 less than 80% of predicted normal (using the 
Global Lung Function Initiative reference range; Quanjer et al., 2012 
[8]) and an absolute FEV1 >700 mL at Visit 2. 
5. Current smoker or ex-smoker, with a history of at least 10 pack-years of 
tobacco smoking. Ex-smokers must have stopped smoking >6 months 
prior to Visit 1. 
Formulae for pack-years: 
• 
Average number of cigarettes per day x 1/20 x years of smoking 
Or 
• 
Ounces of tobacco per week x 2/7 x years of smoking 
Or 
• 
Grams of tobacco per week x 2/175 x years of smoking 
6. Capable of self-administering (or with the help of a caregiver) study 
medication, assessed at training at Visit 1 and Visit 3. 
7. Able to understand and complete the study requirements (including 
literacy, to enable diary and questionnaire completion), provide written 
informed consent, and agree to abide by the study protocol and its 
restrictions. 
Exclusion Criteria 
1. Previously dosed with revefenacin. 
2. Current diagnosis of asthma.  
3. Alpha-1 anti-trypsin deficiency.  
4. Other chronic or active respiratory disorder (e.g., clinically significant 
[as determined by the Investigator] bronchiectasis, pulmonary fibrosis, 
sarcoidosis, pneumoconiosis, active tuberculosis). 


 
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5. Symptoms of, or treatment for an AECOPD requiring antibiotics and/or 
oral/systemic corticosteroids or in-patient hospitalization during the 
28 days preceding screening or during the screening period between 
Visit 1 and Visit 3. An AECOPD is defined as an acute event in the 
natural course of the disease warranting a change in the subject’s regular 
medication specifically to address the exacerbation event, characterized 
by: 
Worsening, beyond normal day-to-day variation, of two or more of the 
following major symptoms for at least two consecutive days: 
• 
Dyspnea 
• 
Sputum volume 
• 
Sputum purulence 
or 
Worsening, beyond normal day-to-day variation, of any one major 
symptom outlined above plus any one of the following minor symptoms 
for at least two consecutive days: 
• 
Sore throat 
• 
Colds (nasal discharge and/or nasal congestions) 
• 
Fever without other cause 
• 
Increased cough 
• 
Increased wheeze 
6. Pneumonia requiring hospitalization within 28 days prior to screening or 
during the screening period between Visit 1 and Visit 3. 
7. Lower respiratory tract infection requiring treatment with antibiotics 
during the 28 days preceding screening or during the screening period 
between Visit 1 and Visit 3. 
8. History or presence of pulmonary hypertension, respiratory failure, cor 
pulmonale or right ventricular failure which may impact the safety of the 
subject in the clinical judgement of the Investigator. 
9. History of pulmonary lobectomy, lung volume reduction surgery, or 
lung transplantation. 
10. Use of supplemental oxygen therapy for more than 15 hours per day 
(includes night-time use). 
11. Subjects participating in or planning to participate in the active phase of 
a supervised pulmonary rehabilitation program during the trial 
(maintenance program is permitted). 
12. Clinically significant, abnormal chest X-ray at screening indicating an 
active/significant disease process other than COPD. If a prior chest 
X-ray or thoracic high-resolution CT scan within 12 months prior to 
screening is available this will be acceptable. 
13. History of long QT syndrome or screening ECG with QTcF greater than 
500 milliseconds (0.500 seconds).  
14. History within past 5 years of paroxysmal atrial fibrillation. Subjects 
with continuous atrial fibrillation controlled with a rate control strategy 
(i.e., cardioselective β-blocker, calcium channel blocker, pacemaker 
placement, digoxin or ablation therapy) for at least 6 months may be 


 
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included if the ventricular rate is below 100 bpm. 
15. Any other clinically significant abnormality on the 12-lead ECG at 
screening which in the judgment of the Investigator would put the 
subject at potential risk if enrolled into the trial (these subjects should 
not be re-screened). Clinically significant abnormalities may include but 
are not limited to the following: left bundle branch block, 
Wolff-Parkinson-White syndrome, clinically significant arrhythmias 
(e.g., ventricular tachycardia).  
16. Current evidence of, or history within the 6 months prior to screening of 
unstable ischemic heart disease, NYHA Class III/IV left ventricular 
failure, or myocardial infarction. 
17. Subjects with hepatic impairment. A history of hepatitis B or hepatitis C 
may be permitted at the discretion of the Investigator, provided the 
subject has no signs of hepatic impairment, is asymptomatic, and liver 
transaminases (ALT/AST) are ≤1.5 times the upper limit of normal 
(ULN) at Screening. 
18. History of malignancy of any organ system treated or untreated, within 
the past 5 years whether or not there is evidence of local recurrence or 
metastases. The only exceptions are previous in situ carcinoma of the 
cervix, localized basal cell carcinoma of the skin or localized squamous 
carcinoma of the skin if the subject has been treated and is considered 
cured. 
19. Subject 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. 
20. Use of any investigational drug within 28 days, or 5 half-lives, prior to 
screening whichever is longer. 
21. Use of medications with the potential to interact with revefenacin, 
salbutamol or ipratropium bromide (as indicated in respective 
Investigator Brochure (IB) or product labels), or medications with the 
potential to affect or confound COPD disease status. Drugs should be 
washed out prior to screening (further details of washout periods prior to 
screening are in Table 5-1) and not taken thereafter during the study 
until after the final dose of study drug:  
1. Oral anticholinergics. 
2. Oral or “systemic” (parenteral; intravenous or intra-articular, 
intramuscular, spinal) corticosteroids. 
3. OATP1B1 and OATP1B3 inhibitors (e.g., rifampicin, cyclosporine) 
4. Strong CYP3A4 inhibitors. 
5. Use of marijuana. 
6. Herbal medications and Traditional Chinese Medications. 
22. History of reactions/hypersensitivity to any of the following inhaled 
drugs or drugs of a similar class: short- or long- acting β2 agonists (e.g., 
salbutamol, formoterol), anticholinergic agents (e.g., tiotropium, 
ipratropium bromide), corticosteroids, sympathomimetic amines. 
Subjects with previous reaction to inhaled agents due to lactose 


 
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sensitivity alone will be permissible for this study. 
23. Subjects who are unable to stop any of the following medications, and 
refrain from their use throughout the study until the final dose of study 
drug (further details in Table 5-1): 
• 
Short-acting β2 agonists (except study-supplied salbutamol). 
• 
Short-acting anticholinergic agents (except those used for 
reversibility testing). 
• 
Long-acting anticholinergics (except study supplied medication). 
• 
Combination β2 agonists/anticholinergic agents. 
• 
Combination β2 agonists/inhaled corticosteroids/anticholinergic 
agents. 
• 
Phosphodiesterase 4 inhibitors. 
• 
Theophyllines. 
• 
Leukotriene inhibitors.  
• 
Orally inhaled nedocromil or cromolyn sodium. 
• 
Oral or parenteral corticosteroids. 
24. Pregnant or nursing females or females intending to become pregnant 
during the course of the study.  
25. Clinically significant abnormal laboratory test(s) at screening deemed 
exclusionary by the Investigator.  
26. History of illegal or recreational drug or alcohol abuse within the past 
5 years. 
27. Other acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study 
participation or investigational product administration or may interfere 
with the interpretation of study results and, in the judgment of the 
Investigator, would make the subject inappropriate for entry into this 
study. 
Planned 
Number of 
Subjects 
Approximately N=320 subjects will be randomized in a 1:1 ratio to revefenacin 
or matching placebo (N=160 on revefenacin and N=160 for placebo). 
Statistical 
Methods 
Sample size estimation 
The null hypothesis is that there is no difference in the mean change from 
baseline trough FEV1 on Day 85 between revefenacin and placebo.  The 
alternative hypothesis is that there is a difference. 
A sample size of 256 evaluable subjects (128:128; a 1:1 ratio of revefenacin to 
placebo) is required to provide at least 90% power to detect a difference between 
revefenacin and placebo of 100 mL in the analysis of the change from baseline 
trough FEV1 at Day 85 assuming a standard deviation of 245 mL and a 
two-sided 5% significance level. 
To allow for a 20% dropout rate, approximately 320 subjects in total will be 
randomized. In the event of a public health emergency such as COVID-19, the 
Sponsor may consider increasing enrollment to overcome any additional loss of 


 
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information for the primary endpoint due to the inability of subjects to attend for 
scheduled clinic visits.  The maximum number of subjects to be randomized 
under such circumstances will be limited to 428 (an additional 20% increase in 
enrollment). 
Analysis Populations 
The following 4 analysis populations are planned for this study: 
• 
Full Analysis Set (FAS): all randomized subjects who received at least 
one dose of study drug and have at least one recorded post-baseline 
efficacy assessment.   
• 
Safety Analysis Set (SS): all subjects who received at least one dose of 
study drug. 
• 
Per Protocol Set (PP): all subjects in the FAS who had no major protocol 
violation that would impact significantly on the primary efficacy 
endpoints.   
• 
Population Pharmacokinetic Analysis Set (PPK): all randomized 
subjects who receive at least one dose of study drug and who provide at 
least one evaluable post dose concentration sample for the PPK analysis. 
Statistical Analyses 
 
Primary Efficacy Endpoint  
The primary endpoint is trough FEV1 on Day 85. Trough FEV1 will also be 
measured on Days 29 and 57. 
 
The analysis of the primary endpoint will be based on a mixed model repeated 
measures (MMRM) analysis including changes from baseline trough FEV1 
measurements on Days 29, 57 and 85 as the dependent variable. The model will 
include independent fixed-effect terms for concomitant LABA use, reversibility 
to ipratropium, smoking status, age, sex, concomitant LABA, reversibility, 
treatment and baseline FEV1 as a covariate. A time effect (visit) and its 
interaction terms with treatment and baseline FEV1 will be included. The 
variance estimation will be based on an unstructured covariance matrix. The 
Kenward-Roger method for approximating the denominator degrees of freedom 
will be used.   
 
Primary Efficacy Analysis  
The primary analysis of the primary efficacy endpoint will be based on the FAS 
population. Available data for a subject prior to discontinuing study treatment 
will be used in the MMRM analysis. Missing data is assumed as missing at 
random (MAR). The difference between revefenacin and placebo on Day 85 will 
be estimated from the least squares means (LSmeans) along with the 95% 
confidence interval (CI) and associated 2-sided p-values. 
 
Primary Efficacy Sensitivity Analyses  
The primary efficacy analysis will be repeated for pre-defined subgroups and in 
the PP population.  
 


 
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Missing data in the primary efficacy analysis is assumed as missing at random 
(MAR). The following missing data imputation methods will be used in 
sensitivity analyses to test the robustness of the conclusions to this assumption: 
• 
A two-dimensional tipping point multiple imputation method will be 
applied to the MMRM analysis (FAS population). 
• 
A Last-Observation-Carried-Forward (LOCF) single imputation method 
for the changes from baseline trough FEV1 at Day 85 will be used and 
analyzed using an Analysis of Covariance (ANCOVA) model. 
 
Secondary Efficacy Analyses   
In all the secondary efficacy analyses, missing data will not be imputed and will 
be assumed to be missing at random (MAR). Secondary efficacy analyses will 
be performed using the FAS population and include, but is not limited to, the 
following comparisons: 
• 
Peak FEV1 (0-2h) on Day 1:  Analysis of Covariance (ANCOVA) will 
be used to assess the difference between treatment groups for change 
from baseline Peak FEV1 after the first dose on Day 1. The ANCOVA 
model will include fixed-effect terms for concomitant LABA use, 
reversibility to ipratropium, smoking status, age, sex, treatment and 
baseline FEV1 as a covariate.  The difference between revefenacin and 
placebo on Day 1 will be estimated from the LSmeans along with the 
95% CI and associated 2-sided p-values. 
• 
SGRQ responders (total score >=4 units) on Day 85: The number and 
percentage of responders on Day 85 in each treatment group will be 
summarized. A comparison between revefenacin and placebo will be 
evaluated with the odds ratio (OR) and corresponding 95% confidence 
interval from a logistic regression model. The model will include 
fixed-effect terms for concomitant LABA use, reversibility to 
ipratropium, smoking status, age, sex, treatment and baseline SGRQ 
total score as a covariate. For subjects who discontinue study treatment, 
the SGRQ completed at the Early Termination (ET) visit will be carried 
forward and used in the analysis. 
• 
BDI/TDI on Day 85: The TDI focal score will be analyzed using the 
same MMRM analysis described for the primary analysis of the primary 
endpoint. The baseline FEV1 covariate will be replaced with the BDI 
focal score. Estimates for TDI on Day 85 will be derived from the 
model. The difference between revefenacin and placebo on Day 85 will 
be estimated from the LSmeans along with the 95% CI and associated 
2-sided p-values 
• 
Average Count of Salbutamol Puffs Per Day (Days 1-85):  The average 
count of salbutamol puffs per day will be analyzed using the same 
MMRM analysis described for the primary analysis of the primary 
endpoint with the time variable Month (1, 2, 3) replacing Visit. The 
average count of salbutamol puffs per day for the study (Days 1-85) will 
be estimated from the model-derived average of each of the 3 months 
using an appropriate contrast statement along LSmean differences, 95% 
CI and associated 2-sided p-values. 
• 
Percentage of salbutamol rescue free 24h periods (Days 1-85): The 
percentage of salbutamol rescue free 24h periods will be analyzed using 
the same MMRM analysis described for the primary analysis of the 


 
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primary endpoint with the time variable Month (1, 2, 3) replacing Visit.   
The average percentage of salbutamol rescue free 24h periods for the 
study (Days 1-85) will be estimated from the model-derived average of 
each of the 3 months using an appropriate contrast statement with 
LSmean differences, 95% CI and associated 2-sided p-values. 
 
Safety Analyses  
All safety data will be presented in listings. Descriptive summary tables will be 
provided for treatment-emergent adverse events (TEAE), laboratory evaluations, 
vital signs, 12-lead ECG parameters, and concomitant medications. Safety data 
will be presented using the SS population. 
 
A summary of acute exacerbations of COPD (AECOPD) reported with an AE 
preferred term of COPD will be descriptively summarized by severity. 
Exacerbation data will be summarized (N, %) for all exacerbations; moderate 
and severe exacerbations; and severe only exacerbations. 
 
PK Analyses 
Plasma concentration data for revefenacin and THRX-195518 will be listed, 
summarized on the basis of time intervals, and plotted using a scatter plot with 
time relative to the preceding revefenacin dosing time. Summary statistics 
(mean, standard deviation, minimum, maximum, number of subjects, and 
coefficient of variation) will be calculated for plasma concentrations for each 
time interval and by treatment group. 
 
All analyses using the PPK set will group subjects according to treatment 
actually received. Full details of the PPK analysis, including methods for 
handling data (missing values, outliers), etc., will be documented in a PPK 
analysis plan and will be conducted and reported separately. 
 
 
Confidentiality: This protocol is the confidential, intellectual property of Mylan Pharma UK 
Ltd. It should not be disclosed to a third party with the exception of regulatory agencies and 
study audit personnel that being Mylan employees, representatives, agents and/or contractors 
responsible for conducting the clinical study/trial, audits. Reproduction, modification, or 
adaptation in part or in total is strictly forbidden without prior written approval by Mylan 
Pharma UK Ltd.


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 19 
1 
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES ............................. 21 
2 
INTRODUCTION ........................................................................................................... 24 
2.1 
Indication ................................................................................................................. 24 
2.2 
Background and Rationale ....................................................................................... 24 
2.2.1 Rationale for Dose Selection ............................................................................... 26 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 27 
3.1 
Objectives ................................................................................................................ 27 
3.1.1 Primary Objectives............................................................................................... 27 
3.1.2 Secondary Objectives........................................................................................... 27 
3.2 
Endpoints ................................................................................................................. 27 
3.2.2 Secondary Endpoints ........................................................................................... 27 
3.2.2.1 Efficacy ......................................................................................................... 27 
3.2.2.2 Safety ............................................................................................................. 28 
3.2.3 Pharmacokinetic (PK) .......................................................................................... 28 
4 
STUDY POPULATION .................................................................................................. 28 
4.1 
Study Population ...................................................................................................... 28 
4.2 
Inclusion and Exclusion Criteria .............................................................................. 28 
4.2.1 Inclusion Criteria ................................................................................................. 28 
4.2.2 Exclusion Criteria ................................................................................................ 29 
4.2.3 Randomization Criteria ........................................................................................ 32 
4.2.4 Criteria for Study Drug Termination, Withdrawal from the Study and Study 
Termination ...................................................................................................................... 33 
4.3 
Lifestyle Guidelines ................................................................................................. 34 
4.3.1 Meals and Dietary Restrictions ............................................................................ 34 
4.3.2 Alcohol, Caffeine and Tobacco ........................................................................... 34 


 
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4.3.3 Activity ................................................................................................................ 34 
4.3.4 Other Restrictions ................................................................................................ 34 
4.4 
Contraception ........................................................................................................... 34 
4.4.1 Females - Non-childbearing Potential ................................................................. 34 
4.4.2 Females - Childbearing Potential ......................................................................... 35 
4.5 
Pregnancy Testing .................................................................................................... 35 
5 
STUDY DRUG ................................................................................................................ 35 
5.1 
Investigational Drug................................................................................................. 35 
5.1.1 Administration of Study Drugs ............................................................................ 36 
5.1.2 Study Medication Compliance ............................................................................. 36 
5.2 
Drug Inventory ......................................................................................................... 37 
5.3 
Study Medication Complaints.................................................................................. 37 
5.4 
Storage, Disposition of Used and Unused Study Drug and Drug Accountability ... 37 
5.5 
Randomization ......................................................................................................... 38 
5.6 
Breaking the Blind ................................................................................................... 38 
5.7 
Concomitant Medications ........................................................................................ 39 
5.8 
Recommended Procedure in a Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug ............................................................. 41 
6 
STUDY CONDUCT ........................................................................................................ 42 
6.1 
Screening Procedures ............................................................................................... 42 
6.1.1 Screening (Visits 1 and 2) .................................................................................... 43 
6.2 
Treatment Phase ....................................................................................................... 44 
6.2.1 Visit 3 (Day 1) ..................................................................................................... 44 
6.2.2 Visit 4 (Day 29 ± 7 days) ..................................................................................... 46 
6.2.3 Visit 5 (Day 57 ± 7 days) ..................................................................................... 46 
6.2.4 Visit 6, EoT (Day 85 ± 7 days) ............................................................................ 47 
6.2.5 Early Study Drug Termination (ET) Visit ........................................................... 48 


 
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6.3 
Follow Up (telephone call 7-14 days after the last dose of study medication [EoT 
Visit]) 49 
6.4 
Treatment Procedures .............................................................................................. 50 
6.4.1 Blood Volume ...................................................................................................... 50 
6.4.2 Spirometry............................................................................................................ 50 
6.4.3 Bronchodilator Reversibility ................................................................................ 51 
6.4.4 Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) ....................... 51 
6.4.5 Modified Medical Research Council Dyspnea Scale (mMRC) ........................... 52 
6.4.6 St. George’s Respiratory Questionnaire (SGRQ) ................................................ 52 
6.4.7 Pharmacokinetics ................................................................................................. 52 
6.4.8 Safety Testing ...................................................................................................... 53 
6.4.8.1 Adverse Event Assessment ........................................................................... 53 
6.4.8.2 Laboratory Safety .......................................................................................... 54 
6.4.8.3 Blood Pressure and Pulse Rate ...................................................................... 55 
6.4.8.4 12-lead ECG .................................................................................................. 56 
6.4.8.5 General Physical Examination ...................................................................... 56 
6.5 
Restrictions .............................................................................................................. 57 
6.6 
Mitigation in the event of a public health emergency .............................................. 57 
7 
STATISTICAL ANALYSIS ........................................................................................... 57 
7.1 
Sample Size Considerations ..................................................................................... 58 
7.2 
Analysis Set Definitions .......................................................................................... 58 
7.2.1 Safety Analysis Set .............................................................................................. 58 
7.2.2 Full Analysis Set .................................................................................................. 58 
7.2.3 Per Protocol Analysis Set..................................................................................... 58 
7.2.4 Population Pharmacokinetic Analysis Set ........................................................... 58 
7.3 
Primary Endpoints ................................................................................................... 59 
7.3.1 Definition of Primary Endpoints .......................................................................... 59 


 
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7.3.2 Statistical Methodology for Primary Endpoints .................................................. 59 
7.3.3 Primary Analysis for Primary Endpoint .............................................................. 59 
7.3.4 Secondary/Sensitivity Analyses for Primary Endpoint........................................ 59 
7.3.5 Missing Data ........................................................................................................ 60 
7.3.6 Sub-Group Analyses ............................................................................................ 60 
7.4 
Secondary Efficacy Endpoints ................................................................................. 60 
7.4.1 Spirometry............................................................................................................ 60 
7.4.1.1 Trough FEV1 on Days 29 and 57 .................................................................. 60 
7.4.1.2 Trough FVC on Days 29, 57 and 85 ............................................................. 61 
7.4.1.3 Peak FEV1 (0-2h) on Day 1 and Day 85 ....................................................... 61 
7.4.1.4 Weighted Mean FEV1 (0-2h) on Day 1 and Day 85 ..................................... 61 
7.4.2 Patient Reported Outcomes (PROs)..................................................................... 61 
7.4.2.1 SGRQ on Day 85 (continuous endpoint) ...................................................... 61 
7.4.2.2 SGRQ Responders (total score 4 units) on Day 85 ..................................... 62 
7.4.2.3 BDI/TDI on Days 29, 57 and 85 ................................................................... 62 
7.4.2.4 TDI Responders (focal score 1 unit) on Days 29, 57 and 85 ...................... 62 
7.4.3 Rescue Medication Usage .................................................................................... 63 
7.4.3.1 Average Count of Salbutamol Puffs Per Day (Days 1-85) ........................... 63 
7.4.3.2 Percentage of Salbutamol Rescue Free 24h Periods (Days 1-85) ................. 63 
7.5 
Safety Endpoints ...................................................................................................... 63 
7.5.1 Adverse Events .................................................................................................... 63 
7.5.2 Acute Exacerbations of COPD (AECOPD) ......................................................... 63 
7.5.3 Other Safety Endpoints ........................................................................................ 64 
7.5.3.1 Vital Signs ..................................................................................................... 64 
7.5.3.2 12-lead ECG .................................................................................................. 64 
7.5.3.3 Laboratory Tests ............................................................................................ 64 
7.6 
PK Analyses ............................................................................................................. 64 


 
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7.7 
Other Analyses ......................................................................................................... 65 
7.8 
Interim Analyses ...................................................................................................... 65 
8 
ADMINISTRATIVE PROCEDURES ............................................................................ 65 
8.1 
Source Documentation Forms.................................................................................. 65 
8.2 
Access to Data/Source Documentation .................................................................... 65 
8.3 
Final Clinical Study Report and Case Report Forms (CRFs) .................................. 65 
8.4 
Adherence to Protocol.............................................................................................. 66 
8.5 
Data Handling and Record Retention ...................................................................... 66 
8.6 
Confidentiality ......................................................................................................... 66 
8.7 
Ethics and Regulatory Authorities ........................................................................... 67 
8.7.1 Institutional Review Board/Ethics Committee .................................................... 67 
8.7.2 Regulatory Authority ........................................................................................... 67 
8.8 
Informed Consent..................................................................................................... 67 
8.9 
Disclosure and Publication of Clinical Study Data.................................................. 67 
8.10 
End of Trial .............................................................................................................. 68 
9 
Adverse Event Reporting ................................................................................................. 68 
9.1 
Assessment of Safety ............................................................................................... 68 
9.1.1 Safety Parameters................................................................................................. 68 
9.2 
Definitions................................................................................................................ 68 
9.2.1 Adverse Event ...................................................................................................... 68 
9.2.2 Serious Adverse Event (SAE) .............................................................................. 70 
9.2.3 Adverse Drug Reaction ........................................................................................ 71 
9.2.4 Expected/Unexpected Adverse Event .................................................................. 71 
9.2.5 Pre-existing Condition ......................................................................................... 71 
9.2.6 General Physical Examination Findings .............................................................. 71 
9.2.7 Post-study Adverse Event/Serious Adverse Event .............................................. 72 
9.3 
Special Situations ..................................................................................................... 72 


 
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9.4 
Collection and Recording of Adverse Events .......................................................... 72 
9.5 
Classification of an Adverse Event .......................................................................... 73 
9.5.1 Severity ................................................................................................................ 73 
9.5.2 Causality .............................................................................................................. 73 
9.5.3 Expectedness ........................................................................................................ 75 
9.5.4 Outcome ............................................................................................................... 75 
9.6 
Reporting of Serious Adverse Events and Pregnancy Exposures ............................ 76 
9.6.1 Investigator Reporting: Notifying the Study Sponsor ......................................... 76 
9.6.2 Follow-up ............................................................................................................. 77 
9.6.3 Investigator Reporting: Notification of Ethics Committee .................................. 77 
9.6.4 Investigator Reporting of Pregnancy - Notifying the Study Sponsor .................. 77 
10 REFERENCE LIST ......................................................................................................... 79 
11 Patient Reported Measures .............................................................................................. 80 
11.1 
BDI/TDI ................................................................................................................... 80 
11.2 
mMRC...................................................................................................................... 86 
11.3 
SGRQ ....................................................................................................................... 87 
12 PROTOCOL AMENDMENT DETAILS ........................................................................ 93 
TABLE OF TABLES 
Table 1-1: Study Schedule ....................................................................................................... 22 
Table 5-1: Restricted Medications ........................................................................................... 40 
Table 6-1: Blood Volume ........................................................................................................ 50 
Table 6-2: Laboratory Safety Tests.......................................................................................... 55 
 
TABLE OF FIGURES 
Figure 1-1: Study Diagram ...................................................................................................... 21 
 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
 
IUD 
Intrauterine Device 
AECOPD  
Acute Exacerbation of COPD 
 
IUS 
Intrauterine System 
ALT 
Alanine Transaminase 
 
IVRS/ 
IWRS 
Interactive Voice Response 
System/ Interactive Web 
Response System 
ANCOVA Analysis of Covariance 
 
LABA 
Long-acting beta-
adrenoceptor agonist 
AST 
Aspartate Transaminase 
 
LAMA 
Long-acting muscarinic 
receptor antagonist  
ATS 
American Thoracic Society 
 
LOCF 
Last Observation Carried 
Forward 
AUC 
Area Under the Curve 
 
LSmean 
Least Squares Mean 
BDI  
Baseline Dyspnea Index 
 
MAR 
Missing At Random 
BDR 
Blinded Data Review 
 
Max/Min 
Maximum/Minimum 
BID 
Bis in die (two times a day) 
 
mcg 
Microgram 
BP 
Blood Pressure 
 
MCID 
Minimally Clinically 
Important Difference 
bpm 
beats per minute 
 
mL 
Milliliter 
CI  
Confidence Interval 
 
mM 
Millimolar 
Cmax 
Maximum observed plasma 
concentration 
 
mmHg 
Millimeter of Mercury 
COPD 
Chronic Obstructive 
Pulmonary Disease 
 
mMRC 
Modified Medical Research 
Council Dyspnea Scale 
CRF 
Case Report Form 
 
MMRM 
Mixed Model Repeated 
Measures 
CRP 
C-reactive Protein 
 
ms 
Millisecond 
Ctrough 
Trough plasma concentration 
 
NYHA 
New York Heart Association  
CYP 
Cytochrome P450 
 
OR 
Odds Ratio 
CT 
Computed Tomography 
 
PI 
Principal Investigator 
ECG 
Electrocardiogram 
 
pMDI 
Pressurized Metered Dose 
Inhaler  
EoT 
End of Treatment 
 
PP 
Per Protocol  
ERS 
European Respiratory Society 
 
PPK 
Population Pharmacokinetics 
ET 
Early Termination 
 
PRN 
pro re nata 
FAS 
Full Analysis Set 
 
PRO 
Patient Reported Outcome 
FDA 
Food and Drug Administration 
 
QD 
Quaque die (once a day) 
FEV1 
Forced Expiratory Volume in 
1 second 
 
QTc 
QT corrected 


 
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FSH 
Follicle Stimulating Hormone 
 
QTcF 
QT corrected (Fridericia’s 
correction) 
FVC 
Forced Vital Capacity 
 
RBC 
Red Blood Cell 
GCP 
Good Clinical Practice 
 
SAE 
Serious Adverse Event 
GOLD 
Global Initiative for Chronic 
Obstructive Lung Disease 
 
SAP 
Statistical Analysis Plan 
hCG 
Human Chorionic 
Gonadotropin 
 
SGRQ 
St. George’s Respiratory 
Questionnaire 
HR 
Heart Rate 
 
SID 
Subject Identification 
IB 
Investigator’s Brochure 
 
SS 
Safety Analysis Set 
ICF 
Informed Consent Form 
 
SOP 
Standard Operating Procedure 
ICH 
International Council for 
Harmonisation of Technical 
Requirements for 
Pharmaceuticals for Human 
Use 
 
TDI 
Transition Dyspnea Index 
ICS 
Inhaled Corticosteroid 
 
TEAE 
Treatment Emergent Adverse 
Event 
ID 
Identification 
 
ULN 
Upper Limit of Normal 
IEC 
Independent Ethics Committee 
 
US 
United States 
IRB 
Institutional Review Board 
 
WBC 
White Blood Cell 
ITT 
Intent To Treat 
 
WM 
Weighted-Mean 
 


 
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1 
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES 
The Schedule of Activities table (Table 1-1) provides an overview of the protocol visits and procedures. Refer to the Study Conduct (Section 6) 
for detailed information on each procedure and assessment required for compliance with the protocol. 
Figure 1-1: Study Diagram 
 
 


 
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Table 1-1: Study Schedule 
VISIT 
1 
(Screen 1) 
2 
(Screen 2)1  
3 
Randomization 
4 
5 
6 
(EoT) 
Early term 
(ET) 
Follow up 
(Telephone) 
NOMINAL DAY 
(ALLOWABLE WINDOW) 
-14 
(-30 to -4)  
-7 
(-10 to -4) 
1 
29 
(22-36) 
57 
(50-64) 
85 
(78-92) 
 
7-14 days 
after V6/ET 
NOMINAL WEEK 
-2 
-1 
0 
4 
8 
12 
 
 
Written informed consent 
x 
 
 
 
 
 
 
 
IVRS/IWRS transaction 
x 
 
x 
x 
x 
x 
x 
x 
Demography and medical history (incl. 
COPD, smoking, and exacerbation history) 
x 
 
 
 
 
 
 
 
Review concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
 
 
x 
x 
 
Chest X-ray (if not done in past 12 months) 
x 
 
 
 
 
 
 
 
Height and weight 
x 
 
 
 
 
 
 
 
Vital Signs (supine or semi-recumbent blood 
pressure, pulse rate) 
x 
 
x2 
 
 
x2 
x 
 
12-lead ECG (supine or semi-recumbent) 
x 
 
x2 
 
 
x2 
x 
 
Spirometry (FEV1, FVC) 
pre-bronchodilator 
 
x 
 
 
 
 
 
 
Spirometry (FEV1, FVC) 45 min 
post-ipratropium (500 mcg nebulized) 
 
x 
 
 
 
 
 
 
Laboratory Safety – Blood and Urinalysis 
x 
 
 
 
 
x 
x 
 
Pregnancy Test 
x 
 
x 
x 
x 
x 
x 
 
Dispense Rescue Medication (salbutamol 
pMDI) 
x 
 
x 
x 
x 
 
 
 
Dispense Daily Diary 
x 
 
x 
x 
x 
 
 
 
Record Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 


 
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VISIT 
1 
(Screen 1) 
2 
(Screen 2)1  
3 
Randomization 
4 
5 
6 
(EoT) 
Early term 
(ET) 
Follow up 
(Telephone) 
NOMINAL DAY 
(ALLOWABLE WINDOW) 
-14 
(-30 to -4)  
-7 
(-10 to -4) 
1 
29 
(22-36) 
57 
(50-64) 
85 
(78-92) 
 
7-14 days 
after V6/ET 
NOMINAL WEEK 
-2 
-1 
0 
4 
8 
12 
 
 
Medication Training 
x3 
 
x 
 
 
 
 
 
Pre-dose Spirometry (FEV1, FVC), -45 and 
-15 min pre-dose. 
 
 
x 
x 
x 
x 
x 
 
Complete BDI/TDI4 
 
 
x 
x 
x 
x 
x 
 
Complete SGRQ 
 
 
x 
 
 
x 
x 
 
Complete mMRC 
 
 
x 
 
 
 
 
 
Randomization 
 
 
x 
 
 
 
 
 
Administer Study Medication in Clinic 
 
 
x 
x 
x 
x 
 
 
Dispense Outpatient Study Medication 
 
 
x 
x 
x 
 
 
 
Post-dose Spirometry (FEV1, FVC), 5, 15, 
and 30 minutes, and 1, 1.5, and 2h 
 
 
x 
 
 
x 
 
 
PK sampling 
 
 
x5 
x5 
x5 
x5 
 
 
Record Rescue Medication and Study Drug 
in Diary, Review at Clinic Visits 
 
x 
x 
x 
x 
x 
x 
 
 
1. Visit 2 (Screening Visit 2) can be conducted on the same day as Visit 1 (Screening Visit 1) if the subject does not require washout of other COPD 
medications (e.g., 7 days for LAMAs) prior to the ipratropium reversibility test at Visit 2. 
2. Pre-dose and at approximately 1 hour post-dose. 
3. Train subject on rescue medication use. 
4. BDI is performed at V3 and TDI is performed at V4, V5, and V6. 
5. PK sampling will be performed pre-dose (within 30 minutes of dosing) and at any time 1 – 30 minutes post-dose at Visit 3, 4, 5, and 6. At Visit 6, an 
additional PK sample will be collected during the sampling interval of 1 – 4 hours post-dose.


 
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2 
INTRODUCTION 
2.1 
Indication 
Moderate to very severe chronic obstructive pulmonary disease (COPD). 
2.2 
Background and Rationale 
COPD is a respiratory disease characterized by airflow obstruction that is not fully reversible.  
The airflow limitation is usually both progressive and associated with an abnormal 
inflammatory response in the airways and the lung to noxious particles or gases (Global 
Initiative for Chronic Obstructive Lung Disease [GOLD], 2019 [1]). In 2012, it was estimated 
that more than 3 million people died prematurely due to COPD and it is projected to be the 
third leading cause of death worldwide by 2020 (GOLD 2019 [1]). 
In the People's Republic of China, the prevalence rate of COPD was reported to be between 
1.20% and 8.87% depending on the provinces/cities surveyed (Zhu et al., 2018 [2]), and in 
2013 there were 910,809 deaths due to COPD, which represented 31% of total deaths due to 
COPD in the world (Yin et al., 2016 [3]). In addition to the high prevalence of COPD in 
China, a separate survey across 7 provinces found that only 7.9% of patients had regular 
medical treatment for COPD, highlighting the need, in some regions of China at least, for 
improvement in the management of COPD (Zhu et al., 2018 [2]).  
Pharmacologic treatment of COPD with bronchodilators is central to the management of both 
the symptoms and the long-term risks of the condition. Long-acting inhaled bronchodilators 
are convenient and are more effective for long-term symptom relief than short-acting 
bronchodilators; accordingly, widely accepted treatment guidelines such as those produced 
by GOLD recommend the use of long-acting muscarinic antagonist (LAMA) bronchodilators 
as first-line therapies for patients with persistent COPD symptoms (GOLD 2019 [1]).  
For some patients, bronchodilator therapy may most effectively be provided using a nebulizer 
device. An expert panel review (Wise et al., 2016 [9]) suggests that patients with either 
cognitive or physical decline who cannot coordinate or generate sufficient inspiratory force 
for breath-actuated handheld devices are candidates for nebulized therapy. Patient 
characteristics also identified by the panel when considering nebulization therapy are poor 
adherence to current medication, frequent exacerbations despite treatment with handheld 
inhalers, recent hospitalization, and finally, patient preference for nebulizing their 
medication. Revefenacin is a potent muscarinic receptor antagonist that was designed as a 
once-daily agent to be administered via a mouthpiece using a standard jet nebulizer. It was 
approved by the United States Food and Drug Administration (US FDA) in November 2018 
with the tradename Yupelri® for the maintenance treatment of patients with COPD. It is 
active at all of the muscarinic receptor subtypes M1 through M5, but in the lung, its 
pharmacological effects are mediated through competitive inhibition of M3 receptors at the 
smooth muscle preventing acetylcholine-induced bronchoconstriction and leading to 
bronchodilation. 
The effects of revefenacin inhalation solution administered once daily via a standard jet 
nebulizer via a mouthpiece (PARI LC® Sprint Reusable Nebulizer) were evaluated for the 
US filing and subsequent approval in two replicate 12-week, double-blind, placebo-controlled 
Phase 3 efficacy and safety clinical trials (studies 0126 and 0127), and in a 52-week 


 
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long-term, active controlled (tiotropium dry powder inhaler, 18 mcg once daily) safety trial 
(study 0128), in moderate to very severe COPD patients.   
In studies 0126 and 0127, 1229 patients were included of which 395 received the 175 mcg 
dose administered via a standard jet nebulizer. The primary endpoint was change from 
baseline in trough (pre-dose) FEV1 at Day 85. The study population had a mean age of 
64 years (range: 41 to 88) and mean smoking history of 53 pack years, with 48% identified as 
current smokers. At screening, the mean post-bronchodilator percent predicted FEV1 was 
55% (range: 10% to 90%), and the post-bronchodilator FEV1/FVC ratio was 0.54 (range: 0.3 
to 0.7). 
Using the ITT populations in studies 0126 and 0127, revefenacin inhalation solution 175 mcg 
achieved a statistically significant difference from placebo of 146.26 mL, (95% CI 103.74, 
188.78; p<0.0001) and 147.01 mL, (95% CI 96.98, 197.05; p < 0.0001) respectively. 
Furthermore, a pre-specified pooled analysis of both studies demonstrated a statistically 
significant difference from placebo of 148.13 mL, (95% CI 115.20, 181.06; p < 0.0001). This 
treatment effect is considerably greater than the minimally clinically important difference 
(MCID) for trough FEV1 (Donohue 2005 [10]).  
As requested by US FDA, both studies 0126 and 0127 included up to 40% patients that were 
taking concomitant LABA or ICS/LABA. In study 0126, 37.0% of the population were using 
a LABA-containing product and in study 0127, 36.7% of the population were using a LABA 
containing product. This enabled an assessment of the effect of revefenacin inhalation 
solution in a population taking additional maintenance therapy for COPD and the treatment 
effect of revefenacin inhalation solution was similar in those taking concomitant LABA or 
ICS/LABA. In a pre-specified pooled analysis of both 0126 and 0127 studies, for the 
concomitant LABA or ICS/LABA subgroup, where the comparison is placebo + ICS/LABA 
or LABA vs., revefenacin inhalation solution  + ICS/LABA or LABA, revefenacin inhalation 
solution 175 mcg achieved a nominally statistically significant difference from placebo of 
139.19 mL, (95% CI 82.87 to 195.51); (p < 0.0001). 
The 52 week long-term safety study (study 0128) included 1055 subjects, of whom 335 
received revefenacin inhalation solution 175 mcg and 356 received tiotropium dry powder 
18 mcg.  The study population had a mean age of 64 years (range: 41 to 92) and mean 
smoking history of 52 pack-years, with 46% identified as current smokers. At screening, the 
mean post-bronchodilator percent predicted FEV1 was 54% (range: 18% to 80%), and the 
post-bronchodilator FEV1/FVC ratio was 0.53 (range: 0.2 to 0.7). Approximately 50% of 
subjects were taking a background of ICS/LABA or LABA during the study. 
The primary objective was to characterize the safety and tolerability of revefenacin inhalation 
solution administered once daily. Revefenacin inhalation solution was well tolerated in study 
0128; the most frequently reported TEAE overall was chronic obstructive pulmonary disease 
(worsening or exacerbation of COPD), which was reported for 73/335 (21.8%) in the 
revefenacin inhalation solution 175 mcg group, and 100/356 (28.1%) in the tiotropium group.  
The percentages of subjects reporting any treatment-related TEAE were generally small 
across treatment groups (12% to 15%). The TEAEs most frequently considered related to the 
study drug were worsening/exacerbation of COPD and dyspnea. The incidence of study 
drug-related worsening/exacerbation of COPD was similar between treatment groups (3.6%, 
and 2.8% in the revefenacin inhalation solution 175 mcg group and tiotropium group, 
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The incidence of TEAEs potentially related to anti-muscarinic activity (constipation, dry 
mouth, and dysuria) was low (7/335 [2.1%] in the revefenacin inhalation solution 175 mcg 
group, and 15/356 [4.2%] in the tiotropium group), suggesting that systemic anti-muscarinic 
effects were minimal during the study. 
Revefenacin inhalation solution 175 mcg was well tolerated and had an adverse event profile 
similar to tiotropium inhalation powder (18 mcg) in study 0128; this is consistent with all 
other studies in the revefenacin inhalation solution clinical program where the adverse event 
profile has been similar to placebo and consistent with that reported for other orally inhaled 
anti-muscarinic products. 
Although the data from studies 0126, 0127 and 0128 were derived from clinical trials with 
patients of predominantly Caucasian ethnicity, based on metabolism of the drug, it is unlikely 
to exhibit different exposure in Chinese patients, making these studies highly relevant for 
extrapolating the risk-benefit of revefenacin inhalation solution to the proposed study (see 
Section 2.2.1).  
Clinical trials on other inhaled LAMAs conducted in East Asian COPD patients have 
demonstrated comparable efficacy and safety compared to large global registration trials 
conducted primarily in Caucasian patients, suggesting comparable sensitivity to this class of 
drugs between ethnicities. For example, Wang et al., (2015 [5]) reported that the efficacy and 
safety results of the GLOW7 trial on glycopyrronium in predominantly Chinese patients with 
moderate to severe COPD were similar to previous trials conducted in predominantly 
Caucasian patients. Likewise, a comparison of the efficacy data for East Asian patients 
compared to the overall study population of the TONADO trial on tiotropium/olodaterol 
versus its mono-components concluded that the lung function responses were consistent and 
there were no significant differences in safety outcomes between the two populations (Bai et 
al., 2017 [6]).  
The objective of this study is therefore to confirm the safety and efficacy of revefenacin 
inhalation solution for the treatment of Chinese patients with moderate to very severe COPD, 
in order to provide a bridge for this population to the existing body of data derived from 
clinical trials with patients of predominantly Caucasian ethnicity.  
Complete preclinical and clinical information for revefenacin inhalation solution may be 
found in the Single Reference Safety Document, which for this study is the Investigator 
Brochure. 
2.2.1 Rationale for Dose Selection 
The dose of revefenacin selected for this study is 175 mcg once daily, which has consistently 
shown to be safe and efficacious in COPD subjects. This is the approved dose of Yupelri® 
for maintenance treatment of COPD by the US FDA.  
Compared to the Caucasian population, Chinese ethnicity does not appear to confer any 
altered sensitivity to inhaled LAMA as a class (Wang et al., 2015 [5] and Bai et al., 2017 [6]; 
see Section 2.2) and based on the metabolic profile of revefenacin it is considered unlikely to 
exhibit different exposure in Chinese patients despite the known ethnic differences in 
metabolizing enzymes and transporters. 


 
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In terms of clinical safety profile above the approved dose, daily doses of revefenacin 
inhalation solution of up to 700 mcg (for 7 days) or 350 mcg (for 1 month) have been shown 
to be safe and well tolerated in COPD patients in Phase 2 clinical studies, and single doses of 
700 mcg have been shown to be without effect on cardiac repolarization in a thorough QT 
study in healthy subjects. 
3 
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 Primary Objectives 
The primary objective of the study is as follows: 
• To confirm the efficacy of revefenacin inhalation solution 175 mcg administered once 
daily via nebulization for 12 weeks compared to placebo in a population of Chinese 
subjects with moderate to very severe COPD. 
3.1.2 Secondary Objectives 
The secondary objectives of the study are as follows: 
• To confirm the safety of revefenacin inhalation solution 175 mcg administered once 
daily via nebulization for 12 weeks compared to placebo in a population of Chinese 
subjects with moderate to very severe COPD 
• To characterize the effect of revefenacin inhalation solution 175 mcg on patient 
reported outcomes compared to placebo in a population of Chinese subjects with 
moderate to very severe COPD. 
• To collect PK samples for population PK analysis of revefenacin inhalation solution 
175 mcg in a population of Chinese subjects with moderate to very severe COPD. 
3.2 
Endpoints 
3.2.1 Primary Endpoints  
• Trough FEV1 on Day 85 (mean of measurements at -45 and -15 minutes pre-dose) 
3.2.2 Secondary Endpoints 
3.2.2.1 Efficacy 
• Peak FEV1 (0-2h) on Day 1 
• St. George’s Respiratory Questionnaire (SGRQ) responders (total score ≥4 units) on 
Day 85 
• Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) on Day 85 
• Average count of salbutamol puffs per day (Days 1-85) 


 
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• Percentage of salbutamol rescue free 24h periods (Days 1-85)  
• Trough FEV1 on Days 29 and 57 
• BDI/TDI on Days 29 and 57 
• Weighted Mean FEV1 (0-2h) on Day 1 and Day 85 
• Peak FEV1 (0-2h) on Day 85 
• Trough forced vital capacity (FVC) on Days 29, 57 and 85 
• SGRQ on Day 85 (continuous endpoint) 
• TDI responders (focal score 1) on Day 85  
3.2.2.2 Safety 
• Adverse events (AE) 
• Acute exacerbations of COPD (AECOPD) 
• Laboratory tests 
• Vital Signs (blood pressure and pulse rate) 
• 12-lead ECG 
3.2.3 Pharmacokinetic (PK) 
• Population PK parameters for revefenacin inhalation solution (Cmax, Ctrough) 
4 
STUDY POPULATION 
4.1 
Study Population 
Approximately 320 subjects with moderate to very severe COPD will be randomized to 
ensure that at least 256 subjects complete the study. 
Screening to discharge will be approximately 4 months in duration. 
4.2 
Inclusion and Exclusion Criteria 
4.2.1 Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the Investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the 
study: 


 
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1. Males and females of Chinese ethnicity, at least 40 years of age. Females may be of either 
childbearing or non-childbearing potential. All females of childbearing potential must be 
using an acceptable, highly effective method of contraception and have a negative 
pregnancy test at screening.   
2. A clinical diagnosis for at least 6 months prior to screening of COPD according to GOLD 
guidelines (GOLD, 2019 [1]).  
3. Subject is capable of performing reproducible spirometry maneuvers as described by 
current American Thoracic Society/European Respiratory Society (ATS/ERS) Guidelines 
(Graham et al., 2019 [7]) and has a post-ipratropium (500 mcg nebulized) FEV1/FVC ratio 
<0.7 at Visit 2. 
4. Subject has moderate to very severe COPD with a post-ipratropium (500 mcg nebulized) 
FEV1 less than 80% of predicted normal (using the Global Lung Function Initiative 
reference range; Quanjer et al., 2012 [8]) and an absolute FEV1 >700 mL at Visit 2  
5. Current smoker or ex-smoker, with a history of at least 10 pack-years of tobacco 
smoking. Ex-smokers must have stopped smoking >6 months prior to Visit 1. 
Formulae for pack-years: 
• Average number of cigarettes per day x 1/20 x years of smoking 
Or 
• Ounces of tobacco per week x 2/7 x years of smoking 
Or 
• Grams of tobacco per week x 2/175 x years of smoking 
6. Capable of self-administering (or with the help of a caregiver) study medication, assessed 
at training at Visit 1 and Visit 3. 
7. Able to understand and complete the study requirements (including literacy, to enable 
diary and questionnaire completion), provide written informed consent, and agree to 
abide by the study protocol and its restrictions. 
4.2.2 Exclusion Criteria 
Subject candidates must not be enrolled in the study if they meet any of the following criteria: 
1. Previously dosed with revefenacin. 
2. Current diagnosis of asthma.  
3. Alpha-1 anti-trypsin deficiency.  
4. Other chronic or active respiratory disorder (e.g., clinically significant [as determined by 
the Investigator] bronchiectasis, pulmonary fibrosis, sarcoidosis, pneumoconiosis, active 
tuberculosis). 


 
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5. Symptoms of, or treatment for an AECOPD requiring antibiotics and/or oral/systemic 
corticosteroids or in-patient hospitalization during the 28 days preceding screening or 
during the screening period between Visit 1 and Visit 3. An AECOPD is defined as an 
acute event in the natural course of the disease warranting a change in the subject’s 
regular medication specifically to address the exacerbation event, characterized by: 
Worsening, beyond normal day-to-day variation, of two or more of the following major 
symptoms for at least two consecutive days: 
• Dyspnea 
• Sputum volume 
• Sputum purulence 
or 
Worsening, beyond normal day-to-day variation, of any one major symptom outlined 
above plus any one of the following minor symptoms for at least two consecutive days: 
• Sore throat 
• Colds (nasal discharge and/or nasal congestions) 
• Fever without other cause 
• Increased cough 
• Increased wheeze 
6. Pneumonia requiring hospitalization within 28 days prior to screening or during the 
screening period between Visit 1 and Visit 3. 
7. Lower respiratory tract infection requiring treatment with antibiotics during the 28 days 
preceding screening or during the screening period between Visit 1 and Visit 3. 
8. History or presence of pulmonary hypertension, respiratory failure, cor pulmonale or right 
ventricular failure which may impact the safety of the subject in the clinical judgement of 
the Investigator. 
9. History of pulmonary lobectomy, lung volume reduction surgery, or lung transplantation. 
10. Use of supplemental oxygen therapy for more than 15 hours per day (includes night-time 
use). 
11. Subjects participating in or planning to participate in the active phase of a supervised 
pulmonary rehabilitation program during the trial (maintenance program is permitted). 
12. Clinically significant, abnormal chest X-ray at screening indicating an active/significant 
disease process other than COPD. If a prior chest X-ray or thoracic high-resolution CT 
scan within 12 months prior to screening is available this will be acceptable. 


 
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13. History of long QT syndrome or screening ECG with QTcF greater than 500 milliseconds 
(0.500 seconds).  
14. History within past 5 years of paroxysmal atrial fibrillation. Subjects with continuous 
atrial fibrillation controlled with a rate control strategy (i.e., cardioselective β-blocker, 
calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 
6 months may be included if the ventricular rate is below 100 bpm. 
15. Any other clinically significant abnormality on the 12-lead ECG at screening which in the 
judgment of the Investigator would put the subject at potential risk if enrolled into the 
trial (these subjects should not be re-screened). Clinically significant abnormalities may 
include but are not limited to the following: left bundle branch block, Wolff-Parkinson-
White syndrome, clinically significant arrhythmias (e.g., ventricular tachycardia).  
16. Current evidence of, or history within the 6 months prior to screening of unstable 
ischemic heart disease, NYHA Class III/IV left ventricular failure, or myocardial 
infarction. 
17. Subjects with hepatic impairment. A history of hepatitis B or hepatitis C may be 
permitted at the discretion of the Investigator, provided the subject has no signs of hepatic 
impairment, is asymptomatic, and liver transaminases (ALT/AST) are ≤1.5 times the 
upper limit of normal (ULN) at Screening. 
18. History of malignancy of any organ system treated or untreated, within the past 5 years 
whether or not there is evidence of local recurrence or metastases. The only exceptions 
are previous in situ carcinoma of the cervix, localized basal cell carcinoma of the skin or 
localized squamous carcinoma of the skin if the subject has been treated and is considered 
cured. 
19. Subject 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. 
20. Use of any investigational drug within 28 days, or 5 half-lives, prior to screening 
whichever is longer. 
21. Use of medications with the potential to interact with revefenacin, salbutamol or 
ipratropium bromide (as indicated in respective Investigator Brochure or product labels), 
or medications with the potential to affect or confound COPD disease status. Drugs 
should be washed out prior to screening (further details of washout periods prior to 
screening are in Table 5-1) and not taken thereafter during the study until after the final 
dose of study drug:  
• Oral anticholinergics. 
• Oral or “systemic” (parenteral; intravenous or intra-articular, intramuscular, spinal) 
corticosteroids. 
• OATP1B1 and OATP1B3 inhibitors (e.g., rifampicin, cyclosporine) 
• Strong CYP3A4 inhibitors. 


 
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• Use of marijuana. 
• Herbal medications and Traditional Chinese Medications. 
22. History of reactions/hypersensitivity to any of the following inhaled drugs or drugs of a 
similar class: short- or long- acting β2 agonists (e.g., salbutamol, formoterol), 
anticholinergic agents (e.g., tiotropium, ipratropium bromide), corticosteroids, 
sympathomimetic amines. Subjects with previous reaction to inhaled agents due to lactose 
sensitivity alone will be permissible for this study. 
23. Subjects who are unable to stop any of the following medications, and refrain from their 
use throughout the study until the final dose of study drug (further details in Table 5-1): 
• Short-acting β2 agonists (except study-supplied salbutamol). 
• Short-acting anticholinergic agents (except those used for reversibility testing). 
• Long-acting anticholinergics (except study supplied medication). 
• Combination β2 agonists/anticholinergic agents. 
• Combination β2 agonists/inhaled corticosteroids/anticholinergic agents. 
• Phosphodiesterase 4 inhibitors. 
• Theophyllines. 
• Leukotriene inhibitors.  
• Orally inhaled nedocromil or cromolyn sodium. 
• Oral or parenteral corticosteroids. 
24. Pregnant or nursing females or females intending to become pregnant during the course 
of the study.  
25. Clinically significant abnormal laboratory test(s) at screening deemed exclusionary by the 
Investigator. 
26. History of illegal or recreational drug or alcohol abuse within the past 5 years. 
27. Other acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the Investigator, would make the subject inappropriate for entry into this 
study. 
4.2.3 Randomization Criteria 
Subjects satisfying all of the inclusion and exclusion criteria will be eligible for 
randomization. 


 
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Subjects must be able to provide a technically valid baseline FEV1 that fully meets the 
ATS/ERS criteria (Graham et al., 2019 [7]) at Visit 3 (Day 1, pre-dose). 
Subjects must not have symptoms of, or treatment for, an AECOPD requiring antibiotics 
and/or oral/systemic corticosteroids or in-patient hospitalization in the period between 
screening and randomization. 
4.2.4 Criteria for Study Drug Termination, Withdrawal from the Study and Study 
Termination 
Subjects will be free to request termination of study drug or withdrawal from the study at any 
time for any reason. 
Subjects must be withdrawn from the study prior to randomization under the following 
circumstances: 
• Failure to satisfy all of the inclusion and exclusion criteria. If a subject is found to 
have not met all of the inclusion and exclusion criteria only after the subject has been 
randomized, then this should be documented as a protocol deviation, but the subject 
should not be withdrawn from the study unless requested by the subject or if there is a 
safety reason for withdrawing the subject. 
A subject must terminate study drug for safety reasons under the following circumstances: 
• An exacerbation of COPD that is classified as moderate or severe:  
- Moderate: 
Worsening symptoms that require treatment with oral/systemic corticosteroids 
and/or antibiotics, but do not require in-patient hospitalization (i.e., 
admission). 
- Severe: 
Worsening symptoms of COPD that require treatment with in-patient 
hospitalization (i.e., admission). 
• The subject becomes pregnant during any stage from Visit 3 (Day 1). 
• The subject displays findings consistent with narrow angle glaucoma. 
• The subject displays findings consistent with uncontrolled prostatic hyperplasia or 
bladder neck obstruction. 
A subject may be required to terminate study drug for other reasons including the following: 
• If it is in the subject’s best interest based on decision of the Principal Investigator (PI) 
or Sub-Investigator e.g., due to occurrence of an AE and/or other findings considered 
to present a safety concern to continued dosing with study drug. 
• Despite education/reinforcement, the subject shows persistent inadequate compliance 
with required study visits/procedures, potentially compromising safety monitoring 
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• The subject takes contra-indicated medications presenting a safety concern to 
continued dosing with study drug. 
Unless consent is withdrawn, subjects who prematurely terminate study drug will have an 
Early study drug Termination (ET) visit scheduled as soon as possible after their last dose 
of study drug, in order to minimize missing data.  
The Principal Investigator and/or Mylan reserves the right to terminate the study for any 
reason. 
The study will be terminated early if there are significant safety concerns. 
4.3 
Lifestyle Guidelines 
Subjects are to observe the restrictions below during the study. 
4.3.1 Meals and Dietary Restrictions 
In order to avoid interference with pulmonary function testing, subjects should not consume 
excessively large meals immediately before clinic visits during which spirometry will be 
performed. 
4.3.2 Alcohol, Caffeine and Tobacco 
At all study visits, subjects will be required to:  
• Abstain from alcohol for at least 4 hours prior to a clinic visit and continue abstaining 
from alcohol until after the final assessment of each visit.  
• Abstain from smoking for at least 1 hour prior to each spirometry session. 
• Abstain from xanthine (caffeine) containing products (coffee, tea, cola, chocolate, 
etc.) for 2 hours prior to the clinic visit and continue abstaining until after the final 
assessment of each visit. 
4.3.3 Activity 
For the 2 hours prior to spirometry testing, subjects should make every effort to refrain from 
unfamiliar or excessive exercise or the direct inhalation of cold air; in order to reduce the 
impact of breathing cold air, subjects may need to rest for a period of time (as judged by the 
Investigator) in the clinic prior to commencement of spirometry testing. 
4.3.4 Other Restrictions 
• Abstain from use of herbal medications and Traditional Chinese medications. 
4.4 
Contraception 
4.4.1 Females - Non-childbearing Potential 
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1. Postmenopausal, defined as: 
• Aged 45 years or above  
• Amenorrheic for at least 2 years, or if amenorrheic for less than 2 years, have a serum 
FSH level >30 IU/L in the absence of hormone replacement therapy. 
2. A documented hysterectomy and/or bilateral oophorectomy. 
All other females will be considered to be of childbearing potential. 
4.4.2 Females - Childbearing Potential 
Female subjects of child-bearing potential must use an acceptable, highly effective method of 
contraception (i.e., a method with a failure rate <1% when used consistently and correctly) 
starting from screening through to at least 7 days after the final dose of study drug. For this 
study, such methods include at least one of the following: 
• Abstinence (periodic abstinence is not acceptable). 
• Tubal ligation. 
• Intrauterine device (IUD) or intrauterine system (IUS). 
• Condom. 
• Male partner who has had a vasectomy for at least 6 months. Male partners with 
vasectomies of <6 months are NOT considered protected. 
• Hormonal contraceptives (oral, injected, transdermal or implanted) with the exception 
of low dose gestagens, i.e., only containing lynestrenol or norethisterone, since they 
do not inhibit ovulation and are therefore not considered as highly-effective. The 
subject must remain on the hormonal contraceptive throughout the study and must 
have been using hormonal contraceptives for an adequate period prior to the study to 
ensure effectiveness (e.g., 3 months). 
4.5 
Pregnancy Testing 
Serum or urinary pregnancy testing will be performed on all females of childbearing potential 
as described in the schedule of activities (results will be reviewed and must be negative prior 
to dosing). In the event of a positive test, the subject will be withdrawn from the study (or 
will not enter the study if during screening). 
Any pregnancy occurring after randomization to study drug will be followed up and reported 
to the Sponsor as per Section 9.6. 
5 
STUDY DRUG 
5.1 
Investigational Drug 
Eligible subjects will be randomly assigned to receive one of the two following 
investigational drugs: 


 
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A. Revefenacin inhalation solution for inhalation: 175 mcg revefenacin in a sterile, clear, 
colorless, aqueous solution for nebulization, supplied in an individually-pouched 
3 mL low-density polyethylene unit-dose vial with a twist off top 
B. Matching placebo: a sterile, clear, colorless, aqueous solution for nebulization, 
supplied in an individually-pouched 3 mL low-density polyethylene unit-dose vial 
with a twist off top 
5.1.1 Administration of Study Drugs 
Revefenacin inhalation solution and its matching placebo will be administered using a 
centrally-provided, standard jet nebulizer (PARI LC Sprint) and compressor (PARI 
TurboBOY) via a mouthpiece. Subjects, and if applicable their caregiver(s), will be trained at 
Visit 3 to administer the study drug until nebulization of the study drug solution is complete, 
which will take up to approximately 10 minutes and will be evidenced by spluttering of the 
nebulizer. They will also be trained on the cleaning and maintenance of their nebulizer in 
accordance with the manufacturer’s instructions. 
The first dose will be administered on the morning of Day 1/Visit 3 at the study site. 
Subsequent doses will be self-administered at home by the subject except on days with a 
scheduled visit to the study site. They will be advised to administer the study drug every 
morning at approximately the same time within the window of 06:00 and 11:00. The time of 
administration will be recorded by the subjects in their diary. 
Subjects will be required to bring their nebulizer and both used and unused vials back to the 
study site at each scheduled visit. 
Study drug administration must be performed in a different room from that used for PK blood 
sampling and processing to avoid contamination of PK samples. 
In the event of any significant dosing errors, the Medical Monitor, or Mylan study contact 
should be contacted immediately. 
5.1.2 Study Medication Compliance 
Study medication compliance will be assessed during the study on the basis of: 
1. Number of used and unused vials at each visit. 
2. Subject diary entries. 
The primary assessment of compliance will be a count of the used and unused vials; however, 
in the event of missing vials, the subject diary entries will be utilized to assess and record 
study medication compliance. The number of used and unused vials and/or diary card data on 
compliance will be recorded in the CRF. 
Study medication compliance will be checked at Visits 4-6 to ensure that subjects are 
compliant (i.e., who are considered to have received 80% - 120% of the total number of doses 
that should have been administered in between study visits). Subjects who are non-compliant 
will be re-trained on the requirements of the study. 


 
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5.2 
Drug Inventory 
The subject will be supplied with:  
• The investigational drug: revefenacin inhalation solution, or its matching placebo 
• The nebulizer and compressor required to administer the investigational drug, 
revefenacin inhalation solution, or its matching placebo 
• Salbutamol 100 mcg/dose, in a pressurized metered dose inhaler (pMDI) containing 
200 doses will be provided as rescue medication. The pMDI will have a dose counter 
and will be supplied/re-supplied during the study to ensure subjects are provided with 
enough rescue medication considering their usual / actual use. 
The Investigator site will also be provided with: 
• Ipratropium 500 mcg as a solution for administration via jet nebulizer for reversibility 
testing during screening. The nebulizer used for ipratropium administration must be 
different from the one used by the subject for administration of investigational study 
drug. 
5.3 
Study Medication Complaints 
In the event the subject has a complaint/concern during study participation regarding the 
study supplied study medication, they should contact the site. 
In the event of a complaint/concern regarding any study medication provided by Mylan for 
this study, as a minimum the following information should be sent by the site via e-mail to 
. 
• Study number. 
• Principal Investigator name. 
• Subject ID. 
• Date of occurrence of incident/complaint. 
• Description of incident/complaint (facts). 
• Confirmation if the complaint caused or resulted in a SAE? If “Yes”, confirmation 
that the SAE has been reported. 
Additional information and potentially the return of study medication may be requested by 
Mylan in order to investigate the complaint. 
5.4 
Storage, Disposition of Used and Unused Study Drug and Drug Accountability 
The Investigator, or an approved representative, e.g., pharmacist, will ensure that all 
investigational drugs are stored in a secured area under recommended storage conditions and 
in accordance with applicable regulatory requirements while at the Investigator site. 


 
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Study drug should be stored in accordance with the drug label. Storage conditions stated in 
the Investigator’s Brochure may be superseded by the label storage. 
Temperature of storage facilities should be monitored and recorded on a daily basis using 
validated devices that record maximum and minimum temperatures. Should the storage 
facility experience any excursion of temperature outside of the labelled storage condition this 
must be reported immediately to Mylan or designee. At sites where daily monitoring and 
recording is not possible at weekends, then on the next working day after the weekend the 
temperature record (e.g., max/min thermometers) should be checked immediately for any 
temperature excursions. Devices used for temperature monitoring should be regularly 
calibrated. Affected material must be placed into quarantine until the impact of the excursion 
has been assessed and confirmed by Mylan.  
The Investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the study drug. If Mylan supply drug accountability forms these must be used. 
Alternatively, Mylan may approve use of standard institution forms. In either case, the forms 
must identify the study drug, including batch or code numbers, and account for its disposition 
on a subject-by-subject basis, including specific dates and quantities. The forms must be 
signed by the individual who dispensed the drug, and copies must be provided to Mylan or 
designee. 
At the end of the study, Mylan will provide instructions as to disposition of any unused 
investigational drug. If Mylan authorizes destruction at the study site, the Investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Mylan. Destruction 
must be adequately documented. 
5.5 
Randomization  
Assignment of Subject Identification number (SID), randomization number and study drug, 
as well as site drug inventory control will be managed by an automated Interactive 
Voice/Web Response system (IVRS/IWRS). A manual containing complete instructions for 
Web or telephone access and use will be provided to each site prior to study start. At their 
first clinic visit, the IVRS/IWRS will assign a SID. Each SID will be unique and serve as the 
primary subject identifier throughout all phases of the study. The SID must appear on all CRF 
pages, source documents, laboratory data, central spirometry, ECG, diary data, and PRO data. 
Subjects qualifying to enter the drug treatment phase, will be assigned an additional 
“randomization number” by the IVRS/IWRS at randomization. Subjects will be allocated to 
treatment within blocks for the given allocation ratio. 
At Visit 3 (Day 1 of dosing), eligible subjects will be randomized to receive 175 mcg 
revefenacin inhalation solution or matching placebo in a 1:1 ratio through the IVRS/IWRS.  
The randomization will be stratified according to the subject’s concomitant LABA use (Yes, 
No) and reversibility to ipratropium (Yes, No). 
5.6 
Breaking the Blind 
Emergency subject unblinding will be managed by an automated IVRS/IWRS. A manual 
containing complete instructions for Web or telephone access and use will be provided to 
each site prior to study start. 


 
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5.7 
Concomitant Medications 
All concomitant medications taken during the study (from signing informed consent to 
post-study follow-up) must be recorded with indication, daily dose, and start and stop dates of 
administration in the CRF. All subjects will be questioned about concomitant medication at 
each clinic visit and at follow up. 
Medications taken within 28 days prior to screening and prior to dosing with study 
medication will be documented as a prior medication. Medications taken after dosing with 
study medication will be documented as concomitant medications. 
Subjects will abstain from all prohibited medications as described in the exclusion criteria 
section of this protocol (Section 4.2.2). Use of prohibited medication during the study will be 
deemed a protocol deviation and such subjects will be assessed by Mylan or designee 
regarding potential need to early terminate study drug (e.g., for safety reasons – see 
Section 4.2.4). 
Prior to the ipratropium reversibility testing during screening, short acting bronchodilators 
must be withheld for ≥6 hours. 
Inhaled maintenance corticosteroid therapy will be continued at the allowed maintenance 
dose throughout the treatment and washout periods. Salbutamol will be allowed as required 
(or “PRN”) during the study. Salbutamol must be withheld for ≥6 hours before the first 
spirometry performed at each study visit and during the course of the entire visit when serial 
spirometry is performed. 
Use of salbutamol as a rescue medication (number of daily puffs) will be documented in the 
daily diary and recorded in the eCRF. If a subject has used rescue medication on the same 
day as the clinic visit, prior to spirometry assessments, then both the number of puffs and the 
time of administration will be documented to allow evaluation of impact, if any, on 
spirometry measurements. 
Subjects who are receiving a LABA or ICS/LABA (either QD or BID) may be enrolled into 
the study provided that the dose has been stable for at least 30 days prior to Visit 1 and the 
steroid component is equivalent to fluticasone propionate ≤1000 mcg/day. For reversibility 
testing at screening, subjects who are on a QD regimen should not have had their last dose 
within approximately the last 24 hours, and for those on a BID regimen, not within 
approximately the last 12 hours, prior to the reversibility test. Once randomized it is 
important to standardize administration of the subject’s LABA or ICS/LABA together with 
the study drug, as the post-dose spirometry will be measuring the combined effect of 
receiving the LABA and the study drug. These subjects should administer their LABA or 
ICS/LABA in the morning after the pre-dose FEV1 measurement and immediately prior to 
the nebulization of study drug. This administration should be documented in the source 
documents on study visit days and subjects should be instructed to follow the same procedure 
while at home between study visits. If subjects have used their LABA or ICS/LABA less than 
24 hours (for QD products) or less than 12 hours (for BID products) prior to study visit 
spirometry (approximately) instead of taking it in-clinic after pre-dose FEV1 measurement 
and immediately prior to study drug nebulization, then the study visit should be rescheduled. 


 
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Table 5-1 lists the medications that require washout or modification. These medications are 
also prohibited throughout the study to completion of Visit 6 inclusive. Subjects will be 
permitted to restart their routine medications after the completion of Visit 6. 
Table 5-1: Restricted Medications 
Medication 
Washout Required (or Modification) and 
Prohibited Time Period 
Any ICS at a dose of >1000 mcg/day fluticasone 
propionate or equivalent. 
Subjects on a dose >1000 mcg/day fluticasone 
propionate or equivalent should have their dose 
modified to be on a stable dose of ≤1000 mcg 
fluticasone propionate or equivalent for at least 
30 days prior to the Ipratropium Reversibility test 
at screening and continued through to end of V6. 
LAMA – e.g., tiotropium, glycopyrronium 
bromide, aclidinium, umeclidinium. 
PDE4 inhibitors – roflumilast. 
7 days prior to the Ipratropium Reversibility test 
at screening and prohibited during the course of 
the study through to end of V6. 
LABA – e.g., salmeterol, formoterol fumarate, 
arformoterol tartrate, indacaterol, vilanterol, 
olodaterol. 
ICS/LABA products, e.g., salmeterol/fluticasone 
propionate, vilanterol/fluticasone furoate, 
formoterol/budesonide. 
LAMA/LABA combination products, e.g., 
umeclidinium/vilanterol. 
LAMA/ICS/LABA combination products, e.g., 
umeclidinium/vilanterol/fluticasone furoate. 
Subjects on a LABA or ICS/LABA 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 end of V6. The 
steroid component should be ≤1000 mcg/day 
fluticasone propionate or equivalent. 
Subjects should abstain from LABA use prior to 
performing the Ipratropium Reversibility test, 
however (i.e., 24 hours for QD LABAs and 12 
hours for BID LABAs). 
Subjects on a LAMA/LABA combination need to 
be switched to the LABA only product at least 
7 days prior to the Ipratropium Reversibility test 
at screening and maintained during the course of 
the study through to end of V6. 
Subjects on a LAMA/ICS/LABA combination 
need to be switched to the ICS/LABA product at 
least 7 days prior to the Ipratropium Reversibility 
test at screening and maintained during the course 
of the study through to end of V6. 
Oral theophyllines e.g., theophylline, 
aminophylline. 
 
12 hours prior to the Ipratropium Reversibility 
test at screening. Theophyllines must be withheld 
at least 12 hours prior to any spirometry and 
during the entire visit when serial spirometry is 
being performed. 
Oral leukotriene inhibitors e.g., montelukast, 
pranlukast. 
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 end of V6. 
Sodium cromoglycate 
Nedocromil sodium 
24 hours prior to the Ipratropium Reversibility 
test at screening and prohibited during the course 
of the study through to end of V6. 


 
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Medication 
Washout Required (or Modification) and 
Prohibited Time Period 
Short acting beta-agonists 
Short acting anti-muscarinics 
6 hours prior to the Ipratropium Reversibility test 
at screening. Subjects will be provided with 
salbutamol to be used as rescue medication 
during screening and throughout the course of the 
study. Salbutamol must be withheld at least 
6 hours prior to any spirometry performed during 
the study and during the entire visit when serial 
spirometry is being performed. Short acting 
anti-muscarinics must be washed out (at least 
8 hours) prior to the Ipratropium Reversibility 
test and are prohibited during the course of the 
study through to V6. 
Oral or parenteral corticosteroids 
28 days prior to Screening (V1) and prohibited 
during the course of the study through to V6. 
If oral/parenteral corticosteroids are required to 
treat an AECOPD during the study, the subject 
should be withdrawn because of the AECOPD. If 
oral/parenteral corticosteroids are required for 
treatment of any other non-respiratory condition, 
then the subject’s continued participation in the 
study will be assessed on a case-by-case basis. 
(Intranasal, topical, and ophthalmic 
corticosteroids are permitted throughout the 
study). 
Oral beta agonists 
48 hours before each visit where spirometry is 
performed. 
OATP1B1 and OATP1B3 inhibitors, e.g., 
rifampicin, cyclosporine. 
28 days prior to Screening (V1) and prohibited 
during the course of the study through to V6. 
 
In addition to the prohibited concomitant medications listed in Table 5-1, subjects should not 
be taking any other medications that are not part of a stable regimen. Prior to randomization, 
subjects should not be considered 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 PRN medications for conditions other than COPD must be approved by the 
Investigator. 
 
5.8 
Recommended Procedure in a Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug 
High doses of revefenacin may lead to anti-cholinergic signs and symptoms such as dry 
mouth, constipation, urinary retention, bowel obstruction, dilated pupils, blurred vision, 
increased heart rate, decreased sweating, impaired concentration, confusion, attention deficit, 
and memory impairment. 
Treatment of over dosage consists of discontinuation of revefenacin together with institution 
of appropriate symptomatic and/or supportive therapy. 


 
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6 
STUDY CONDUCT 
Subjects eligible for study recruitment will have the nature, purpose, and risks of the study 
explained to them by the Investigator. They will be provided with a written copy of the 
informed consent form (ICF) for the study and given sufficient time to consider the study’s 
implications before deciding to participate. Subjects agreeing to participate in the study will 
sign the ICF and be given a duplicate copy before undergoing any screening or pre-screening 
(if required) procedures. A unique SID will be issued at the time of consent by IVRS/IWRS 
system.  
Once a subject is randomized in this trial the site will make every effort to retain the subject 
for the planned duration of the trial. Clinical trial site staff are responsible for developing and 
implementing support and retention plans. Elements of this plan may include the following. 
• Thorough explanation of the complete clinical trial visit schedule and procedural 
requirements during the informed consent process and re-emphasis at each clinic visit. 
• A simple explanation of the key data and key time points that are critical for the trial's 
successful analysis, and the importance of all the treatment groups to the overall 
success of the trial. 
• Discussion at screening, and subsequent regular review of possible barriers to clinic 
visit attendance and full study participation and compliance. 
• Collection of contact information at screening (address, phone numbers, email), 
which is regularly reviewed at subsequent clinic visits. 
• Use of appropriate and timely study visit reminders. 
• Immediate and multifaceted follow-up on missed clinic visits, including the possible 
use of trained staff to complete in-person contact with subjects at their homes. 
In cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject so that they can appropriately be withdrawn from the study. All contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the study 
with a primary reason of "Lost to Follow-up." For all other subjects withdrawing from the 
study, an alternative reason for discontinuation should be recorded in the CRF. Regardless of 
site plans to support and retain subjects within the trial, subjects may voluntarily withdraw 
from the trial for any reason and at any time. 
For a subject that completes the study and all procedures it is anticipated that the duration of 
study would be approximately 4 months.  
For details and timings of assessments, refer to Section 6.4. 
6.1 
Screening Procedures 
Each prospective subject must agree to participate in screening procedures by signing the 
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Medical Sub-Investigator will review the inclusion and exclusion criteria to confirm 
eligibility of each subject prior to randomization. This should be documented in the subject’s 
source documentation. 
6.1.1 Screening (Visits 1 and 2) 
Subjects will commence screening procedures within 30 days prior to randomization, to 
confirm that they meet the selection criteria for the study. If the time between screening 
procedures and potential randomization exceeds 30 days as a result of unexpected delays, 
then the subject will need to be discussed with Mylan or designee to consider potential for 
re-screening (if re-screening is agreed, the subject will need to be reconsented and assigned a 
new SID via IVRS/IWRS). Re-screening for other reasons may be possible following 
discussion with Mylan or designee. If re-screening occurs this will be clearly documented 
within the site file. 
The assessments for Visit 1 and Visit 2 may be conducted on the same day if the subject does 
not require washout of other COPD medications (e.g., 7 day washout for LAMAs: see Table 
5-1 for more a more comprehensive list) prior to the spirometry assessments. 
At Screening Visit 1 (Week – 2: Day -30 to Day -4 prior to Visit 3), the following will be 
completed in the specified order: 
• Written informed consent.  
• IVRS/IWRS registration.  
• Complete demographics and medical history, including COPD, smoking, and 
exacerbation history. Exacerbation history includes the number of exacerbations and 
if they resulted in hospitalization or use of medication to treat and categorization per 
the descriptions in Section 6.4.8.1.1. If the subject’s smoking status changes during 
the study this should be recorded in the CRF. 
• Complete history of all prescription or non-prescription drugs, dietary supplements, 
and Traditional Chinese Medicines taken within 28 days prior to consent. History of 
alcohol or illicit drug use. 
o Ensure the subject is able to discontinue restricted medications (Section 5.7). 
o Ensure sufficient washout of COPD medications per Table 5-1. 
• General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland. 
• Measure height and weight. 
• Record vital signs – supine or semi-recumbent blood pressure and pulse rate.  
• Record 12-lead ECG – supine or semi-recumbent (single measurement). 
• Urine or serum pregnancy test (if female of child-bearing potential).  


 
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• Urinalysis (dipstick for blood, protein etc.). Sample to be sent for microscopy/culture 
if positive for blood, protein, nitrites or leukocyte esterase. 
• Blood will be collected for safety laboratory tests. Laboratory tests at screening 
include confirmation of non-child bearing potential in any female who is 45 years of 
age and above who has been amenorrheic for less than 2 years, via serum FSH.  
• Assess and record AEs (AEs are to be recorded starting from signature of consent). 
• Check study inclusion/exclusion criteria. 
• Dispense rescue medication (salbutamol pMDI) and train the subject (and caregiver, if 
applicable) on its use. 
• Dispense daily diary. 
• If results for a chest X ray or thoracic high resolution CT that was performed within 
12 months prior to screening are not available, schedule and perform a chest X-ray so 
that the results are available prior to randomization. 
• Schedule Visit 2 (if required) and remind the subject of lifestyle, study drug and 
concomitant medication requirements for visits. 
Subjects may be discharged from the clinic following completion of all assessments. 
At Screening Visit 2 (week -1; 7 (Day -10 to Day -4 prior to Visit 3), the following will be 
completed in the specified order: 
• Review and record concomitant medications. 
• Ensure sufficient washout of restricted medications per Table 5-1 prior to spirometry 
assessments. 
• Spirometry reversibility testing pre- and post-dosing with ipratropium. Spirometry 
(FEV1, FVC) will be performed pre-dose after withholding bronchodilators as 
specified in Table 5-1 and 45 minutes after dosing with 500 mcg ipratropium solution 
for inhalation administered by jet nebulizer. 
• Assess and record AEs. 
• Review rescue medication use recorded in daily diary. Rescue medication use should 
be recorded as the number of doses per day, where each puff of salbutamol is one 
dose. 
6.2 
Treatment Phase 
6.2.1 Visit 3 (Day 1) 
Procedures will be completed in the following order: 
• Ensure sufficient washout of restricted medications per Table 5-1 prior to spirometry 
assessments. 


 
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• Complete the following questionnaires in this sequence: BDI, mMRC, SGRQ.  
• Assess and record AEs. 
• Review and record concomitant medications. 
• Collect and review rescue medication use recorded in daily diary. 
• Record vital signs – supine or semi-recumbent blood pressure and pulse rate – pre-
dose.  
• Record 12-lead ECG (single measurement; supine or semi-recumbent) pre-dose. ECG 
must be performed prior to spirometry and blood sampling if scheduled at the same 
timepoint. 
• Urine or serum pregnancy test (if female of child-bearing potential).  
• Blood will be collected within 30 minutes pre-dose for PK analysis.  
• Spirometry (FEV1, FVC) at -45 and -15 minutes pre-dose 
o Note that to be eligible for the study the spirometry measures must fully meet 
the ATS/ERS guidelines for quality and reproducibility. 
• Review inclusion and exclusion criteria. 
• Randomization via IVRS/IWRS (subject eligibility must be confirmed and 
documented by Investigator before randomizing subject). Dispense study drug via 
IVRS/IWRS. 
• Training the subject and/or caregiver for use and maintenance of the nebulizer for 
study drug administration. 
• Administer LABA or ICS/LABA if the subject is taking one of these drugs. 
• Study drug dosing via nebulizer. Dosing time will be recorded in date, hours, and 
minutes corresponding to the start and completion of nebulization. Pre-dose 
assessment time is defined relative to the start of nebulization. Post-dose assessment 
time is defined relative to the completion of nebulization. Study drug administration 
must be performed in a different room from that used for PK blood sampling and 
processing to avoid contamination of PK samples. 
• Spirometry (FEV1, FVC) at the following times post-dose: 5, 15, and 30 minutes, and 
1, 1.5, and 2 hours. 
• Blood will be collected at any time between 1 – 30 minutes post-dose for PK analysis. 
The actual PK sampling time will be recorded in date, hours, and minutes. 
• Record vital signs – supine or semi-recumbent blood pressure and pulse rate – at 
approximately 1 hour post-dose. 


 
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• Record 12-lead ECG - supine or semi-recumbent (single measurement) at 
approximately 1 hour post-dose.  ECG must be performed prior to spirometry and 
blood sampling if scheduled at the same timepoint. 
• Dispense rescue medication as needed. 
• Dispense daily diary. 
6.2.2 Visit 4 (Day 29 ± 7 days) 
Procedures will be completed in the following order: 
• Ensure sufficient washout of restricted medications per Table 5-1 prior to spirometry 
assessments. 
• Complete the following questionnaire: TDI.  
• Assess and record AEs. 
• Review and record concomitant medications. 
• Compliance check for study drug via drug returns or daily diary.  
• Collect and review rescue medication use recorded in daily diary. 
• Urine or serum pregnancy test (if female of child-bearing potential).  
• Dispense study drug via IVRS/IWRS. 
• Spirometry (FEV1, FVC) at -45 and -15 minutes pre-dose. 
• Blood will be collected within 30 minutes pre-dose for PK analysis.  
• Administer LABA or ICS/LABA if the subject is taking one of these drugs. 
• Study drug dosing via nebulizer. Dosing time will be recorded in date, hours, and 
minutes corresponding to the start and completion of nebulization. Pre-dose 
assessment time is defined relative to the start of nebulization. Post-dose assessment 
time is defined relative to the completion of nebulization. Study drug administration 
must be performed in a different room from that used for PK blood sampling and 
processing to avoid contamination of PK samples. 
• Blood will be collected at any time between 1 – 30 minutes post-dose for PK analysis. 
The actual PK sampling time will be recorded in date, hours, and minutes. 
• Dispense rescue medication as needed. 
• Dispense daily diary. 
6.2.3 Visit 5 (Day 57 ± 7 days) 
Procedures will be completed in the following order: 


 
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• Ensure sufficient washout of restricted medications per Table 5-1 prior to spirometry 
assessments. 
• Complete the following questionnaire: TDI.  
• Assess and record AEs. 
• Review and record concomitant medications. 
• Compliance check for study drug via drug returns or daily diary.  
• Collect and review rescue medication use recorded in daily diary. 
• Urine or serum pregnancy test (if female of child-bearing potential). 
• Dispense study drug via IVRS/IWRS. 
• Spirometry (FEV1, FVC) at -45 and -15 minutes pre-dose. 
• Blood will be collected within 30 minutes pre-dose for PK analysis. 
• Administer LABA or ICS/LABA if the subject is taking one of these drugs. 
• Study drug dosing via nebulizer. Dosing time will be recorded in date, hours, and 
minutes corresponding to the start and completion of nebulization. Pre-dose 
assessment time is defined relative to the start of nebulization. Post-dose assessment 
time is defined relative to the completion of nebulization. Study drug administration 
must be performed in a different room from that used for PK blood sampling and 
processing to avoid contamination of PK samples. 
• Blood will be collected at any time between 1 – 30 minutes post-dose for PK analysis. 
The actual PK sampling time will be recorded in date, hours, and minutes. 
• Dispense rescue medication as needed. 
• Dispense daily diary. 
6.2.4 Visit 6, EoT (Day 85 ± 7 days) 
Procedures will be completed in the following order: 
• Ensure sufficient washout of restricted medications per Table 5-1 prior to spirometry 
assessments. 
• Complete the following questionnaires in this sequence: TDI, SGRQ.  
• Assess and record AEs. 
• Review and record concomitant medications. 
• Compliance check for study drug via drug returns or daily diary. 


 
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• Collect and review rescue medication use recorded in daily diary. 
• Record vital signs – supine or semi-recumbent blood pressure and pulse rate – pre-
dose.  
• Record 12-lead ECG – supine or semi-recumbent (single measurement) pre-dose. 
ECG must be performed prior to spirometry and blood sampling if scheduled at the 
same timepoint. 
• Urine or serum pregnancy test (if female of child-bearing potential). 
• Blood and urine will be collected for safety laboratory tests. 
• Blood will be collected within 30 minutes pre-dose for PK analysis. 
• Spirometry (FEV1, FVC) at -45 and -15 minutes pre-dose. 
• Administer LABA or ICS/LABA if the subject is taking one of these drugs. 
• Study drug dosing via nebulizer. Dosing time will be recorded in date, hours, and 
minutes corresponding to the start and completion of nebulization. Pre-dose 
assessment time is defined relative to the start of nebulization. Post-dose assessment 
time is defined relative to the completion of nebulization. Study drug administration 
must be performed in a different room from that used for PK blood sampling and 
processing to avoid contamination of PK samples. 
• Spirometry (FEV1, FVC) at the following times post-dose: 5, 15, and 30 minutes, and 
1, 1.5, and 2 hours. 
• Blood will be collected at any time between 1 – 30 minutes post-dose and an 
additional sample will be collected during the sampling interval of 1 – 4 hours post-
dose for PK analysis. The actual PK sampling time will be recorded in date, hours, 
and minutes. 
• Record vital signs – supine or semi-recumbent blood pressure and pulse rate – at 
approximately 1 hour post-dose. 
• Record 12-lead ECG – supine or semi-recumbent (single measurement) at 
approximately 1 hour post-dose.  ECG must be performed prior to spirometry and 
blood sampling if scheduled at the same timepoint. 
• General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland. 
6.2.5 Early Study Drug Termination (ET) Visit 
Subjects may request termination of study drug or withdrawal from the study at any time, or 
be required to withdraw or terminate study drug by the Investigator or Sponsor for reasons as 
per Section 4.2.4. If study drug is terminated or the subject withdraws or is withdrawn, the 
reason for termination/withdrawal should be established and recorded. If a subject does not 


 
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return for a scheduled visit, every effort should be made to contact the subject. In any 
circumstance, every effort should be made to document the outcome of subject contact 
attempt, if possible. The Investigator will contact Mylan or designee in the event that a 
subject fails to complete the study or violates the protocol. 
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
Unless consent is withdrawn, subjects who prematurely terminate study drug will be asked to 
return to the clinic for an ET visit and will have this scheduled as soon as possible after their 
last dose of study drug.  
At the ET visit the following procedures will be completed: 
• Complete the following questionnaires in this sequence: TDI, SGRQ.  
• Record vital signs – supine or semi-recumbent blood pressure and pulse rate.  
• Record 12-lead ECG – supine or semi-recumbent (single measurement). ECG must be 
performed prior to spirometry and blood sampling. 
• Urine or serum pregnancy test (if female of child-bearing potential). 
• Blood and urine will be collected for safety laboratory tests. 
• General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland. 
• Review and record concomitant medications. 
• Collect and review rescue medication use recorded in daily diary. 
• Two spirometry (FEV1, FVC) assessments corresponding to -45 and -15 minutes pre-
dose assessments at previous visits. 
• Assess and record AEs. 
Subjects may be discharged from the clinic at the discretion of the Investigator following 
completion of all ET assessments. 
6.3 
Follow Up (telephone call 7-14 days after the last dose of study medication [EoT 
Visit]) 
• Review and record concomitant medications  
• Assess and record AEs. 
Subjects who have a follow-up call will be reminded that AEs should be reported to the study 
staff up to 30 days after the last dose of study medication. 


 
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6.4 
Treatment Procedures 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to 
perform the test. In these cases the Investigator or designated representative will take all steps 
necessary to ensure the safety and well-being of the subject. When a protocol required test 
cannot be performed the Investigator or designated representative will document the reason 
for this and any corrective and preventive actions which he/she has taken to ensure that 
normal processes are adhered to as soon as possible. The Mylan study team will be informed 
of these incidents in a timely fashion. 
Activities specific to this protocol are expanded upon further below. 
6.4.1 Blood Volume 
Total blood sampling volume for an individual subject is estimated in Table 6-1 below. 
Additional blood samples may be taken for safety assessments, provided the total volume 
taken during the study does not exceed 300 mL (or the total volume permitted in the local 
region) during any period of 30 consecutive days, and the ethics committee/IRB is notified of 
the blood collection. 
Table 6-1: Blood Volume 
Sample Type 
Sample Volume (mL) 
Number of Sampling Times 
Total Volume (mL) 
Screening 
Study Period 
Safety Labs 
20 
1 
1 
40 
PK 
6 
0 
9 
54 
TOTAL 
 
 
 
94 
 
6.4.2 Spirometry 
Standardized, centralized spirometry equipment will be provided to the sites. 
Spirometry will be performed in accordance with the ATS/ERS guidelines (Graham et al., 
2019 [7]) using standardized equipment to ensure quality, reproducibility and repeatability.  
Spirometers will be calibrated according to manufacturer’s guidelines. 
Spirometry testing should be performed in the seated position, with nose clips and the subject 
should remain in an upright position (not bending forward) while performing the maneuvers.  
Sufficient forced expiratory maneuvers (up to a maximum of 8) will be performed at each 
session to produce a minimum of 3 technically acceptable and reproducible traces. The 
largest FEV1 and greatest FVC measured from technically acceptable and repeatable 
measurements will be recorded.  
Spirometry data that is judged not to be of sufficient quality, e.g., those demonstrating clear 
hesitation or cough within the first second of measurement will not be acceptable for use. 
Spirometry data will be assessed and over-read centrally for quality purposes by a spirometry 
vendor. 


 
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Acceptable repeatability is achieved when the difference between the largest and the next 
largest FVC is ≤0.150 L and the difference between the largest and next largest FEV1 is 
≤0.150 L.  For those with an FVC of ≤1.0 L, both these values are 0.100 L. 
If repeatability is not achieved after up to 8 attempts but the trace selected is of sufficient 
quality, i.e., there are no significant artefacts, this can still be utilized in the data analyses and 
will not be considered a protocol deviation. 
However, at Visit 3 the two pre-dose assessments must meet all quality and repeatability 
requirements as described above for the subject to be eligible. 
The FEV1 will be recorded as absolute volume in liters (recorded and reported to at least 
3 decimal places) and, during Screening only the post-ipratropium FEV1, in terms of percent 
of predicted normal values according to age, height, race and sex using the Global Lung 
Function Initiative reference range programmed in the centralized spirometry equipment 
(Quanjer et al., 2012 [8]). 
At each visit where spirometry is scheduled, subjects will be required to withhold salbutamol 
for 6 hours prior to the first session of spirometry maneuvers and other COPD medications 
per Table 5-1. 
  
A single spirometry session will be conducted for pre- and post-bronchodilator measurements 
at Screening (Visit 2) but two pre-dose spirometry sessions will be conducted at Visit 3 (Day 
1) through to Visit 6 (Day 85), with assessments at approximately -45 and -15 minutes prior 
to dosing (subjects should rest for at least 10 minutes between sessions). 
At Visit 3 (Day 1) and Visit 6 (Day 85), all subjects will perform spirometry assessments up 
to 2 hours post-dose (time points 5, 15, and 30 minutes, and 1, 1.5, and 2 hours; single 
sessions at each time point). Spirometry should be commenced at the nominal time ±10% (for 
example 60 ±6 minutes). 
• If a subject needs to use rescue medication during the serial spirometry session, 
the time of dosing must be recorded and a protocol deviation documented. 
6.4.3 Bronchodilator Reversibility 
Bronchodilator reversibility will be performed at Visit 2 with ipratropium 500 mcg solution 
for inhalation administered by jet nebulizer, after withholding short-acting bronchodilators 
for at least 6 hours and other restricted medication for the periods specified in Table 5-1. If 
the subject has not observed the required withholding interval, then the visit should be 
rescheduled. 
Spirometry will be performed pre-dose and 45 minutes after dosing with ipratropium. 
Reversibility to ipratropium is defined as a post-bronchodilator increase of ≥12% and at least 
a 200 mL increase in FEV1.  
6.4.4 Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) 
At Visit 3 (Day 1), Visit 4 (Day 29), Visit 5 (Day 57), Visit 6 (Day 85), and/or the Early 
Termination visit (if applicable), the subject’s dyspnea will be assessed using the 
interviewer-administered BDI/TDI with the result recorded in the CRF. 


 
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The BDI scores the magnitude of effort, types of tasks, both work and non-work, which make 
the patient breathless, as well as the level of functional impairment. The TDI measures 
changes from this baseline state.  
The BDI will be administered at Visit 3 (Day 1), the TDI will be administered at subsequent 
visits. 
The assessments should be administered at the start of the visit, with the same interviewer 
administering the assessment for an individual subject at each visit, where possible. 
Further details of the BDI/TDI are described in Section 11.1. 
6.4.5 Modified Medical Research Council Dyspnea Scale (mMRC)  
At Visit 3 (Day 1), the subject’s level of dyspnea based on the mMRC dyspnea scale will be 
administered by study staff with the result recorded in the CRF. 
The mMRC assessment will be administered after the BDI/TDI. 
Further details of the mMRC are described in Section 11.2. 
6.4.6 St. George’s Respiratory Questionnaire (SGRQ) 
At Visit 3 (Day 1), Visit 6 (Day 85), and/or the Early Termination visit (if applicable), the 
subject’s COPD health status based on the SGRQ will be administered by study staff with the 
result recorded in the CRF. 
The SGRQ will be administered after the mMRC. 
Further details of the SGRQ are described in Section 11.3. 
6.4.7 Pharmacokinetics 
Population PK sampling will be performed in subjects within 30 minutes pre-dose and at any 
time 1 - 30 minutes post-dose at Visits 3, 4, 5, and 6. An additional PK sample will be 
collected any time during a sampling window of 1 - 4 hours post-dose at Visit 6. The 
post-dose sampling time is relative to the end of nebulization. Blood samples for plasma PK 
assay will be collected, centrifuged, and split into two aliquots; each will be sent to the assay 
laboratory as directed by the Sponsor in separate shipments. The actual date and time of the 
sample collection (in date, hour, and minute) must be recorded.  
PK blood sampling and processing must be performed in a different room from that used for 
study drug administration to avoid contamination of PK samples.  
Detailed procedures for the collection of plasma PK samples are provided in the Central Lab 
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6.4.8 Safety Testing 
6.4.8.1 Adverse Event Assessment 
If a subject reports any symptoms before drug administration, they will be evaluated by 
medical staff and necessary measurements will be performed. The Principal Investigator or 
Medical Sub-Investigator will be notified before dosing to determine the course of action. 
Findings from screening procedures, e.g., laboratory tests or physical examinations will be 
recorded as medical history. Clinically significant changes from the screening procedures will 
be recorded as adverse events. 
Subjects will be routinely queried in regard to the presence or absence of adverse events 
using open ended questions. The clinic will provide documentation of any adverse events in 
the subject’s CRF. The adverse event source documentation will minimally include the 
following information: date and time of assessment, the outcome of the response, and 
identification of the clinic staff member collecting the information. 
Adverse events of special interest relevant to anti-muscarinic effects, given the treatment 
class of revefenacin, include the following: 
• Constipation 
• Dry mouth 
• Dysuria 
• Worsening of urinary retention 
• Worsening of narrow-angle glaucoma 
6.4.8.1.1 Acute Exacerbation of COPD (AECOPD) 
Throughout the study, subjects will be encouraged to spontaneously report symptoms and 
respiratory medication increase or change that may signify worsening of disease, including 
AECOPD. Subjects should be evaluated by study staff at each visit for AECOPD events since 
the preceding visit. 
An AECOPD is defined as an acute event in the natural course of the disease, warranting a 
change in the subject’s regular medication specifically to address the exacerbation event, 
characterized by: 
1. Worsening, beyond normal day-to-day variation, of two or more of the following 
major symptoms for at least two consecutive days: 
• Dyspnea. 
• Sputum volume. 
• Sputum purulence. 
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2. Worsening, beyond normal day-to-day variation, of any one major symptom outlined 
above plus any one of the following minor symptoms for at least two consecutive 
days: 
• Sore throat. 
• Colds (nasal discharge and/or nasal congestions). 
• Fever without other cause. 
• Increased cough. 
• Increased wheeze. 
The severity of a COPD exacerbation should be categorized using the definitions outlined 
below.  
• Mild exacerbation: worsening symptoms that are managed with bronchodilators but do 
not require use of antibiotics or oral or systemic (e.g., intravenous, intramuscular) 
corticosteroids. 
• Moderate exacerbation: worsening symptoms that require treatment with oral/systemic 
corticosteroids and/or antibiotics, but do not require in-patient hospitalization (i.e., 
admission). 
• Severe exacerbation: worsening symptoms of COPD that require treatment with 
in-patient hospitalization (i.e., admission). 
An AECOPD should be recorded as an AE. 
If an exacerbation starts off mild but progresses in severity, the exacerbation should be 
classified by its highest level of severity. Two mild exacerbations can, at Investigator 
discretion, be combined into one if the two exacerbations are separated by no more than 3 
exacerbation free days. 
Subjects that experience a moderate or severe AECOPD should be discontinued from the 
study. 
6.4.8.2 Laboratory Safety 
The following safety laboratory tests will be performed and the data recorded in the CRF at 
times defined in the study schedules in Table 1-1 and Section 6. 


 
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Table 6-2: Laboratory Safety Tests 
Hematology 
Chemistry 
Urinalysis 
Other  
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Urea and Creatinine 
Glucose (non-fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (Bicarbonate) 
AST, ALT 
Total Bilirubin 
Direct/Indirect bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
CRP 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Microscopy/culturea 
Serum FSHb 
Urine hCGc,d 
Breath/blood alcohol 
teste 
a. Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase. 
b. Females who are 45 years of age and above who are amenorrheic for less than 2 years at Screening. 
c. At Screening, at visits 3-6, and the Early Termination visit, if applicable. 
d. Urine or serum hCG for females of childbearing potential. 
e. At the Investigator’s discretion an alcohol test may be performed. Where necessary blood or breath alcohol 
tests can be performed. 
 
Hematology and chemistry will be analyzed by local laboratory. Urinalysis will be conducted 
by dipstick at site and if urine is positive for blood, protein, nitrites, or leukocyte esterase, 
will be analyzed via microscopy/culture by a local laboratory.  
Any clinically significant findings in laboratory safety data should be recorded as an AE. 
Determination of clinical significance and seriousness will be based on the Investigator's 
medical judgment. 
6.4.8.3 Blood Pressure and Pulse Rate 
Blood pressure and pulse rate will be measured at times specified in Study Schedule (Table 
1-1) and the results will be recorded in the CRF.  
Additional collection times, or changes to collection times of blood pressure and pulse rate 
will be permitted, as necessary, to ensure appropriate collection of safety data. 
Supine or semi-recumbent blood pressure will be measured with the subject’s arm supported 
at the level of the heart and recorded to the nearest mmHg after 5 minutes of rest. The same 
arm (preferably the dominant arm) and the same posture (i.e., supine or semi-recumbent) will 
be used throughout the study for each individual subject. 
The same size blood pressure cuff, which has been properly sized and calibrated, will be used 
to measure blood pressure each time. The use of automated devices for measuring blood 
pressure (BP) and pulse rate are acceptable, although, when done manually, pulse rate will be 
measured in the brachial/radial artery for at least 30 seconds.  


 
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Any clinically significant changes in blood pressure and pulse rate should be recorded as an 
AE. Determination of clinical significance and seriousness will be based on the Investigator's 
medical judgment. 
6.4.8.4 12-lead ECG 
In this study, 12-lead ECGs will be recorded using appropriately calibrated ECG devices. 
ECGs should be collected at times specified in the Study Schedule (Table 1-1) and the results 
will be recorded in the CRF or transferred directly to the database.  
All 12-lead ECGs will be single recordings. 
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine or semi-recumbent position. The same posture (i.e., supine or semi-
recumbent) will be used throughout the study for each individual subject. Pre-dose ECGs 
should be performed prior to commencing pre-dose spirometry and blood sampling.  
To ensure safety of the subjects, a medically qualified individual at the site will assess ECG 
recordings and make any comparisons to baseline measurements.  
At screening, the QTcF must be ≤500 msec, and the ECG must show no clinically significant 
rate or rhythm abnormalities for the subject to be eligible (See Section 4.2.2).  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  
Any clinically significant ECG abnormalities measured at screening should be assessed for 
their effects on subject eligibility of the study and recorded in medical history. Any clinically 
significant changes between the screening and subsequent ECGs should be recorded as an 
AE. Determination of clinical significance and seriousness will be based on the Investigator's 
medical judgment. 
6.4.8.5 General Physical Examination 
A full general physical examination will consist of an examination of the respiratory, 
cardiovascular, gastrointestinal, musculoskeletal, neurological systems, lymph nodes, skin, 
extremities, head, ears, eyes, nose, and thyroid gland by trained medical personnel at the site. 
A full physical examination will be performed at Visit 1 (Screening) and Visit 6 (Day 85) or 
at an Early Termination visit, if applicable. 
Physical examination results will be recorded in the CRF. 
Height and weight will be assessed at Visit 1.  
Any clinically significant finding at Screening (Visits 1 and 2) should be recorded under 
medical history and changes between Screening (Visits 1) and subsequent examinations 
should be recorded as an AE. Determination of clinical significance and seriousness will be 
based on the Investigator's medical judgment. 


 
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6.5 
Restrictions 
Study restrictions include all items listed in the Lifestyle Guidelines (Section 4.3) and the 
concomitant medications as described in the Exclusion Criteria (Section 4.2.2) and the 
Concomitant Medications (Section 5.7) sections of this protocol and will be prohibited 
throughout the duration of the study. If concomitant medications change during the study, a 
discussion between the Principal Investigator or a Medical Sub-Investigator along with 
Mylan should occur, and a decision to continue or discontinue the subject will be made based 
on the medication’s pharmacology and pharmacokinetics. 
6.6 
Mitigation in the event of a public health emergency 
In the event of any circumstances impacting the ability of enrolled subjects to attend for 
scheduled visits at the investigator site, such as travel restrictions imposed due to COVID-19, 
investigators must notify the Sponsor and make the necessary arrangements to ensure the 
safety of their enrolled subjects. They should also evaluate whether their subjects should 
continue in the clinical trial. Those that have not been randomized yet should be withdrawn 
from the study. 
Where it is possible for randomized subjects to continue, the following operational 
contingencies will be implemented: 
• Study medication, rescue medication, and other study supplies such as diary cards will 
be sent to the subject’s residence to ensure sufficient quantities are available.  
• Virtual visits will be conducted by telephone in place of the scheduled visits, whereby 
the investigator will perform those procedures specified in Section 6.2 that are 
feasible to be performed by telephone, such as questioning on adverse events, 
concomitant medications, and rescue medication use, completion of TDI, etc). 
• Subjects will be reminded to bring (or send) all used and unused study medication, 
rescue medication, and diary cards to the site as soon as they are able after travel 
restrictions have been lifted. 
Protocol deviations arising under such circumstances (eg, missed or delayed visits, 
assessments not performed, etc) will be clearly documented in the CRF and the reasons will 
be collected. 
7 
STATISTICAL ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the Sponsor. This will include any plans for summarizing and analyzing data impacted by 
a public health emergency. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition and/or its analysis will 
also be reflected in a protocol amendment. 


 
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7.1 
Sample Size Considerations 
The null hypothesis is that there is no difference in the mean change from baseline trough 
FEV1 on Day 85 between revefenacin and placebo. The alternative hypothesis is that there is 
a difference. 
The estimate for the difference in mean change from baseline trough FEV1 at Day 85 and the 
common standard deviation are based on the sample size assumptions for the revefenacin US 
pivotal studies (0126 and 0127) in a Western population and the GLOW7 study - a similarly 
designed study in a predominantly Chinese population (Wang et al., 2015 [5]). 
A sample size of 256 evaluable subjects (128:128; a 1:1 ratio of revefenacin to placebo) is 
required to provide at least 90% power to detect a difference between revefenacin and 
placebo of 100 mL in the analysis of the change from baseline trough FEV1 at Day 85 
assuming a standard deviation of 245 mL and a two-sided 5% significance level. 
To allow for an anticipated 20% dropout rate, approximately 320 subjects in total will be 
randomized. In the event of a public health emergency such as COVID-19, the Sponsor may 
consider increasing enrollment to overcome any additional loss of information for the 
primary endpoint due to the inability of subjects to attend for scheduled clinic visits. The 
maximum number of subjects to be randomized under such circumstances will be limited to 
428 (an additional 20% increase in enrollment). 
7.2 
Analysis Set Definitions 
7.2.1 Safety Analysis Set 
The safety analysis set (SS) will include all subjects who received at least one dose of study 
drug. Data will be summarized according to the treatment a subject actually received. 
7.2.2 Full Analysis Set 
The full analysis set (FAS) will include all randomized subjects who received at least one 
dose of study drug and have at least one recorded post-baseline efficacy assessment. Data 
will be summarized and analyzed according to the treatment a subject was assigned to receive 
at randomization.  
7.2.3 Per Protocol Analysis Set 
The per protocol analysis set (PP) will include all subjects in the FAS who had no major 
protocol violation that would impact significantly on the primary efficacy endpoint. The list 
of major protocol deviations will be finalized prior to database lock. All decisions to exclude 
subjects from the PP analysis set will be made prior to unblinding in the final blinded data 
review (BDR) meeting and report. Data will be summarized and analyzed according to the 
treatment a subject actually received at randomization. 
7.2.4 Population Pharmacokinetic Analysis Set 
The population pharmacokinetic analysis set (PPK) will include all subjects who receive at 
least one dose of study medication and who provide at least one post dose concentration 
sample for the Population PK analysis. All analyses using the PPK set will group subjects 
according to treatment actually received. 


 
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7.3 
Primary Endpoints 
7.3.1 Definition of Primary Endpoints 
The primary efficacy endpoint is the change from baseline trough FEV1 on Day 85.   
 
• Baseline FEV1 is defined as the average of the -45 and -15 minute measurements prior 
to dosing of study medication on Day 1 (Visit 3). 
• Trough FEV1 measurements will be the pre-dose FEV1 measures on Day 29, 57 and 
85 calculated as the average of the -45 and -15 minute measurements prior to dosing 
of study medication. 
• If a public health emergency prevents FEV1 data from being measured at site then 
information on the reasons for the missing assessments will be recorded in the CRF. 
 
7.3.2 Statistical Methodology for Primary Endpoints 
The analysis of the primary endpoint will be based on a mixed model repeated measures 
(MMRM) analysis including changes from baseline trough FEV1 measurements on Days 29, 
57 and 85 as the dependent variable. The model will include independent fixed-effect terms 
for concomitant LABA use, reversibility to ipratropium, smoking status, age, sex, treatment 
and baseline FEV1 as a covariate. A time effect (visit) and its interaction terms with treatment 
and baseline FEV1 will be included. The variance estimation will be based on an unstructured 
covariance matrix. The Kenward-Roger method for approximating the denominator degrees 
of freedom will be used.   
7.3.3 Primary Analysis for Primary Endpoint 
The primary analysis of the primary efficacy endpoint will be based on the FAS population 
and includes all randomized subjects who received at least one dose of study drug and have at 
least one recorded post-baseline FEV1 assessment. Available data for a subject prior to 
discontinuing study treatment will be used in the MMRM analysis. Missing data is assumed 
as missing at random (MAR). The robustness of the conclusions to this assumption will be 
assessed with a missing data sensitivity analysis. 
 
The difference between revefenacin and placebo on Day 85 will be estimated from the least 
squares means (LSmeans) along with the 95% confidence interval (CI) and associated 2-sided 
p-values. 
7.3.4 Secondary/Sensitivity Analyses for Primary Endpoint 
The same primary analysis model will be replicated in the PP population.   
A sensitivity analysis using a two-dimensional tipping point imputation method will be 
applied to the MMRM analysis (FAS population) to assess the robustness of the conclusions 
to the assumption that missing data is MAR. In the tipping point analysis a succession of 
delta adjustments via multiple imputation methods will be used to impute the missing 
revefenacin and placebo trough FEV1 values at each timepoint. The tipping point is denoted 
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significant result. Clinical judgement will be applied to the plausibility of the tipping point. 
The detail of the imputation method will be included in the SAP. 
In addition, missing trough FEV1 data on Day 85 will be imputed using a Last-Observation-
Carried-Forward (LOCF) single imputation method. Change from baseline FEV1 at Day 85 
will be analyzed using an analysis of covariance (ANCOVA) using the FAS population. The 
model will include independent fixed-effect terms for concomitant LABA use, reversibility to 
ipratropium, smoking status, age, sex, treatment and baseline FEV1 as a covariate.   
LSmeans for Day 85 will be derived for both treatment groups. The difference between 
revefenacin and placebo on Day 85 will be estimated from the LSmeans along with the 95% 
CI and associated 2-sided p-values. 
7.3.5 Missing Data 
Missing imputed data methods will be performed in the primary and sensitivity analyses as 
described above for trough FEV1. Otherwise, missing data will not be imputed. 
7.3.6 Sub-Group Analyses 
For the primary endpoint the follow subgroups are pre-defined for the purpose of sensitivity 
analyses: 
− Baseline smoking status [current smoker, ex-smoker] 
− Age group [<65, >=65 years] 
− Sex [Male, Female] 
− Reversibility to ipratropium [yes, no] 
− Concomitant ICS use [yes, no] 
− Concomitant LABA use [yes, no] 
− Baseline post bronchodilator % predicted FEV1 [50% to <80%, 
30% to <50%, <30%] 
− GOLD categories [A, B, C, D] 
 
Forest plots will be produced for these subgroups. Additional subgroups and analyses may be 
defined in the SAP. 
7.4 
Secondary Efficacy Endpoints 
In all the secondary efficacy analyses missing data will not be imputed and will be assumed 
to be missing at random (MAR). Secondary efficacy analyses will be performed using the 
FAS population. If a public health emergency prevents data from being measured or requires 
data to be assessed remotely via a virtual visit, then information on the reasons and the data 
impacted will be recorded in the CRF. 
7.4.1 Spirometry 
7.4.1.1 Trough FEV1 on Days 29 and 57 
The changes from baseline trough FEV1 on Days 29 and 57 will be estimated from the 
MMRM analysis used for the primary analysis of the primary endpoint. 


 
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7.4.1.2 Trough FVC on Days 29, 57 and 85 
The changes from baseline trough FVC on Days 29, 57 and 85 will be analyzed using the 
same MMRM analysis described for the primary analysis of the primary endpoint. The 
baseline FEV1 covariate will be replaced with the baseline trough FVC recorded on Day 1.   
7.4.1.3 Peak FEV1 (0-2h) on Day 1 and Day 85 
Lung function assessments will be made after study treatments (5, 15, and 30 minutes, and 1, 
1.5, and 2 hours) on Days 1 and 85.   
Analysis of Covariance (ANCOVA) model will be used to assess the difference between 
treatment groups for change from baseline Peak FEV1 after the first dose on Day 1. The 
ANCOVA model will include fixed-effect terms for concomitant LABA use, reversibility to 
ipratropium, smoking status, age, sex, treatment and baseline FEV1 as a covariate.   
The difference between revefenacin and placebo on Day 1 will be estimated from the 
LSmeans along with the 95% CI and associated 2-sided p-values. 
A separate analysis will be performed for Peak FEV1 on Day 85 using the same ANCOVA 
model. 
7.4.1.4 Weighted Mean FEV1 (0-2h) on Day 1 and Day 85 
Lung function assessments will be made after study treatments (5, 15, and 30 minutes, and 1, 
1.5, and 2 hours) on Days 1 and 85.  
The area under the curve (AUC), (0 to 2h) will be calculated using the trapezoidal rule 
including observed data points from pre-dose (0 hours) through to the 2 hour observation. For 
all observations the nominal time of the observation should be used. For the calculation of 
AUC, the first, last and at least one time point between first and last must be available. 
Otherwise, the AUC is set to missing.  
The weighted mean (WM) FEV1 is derived by dividing AUC by the total time (nominally 
2 hours). 
An ANCOVA model will be used to assess the difference between treatment groups for WM 
FEV1 on Day 1 and Day 85 in separate models. Each ANCOVA model will include fixed-
effect terms for concomitant LABA use, reversibility to ipratropium, smoking status, age, 
sex, treatment and baseline FEV1 as a covariate.   
The difference between revefenacin and placebo on Day 1 and Day 85 will be estimated from 
the LSmeans along with the 95% CI and associated 2-sided p-values. 
7.4.2 Patient Reported Outcomes (PROs) 
7.4.2.1 SGRQ on Day 85 (continuous endpoint) 
Baseline SGRQ endpoints will be those recorded on Day 1. The change from baseline SGRQ 
scores on Day 85 will be summarized and analyzed as a continuous endpoint. 


 
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An ANCOVA model will be used to assess the difference between treatment groups for 
change from baseline SGRQ on Day 85. The ANCOVA model will include fixed-effect terms 
for concomitant LABA use, reversibility to ipratropium, smoking status, age, sex, treatment 
and baseline SGRQ as a covariate. For subjects who discontinue study treatment, the data 
from the SGRQ completed at the Early Termination (ET) visit will be carried forward in the 
analyses. 
The difference between revefenacin and placebo on Day 85 will be estimated from the 
LSmeans along with the 95% CI and associated 2-sided p-values. 
7.4.2.2 SGRQ Responders (total score 4 units) on Day 85 
A decrease from baseline of 4 units in SGRQ total score is considered clinically meaningful 
and will be defined as a responder.  
The number and percentage of responders on Day 85 in each treatment group will be 
summarized. A comparison between revefenacin and placebo will be evaluated with the odds 
ratio (OR) and corresponding 95% confidence interval from a logistic regression model. The 
model will include fixed-effect terms for concomitant LABA use, reversibility to 
ipratropium, smoking status, age, sex, treatment and baseline SGRQ total score as a 
covariate. 
For subjects who discontinue study treatment, the SGRQ completed at the Early Termination 
(ET) visit will be carried forward and used to derive a responder. 
7.4.2.3 BDI/TDI on Days 29, 57 and 85 
Baseline BDI score will be recorded on Day 1. The TDI represents changes from baseline and 
will be recorded on Days 29, 57 and 85. 
The TDI focal score will be analyzed using the same MMRM analysis described for the 
primary analysis of the primary endpoint. The baseline FEV1 covariate will be replaced with 
the BDI focal score.  Estimates for TDI on Days 29, 57 and 85 will be derived from the 
model. 
The difference between revefenacin and placebo on Days 29, 57 and 85 will be estimated 
from the LSmeans along with the 95% CI and associated 2-sided p-values. 
7.4.2.4 TDI Responders (focal score 1 unit) on Days 29, 57 and 85 
A TDI focal score of 1 unit is considered clinically meaningful and will be defined as a 
responder.  
The number and percentage of responders on Days 29, 57 and 85 in each treatment group will 
be summarized. A comparison between revefenacin and placebo will be evaluated with the 
odds ratio (OR) and corresponding 95% confidence interval from a logistic regression model 
including the proportion of responders at each visit (Days 29, 57 and 85) as the dependent 
variable. The MMRM logistic model will include the same independent fixed-effect terms as 
for the primary analysis of the primary endpoint. The baseline FEV1 covariate will be 
replaced with the BDI focal score as a covariate. Estimates for the proportion of TDI 
responders on Days 29, 57 and 85 will be derived from the model.   


 
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7.4.3 Rescue Medication Usage 
7.4.3.1 Average Count of Salbutamol Puffs Per Day (Days 1-85) 
The average count of rescue salbutamol puffs per day will be calculated for each monthly 
interval by dividing the total salbutamol puff counts for each of the 3 monthly intervals by the 
total number of days on study for that month. 
The average count of salbutamol puffs per day will be analyzed using the same MMRM 
analysis described for the primary analysis of the primary endpoint with the time variable 
Month (1, 2, 3) replacing Visit. The average count of salbutamol puffs per day for the study 
(Days 1-85) will be estimated from the model-derived average of each of the 3 months using 
an appropriate contrast statement as well as the LSmean differences, 95% CI and associated 
2-sided p-values. 
7.4.3.2 Percentage of Salbutamol Rescue Free 24h Periods (Days 1-85) 
A 24h rescue-free period is defined as a day without a “yes” for rescue use per the daily 
diary.   
The percentage of salbutamol rescue free 24h periods will be calculated for each monthly 
interval by dividing the number of 24h rescue-free periods for each of the 3 monthly intervals 
by the total number of days on study for that month. 
The percentage of salbutamol rescue free 24h periods will be analyzed using the same 
MMRM analysis described for the primary analysis of the primary endpoint with the time 
variable Month (1, 2, 3) replacing Visit. The average percentage of salbutamol rescue free 
24h periods for the study (Days 1-85) will be estimated from the model-derived average of 
each of the 3 months using an appropriate contrast statement as well as the LSmean 
differences, 95% CI and associated 2-sided p-values. 
7.5 
Safety Endpoints 
Safety endpoints will be summarized using the SS population.  There are no planned analyses 
for the comparison of treatments for the safety endpoints. 
7.5.1 Adverse Events 
Adverse events will be summarized and listed. All AEs that occur after the first dose of study 
medication through 30 days after the last dose will be considered to be treatment emergent 
AEs. The number and percentage of subjects with at least one treatment emergent AE will be 
presented by treatment group and events further summarized by maximum severity and 
relationship to study medication. Summary statistics (N, %) of AEs of special interest will be 
also be separately tabulated.  
7.5.2 Acute Exacerbations of COPD (AECOPD) 
A summary of acute exacerbations of COPD reported with an AE preferred term of COPD 
will be descriptively summarized by severity. Exacerbation data will be summarized (N, %) 
for all exacerbations; moderate and severe exacerbations; and severe only exacerbations. 


 
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7.5.3 Other Safety Endpoints 
Descriptive statistics will be provided for the following safety data. No inferential analysis of 
this safety data is planned. Any ECG, BP, and pulse rate abnormalities of potential clinical 
concern will be described. 
7.5.3.1 Vital Signs 
Pre-dose systolic BP, diastolic BP and pulse rate will be listed and descriptively summarized 
(N, mean, standard deviation, minimum and maximum) by treatment group and visit. 
Baseline (defined as the pre dose value collected on Visit 3) and changes from baseline will 
be similarly summarized.  
7.5.3.2 12-lead ECG 
ECG data; QT, QTc (Fridericia’s), heart rate (HR), QRS duration, PR and RR interval will be 
listed. 
Baseline and change from baseline for QT, QTcF, HR, QRS, RR and PR will be summarized 
using descriptive statistics (N, mean, standard deviation, minimum and maximum) by 
treatment and study week.  
For QTcF a classification of absolute values and increases from baseline will be performed. 
The number of subjects with maximum absolute QTcF <450 msec, 450 msec ≤QTcF 
<480 msec, 480 msec ≤QTcF <500 msec and QTcF values ≥500 msec will be tabulated by 
treatment and visit. The number of subjects with maximum increase from baseline QTcF 
<30 msec, 30 msec ≤QTcF <60 msec and QTcF ≥60 msec will be tabulated by treatment and 
visit. 
7.5.3.3 Laboratory Tests 
Laboratory data (clinical chemistry, hematology, and urinalysis parameters) will be listed and 
descriptively summarized (N, mean, standard deviation, minimum and maximum) by 
treatment group and visit. 
Baseline (defined as the data collected at Visit 3) and changes from baseline will be similarly 
summarized. 
Changes from baseline that result in out of normal range values will be listed and 
summarized. 
7.6 
PK Analyses 
For all pharmacokinetic data analyses, the PPK population will be used. 
Samples for PK determination of drug concentrations of revefenacin and its major metabolite, 
THRX-195518, in plasma will be determined by a bioanalytical laboratory using validated 
bioanalytical methods. Details of the validated bioanalytical method used will be provided in 
a separate bioanalytical report. 
The plasma concentration data for revefenacin and THRX-195518 will be listed, summarized 
on the basis of time intervals, and plotted using a scatter plot with time relative to the 


 
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preceding revefenacin dosing time. Summary statistics (mean, standard deviation, minimum, 
maximum, number of subjects, and coefficient of variation) will be calculated for plasma 
concentrations for each time interval and by treatment group. 
Population PK analysis of revefenacin concentrations in COPD subjects will be performed 
using modeling. The population PK analysis will be conducted and reported separately. 
Details of the PPK model building will be described in a separate population PK analysis 
plan. 
Exploratory exposure-response analysis may be conducted using individual predictions of 
exposure from the population PK analysis in this study. Outcomes from this analysis will be 
reported separately, if conducted. 
7.7 
Other Analyses 
Summary statistics will be provided for demographics and baseline characteristics, medical 
history and prior and concomitant medications. 
7.8 
Interim Analyses 
An interim analysis is not planned for this study. 
8 
ADMINISTRATIVE PROCEDURES 
8.1 
Source Documentation Forms 
All clinical data will be recorded by the clinical staff on raw data sheets and/or recorded 
electronically using validated software. If computerized systems are used to create, modify, 
maintain, archive, retrieve or transmit source data, they must comply with the applicable 
regulatory regulations and/or guidance. 
The nature and location of all source documents will be documented separately. Source data 
may be directly captured from devices, transferred from 3rd parties (e.g. laboratory data) or 
entered manually into CRF/database. 
8.2 
Access to Data/Source Documentation 
The Investigator or designated representative will permit full access to data and source 
documentation for the purpose of clinical monitoring, audits, IRB/IEC review and regulatory 
inspections. 
8.3 
Final Clinical Study Report and Case Report Forms (CRFs) 
A written clinical study report will be provided in accordance with the International 
Conference on Harmonization (ICH) E-3 guidelines including Annex I (Synopsis) 
documenting the clinical execution of the study. This report will include a description of any 
protocol deviations. The final report will also include reasons for withdrawals and any 
necessary treatment(s). The report will also include tables presenting demographics (separate 
summary tables for enrolled and completed subjects), and adverse events recorded during the 
study. In addition, the clinical study report will include a Quality Assurance statement, 
documenting that the report has been reviewed for completeness, accuracy, and compliance 
with the protocol and applicable local and federal regulations. For final clinical reporting 


 
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purposes only, adverse events deemed “definite”, “probable” or “possible” will be included in 
the treatment-related summaries/listings. 
Case Report Forms (CRFs) containing data transcribed from subject source documents (as 
appropriate) and copies of other source documents will be supplied by the clinical site. The 
Principal Investigator must sign each subject’s CRF after completion of data entry, signifying 
that the data entered in the CRF is complete and accurate. Electronic CRFs may be provided. 
8.4 
Adherence to Protocol 
Except for an emergency situation in which proper care for the protection, safety and well-
being of the study subjects requires medical treatment, the study will be conducted as 
described in the approved protocol (and amendments, if applicable), GCP and applicable 
SOPs. In addition, the study will be conducted in accordance with the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. Any deviation(s) from the protocol will be recorded and 
presented in the final report. 
All protocol deviations will be reviewed in a blinded manner during the course of the study 
and decisions to exclude subjects from statistical analysis sets will be made prior to 
unblinding and the reasons documented. 
8.5 
Data Handling and Record Retention 
All clinical information shall be recorded, handled and stored in such a way that it can be 
accurately reported, interpreted and verified, while the confidentiality of records of the trial 
subjects remains protected. 
A CRF is required to be completed for each subject receiving study medication. The CRF is 
property of the Sponsor and the Investigator must review all CRFs prior to submission to the 
Sponsor. 
The CRF may be considered as the source document. The Investigator must seek prospective 
agreement to the Sponsor in writing to use the CRF as source document prior the start of the 
study. In addition, items directly recorded in the CRF must be documented that they will be 
considered as source. 
All records pertaining to the receipt and return of study supplies (particularly study 
medication) and copies of final case report forms, worksheets, and other pertinent source 
documents must be retained in accordance with ICH-GCP and the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. 
The Investigator must obtain in writing the Sponsor’s agreement to dispose of any records, 
even if the retention period has been reached. 
8.6 
Confidentiality 
Information furnished to Clinical Investigators and IRBs/Ethics Committees will be 
maintained in confidence by the Clinical Investigator and IRB/Ethics Committee. By signing 
this protocol, the Investigator affirms to the Sponsor that he/she will maintain, in confidence, 


 
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information furnished to the IRB/Ethics Committee relevant to this study under appropriate 
understanding of confidentiality with such IRB/Ethics Committee. 
By signing the protocol, the Investigator agrees that within local regulatory restrictions and 
institutional and ethical considerations, the Sponsor may consult and/or copy source 
documents (e.g., laboratory/X-ray reports, ECG tracings, workbooks, medical records) in 
order to verify CRF data. 
8.7 
Ethics and Regulatory Authorities 
Guidelines will be followed with regard to the treatment of human subjects in the study, in 
accordance with the requirements of the Declaration of Helsinki and the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH-E6) 
in addition to the regulatory requirements of the country where the study is being conducted 
as well as the country where the study will be submitted. 
8.7.1 Institutional Review Board/Ethics Committee 
The Investigator is responsible for obtaining initial and continuing review (at intervals not 
more than once per year) of the study by an IRB/Ethics Committee, or in accordance with 
applicable government regulations of the country where the study is being conducted as well 
as the country where the study will be submitted. This study will not enroll any subjects until 
the IRB/Ethics Committee provides written approval of the protocol and the informed 
consent to the Investigator. In addition, a copy of the IRB/Ethics Committee approval 
documents must be provided to the Sponsor prior to enrolling any subjects into the study. 
8.7.2 Regulatory Authority 
This clinical study protocol, title and a list of investigational sites, IEC(s)/IRB(s) approvals, 
as well as other relevant documentation will be submitted to the local Regulatory Authorities 
for review and approval prior to trial start. Upon completion, the Regulatory Authorities will 
be notified the study has ended. The study will only be undertaken in compliance with the 
local regulatory requirements. 
8.8 
Informed Consent 
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each volunteer prior to entering the study. A copy 
of the informed consent document to be used will be submitted by the Investigator to an 
independent institutional review board (e.g., IRB or ethics committee) and the Sponsor and/or 
its agent for review and approval prior to the start of the study. The Investigator shall provide 
a copy of the signed and dated informed consent to the subject, and a signed and dated copy 
shall be maintained in the volunteer’s medical record. 
8.9 
Disclosure and Publication of Clinical Study Data 
The disclosure and publication of clinical study data will be detailed in the clinical trial 
agreement with the Investigators. 


 
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8.10 End of Trial 
The end of trial is considered to be the date of last subject last visit or the date of early 
termination of the study whichever is the later. 
9 
ADVERSE EVENT REPORTING 
9.1 
Assessment of Safety 
9.1.1 Safety Parameters 
Safety will be assessed by the monitoring of adverse clinical events, electrocardiograms, 
vital signs, clinical laboratory evaluations, and physical examinations. All adverse events 
occurring during the study must be recorded according to Section 9.2. 
Findings from screening procedures, e.g., laboratory tests or physical examinations will be 
recorded as medical history. Clinically significant changes from the screening procedures will 
be recorded as adverse events. 
The adverse event collection period begins at signing of informed consent and continues until 
30 days after the last dose of study medication.  Adverse events occurring during this period 
need to be reported to the Sponsor according to Section 9.4 (Collection and Recording of 
Adverse Events). The Investigator is also responsible for notifying the Sponsor if he/she 
becomes aware of any adverse event after the study period has ended and it is considered 
related to the study medication (i.e., an adverse drug reaction). Once an AE is detected, it 
should be followed until its resolution or until it is judged by the Principal Investigator to be 
stable or permanent. 
9.2 
Definitions 
Adapted from ICH Harmonised Tripartite Guideline: Clinical Safety Data Management 
Definition and Standards for Expedited Reporting: E2A  
9.2.1 Adverse Event  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.  
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory or physical findings, symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product whether or not considered related to the 
medicinal product. 
Clinically significant changes from baseline in laboratory assessments, vital signs, ECGs, and 
physical examination are to be recorded as adverse events. Clinically significant 
abnormalities include: 
• a result associated with accompanying signs/symptoms  
• a result that requires additional diagnostic testing or medical/surgical intervention  


 
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• a result that leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy  
• a result considered to be an adverse event by the Investigator or Sponsor 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.  
An abnormal safety assessment (e.g., laboratory, vital signs, ECG) associated with a clinical 
diagnosis that has been recorded as an AE does not require a separate AE entry 
Events meeting the definition of an AE also include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug or drug-food 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. (Please refer to the Section 9.3: Special 
Situations for further details)  


 
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• A symptom or medical complication related to a protocol-mandated intervention, 
including screening procedures 
9.2.2 Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• Fatal 
• Life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: In patient hospitalization is defined as 24 hours in a hospital or an overnight 
stay. An elective hospital admission to treat a condition present before exposure to the 
study drug or a hospital admission for a diagnostic evaluation of an AE, does not 
qualify the condition or event as an SAE. Further, an overnight stay in the hospital 
that is only due to transportation, organization or accommodation problems and 
without medical background does not need to be considered an SAE. 
Events NOT to be reported as SAEs are hospitalizations for the following:  
- Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
- Treatment, which was elective or pre-planned, for a pre-existing condition that is 
unrelated to the indication under study and did not worsen  
- Admission to a hospital or other institution for general care due to social or 
economic reasons (e.g., no access to local ambulatory medical care)  
- Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission  
Hospitalization also does not include the following:  
- Rehabilitation facilities  
- Hospice facilities  
- Respite care (e.g., caregiver relief)  
- Skilled nursing facilities  
- Nursing homes  
• Results in persistent or significant disability or incapacity 


 
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• A congenital anomaly or birth defect 
• An important medical event 
- NOTE: medical and scientific judgment should be exercised in deciding whether 
it is appropriate to consider other situations serious, such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject and / or may require intervention to 
prevent one of the other outcomes listed in the definition above. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse.  
- The seriousness criterion of “medically significant” should only be selected when 
none of the other seriousness criteria apply to the event but the Investigator still 
considers the event as serious. 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
9.2.3 Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose of the 
investigational product should be considered adverse drug reactions (ADRs). The phrase 
“responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility. All AEs judged by 
either the reporting Investigator or the Sponsor as having a reasonable causal relationship to 
an investigational product will be designated as ADRs. 
All AEs, with the causal relationship to the study drug reported as “possible”, “probable” or 
“definite” will be considered ADRs. If the relationship to the study drug is not given, then the 
AE must be treated as if the relationship were “possible.” 
9.2.4 Expected/Unexpected Adverse Event 
An expected AE is defined as one whose nature, severity or outcome is consistent with the 
applicable reference safety information described of the study drugs.  
9.2.5 Pre-existing Condition 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline medical history and not reported as an AE. A baseline or preexisting 
condition should be recorded as an adverse event only if the frequency, intensity, or the 
character of the condition worsens during the study period. 
9.2.6 General Physical Examination Findings 
Any new clinically significant findings/abnormalities that meet the definition of an adverse 
event must also be recorded and documented as an adverse event.  


 
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9.2.7 Post-study Adverse Event/Serious Adverse Event 
At the last scheduled contact with the subject the Investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study.  The Investigator should notify the 
study Sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study. 
The Sponsor should also be notified if the Investigator becomes aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has 
participated in this study. 
9.3 
Special Situations 
The following situations may by associated with a serious outcome and should be evaluated 
for expedited reporting to the Sponsor. 
• Any diagnosis of Cancer or Neoplasm is to be reported as a serious adverse event. 
• Emergency Room Visits: Events that result in emergency room visits that do not 
result in admission to the hospital are not routinely considered to be serious events; 
however, these events should be evaluated for one of the other serious outcomes (e.g., 
life-threatening, other serious [medically significant] events). 
• Overdose: Overdose per se will not be reported as an AE/SAE unless this is an 
intentional overdose taken with possible suicidal/self-harming intent; this should be 
reported regardless of sequelae. Signs and symptoms associated with accidental 
overdose are to be recorded as adverse events or as serious AEs. If adverse events 
associated with overdose fulfil any of the serious criteria (as defined in section 
‘Serious Adverse Event’), a completed SAE report form is required to be submitted. 
• Reports of Drug-drug interaction and Drug Abuse and Medication Errors: drug 
interactions or abuse of the study medication must be recorded as AEs. Medication 
errors will be captured as protocol deviations while any associated signs or symptoms 
must be recorded as AEs on the CRF. In addition, any serious consequence of drug 
interactions, drug abuse, or medication error must be reported immediately if these 
fulfil any of the SAE criteria. 
9.4 
Collection and Recording of Adverse Events 
During the Adverse Event Reporting Period, the Investigator will record all adverse events. 
At each contact with the subject, the Investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and in the appropriate adverse event 
module of the case report form (CRF). Information to be collected includes AE name or term 
(in standard medical terminology) and final diagnosis, event description, time and date of 
onset, clinician’s assessment of severity, seriousness, relationship to study product (assessed 
only by those with the training and authority to make a diagnosis), action taken with the study 
drug, treatment for the event and time (if available) and date of resolution/stabilization of the 
event. 


 
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Any findings from protocol specified safety assessments that are associated with the 
indication being studied are not to be reported as AEs or SAEs, unless judged by the 
Investigator to be more severe than expected for the subject’s condition.  
All clearly related signs, symptoms, and abnormal results of diagnostic procedures should be 
grouped under one diagnosis on the CRF where possible and appropriate. 
The clinical course of each event should be followed until resolution or stabilization.  
Adverse events that are still ongoing at the end of the study period must be followed up to 
determine the outcome. Any adverse event that occurs after the study period and is related to 
the study treatment or study participation should be recorded; and if serious, the Investigator 
should also immediately report it to the Sponsor. 
9.5 
Classification of an Adverse Event 
9.5.1 Severity 
The Investigator will assign a severity rating to each AE. For purposes of consistency, the 
following scale is to be used: 
Grade 1 - MILD 
Does not interfere with subject's usual function 
Grade 2 - MODERATE 
Interferes to some extent with subject's usual function 
Grade 3 - SEVERE 
Interferes significantly with subject's usual function 
 
It is important to distinguish between severe AEs and Serious AEs. Severity is a classification 
of intensity, whereas an SAE is an AE that meets any of the regulatory specified criteria (see 
definitions, Serious Adverse Event).  
NOTE: an acute exacerbation of COPD (AECOPD) should have the severity graded per the 
definitions in Section 6.4.8.1.1. 
9.5.2 Causality 
For all adverse events, sufficient information should be obtained by the Investigator to 
determine the causality of the adverse event. The Investigator is required to assess causality 
of each AE. 
An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE. The 
Investigator must make an assessment of the relationship of each AE (serious and 
non-serious) to the study treatment(s) and record this relationship in the CRF. 
Factors that need to be considered when making a causality assessment include: Temporal 
relationship, Clinical and pathological characteristics of the event(s), Pharmacological 
plausibility, Exclusion of confounding factors (medical and medication history), Drug 
interactions, De-challenge/re-challenge, Dose relationship. 


 
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A suspected relationship (definite, probable, possible) between the events and the study 
medication means, in general, that there are facts (evidence) or arguments to suggest a causal 
relationship. Receipt of additional or clarifying information may warrant reassessment of 
causality. The Investigator is responsible for assessing relationship of AEs to study treatment 
in accordance with the following definitions: 
Category 
Causality 
Description 
DEFINITE 
Causal relationship is 
certain 
For example: the temporal relationship 
between drug exposure and the adverse event 
(AE) onset/course is reasonable, there is a 
clinically compatible response to de-
challenge, other causes have been eliminated; 
the event must be definitive 
pharmacologically or phenomenologically, 
using a satisfactory re-challenge procedure if 
necessary. 
PROBABLE 
High degree of 
certainty for causal 
relationship 
For example: the temporal relationship 
between drug exposure and AE onset/course 
is reasonable, there is a clinically compatible 
response to de-challenge (re-challenge is not 
required), and other causes have been 
eliminated or are unlikely. 
POSSIBLE 
Causal relationship is 
uncertain 
For example: the temporal relationship 
between study treatment exposure and the AE 
onset/course is reasonable or unknown, 
dechallenge information is either unknown or 
equivocal; could also be explained by disease 
or other drugs. 
UNLIKELY 
Causal relationship is 
improbable 
Another explanation is more likely such as 
disease, environment, or other medication. 
Does not represent a known reaction to study 
drug. 
UNRELATED/NOT 
RELATED 
No possible 
relationship 
The temporal relationship between drug 
exposure and the AE onset/course is 
unreasonable or incompatible, or a causal 
relationship to study drug is impossible 
 
For SAEs, if the relationship to the study treatment(s) is considered to be unlikely or not 
related, an alternative suspected etiology should be provided when possible (e.g., 
concomitant medications, intercurrent illness/events, study-related procedure). 


 
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9.5.3 Expectedness 
The Sponsor or its designated representative will be responsible for determining whether an 
AE is expected or unexpected.   
9.5.4 Outcome 
For all adverse events, the Investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Sponsor or its 
designated representative. 
The outcome at the time of last observation will be classified as: 
RECOVERED/RESOLVED where the subject recuperated and is free of any pathological 
conditions resulting from the prior disease or injury 
RECOVERED WITH SEQUELAE where the subject recuperated but retained pathological 
conditions resulting from the prior disease or injury.  
NOT RECOVERED/NOT RESOLVED (i.e., ongoing) where the subject has not recuperated 
from the condition or injury and the event is still considered ongoing 
RECOVERING where the subject has begun to recuperate from the condition or injury but 
the event is considered ongoing at a reduced intensity 
FATAL where the condition or injury results in the subject’s death. The Investigator should 
identify the principal cause of death and assign Fatal outcome to that event. Other concurrent 
ongoing AE/SAEs present at the time of death would remain Not recovered/Not resolved. 
UNKNOWN can be selected if none of the other situations apply or are known.  Follow-up 
should be conducted to obtain one of the preceding outcomes. 
Action Taken with the Study Treatment and combination treatment for an Adverse Event: 
Action 
Description 
Dose reduced 
The dose regimen was reduced by changing its frequency, 
strength, or amount 
Treatment interrupted 
The treatment was temporarily discontinued 
Treatment withdrawn 
The treatment was permanently discontinued 
Unknown 
Not known, not observed, not recorded, or refused 
No action taken 
The AE did not result in any modification of dose or frequency 
of dosing 
Not applicable 
The AE occurred prior to first dose or following last scheduled 
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9.6 
Reporting of Serious Adverse Events and Pregnancy Exposures 
Investigators and the Sponsor or its designated representative must conform to the serious 
adverse event reporting timelines, formats and requirements of the various entities to which 
they are responsible. 
9.6.1 Investigator Reporting: Notifying the Study Sponsor 
Immediate notification of SAEs by the Investigator to Sponsor or its designated 
representative is essential so that legal obligations and ethical responsibilities towards the 
safety of subjects are met. 
Sponsor or its designated representative will comply with country specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) and Investigators. 
Serious adverse events must be reported to the study Sponsor within 24 hours. To report such 
events, a Serious Adverse Event (SAE) Report form must be completed and signed by the 
Investigator or designee and forwarded to: 
Email: 
 
Fax:  
 
If the initial notification using the completed ‘SAE report form’ is not possible, the 
notification may be made via email/fax or over telephone with the following minimum 
necessary information: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Current status (outcome of event-if known and whether study medication is 
continuing) 
• The reason why the event is classified as serious 
• Investigator assessment of the causality between the event and study treatment 
The Investigator should provide further information on the SAE as soon as possible, 
preferably within 48 hours of awareness.  This should include a copy of the completed SAE 
Report form, and any other diagnostic information and medical records that will assist in the 
understanding of the event.   
Subject identifying information must not be visible on SAE forms or any supporting 
documentation provided by the Investigator. Any information that could be used to identify 


 
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the subject (e.g., name, address, medical record number) must be de-identified before 
submission to Mylan or its designee. The subject’s study specific ID number should be 
recorded on every page of documentation forwarded to the Sponsor. 
The PI should provide the final diagnosis as the SAE term whenever possible in the SAE 
report form and CRF. The signs and symptoms should be provided in the narrative only, not 
as SAE terms. The PI should only list all signs and symptoms as SAE terms if no diagnosis is 
available at the time of report. 
9.6.2 Follow-up 
New information and any important missing information from prior reports on a serious 
adverse event must be provided promptly to the study Sponsor. In addition, the Investigator 
may be requested by Sponsor/designee to obtain specific additional follow-up information in 
an expedited fashion. The Investigator should respond to targeted follow-up requests as soon 
as possible and preferably within 48 hours from receipt of the request. 
9.6.3 Investigator Reporting: Notification of Ethics Committee 
Investigators are responsible for safety reporting to their local Ethics Committee (LEC) and 
complying with their local EC’s reporting requirements. Copies of each report and 
documentation of LEC notification and receipt will be kept in the Investigator’s study file. 
9.6.4 Investigator Reporting of Pregnancy - Notifying the Study Sponsor  
All subjects who participate in the study should be counseled on the need to practice adequate 
birth control and on the importance of avoiding pregnancy during study participation as 
detailed in the inclusion and exclusion criteria. Pregnancy testing will be conducted 
throughout the study, as detailed in the schedule of assessments. 
A subject who is found to be pregnant at the screening visit will be excluded from the study 
and will be a screening failure.  
Subjects who have been enrolled in the study should be instructed to contact the Investigator 
or study staff immediately if pregnancy occurs or is suspected. Early Termination visit 
assessments are required as soon as possible after learning of the pregnancy. Pregnant 
females will be discontinued from study treatment by the Investigator. A male that has a 
partner that becomes pregnant during the study will not be discontinued from study treatment.  
Details of the pregnancy should be recorded on the Pregnancy Report form and reported to 
Sponsor or designee within 24 hours of awareness by email (
) or 
facsimile (
) from the time of initial awareness, even if beyond the closure of 
the clinical database.  
The Investigator is also responsible for following the pregnancy every 3 months or until 
delivery or termination and informing the Sponsor about its outcome. Reports where the 
embryo or fetus may have been exposed to the study drug(s), should be followed-up in order 
to collect information on the: 
• outcome of the pregnancy,   


 
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• outcome for both mother and fetus (malformation/anomalies diagnosed since initial 
report) 
• development of the child after birth (developmental assessment, infant illnesses, 
hospitalizations, drug therapies, breastfeeding) 
Healthy newborns should be followed-up at 1 month after birth to confirm no congenital 
anomalies were subsequently detected (if possible). 
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
termination of a pregnancy for medical reasons will be recorded as an AE or an SAE. A 
spontaneous abortion is always considered to be a SAE and will be reported to the Sponsor. 
Elective termination (i.e., without medical reasons) of an uncomplicated pregnancy is 
considered an elective procedure and not an AE; nevertheless, Mylan requests the outcome 
(e.g., elective termination) be reported within 24 hours of awareness and sent as a follow-up 
on the Delivery and Infant Follow-up Form).  
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention 
after the subject has completed the study and considered by the Investigator as at least 
possibly related to the study treatment, must be promptly reported to Sponsor or designee. 
IF THE STUDY CENTER BECOMES AWARE OF A PREGNANCY IN A FEMALE 
PARTNER OF A MALE SUBJECT, STUDY PERSONNEL SHOULD CONTACT 
THEIR CLINICAL RESEARCH ASSOCIATE TO OBTAIN A PARTNER 
PREGNANCY ICF. CONSENT OF THE PREGNANT PARTNER MUST BE 
OBTAINED BEFORE ANY DETAILS OF THE PREGNANCY CAN BE SHARED 
WITH SPONSOR OR ITS DESIGNATED REPRESENTATIVE. IF THE PREGNANT 
PARTNER PROVIDES CONSENT TO HAVE THE PREGNANCY FOLLOWED, 
THE STUDY CENTER SHOULD COLLECT THE INFORMATION SPECIFIED ON 
THE PREGNANCY REPORT FORM AND FORWARD THE COMPLETED FORM 
TO SPONSOR EVERY 3 MONTHS UNTIL THE PREGNANCY OUTCOME HAS 
BEEN OBTAINED.


 
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10 REFERENCE LIST 
1. Global initiative for chronic obstructive lung disease (GOLD). Global strategy for the 
diagnosis, management and prevention of chronic obstructive pulmonary disease. 2019. 
Available at: http://goldcopd.org 
2. Zhu B, Wang Y, Ming J, Chen W, Zhang L. Disease burden of COPD in China: a 
systematic review. Int J Chron Obstruct Pulmon Dis. 2018 Apr 27;13:1353-1364. 
3. Yin P, Wang H, Vos T, Li Y, Liu S, Liu Y, Liu J, Wang L, Naghavi M, Murray CJ, Zhou 
M. A Subnational Analysis of Mortality and Prevalence of COPD in China From 1990 to 
2013: Findings From the Global Burden of Disease Study 2013. Chest. 2016 
Dec;150(6):1269-1280. 
4. YUPELRI® Package Insert. Morgantown, WV: Mylan Specialty L.P; 11-2018 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210598s000lbl.pdf 
5. Wang C, Sun T, Huang Y, Humphries M, Bai L, Li L, Wang Q, Kho P, Firth R, D'Andrea 
P. Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients 
with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study. Int J 
Chron Obstruct Pulmon Dis. 2015 Jan 5;10:57-68. 
6. Bai C, Ichinose M, Lee SH, Lee KH, Jöns O, Bothner U, Zhao Y, Buhl R. Lung function 
and long-term safety of tiotropium/olodaterol in East Asian patients with chronic 
obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2017 Nov 20;12:3329-
3339. 
7. Graham, BL, Steenbruggen I, Miller MR, 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, 200(8): e70-e88.  
8. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012 Dec;40(6):1324-43. 
9. Wise, RA, Acevedo RA, Anzueto AR, et al. Guiding principles for the use of nebulized 
long acting beta2-agonists in patients with COPD: An expert panel consensus. Chronic 
Obstr Pulm Dis. 2016;4:7-20. 
10. Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 
2005 Mar;2(1):111-24. 
11. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. 
Contents, interobserver agreement, and physiologic correlates of two new clinical 
indexes. Chest. 1984 Jun;85(6):751-8. 


 
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11 PATIENT REPORTED MEASURES 
11.1 BDI/TDI 
At Visit 3 (Day 1), Visit 4 (Day 29), Visit 5 (Day 57), Visit 6 (Day 85), and the Early 
Termination Visit, if applicable, the subject’s dyspnea will be assessed using the 
interviewer-administered BDI/TDI. 
This appendix consists of 3 parts: Part I: Instructions for administration of both dyspnea 
indices; Part II: The BDI; Part III: The TDI.  
The content of these Indexes is as published (Mahler et al., 1984 [11]). 
PART I: Instructions for application of dyspnea indexes 
General comments 
The objective of the BDI and TDI is to measure or quantitate the severity of breathlessness 
(shortness of breath) in symptomatic patients. 
The initial questions to the patient should be, “Do you experience shortness of breath?” If the 
patient answers “No,” the interviewer should ask whether any physical activities cause the 
patient to experience breathlessness. If the answer to the question is “Yes,” additional 
questions will be necessary. 
The Dyspnea Indexes were devised so that grading breathlessness could be performed as part 
of obtaining a history from the patient. Specific questions should be asked based on the 
criteria of the various grades for functional impairment, magnitude of task, and magnitude of 
effort that provoke breathlessness. This approach was selected instead of a questionnaire 
answered by the patient in order to allow an interviewer with some medical training and/or 
background to grade breathlessness in a simple and brief encounter. Our past and present 
experience indicates that the grading process can be completed easily within 4-5 minutes of 
conversation with the patient. 
Furthermore, the Dyspnea Indexes were devised so that a variety of medical personnel would 
be able to interview the patient and grade his or her breathlessness. These individuals include 
physicians, nurses, respiratory therapists, cardiopulmonary technicians, as well as others with 
some medical experience. Note however, that it is important that for a given patient, the same 
individual should perform the interviews and complete the BDI and all subsequent TDI 
measurements. 
Specific Comments 
BDI 
1A. Functional Impairment: Activities 
Ask if patient has stopped doing any activities because of breathlessness. If so, ask for 
specific examples (e.g., stopped doing housework or yard work). 
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Ask if the patient has stopped work because of breathlessness. 
For retired individuals, ask if the patient would be able to work at his or her last job (i.e., 
ability to work despite breathlessness). 
Combine the patient’s responses for activities and work in order to select a grade for 
Functional Impairment. 
2. Magnitude of Task 
Ask what types of activities make the patient breathless. 
Give examples based on criteria listed or the different grades and then select grade. 
3. Magnitude of Effort 
Ask how much effort in daily activities makes the patient breathless. 
Give examples based on criteria listed for the different grades and then select grade. 
TDI 
This instrument measures change from the baseline state. It is recommended that the 
interviewer refer to the grades from the BDI as references and for reminding the patient of his 
or her comments before picking a grade from the TDI. 
Change in Functional Impairment 
Ask the patient to recall his or her breathlessness at the first or baseline visit, or you may 
describe this information (from the BDI) to the patient. 
Ask whether there has been any change since the first or baseline visit. Any activities started 
or stopped? Any modifications in job/work activities? 
Change in Magnitude of Task 
Ask the patient to recall his or her breathlessness at the first or baseline visit, or you may 
describe this information (from the BDI) to the patient. 
Ask what activities cause breathlessness now (e.g., walking on a level surface, climbing 
stairs, at rest, bathing, etc.). Ask if this represents any change since the first or baseline visit. 
Change in Magnitude of Effort 
Describe the patient’s previous report of breathlessness relative to effort and need to pause 
while performing activities. 
Ask whether there has been any change since the first or baseline visit. 
PART II: BDI 
Functional Impairment 


 
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_____ Grade 4: No Impairment. Able to carry out usual activities and occupation without 
shortness of breath. 
_____ Grade 3: Slight Impairment. Distinct impairment in at least one activity but no 
activities completely abandoned. Reduction, in activity at work or in usual activities, that 
seems slight or not clearly caused by shortness of breath. 
_____ Grade 2: Moderate Impairment. Patient has changed jobs and/or has abandoned at least 
one usual activity due to shortness of breath. 
_____ Grade 1: Severe Impairment. Patient unable to work or has given up most or all usual 
activities due to shortness of breath. 
_____ Grade 0: Very Severe Impairment. Unable to work and has given up most or all usual 
activities due to shortness of breath. 
_____ W: Amount Uncertain. Patient is impaired due to shortness of breath, but amount 
cannot be specified. Details are not sufficient to allow impairment to be categorized. 
_____ X: Unknown. Information unavailable regarding impairment. 
_____ Y: Impaired for Reasons Other than Shortness of Breath. For example, 
musculoskeletal problem or chest pain. 
Usual activities refer to requirements of daily living, maintenance or upkeep of residence, 
yard work, gardening, shopping, etc. 
Magnitude of Task 
_____ Grade 4: Extraordinary. Becomes short of breath only with extraordinary activity such 
as carrying very heavy loads on the level, lighter loads uphill, or running. No shortness of 
breath with ordinary task. 
_____ Grade 3: Major. Becomes short of breath only with such major activities as walking up 
a steep hill, climbing more than three flights of stairs, or carrying a moderate load on the 
level. 
_____ Grade 2: Moderate. Becomes short of breath with moderate or average tasks such as 
walking up a gradual hill, climbing fewer than three flights of stairs, or carrying a light load 
on the level. 
_____ Grade 1: Light. Becomes short of breath with light activities such as walking on the 
level, washing, or standing. 
_____ Grade 0: No Task. Becomes short of breath at rest while sitting, or lying down. 
_____ W: Amount uncertain. Patient’s ability to perform tasks is impaired due to shortness of 
breath, but amount cannot be specified. Details are not sufficient to allow impairment to be 
specified. Details are not sufficient to allow impairment to be categorized. 
_____ X: Unknown. Information unavailable regarding limitation of magnitude of task. 


 
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_____ Y: Impaired for Reasons Other than Shortness of Breath. For example, 
musculoskeletal problem or chest pain. 
Magnitude of Effort 
_____ Grade 4: Extraordinary. Becomes short of breath only with the greatest imaginable 
effort. No shortness of breath with ordinary effort. 
_____ Grade 3: Major. Becomes short of breath with effort distinctly submaximal, but of 
major proportion. Tasks performed without pause unless the task requires extraordinary effort 
that may be performed with pauses. 
_____ Grade 2: Moderate. Becomes short of breath with moderate effort. Tasks performed 
with occasional pauses and requiring longer to complete than the average person. 
_____ Grade 1: Light. Becomes short of breath with little effort. Tasks performed with little 
effort or more difficult tasks performed with frequent pauses and requiring 50-100% longer 
to complete than the average person might require. 
_____ Grade 0: No effort. Becomes short of breath at rest while sitting, or lying down. 
_____ W: Amount Uncertain. Patient’s exertional ability is impaired due to shortness of 
breath, but amount cannot be specified. Details are not sufficient to allow impairment to be 
categorized. 
_____ X: Unknown. Information unavailable regarding limitation of effort. 
_____ Y: Impaired for Reasons Other than Shortness of Breath. For example, 
musculoskeletal problems or chest pain. 
PART III: TDI 
Change in Functional Impairment 
_____ -3: Major Deterioration. Formerly working and has had to stop working and has 
completely abandoned some of usual activities due to shortness of breath. 
_____ -2: Moderate Deterioration. Formerly working and has had to stop working or has 
completely abandoned some of usual activities due to shortness of breath. 
_____ -1: Minor Deterioration. Has changed to a lighter job and/or has reduced activities in 
number or duration due to shortness of breath. Any deterioration less than preceding 
categories. 
_____ 0: No Change. No change in functional status due to shortness of breath. 
_____ +1: Minor Improvement. Able to return to work at reduced pace or has resumed some 
customary activities with more vigor than previously due to improvement in shortness of 
breath. 
_____ +2: Moderate Improvement. Able to return to work at nearly usual pace and/or able to 
return to most activities with moderate restriction only. 


 
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_____ +3: Major Improvement. Able to return to work at former pace and able to return to 
full activities with only mild restriction due to improvement of shortness of breath. 
_____ Z: Further Impairment of Reasons Other than Shortness of Breath. Patient has stopped 
working, reduced work, or has given up or reduced other activities for other reasons. For 
example, other medical problems, being “laid off” from work, etc. 
Change in Magnitude of Task 
_____ -3: Major Deterioration. Has deteriorated two grades or greater from baseline status. 
_____ -2: Moderate Deterioration. Has deteriorated at least one grade but fewer than two 
grades from baseline status. 
_____ -1: Minor Deterioration. Has deteriorated less than one grade from baseline. Patient 
with distinct deterioration within grade, but has not changed grades. 
_____ 0: No Change. No change from baseline. 
_____ +1: Minor Improvement. Has improved less than one grade from baseline. Patient with 
distinct improvement within grade, but has not changed grades. 
_____ +2: Moderate Improvement. Has improved at least one grade but fewer than two 
grades from baseline. 
_____ +3: Major Improvement. Has improved two grades or greater from baseline. 
_____ Z: Further Impairment for Reasons Other than Shortness of breath. Patient has reduced 
exertional capacity, but not related to shortness of breath. For example, musculoskeletal 
problem or chest pain. 
Change in Magnitude of Effort 
_____ -3: Major Deterioration. Severe decrease in effort from baseline to avoid shortness of 
breath. Activities now take 50-100% longer to complete than required at baseline. 
_____ -2: Moderate Deterioration. Some decrease in effort to avoid shortness of breath, 
although not as great as preceding category. There is greater pausing with some activities. 
_____ -1: Minor Deterioration. Does not require more pauses to avoid shortness of breath, 
but does things with distinctly less effort than previously to avoid breathlessness. 
_____ 0: No Change. No change in effort to avoid shortness of breath. 
_____ +1: Minor Improvement. Able to do things with distinctly greater effort without 
shortness of breath. For example, may be able to carry out tasks somewhat more rapidly than 
previously. 
_____ +2: Moderate Improvement. Able to do things with fewer pauses and distinctly greater 
effort without shortness of breath. Improvement is greater than preceding category, but not of 
major proportion. 


 
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_____ +3: Major Improvement. Able to do things with much greater effort than previously 
with few, if any, pauses. For example, activities may be performed 50-100% more rapidly 
than at baseline. 
_____ Z: Further Impairment for Reasons Other than Shortness of Breath. Patient has 
reduced exertional capacity, but not related to shortness of breath. For example, 
musculoskeletal problem or chest pain. 


 
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11.2 mMRC 
The mMRC dyspnea scale will be completed by the subject at Visit 3 (Day 1).  Subjects will 
circle the grade according to the description that best describes them currently. 
Grade 
Description of Breathlessness 
0 
I only get breathless with strenuous exercise. 
1 
I get short of breath when hurrying on the level or walking up a slight hill. 
2 
I walk slower than people of the same age on the level because of 
breathlessness, or I have to stop for breath when walking on my own pace 
on the level. 
3 
I stop for breath after walking about 100 meters or after a few minutes on 
the level. 
4 
I am too breathless to leave the house or I am breathless when dressing or 
undressing. 
 


 
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11.3 SGRQ 
The SGRQ will be completed by the subject at Visit 3 (Day 1) and Visit 6 (Day 85). 
More information on this questionnaire can be found at: 
http://www.healthstatus.sgul.ac.uk/sgrq 
 
 


 
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12 PROTOCOL AMENDMENT DETAILS 
Global Amendment 1, 15 July 2020 
Reasons for Amendment 
The protocol was amended to address comments from the regulatory agency, the local ethics 
committee of the lead investigator site, and the lead investigator, to provide guidance in case 
of a public health emergency restricting subject and investigator movements, and to update 
safety reporting requirements according to the latest applicable guidances: 
• To add the brand name of the nebulizer and compressor used for study drug 
administration as requested by the regulatory agency. 
• To change the responsibility for recording adverse events from the Principal 
Investigator to the Investigator as requested by the local ethics committee of the lead 
investigator site. 
• To reduce the blood volume for pharmacokinetics from 10 mL per sample to 6 mL 
per sample.  
• To add a physical examination at the Early Termination visit.  
• To document the contingencies to be implemented to enable study continuation in the 
event of a public health emergency limiting the ability of subjects and investigators to 
attend the investigator site (eg, increasing the number of subjects that may be 
randomized, shipment of study drug and other study supplies to the subject, 
performing virtual visits by telephone, etc). 
• To update safety reporting requirements according to the latest relevant guidances. 
Additional amendments have been made in order to correct typographical errors and to 
provide further clarification on aspects of the protocol. 
Sections changed 
Synopsis of protocol (Background and Rationale) 
Changed from: 
The airflow limitation is usually both progressive and associated with an abnormal 
inflammatory response in the airways and the lung to noxious particles or gases (Global 
Initiative for the Treatment of Obstructive Lung Disease [GOLD], 2019 [1]). 
Changed to: 
The airflow limitation is usually both progressive and associated with an abnormal 
inflammatory response in the airways and the lung to noxious particles or gases (Global 
Initiative for Chronic Obstructive Lung Disease [GOLD], 2019 [1]). 


 
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Synopsis of protocol (Methodology and Treatments: Study drug administration) 
Changed from: 
Study drug will be administered using a centrally-provided, standard jet nebulizer and 
compressor via a mouthpiece. 
Changed to: 
Study drug will be administered using a centrally-provided, standard jet nebulizer (PARI LC 
Sprint) and compressor (PARI TurboBOY) via a mouthpiece. 
Synopsis of protocol (Inclusion/Exclusion Criteria: Inclusion Criteria) 
Changed from: 
5. History of at least 10 pack-years of tobacco smoking. Ex-smokers must have stopped 
smoking >6 months prior to Visit 1 
Changed to: 
5. Current smoker or ex-smoker, with a history of at least 10 pack-years of tobacco 
smoking. Ex-smokers must have stopped smoking >6 months prior to Visit 1 
Synopsis of protocol (Inclusion/Exclusion Criteria: Exclusion Criteria) 
Changed from: 
17. Subjects with hepatic impairment. A history of hepatitis B or hepatitis C may be 
permitted at the discretion of the Investigator, provided the subject is asymptomatic 
and liver transaminases (ALT/AST) are ≤1.5 times the upper limit of normal (ULN) at 
Screening. 
Changed to: 
17. Subjects with hepatic impairment. A history of hepatitis B or hepatitis C may be 
permitted at the discretion of the Investigator, provided the subject has no signs of 
hepatic impairment, is asymptomatic, and liver transaminases (ALT/AST) are ≤1.5 
times the upper limit of normal (ULN) at Screening. 
Synopsis of protocol (Statistical Methods: Sample size estimation) 
Changed from: 
To allow for a 20% dropout rate, approximately 320 subjects in total will be randomized. 
Changed to: 
To allow for a 20% dropout rate, approximately 320 subjects in total will be randomized. In 
the event of a public health emergency such as COVID-19, the Sponsor may consider 
increasing enrollment to overcome any additional loss of information for the primary 
endpoint due to the inability of subjects to attend for scheduled clinic visits. The maximum 


 
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number of subjects to be randomized under such circumstances will be limited to 428 (an 
additional 20% increase in enrollment). 
Synopsis of protocol (Statistical Methods: Analysis Populations) 
Changed from: 
• Per Protocol Set (PP): all subjects in the FAS who had no major protocol violation 
that would impact on the endpoints of interest.   
Changed to: 
• Per Protocol Set (PP): all subjects in the FAS who had no major protocol violation 
that would impact significantly on the primary efficacy endpoints.   
Table 1-1: Study Schedule 
New addition: 
Physical examination added to Early Term (ET) visit 
2.2 
Background and Rationale 
Changed from: 
The airflow limitation is usually both progressive and associated with an abnormal 
inflammatory response in the airways and the lung to noxious particles or gases (Global 
Initiative for the Treatment of Obstructive Lung Disease [GOLD], 2019 [1]). 
Changed to: 
The airflow limitation is usually both progressive and associated with an abnormal 
inflammatory response in the airways and the lung to noxious particles or gases (Global 
Initiative for Chronic Obstructive Lung Disease [GOLD], 2019 [1]). 
3.2.1  Secondary Endpoints 
Section number changed from 3.2.1 to 3.2.2 
3.2.1.1  Efficacy 
Section number changed from 3.2.1.1 to 3.2.2.1 
3.2.1.2  Safety 
Section number changed from 3.2.1.2 to 3.2.2.2 
3.2.2 Pharmacokinetic (PK) 
Section number changed from 3.2.2 to 3.2.3 


 
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4.2.1  Inclusion Criteria 
Changed from: 
5. History of at least 10 pack-years of tobacco smoking. Ex-smokers must have stopped 
smoking >6 months prior to Visit 1. 
Changed to: 
5. Current smoker or ex-smoker, with a history of at least 10 pack-years of tobacco 
smoking. Ex-smokers must have stopped smoking >6 months prior to Visit 1. 
4.2.2 Exclusion Criteria 
Changed from: 
17. Subjects with hepatic impairment. A history of hepatitis B or hepatitis C may be 
permitted at the discretion of the Investigator, provided the subject is asymptomatic 
and liver transaminases (ALT/AST) are ≤1.5 times the upper limit of normal (ULN) at 
Screening. 
Changed to: 
17. Subjects with hepatic impairment. A history of hepatitis B or hepatitis C may be 
permitted at the discretion of the Investigator, provided the subject has no signs of 
hepatic impairment, is asymptomatic, and liver transaminases (ALT/AST) are ≤1.5 
times the upper limit of normal (ULN) at Screening. 
5.1.1 Administration of Study Drugs 
Changed from: 
Revefenacin inhalation solution and its matching placebo will be administered using a 
centrally-provided, standard jet nebulizer and compressor via a mouthpiece. 
Changed to: 
Revefenacin inhalation solution and its matching placebo will be administered using a 
centrally-provided, standard jet nebulizer (PARI LC Sprint) and compressor (PARI 
TurboBOY) via a mouthpiece. 
Table 6-1: Blood Volume 
Changed from: 
Sample Type 
Sample Volume (mL) 
Number of Sampling Times 
Total Volume (mL) 
Screening 
Study Period 
Safety Labs 
20 
1 
1 
40 
PK 
10 
0 
9 
90 
TOTAL 
 
 
 
130 
 


 
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Changed to: 
Sample Type 
Sample Volume (mL) 
Number of Sampling Times 
Total Volume (mL) 
Screening 
Study Period 
Safety Labs 
20 
1 
1 
40 
PK 
6 
0 
9 
54 
TOTAL 
 
 
 
94 
 
6.2.5 Early Study Drug Termination (ET) Visit 
New text added: 
• General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland. 
6.4.8.5   General Physical Examination 
Changed from: 
A full general physical examination will consist of an examination of the abdomen, 
cardiovascular system, lungs, lymph nodes, musculoskeletal and neurological systems, skin, 
extremities, head, ears, eyes, nose, and thyroid gland by trained medical personnel at the site. 
Changed to: 
A full general physical examination will consist of an examination of the respiratory, 
cardiovascular, gastrointestinal, musculoskeletal, neurological systems, lymph nodes, skin, 
extremities, head, ears, eyes, nose, and thyroid gland by trained medical personnel at the site 
 
New section added: 
6.6 
Mitigation in the event of a public health emergency 
In the event of any circumstances impacting the ability of enrolled subjects to attend for 
scheduled visits at the investigator site, such as travel restrictions imposed due to COVID-19, 
investigators must notify the Sponsor and make the necessary arrangements to ensure the 
safety of their enrolled subjects. They should also evaluate whether their subjects should 
continue in the clinical trial. Those that have not been randomized yet should be withdrawn 
from the study. 
Where it is possible for randomized subjects to continue, the following operational 
contingencies will be implemented: 
• Study medication, rescue medication, and other study supplies such as diary cards will 
be sent to the subject’s residence to ensure sufficient quantities are available.  
• Virtual visits will be conducted by telephone in place of the scheduled visits, whereby 
the investigator will perform those procedures specified in Section 6.2 that are 


 
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feasible to be performed by telephone, such as questioning on adverse events, 
concomitant medications, and rescue medication use, completion of TDI, etc). 
• Subjects will be reminded to bring (or send) all used and unused study medication, 
rescue medication, and diary cards to the site as soon as they are able after travel 
restrictions have been lifted. 
Protocol deviations arising under such circumstances (eg, missed or delayed visits, 
assessments not performed, etc) will be clearly documented in the CRF and the reasons will 
be collected. 
7 
STATISTICAL ANALYSIS 
Changed from: 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the Sponsor. This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 
Changed to: 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the Sponsor. This will include any plans for summarizing and analyzing data impacted by 
a public health emergency. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition and/or its analysis will 
also be reflected in a protocol amendment. 
7.1 
Sample Size Considerations 
Changed from: 
To allow for an anticipated 20% dropout rate, approximately 320 subjects in total will be 
randomized. 
Changed to: 
To allow for an anticipated 20% dropout rate, approximately 320 subjects in total will be 
randomized. In the event of a public health emergency such as COVID-19, the Sponsor may 
consider increasing enrollment to overcome any additional loss of information for the 
primary endpoint due to the inability of subjects to attend for scheduled clinic visits. The 
maximum number of subjects to be randomized under such circumstances will be limited to 
428 (an additional 20% increase in enrollment). 
7.2.3 Per Protocol Analysis Set 
Changed from: 
The per protocol analysis set (PP) will include all subjects in the FAS who had no major 
protocol violation that would impact on the primary efficacy endpoint. Significant protocol 


 
Protocol REV-3001 
Page 99 of 101 
REV-3001 Final Protocol Version 2.0, 15 JUL 2020 
Confidential 
deviations are defined in Section 8.4 and will be further defined in the SAP. The list of major 
protocol deviations will be finalized prior to database lock and unblinding as part of the final 
blinded data review (BDR). Data will be summarized and analyzed according to the treatment 
a subject actually received at randomization. 
Changed to: 
The per protocol analysis set (PP) will include all subjects in the FAS who had no major 
protocol violation that would impact significantly on the primary efficacy endpoint. The list 
of major protocol deviations will be finalized prior to database lock. All decisions to exclude 
subjects from the PP analysis set will be made prior to unblinding in the final blinded data 
review (BDR) meeting and report. Data will be summarized and analyzed according to the 
treatment a subject actually received at randomization. 
7.3.1 Definition of Primary Endpoints 
New text: 
• If a public health emergency prevents FEV1 data from being measured at site then 
information on the reasons for the missing assessments will be recorded in the CRF. 
7.4 
Secondary Efficacy Endpoints 
Changed from: 
In all the secondary efficacy analyses missing data will not be imputed and will be assumed 
to be missing at random (MAR). Secondary efficacy analyses will be performed using the 
FAS population. 
Changed to: 
In all the secondary efficacy analyses missing data will not be imputed and will be assumed 
to be missing at random (MAR). Secondary efficacy analyses will be performed using the 
FAS population.  If a public health emergency prevents data from being measured or requires 
data to be assessed remotely via a virtual visit, then information on the reasons and the data 
impacted will be recorded in the CRF. 
8.4 
Adherence to Protocol 
Changed from: 
The following protocol deviations are defined as major and would be considered to have an 
impact on the analysis of efficacy data: 
• Subject did not meet efficacy-defined inclusion criteria (e.g., inclusion criteria 2, 3, 4, 
5) 
• Subject did not meet exclusion criteria which may potentially impact the primary 
efficacy endpoint (to be reviewed and assessed on a case-by-case basis) 
• Subject who is not 80-120% compliant with study medication 


 
Protocol REV-3001 
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REV-3001 Final Protocol Version 2.0, 15 JUL 2020 
Confidential 
• Subject received an excluded concomitant treatment or medication (e.g., a 
concomitant LAMA) 
Additional criteria may be specified in the SAP. 
Changed to: 
All protocol deviations will be reviewed in a blinded manner during the course of the study 
and decisions to exclude subjects from statistical analysis sets will be made prior to 
unblinding and the reasons documented. 
9.4 
Collection and Recording of Adverse Events 
Changed from: 
During the Adverse Event Reporting Period, the PI will record all adverse events. 
Changed to: 
During the Adverse Event Reporting Period, the Investigator will record all adverse events. 
9.6.1 Investigator Reporting: Notifying the Study Sponsor 
Changed from: 
The Investigator should provide further information on the as soon as possible, preferably 
within 48 hours of awareness. 
Changed to: 
The Investigator should provide further information on the SAE as soon as possible, 
preferably within 48 hours of awareness 


 
Protocol REV-3001 
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REV-3001 Final Protocol Version 2.0, 15 JUL 2020 
Confidential 
In order to meet the signature requirements of institutions that require a wet signature, Global 
Protocol Amendment 1 (Version 2.0, dated 15 JUL 2020) has been wet-signed: 
 
Authored by: 
Signature/Date: 
 
Clinical Scientist 
 
 
 
Approved by: 
 
 
 Global Clinical Respiratory 
 
 
 
 

SAP_001.pdf: 
 
Mylan Pharma UK Ltd. 
 
 
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Statistical Analysis Plan 
 
 
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                        Page 1 of 49 
 
   
 
Mylan Pharma UK Ltd. 
REV-3001 
A Randomized, Double Blind, Placebo-Controlled, Parallel Group Study of Nebulized 
Revefenacin Inhalation Solution in Chinese Subjects with Moderate to Very Severe 
Chronic Obstructive Pulmonary Disease (COPD) 
 Statistical Analysis Plan 
Version: 2.0  
 Project Number: 
 
 
 
NCT05046795 
Document effective date: 16 Oct 2023


 
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                        Page 2 of 49 
 
SPONSOR SIGNATURE PAGE 
 
 
Approved by:  
Signed and dated electronically on last page  
_______________ 
 
  
 
 
                        Date 
 
 Biostatistics 
 
 
Mylan Pharma UK Ltd. 
 
 
 


 
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                        Page 3 of 49 
 
 
 SIGNATURE PAGE 
Signature(s) below confirm that the Statistical Analysis Plan was developed in accordance with 
 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the 
following:  
 
 
 
Signatory 
Author 
 
Project Role: Biostatistics 
   


 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ..............................................................................................................9 
2 
STUDY OBJECTIVES ......................................................................................................9 
2.1 
Primary Objective .......................................................................................................... 9 
2.2 
Secondary Objectives ..................................................................................................... 9 
3 
INVESTIGATIONAL PLAN ............................................................................................9 
3.1 
Overall Study Design and Plan ...................................................................................... 9 
3.1.1 
Study Design ................................................................................................................ 9 
3.1.2 
Schedule of Activities ................................................................................................ 11 
3.1.2.1 
Screening .................................................................................................................15 
3.1.2.2 
Study Treatment Period ...........................................................................................15 
3.2 
Endpoints ..................................................................................................................... 15 
3.2.1 
Efficacy Variables ..................................................................................................... 15 
3.2.2 
Safety Variables ......................................................................................................... 16 
3.2.3 
Pharmacokinetic Variables ........................................................................................ 16 
4 
STATISTICAL METHODS ............................................................................................16 
4.1 
Data Quality Assurance................................................................................................ 16 
4.2 
Randomization and Unblinding Processes ................................................................... 16 
4.3 
General Presentation Considerations ........................................................................... 17 
4.3.1 
Treatment Arms and Labels ....................................................................................... 17 
4.3.2 
Definitions and Derivations ....................................................................................... 17 
4.3.3 
Analysis Windows ..................................................................................................... 19 
4.3.4 
General Reporting Conventions ................................................................................ 19 
4.3.5 
Data Standards ........................................................................................................... 20 
4.3.6 
Software ..................................................................................................................... 20 
4.4 
Study Subjects .............................................................................................................. 20 
4.4.1 
Disposition of Subjects .............................................................................................. 20 
4.4.2 
Protocol Deviations ................................................................................................... 21 
4.5 
Analysis Sets ................................................................................................................ 21 
4.6 
Demographic and Other Baseline Characteristics........................................................ 22 
4.6.1 
Demographics ............................................................................................................ 22 
4.6.2 
Baseline Smoking, Alcohol and Drug History .......................................................... 22 
4.6.3 
Baseline Spirometry ................................................................................................... 23 
4.6.4 
Baseline COPD Disease-Related Characteristics ...................................................... 23 
4.6.5 
Patient Reported Outcomes (PROs) .......................................................................... 23 
4.7 
Medical History ............................................................................................................ 24 
4.8 
Prior and Concomitant Medication .............................................................................. 24 
4.9 
Treatment Compliance ................................................................................................. 25 
4.10 
Efficacy Evaluation ...................................................................................................... 25 


 
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4.10.1 
Analysis and Data Conventions ................................................................................. 27 
4.10.1.1 Multicenter Studies..................................................................................................27 
4.10.1.2 Adjustments for Covariates .....................................................................................27 
4.10.1.3 Handling Missing Data ............................................................................................27 
4.10.1.4 Multiple Comparisons .............................................................................................29 
4.10.1.5 Examination of Subgroups ......................................................................................29 
4.10.1.6 Interim Analyses......................................................................................................29 
4.10.2 
Primary Efficacy Variable – CBL Trough FEV1 on Day 85 ..................................... 29 
4.10.2.1 Primary Analysis .....................................................................................................30 
4.10.2.2 Primary Endpoint Sensitivity Analysis ...................................................................30 
4.10.2.3 Primary Endpoint Subgroup Analysis .....................................................................31 
4.10.3 
Secondary Efficacy Variables .................................................................................... 31 
4.10.3.1 CBL Trough FEV1 and FVC ...................................................................................31 
4.10.3.2 CBL to Peak FEV1 (0-2h) on Days 1 and 85 ..........................................................31 
4.10.3.3 CBL in Weighted Mean FEV1 (0-2h) on Days 1 and 85.........................................32 
4.10.3.4 CBL SGRQ Total Score on Day 85 ........................................................................32 
4.10.3.5 Number (%) of SGRQ Responders (Total Score ≥4 Units) on Day 85 .................33 
4.10.3.6 TDI Focal Score on Days 29, 57 and 85 .................................................................33 
4.10.3.7 Number (%) of TDI Responders (Focal Score ≥1) on Days 29, 57 and 85...........33 
4.10.3.8 Average Count of Salbutamol Puffs Per Day (Days 1-85) .....................................34 
4.10.3.9 Percentage of Salbutamol Rescue Free 24h Periods (Days 1-85) ...........................34 
4.11 
Safety Evaluation ......................................................................................................... 35 
4.11.1 
Extent of Exposure  ................................................................................................... 35 
4.11.2 
Adverse Events .......................................................................................................... 36 
4.11.3 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ................. 37 
4.11.4 
Clinical Laboratory Evaluation .................................................................................. 37 
4.11.5 
Vital Signs, Physical Findings and Other Observations Related to Safety ............... 37 
4.12 
Determination of Sample Size ..................................................................................... 38 
4.13 
Changes in the Conduct of the Study or Planned Analysis .......................................... 39 
5 
REFERENCES .................................................................................................................40 
6 
Appendix ..........................................................................................................................41 
6.1 
Sample SAS code for MMRM ..................................................................................... 41 
6.2 
Sample SAS code for ANCOVA ................................................................................. 41 
6.3 
Tipping-Point Multiple Imputation Method ................................................................ 41 
6.4 
Sample SAS code for Logistic Regression Model ....................................................... 43 
6.5 
Sample SAS code for MMRM logistic model: ............................................................ 43 
6.6 
BDI/TDI Component Score and Focal Score............................................................... 43 
6.7 
SGRQ Component Score and Total Score ................................................................... 44 
6.7.1 
Item Weights .............................................................................................................. 44 
6.7.2 
Scoring Algorithm ..................................................................................................... 46 
6.7.3 
Handling Missed Items .............................................................................................. 47 
6.8 
Best Test Result (BTR)  ............................................................................................... 48 
 


 
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REVISION HISTORY 
 
 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
14 Dec 21 
New document 
1.1 
21 Jan 22 
Corrected the items weight in Appendix 6.7.1 for question 
14. 
Added description in Section 4.11.5 to describe algorithms 
of handling multiple ECG measurements performed at the 
same visit: the average of results used for continues 
variables, the worst result used for categorical variables. 
 
05 Feb 22 
Corrected table number in Section 4.10 
 
15 Feb 22 
Section 4.3.3, for the rule handling multiple records, 
Added “earliest” to illustrate that if there are multiple 
records are nearest, the earliest one will be used. 
 
27 Mar 22 
Removed duplicate ‘X’ in Appendix 6.6 
 
10 May 22 
Corrected the ‘contrast’ statement to ‘estimate’ statement 
for the model based average generation in Section 4.10.3.8 
and 4.10.3.9 
Corrected table number in Appendix 6.3 
 
13 Jul 22 
Corrected spelling in Section 3.2.1 
 
10 Oct 23 
Section 4.10.1.5, Examination of Subgroups 
Added subgroup analysis by ethnicity:  
North East Asian verses South East Asian 
2.0 
16 Oct 23 
Finalized for final analysis 
 
 
 


 
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LIST OF ABBREVIATIONS 
 
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
AECOPD 
Acute exacerbation of COPD 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BDR 
Blinded Data Review 
BDI/TDI 
Baseline Dyspnea Index/Transition Dyspnea Index 
CBL 
Change from Baseline 
CI 
Confidence Interval 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case report form 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EoT 
End of Treatment 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GOLD 
Global Initiative for Obstructive Lung Disease 
HR 
Heart rate 
ICS 
Inhaled Corticosteroid 
IVRS/IWRS 
Interactive Voice Response System/ Interactive Web 
Response System 
LABA 
Long Acting Beta2 Agonist 
LAMA 
Long Acting Muscarinic Antagonist 
LOCF 
Last observation carried forward 
LS mean 
Least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAR 
Missing at random 
MI 
Missing imputation 
mMRC 
modified Medical Research Council 
MMRM 
Mixed model repeated measures 
MNAR 
Missing not at random 
OR 
Odds Ratio 
PP 
Per protocol analysis set 
PR 
Pulse Rate 
PRO 
Patient Reported Outcome 
PT 
Preferred term 
QTc 
QT corrected 
QTcB 
QT corrected (Bazett’s correction) 
QTcF 
QT corrected (Fridericia’s correction) 
PR  
Pulse rate 
SAE 
Serious adverse event 


 
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Abbreviation / Acronym 
Definition / Expansion 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SGRQ 
Saint George’s Respiratory Questionnaire 
SOC 
System organ class 
SS 
Safety analysis set 
TEAE 
Treatment-emergent adverse events 
WHODRUG 
World Health Organization Drug Dictionary 
 


 
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                        Page 9 of 49 
 
1 
INTRODUCTION 
This initial statistical analysis plan (SAP) describes the planned summaries and statistical 
analyses of data for the clinical study REV-3001.   
The overall objectives of this study are to confirm the efficacy and safety of revefenacin 
inhalation solution (175mcg once daily) for the treatment of Chinese subjects with moderate to 
very severe Chronic Obstructive Pulmonary Disease (COPD).  
The analyses described in this SAP are based upon the following study documents: 
• Study Protocol, Version 2.0 (July 15, 2020) 
• electronic Case Report Form (eCRF), Version 4.0 (January 19, 2022) 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to confirm the efficacy of revefenacin inhalation solution 
175 mcg administered once daily via nebulization for 12 weeks compared to placebo in a 
population of Chinese subjects with moderate to very severe COPD. 
Note: “Revefenacin inhalation solution 175 mcg” will be referred to as “revefenacin 175 mcg” 
or “revefenacin” in subsequent sections of the SAP. 
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To confirm the safety of revefenacin 175 mcg administered once daily via nebulization 
for 12 weeks compared to placebo in a population of Chinese subjects with moderate 
to very severe COPD. 
• 
To characterize the efficacy of revefenacin 175 mcg on patient reported outcomes 
compared to placebo in a population of Chinese subjects with moderate to very severe 
COPD. 
• 
To collect pharmacokinetics (PK) samples for population PK analysis of revefenacin 
175 mcg in a population of Chinese subjects with moderate to very severe COPD. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
3.1.1 Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group, multi-center study in 
Chinese subjects with moderate to very severe COPD treated for 12 weeks.  
The study population consists of  


 
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• Males and females of Chinese ethnicity, at least 40 years of age; 
• A clinical diagnosis for at least 6 months prior to screening of COPD according to 
Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines; 
• Subjects capable of performing reproducible spirometry maneuvers and with a post-
ipratropium Forced Expiratory Volume in 1 second/Forced Vital Capacity 
(FEV1/FVC) ratio <0.7 at Screening Visit 2; 
• Subjects with moderate to very severe COPD with a post-ipratropium FEV1 <80% of 
predicted normal FEV1 and an absolute FEV1 > 700 mL at Screening Visit 2; 
• Current smoker or ex-smoker, with a history of at least 10 pack-years of tobacco 
smoking. Ex-smokers must have stopped smoking >6 months prior to Visit 1.  
Subjects who are currently using stable doses of long-acting beta-adrenoceptor agonist 
(LABA)-containing products (LABA monotherapy or inhaled corticosteroid (ICS)/LABA 
fixed dose combination) will be permitted to enroll into the study and continue to take their 
LABA or ICS/LABA COPD medication. All other prohibited COPD medications will be 
required to be stopped. Salbutamol as rescue medication is permitted. 
Eligible subjects will be centrally randomized to receive revefenacin 175 mcg or placebo in a 
1:1 ratio, stratified by concomitant LABA use (Yes, No) and reversibility to ipratropium (Yes, 
No).   
Each subject will receive treatment once daily in the morning for a total of 12 weeks. The two 
treatments will both be administered as a 3 mL solution by inhalation using a jet nebulizer.  
Subjects with a concomitant LABA will dose the LABA or ICS/LABA prior to nebulization. 
The schematic of the study design is shown in Figure 1. 


 
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Figure 1: Study Diagram 
 
 
3.1.2 Schedule of Activities 
The schedule of study procedures is shown in Table 1. 


 
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Table 1: Schedule of Activities 
VISIT 
1 
(Screen 1) 
2 
(Screen 2)1  
3 
Randomization 
4 
5 
6 
(EoT) 
Early term 
(ET) 
Follow up 
(Telephone) 
NOMINAL DAY 
(ALLOWABLE WINDOW) 
-14 
(-30 to -4) 
-7  
(-10 to -4) 
1 
29 
(22-36) 
57 
(50-64) 
85 
(78-92) 
 
7-14 days 
after V6/ET 
NOMINAL WEEK 
-2 
-1 
0 
4 
8 
12 
 
 
Written informed consent 
x 
 
 
 
 
 
 
 
IVRS/IWRS transaction 
x 
 
x 
x 
x 
x 
x 
x 
Demography and medical history (incl. 
COPD, smoking, and exacerbation history) 
x 
 
 
 
 
 
 
 
Review concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
 
 
x 
x 
 
Chest X-ray (if not done in past 12 months) 
x 
 
 
 
 
 
 
 
Height and weight 
x 
 
 
 
 
 
 
 
Vital Signs (supine or semi-recumbent blood 
pressure, pulse rate) 
x 
 
x2 
 
 
x2 
x 
 
12-lead ECG (supine or semi-recumbent) 
x 
 
x2 
 
 
x2 
x 
 
Spirometry (FEV1, FVC) 
pre-bronchodilator 
 
x 
 
 
 
 
 
 
Spirometry (FEV1, FVC) 45 min 
post-ipratropium (500 mcg nebulized) 
 
x 
 
 
 
 
 
 
Laboratory Safety – Blood and Urinalysis 
x 
 
 
 
 
x 
x 
 
Pregnancy Test 
x 
 
x 
x 
x 
x 
x 
 
Dispense Rescue Medication (salbutamol 
pMDI) 
x 
 
x 
x 
x 
 
 
 
Dispense Daily Diary 
x 
 
x 
x 
x 
 
 
 


 
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VISIT 
1 
(Screen 1) 
2 
(Screen 2)1  
3 
Randomization 
4 
5 
6 
(EoT) 
Early term 
(ET) 
Follow up 
(Telephone) 
NOMINAL DAY 
(ALLOWABLE WINDOW) 
-14 
(-30 to -4) 
-7  
(-10 to -4) 
1 
29 
(22-36) 
57 
(50-64) 
85 
(78-92) 
 
7-14 days 
after V6/ET 
NOMINAL WEEK 
-2 
-1 
0 
4 
8 
12 
 
 
Record Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
Medication Training 
x3 
 
x 
 
 
 
 
 
Pre-dose Spirometry (FEV1, FVC), -45 and 
-15 min pre-dose. 
 
 
x 
x 
x 
x 
x 
 
Complete BDI/TDI4 
 
 
x 
x 
x 
x 
x 
 
Complete SGRQ 
 
 
x 
 
 
x 
x 
 
Complete mMRC 
 
 
x 
 
 
 
 
 
Randomization 
 
 
x 
 
 
 
 
 
Administer Study Medication in Clinic 
 
 
x 
x 
x 
x 
 
 
Dispense Outpatient Study Medication 
 
 
x 
x 
x 
 
 
 
Post-dose Spirometry (FEV1, FVC), 5, 15, 
and 30 minutes, and 1, 1.5, and 2h 
 
 
x 
 
 
x 
 
 
PK sampling 
 
 
x5 
x5 
x5 
x5 
 
 
Record Rescue Medication and Study Drug 
in Diary, Review at Clinic Visits 
 
x 
x 
x 
x 
x 
x 
 
 
1. 
Visit 2 (Screening Visit 2) can be conducted on the same day as Visit 1 (Screening Visit 1) if the subject does not require washout of other COPD 
medications (e.g., 14 days for LAMAs) prior to the ipratropium reversibility test at Visit 2. 
2. 
Pre-dose and at approximately 1 hour post-dose. 
3. 
Train subject on rescue medication use. 
4. 
BDI is performed at V3 and TDI is performed at V4, V5, and V6. 


 
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5.   PK sampling will be performed pre-dose (within 30 minutes of dosing) and at any time 1 – 30 minutes post-dose at Visit 3, 4, 5, and 6. At Visit 6, an 
additional PK sample will be collected during the sampling interval of 1 – 4 hours post-dose


 
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3.1.2.1 Screening 
Screening will involve one or two visits, depending on whether a washout period is required 
for prohibited COPD medications. The assessments for Visit 1 and Visit 2 may be conducted 
on the same day if a subject does not require washout of COPD medications prior to the 
spirometry assessments. Hence, initial screening can occur up to 30 days prior to randomization 
with key spirometry assessments occurring ~4-10 days prior to randomization. 
Prior to the ipratropium reversibility testing during screening, short acting bronchodilators 
must be withheld for ≥6 hours.  
A subject may be re-screened, however, the subject would need to be reconsented and would 
be assigned a new Subject ID via IWRS. 
3.1.2.2 Study Treatment Period 
Eligible subjects will be randomized on Day 1 (Visit 3) to double-blind treatment and enter a 
12-week placebo-controlled study period where efficacy and safety are planned to be assessed
in clinic at Visit 4 (Day 29), Visit 5 (Day 57) and Visit 6 (Day 85).
The first dose of study treatment will be administered on the morning of Day 1/Visit 3 at the 
study site. Both the start and end times of the administration of study treatment will be captured. 
Subsequent doses will be self-administered at home by the subject except on days with a 
scheduled visit to the study site. They will be advised to administer the study drug every 
morning at approximately the same time within the window of 6 am and 11 am. The time of 
administration will be recorded by the subjects in their diary. 
Spirometry testing will be performed 45 minutes and 15 minutes prior to dosing of study drug 
at Visits 3-6, and post-dose at 5, 15, 30 minutes and 1, 1.5 and 2 hours after completion of 
nebulized dose of study drug at V3 and V6 only. 
Salbutamol as a rescue medication is permitted but must be withheld for ≥6 hours before the 
first spirometry performed at each study visit and whilst serial spirometry is performed to 2 
hours post-dose on Day 1 and Day 85. Use of salbutamol as a rescue medication will be 
documented in a medication diary and recorded in the eCRF. 
Unless consent is withdrawn, subjects who prematurely terminate study drug will have an early 
termination (ET) visit scheduled as soon as possible after their last dose of study drug. 
3.2 
Endpoints 
3.2.1 Efficacy Variables 
In the following section, the efficacy endpoints have been defined more precisely than they 
were in the protocol.  Therefore, definitions may differ slightly from the protocol.  For example, 
“Change from baseline” is included in the primary endpoint definition. 
•
Primary endpoint
−
Change from baseline (CBL) Trough FEV1 on Day 85
•
Secondary endpoint


 
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− CBL to Peak FEV1 (0-2h) on Day 1 
− Number (%) of St. George’s Respiratory Questionnaire (SGRQ) responders (total 
score ≥4 units) on Day 85 
− Transition Dyspnea Index (TDI) focal score on Day 85 
− Average count of salbutamol puffs per day (Days 1-85) 
− Percentage of salbutamol rescue free 24h periods (Days 1-85) 
− CBL Trough FEV1 on Days 29 and 57 
− TDI focal score on Days 29 and 57 
− CBL in Weighted Mean FEV1 (0-2h) on Days 1 and 85 
− CBL to Peak FEV1 (0-2h) on Day 85 
− CBL Trough FVC on Days 29, 57 and 85 
− CBL SGRQ total score on Day 85 
− Number (%) of TDI responders (focal score ≥1) on Days 29, 57 and 85 
3.2.2 Safety Variables 
− Adverse Events (AEs) 
− Acute Exacerbation of COPD (AECOPD) 
− Laboratory Tests  
− Vital Signs (blood pressure and pulse rate) 
− 12-lead ECG  
3.2.3 Pharmacokinetic Variables 
Pharmacokinetic (PK) data for Population PK analyses will be collected.  The plans for the 
analysis and reporting of this data are outside the scope of this SAP and will be separately 
reported. 
PK sampling will be performed pre-dose (within 30 minutes of dosing) and at any time 1 – 30 
minutes post-dose at Visit 3, 4, 5, and 6. At Visit 6, an additional PK sample will be collected 
during the sampling interval of 1 – 4 hours post-dose. 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked 
for consistency, integrity and in accordance with standard 
 procedures. 
4.2 
Randomization and Unblinding Processes 
Assignment of Subject Identification number (SID), randomization number and study drug, 
as well as site drug inventory control will be managed by an automated Interactive Web 
Response system (IWRS). A manual containing complete instructions for Web access and 
use will be provided to each site prior to study start. At their first clinic visit, the IWRS will 
assign a SID. Each SID will be unique and serve as the primary subject identifier throughout 


 
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all phases of the study. The SID must appear on all CRF pages, source documents, laboratory 
data, central spirometry, ECG, diary data, and PRO data. Subjects qualifying to enter the drug 
treatment phase, will be assigned an additional “randomization number” by the IWRS at 
randomization. Subjects will be allocated to treatment within blocks for the given allocation 
ratio.  
At Visit 3 (Day 1 of dosing), eligible subjects will be randomized to receive revefenacin 
175mg or matching placebo in a 1:1 ratio through the IWRS. The randomization will be 
stratified according to the subject’s concomitant LABA use (Yes, No) and reversibility to 
ipratropium (Yes, No).  
Emergency subject unblinding will be managed by an automated IWRS. A manual containing 
complete instructions for Web or telephone access and use will be provided to each site prior 
to study start.  
Subjects may be allowed to continue on the study drug after emergency unblinding if the 
subject does not meet the criteria for study drug termination and/or withdrawal from the study 
or were accidentally unblinded not due to the reason of safety. These subjects will be 
considered as protocol deviations and excluded from the relevant analysis populations. 
4.3 
General Presentation Considerations 
4.3.1 Treatment Arms and Labels 
In tables, figures and listings, the following treatment labels or abbreviations will be used, 
depending on the column space available: 
− Revefenacin 175 mcg; Placebo 
− REV 175 mcg; Placebo 
4.3.2 Definitions and Derivations 
Baseline Assessments 
Unless otherwise specified in Section 4.6, baseline is defined as the last non-missing 
observation before the first dose of study drug. Both date and time will be included in the 
comparison for the determination of baseline. For assessments that are required to be done on 
the date of first dose and pre-dose, but the time of the assessment is not collected, the last non-
missing observation on the date of first dose will be considered as baseline assessment. 
Reversibility 
Reversibility to ipratropium is defined as post-bronchodilator FEV1 change of ≥12% and ≥200 
mL relative to the pre-bronchodilator FEV1.  Reversibility (Yes, No) is captured directly in the 
CRF as part of the randomization information.     
GOLD Categories 
GOLD 2019 Severity of Airflow Limitation Categories (GOLD 1-4) and GOLD 2019 
categories (GOLD A-D) are defined in Table 2 and Table 3 below.   
 


 
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GOLD 1-4 will be derived from the percent predicted FEV1 (%) collected at screening Visit 2.  
The modified Medical Research Council Dyspnea Scale (mMRC) captures the description of 
breathlessness on a 0-4 scale and will be collected in the CRF and reported.  GOLD A-D will 
be as collected on the CRF at screening as part of COPD History. 
 
Table 2: GOLD Severity of Airflow Limitation Categories 
GOLD airflow category 
Severity 
FEV1 threshold 
GOLD 1 
Mild 
≥ 80% predicted 
GOLD 2 
Moderate 
≥ 50%, <80% predicted 
GOLD 3 
Severe 
≥ 30%, < 50% predicted 
GOLD 4 
Very severe 
< 30% predicted 
 
Table 3: GOLD 2019 Categories 
Moderate or Severe 
Exacerbation History 
Assessment of Symptoms / Risk of Exacerbations 
≥2 or ≥1 leading to hospital 
admission 
C 
D 
0 or 1 (not leading to 
hospital admission) 
A 
B 
mMRC 0-1 
mMRC ≥2 
Symptoms 
 
COPD Duration (years) 
COPD duration is calculated as (date of informed consent – date of first diagnosis of COPD + 
1) ÷ 365.25.  
In case of missing or partial diagnosis date, the imputation rules below will be applied: 
− If day is missing and the month and year are available, the diagnosis date is imputed as 
the mid day of the month (eg 15th ).  
− If day and month are missing and only a year is available, the diagnosis date is imputed 
as the mid day of the year (eg 1st July).  
− If both month and year are missing, no imputation will be done. 
The number of years smoked 
As per the CRF completion guidelines, years of smoking is derived from only the YEAR 
component of a date.  For ex-smoker, calculated as year stopped smoking – year started 
smoking; for current smoker, calculated as year of informed consent – year started smoking. 
Study Day 
When study day is used, the following algorithm will be used: 
• study day = date of assessment – date of first dose of study medication + 1, if the date 
of the assessment is on or after the date of first dose; 


 
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• study day = date of assessment – date of first dose of study medication, if the date of 
the assessment is prior to the date of first dose. 
4.3.3 Analysis Windows 
The summary tables will only include the assessments at scheduled visits, except the 
spirometry measurements. Unscheduled assessments will be included in the listings. 
Unscheduled spirometry measurements with study medication taken on the same day will be 
mapped to corresponding visit and timepoint according to Table 4 and Table 5. Unscheduled 
spirometry measurements with no study medication taken on the same day will not be mapped. 
Spirometry measurements at an early termination visit will be mapped to the schedule visit 
according to Table 4. 
If multiple visits fall within a window, the earliest visit with acceptable spirometry data nearest 
to the scheduled day will be included in the analysis. 
Table 4: Analysis Windows (Days) 
Visit (Day) in 
Protocol 
Analysis Visit 
Target Study Day 
Visit Window  
Visit 3 (1) 
Day 1 (Baseline) 
1 
1 
Visit 4 (29±7) 
Day 29 
29 
2≤ Study Day ≤ 43 
Visit 5 (57±7) 
Day 57 
57 
44 ≤ Study Day ≤ 71 
Visit 6 (85±7) 
Day 85 
85 
72 ≤ Study Day  
 
Table 5: Analysis Windows (Timepoint) 
Analysis Timepoint 
Time Window 
-45 Min 
Timepoint < -30 Min 
-15 Min 
-30 Min ≤ Timepoint < 0 Min 
5 Min 
0 Min < Timepoint ≤ 10 Min 
15 Min 
10 Min < Timepoint ≤ 22 Min 
30 Min 
22 Min < Timepoint ≤ 45 Min 
1 H 
45 Min < Timepoint ≤ 75 Min 
1 H 30 Min 
75 Min < Timepoint ≤ 1H 45 Min  
2 H 
1H 45 Min < Timepoint 
4.3.4 General Reporting Conventions 
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, 
minimum, maximum and number of observations (n), unless otherwise stated. The minimum 
and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database.  The mean and median will be reported to one more decimal place 
than the raw data recorded in the database. The standard deviation will be reported to two 
more decimal places than the raw data recorded in the database. In general, the maximum 
number of decimal places reported shall be four for any summary statistic. 


 
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Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), and percentages. Any planned collapsing of categories will be 
detailed in the SAP text and the data displays. Percentages will be presented to one decimal 
place. Percentages will not be presented for zero counts. Percentages will be calculated using 
the number of subjects in the analysis set (N) as the denominator.  
Descriptive statistics for the 12-week study period will be presented by treatment group and 
visit, as applicable. 
All statistical tests will be two-sided and will be conducted at the 5% significance level, 
unless otherwise specified. 
P-values greater than or equal to 0.0001, in general, will be presented to four decimal places. 
P-values less than 0.0001 will be presented as “<0.0001”. 
4.3.5 Data Standards 
The study data and analysis datasets will conform to the Clinical Data Interchange Standards 
Consortium (CDISC) standards including therapeutic area data standards for COPD.  General 
standards include the Study Data Tabulation Model (SDTM) and Analysis Data Model 
(ADAM) and associated implementation guides.  
4.3.6 Software 
All report outputs will be produced using SAS® version 9.4 for UNIX in a secure and 
validated environment in accordance with 
 procedures.  
4.4 
Study Subjects 
4.4.1 Disposition of Subjects 
The total number of subjects screened and the reasons for failing screening will be reported. 
Subject disposition information will be summarized for all randomized subjects by treatment 
group and overall.  The summaries will include the following information: 
− Subjects randomized 
− Subjects randomized and Treated with Study Drug 
− Subjects completed study treatment 
− Subjects early terminated from study treatment (including by reason for early 
termination of study treatment, and if the reason for early termination of study 
treatment is related to public health emergency) 
− Subjects completed study 
− Subjects discontinuing from study (including by reason for discontinuation of study, 
and if the reason is related to public health emergency) 
Data related to disposition (including the date of informed consent signed, the dates of first 
dose and last dose of study drug, primary reason for subject discontinuation of study 
treatment, the date of last visit, study completion status) will be listed.  


 
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Visit status (performed on time, out of window, missed), type of visit (on site, telephone), the 
impact of public health emergency to the visit will be summarized and listed.  
4.4.2 Protocol Deviations 
Major analysis protocol deviations that could potentially affect the efficacy conclusions of the 
study will be identified prior to database lock. Major analysis protocol deviations may 
include, but are not limited to: 
− Randomized subjects who did not satisfy inclusion criteria 
− Randomized subjects who did not satisfy exclusion criteria 
− Subjects whose randomized and actual treatments differ at any time point 
− Subjects who received an excluded concomitant treatment or medication 
− Subjects who are not 80-120% compliant with study medication 
− Subjects who received rescue medication within 6 hours prior to spirometry testing 
Subjects with major analysis protocol deviations will be identified before the database lock 
and provided in a listing of subjects excluded from per-protocol (PP) efficacy analyses. In 
addition, a listing of all major deviations will be provided whether they impact the analysis or 
not.  All decisions to exclude subjects from the PP analysis set will be made prior to 
unblinding in the final blinded data review (BDR) meeting and report. 
The PD summaries will include the following information, using Randomized Set: 
− the number and percentage of subjects with a major PD by treatment group and 
overall and by type of deviation 
− the number and percentage of subjects with a major PD leading to exclusion from the 
PP by treatment group and overall, and by type of major deviation leading to 
exclusion 
− the number and percentage of subjects with a major PD related to COVID-19 by 
treatment group and by type of deviation 
4.5 
Analysis Sets 
The Screened Set consists of all subjects who sign the study informed consent. Screen 
failures are subjects who sign the study informed consent but fail to meet study requirements 
during screening or prior to randomization. 
The Randomized Set consists of all subjects that are randomized to a treatment on Day 1. 
Subjects in this population will be reported according to the treatment they were randomized 
to, regardless of any dosing error. The Randomized Set will be predominantly used for 
listings of data. 
The Safety Analysis Set (SS) is defined as all subjects who receive at least one dose of study 
drug. Subjects in this population will be summarized according to the actual treatment they 
received. The treatment received will only be different from the randomized treatment if the 
subject took the wrong dose or study drug for > 50% of the entire double-blind treatment 
period. All safety analyses will be performed using the SS. 


 
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The Full Analysis Set (FAS) consists of all randomized subjects who received at least one 
dose of study drug and have at least one recorded post-baseline efficacy assessment. Subjects 
in this set will be analyzed and summarized according to their assigned treatment and strata at 
randomization. The FAS will be used for all efficacy endpoints. 
The Per-Protocol (PP) Analysis Set consists of subjects in the FAS who had no major 
protocol violation that would impact significantly on the primary endpoint. The list of major 
protocol deviations will be finalized prior to database lock. All decisions to exclude subjects 
from the PP analysis set will be made prior to unblinding in the final blinded data review 
(BDR) meeting and report. Data will be summarized and analyzed according to the treatment 
a subject actually received and strata they actually belong to. The PP analysis set will be 
used for the primary endpoint only. 
Analysis Set information will be summarized for all randomized subjects by treatment group 
and overall. The table will include rows for the number (%) of subjects randomized, 
randomized but not treated, Safety Set (SS), Full Analysis Set (FAS), Per-Protocol (PP) 
Analysis Set. 
4.6 
Demographic and Other Baseline Characteristics 
4.6.1 Demographics 
Baseline demographics are collected at the Screening Visit 1.  Descriptive statistics will be 
prepared for the demographics by treatment group and overall using the Full Analysis Set 
(FAS) population. If the Per-Protocol (PP) Analysis Set is different to FAS, a separate 
demographics table will be included for this population as well. If the Randomized Set is 
different to FAS, demographics will also be reported for Randomized Set. The following 
information will be included in the summary: 
− Age in years  
− Age group (<65 years, ≥65 years) 
− Sex (Male, Female) 
− Race (Asian - Chinese, Asian - Not Chinese) 
− Height 
− Weight 
− Body mass index (kg/m2) 
Demographic data will be listed using the Randomized Set. 
4.6.2 Baseline Smoking, Alcohol and Drug History 
Baseline smoking, alcohol and drug history is collected at Screening Visit 1 and will be 
summarized by treatment group and overall (FAS population). The endpoints will include: 
− Smoking status (Current, Former) 
− The number of years smoked (derived) 
− The number of pack-years smoked (as collected) 
− Subject with history of alcohol abuse within the past 5 years (Yes, No) 
− Subject with history of illegal or recreational drug within the past 5 years (Yes, No) 


 
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Smoking, alcohol and drug history will be listed using the Randomized Set. 
4.6.3 Baseline Spirometry 
Baseline spirometry data will be summarized by treatment group and overall (FAS 
population).   Data will be collected at Screening Visit 2 for the following endpoints: 
− pre- and post-bronchodilator FEV1 (L);  
− reversibility to ipratropium (Yes, No as collected); 
− predicted normal FEV1 (L) and percent predicted FEV1 (%) 
− pre- and post-bronchodilator FVC (L);  
− pre- and post-bronchodilator FEV1/FVC ratios.  
All baseline spirometry data will be listed using the Randomized set.  If the Randomized Set 
is different to FAS, demographics will also be reported for the FAS. 
Data for baseline FEV1 and FVC assessments used in the derivation of the primary and 
secondary endpoints will be collected at -45 and -15 minutes prior to dosing of study 
medication on Day 1 (Randomization Visit 3).    
Baseline is defined as the average of the -45 and -15 minute measurements.  If either of the 
two pre-dose measures is missing, the baseline will be set to the value of the remaining non-
missing measure. If both pre-dose values are missing then the baseline will be set to missing. 
This baseline spirometry data will be presented in tables with the primary and secondary 
spirometry endpoints. 
4.6.4 Baseline COPD Disease-Related Characteristics 
Data on COPD disease-related characteristics will be summarized (FAS population) by 
treatment group and overall. Presentations will include:  
− COPD Duration in years (derived); 
− Number of COPD Exacerbations in past 12 months; 
− Number of COPD Exacerbations requiring hospitalization in previous 12 months 
− Concomitant ICS use (Yes, No as collected); 
− Concomitant LABA use (Yes, No as collected); 
− Concomitant ICS/LABA use (Yes, No), derived from Concomitant ICS use and 
Concomitant LABA use; 
− GOLD Airflow Categories 1-4 (derived); 
− GOLD Categories A-D (as collected). 
COPD Disease-Related Characteristics will be listed using the Randomized Set. 
4.6.5 Patient Reported Outcomes (PROs) 
Baseline data for PROs will be collected pre-dose on Day 1 (Randomization Visit 3) and 
summarized and listed to include: 


 
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− Proportion of subjects with baseline mMRC ≥2 (n, %) 
− Baseline SGRQ component scores and total score 
− BDI component scores and focal score 
4.7 
Medical History 
The medical history events except for COPD history will be coded by System Organ Class 
(SOC) and Preferred Term (PT) using the Medical Dictionary for Regulatory Activities 
(MedDRA). The MedDRA version used for reporting the study will be described in the 
relevant table and listing footnotes. The number and percentage of subjects in each SOC and 
PT will be summarized based on FAS by treatment group and overall.  
Each subject’s medical history will be listed by SOC and PT for the Randomized Set. 
4.8 
Prior and Concomitant Medication 
Data on prior and concomitant medication will be summarized based on the Safety Set by 
treatment group and overall.   
Any medication taken prior to the first dose of double-blind study treatment will be 
documented as prior medication.  Any medication taken after the first dose of study drug will 
be documented as a concomitant medication.  
For partial/missing start/end date of the medication, the imputation rule below will be applied 
before the summary: 
• Start date: 
o If Year and Month exists but Day is missing, impute the Day as 1; 
o If Year exists but Month and Day are missing, impute the Month and Day as 
January 1st; 
o If Year is missing or the entire date is missing, do not impute but assume the 
medication started after the first dose and to be considered as a concomitant 
medication. 
• End date: 
o If Year and Month exists but Day is missing, impute the Day as the last day of the 
month; 
o If Year exists but Month and Day are missing, impute the Month and Day as 
December 31st; 
o If Year is missing or the entire date is missing, and the status is not ongoing, do 
not impute but assume the medication ended after the first dose and to be 
considered as a concomitant medication. 
Both prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHODRUG). The WHODRUG version used for reporting the study will 
be described in the relevant table and listing footnotes.  
The Anatomical Therapeutic Chemical (ATC) level 1 term and PTs for prior medications will 
be summarized by treatment group and overall. Concomitant Medications for COPD (e.g. 


 
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concomitant bronchodilators, concomitant corticosteroids) will be identified and summarized 
in a similar manner in separate tables.  
Each subject’s prior and concomitant mediation will be listed by ATC level 1 and PT for the 
Randomized Set. 
4.9 
Treatment Compliance 
Subjects will take nebulized study drug (3mL sealed plastic vial) once daily during the 12- 
week double-blind placebo-controlled treatment period.  
The number of dispensed, used, unused and lost vials will be counted and recorded as part of 
the drug accountability. The primary assessment of compliance will be based on the vial 
counts.  
Compliance is based on the count of number of study drug vials taken as recorded on the 
Drug Accountability eCRF page. Treatment compliance in percent will be calculated as: 
Compliance (%) = (Number of vials taken / Number of expected vials) × 100 
where Number of expected vials = 1 × study drug exposure 
Details of study drug exposure are described in Section 4.11.1. 
The compliance will be classified (e.g. <80%, 80%-120%, >120%). If the compliance is 
outside of 80%-120%, a subject is considered non-compliant. The number and percentage of 
subjects in the above categories will be summarized based on Safety Set by treatment group 
and overall. 
4.10 Efficacy Evaluation 
For all efficacy analyses the Full Analysis Set (FAS) will be used unless otherwise specified.  
Efficacy will be assessed based on spirometry, subject-reported outcomes (SGRQ, BDI/TDI) 
and rescue medication usage.  A summary of the efficacy variables used in the statistical 
analyses is given in Table 6. 
Table 6: Summary of Efficacy Endpoints 
Efficacy Variable 
Analysis 
Set 
Objective 
Visit Day 
Data Type 
Analysis 
Model 
Spirometry 
CBL 
Trough 
FEV1 
FAS 
Primary 
Day 85 
Continuous 
MMRM 
(MAR) 
CBL 
Trough 
FEV1 
PP 
Supportive 
Day 85 
Continuous 
MMRM 
(MAR) 


 
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CBL 
Trough 
FEV1 
FAS 
Sensitivity 
Day 85 
Continuous 
ANCOVA 
(LOCF) 
CBL 
Trough 
FEV1 
FAS 
Sensitivity 
Day 85 
Continuous 
MMRM 
(Tipping 
Point MI) 
CBL 
Trough 
FEV1 
FAS 
Sensitivity 
Day 85 
Continuous 
MMRM 
(Subgroup 
Analyses) 
CBL 
Trough 
FEV1 
FAS 
Secondary 
Day 29, 57 
Continuous 
MMRM 
CBL 
Trough 
FVC  
FAS 
Secondary 
Day 29, 57 
and 85 
Continuous 
MMRM 
CBL Peak 
FEV1 0-2h 
FAS 
Secondary 
Day 1 
Continuous 
ANCOVA 
CBL Peak 
FEV1 0-2h 
FAS 
Secondary 
Day 85 
Continuous 
ANCOVA 
CBL 
Weighted 
Mean 
FEV1 0-2h 
FAS 
Secondary 
Day 1, 85 
Continuous 
ANCOVA 
SGRQ 
SGRQ 
responder 
FAS 
Secondary 
Day 85 
Binary 
Logistic 
Regression 
CBL 
SGRQ 
total score 
FAS 
Secondary 
Day 85 
Continuous 
ANCOVA 
CBL 
SGRQ 
component 
scores (3) 
FAS 
Other 
Day 85 
Continuous 
ANCOVA 
BDI/TDI 
TDI focal 
score 
FAS 
Secondary 
Day 85 
Continuous 
MMRM 
TDI focal 
score 
FAS 
Secondary 
Day 29, 57 
Continuous 
MMRM 
TDI 
component 
scores (3) 
FAS 
Other 
Day 29, 57, 
85 
Continuous 
MMRM 


 
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TDI 
responder 
FAS 
Secondary 
Day 29, 57, 
85 
Binary 
MMRM 
logistic 
model 
Rescue 
Medication 
Usage 
Average 
Count of 
Salbutamol 
Puffs Per 
Day 
FAS 
Secondary 
Month 1,2,3 
and Overall 
(Day1-85) 
Continuous 
MMRM 
Percentage 
of monthly 
salbutamol 
rescue free 
24-hour 
periods 
FAS 
Secondary 
Month 1,2,3 
and Overall 
(Day1-85) 
Continuous 
MMRM 
 
4.10.1 Analysis and Data Conventions 
4.10.1.1 Multicenter Studies 
This multicenter study utilizes a central randomization stratified by concomitant LABA use 
and reversibility to ipratropium. All centers will be in China. Center will not be included as a 
fixed effect covariate in the statistical analyses due to the small numbers at each site.  
4.10.1.2 Adjustments for Covariates 
As the randomization is stratified by concomitant LABA use (Yes, No) and reversibility to 
ipratropium (Yes, No), these will be included as covariates in all analysis models.   
Other factors to be included in the statistical models for efficacy as fixed-effect class terms 
are smoking status (current smoker, ex-smoker); age category (<65, ≥65); Sex (Male, 
Female).  
A covariate for baseline FEV1 will be included in all FEV1 analysis models. Full details of 
the covariates used in each statistical model are outlined by endpoint in Sections 4.10.2 and 
4.10.3. 
4.10.1.3 Handling Missing Data 
Missing or unavailable data will be queried by Data Management. Data that remains missing 
will be identified in summaries and analyses of that data item.   
For any subject who withdraws prematurely from study treatment, all available data up to the 
time of discontinuation of study treatment will be considered for inclusion in the analyses. An 
Early Termination visit will occur as soon as possible after their last dose of study drug.   


 
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The following graphical representations are examples of plots that may be used to explore the 
data and help to explain any dropout patterns. The actual plots used will be dependent on the 
final dropout rate/pattern for the study:  
− Kaplan-Meier plots of time to discontinuation of study treatment split by treatment 
group.   
− Kaplan-Meier plots of time to discontinuation of study treatment split by treatment 
group and reason for discontinuation (e.g. Lack of Efficacy, Adverse Events). 
− Kaplan-Meier plots of time to discontinuation of study treatment split by treatment 
group and relationship to public health emergency (related, not related). 
Imputing Missing Data 
Missing data will only be imputed in the sensitivity analyses for the primary analysis of the 
primary endpoint (change from baseline trough FEV1 at Day 85). Otherwise, missing data 
will not be imputed. 
Missing data in the primary efficacy analysis is not directly imputed and is assumed to be 
missing at random (MAR). In sensitivity analyses the following approaches will be used for 
imputing missing data: 
Non-monotone missing data (e.g. subjects have missing values for intermediate visits, but 
have available data at subsequent visits) will be assumed to be MAR. For monotone missing 
data the following missing data imputation methods will be used to assess the robustness of 
the conclusions to the MAR assumption since it may be biased and attribute treatment benefit 
to withdrawals even though they are no longer taking the study treatment: 
• Last-Observation-Carried Forward (LOCF) single imputation method 
• Two-dimensional Tipping-point multiple imputation method  
LOCF Analysis 
Missing trough FEV1 data on Day 85 will be imputed using LOCF single imputation method. 
Changes from baseline on Day 85 that include the LOCF imputed values will then be 
analyzed using an Analysis of Covariance (ANCOVA) model. 
Tipping-Point Analysis 
A Tipping-point analysis will be performed. Monotone missing data at all missing scheduled 
visits will have the value of a shift parameter (e.g. 50 mL) subtracted from the revefenacin 
treatment arm (worsening results) and added to the placebo arm (improving results) for 
change from baseline trough FEV1. The imputed datasets will then be analyzed using the 
MMRM primary analysis method and an estimate for the difference between the two 
treatments and associated 95% CI and p-value calculated. This method will be applied 
iteratively where at each iteration, monotone missing values are adjusted with a larger shift 
parameter than at the previous iteration (e.g. by 50 mL from 0 mL to -500 mL on revefenacin 
and 0 mL to +500 mL on placebo). This process continues until the difference between 
revefenacin and placebo is no longer statistically significant. This point is called the tipping 
point. The plausibility of the value of the shift parameters needed to change a statistically 
significant result (p<=0.05) to not significant (p>0.05) will be clinically assessed. 


 
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Details of tipping-point multiple imputation method are described can be found in Appendix. 
4.10.1.4 Multiple Comparisons 
No adjustment for multiple comparisons is required.   
4.10.1.5 Examination of Subgroups 
The intent of the subgroup analyses is to demonstrate the consistency of response of a 
treatment across a wide range of the intended treated population. The subgroups of interest 
are defined below: 
− Baseline Smoking status [current smoker, former smoker] 
− Age group [<65 years, ≥65 years] 
− Sex [Male, Female] 
− Reversibility to ipratropium [yes, no] 
− Concomitant ICS use [yes, no] 
− Concomitant LABA use [yes, no] 
− Baseline post bronchodilator % predicted FEV1[50% to <80%, 30% to <50%, <30%] 
(GOLD airflow categories [2, 3, 4]) 
− GOLD categories [A, B, C, D] 
− Ethnicity [North East Asian, South East Asian], provided by external data vendor of 
spirometry assessments. 
North East Asian defined as China north of the Huaihe River and Qinling Mountains. 
South East Asian defined as China south of the Huaihe River and Qinling Mountains. 
4.10.1.6 Interim Analyses 
Not Applicable 
4.10.2 Primary Efficacy Variable – CBL Trough FEV1 on Day 85 
The primary efficacy variable is the change from baseline trough FEV1 on Day 85.   
 
− Baseline FEV1 is defined as the average of the -45 and -15 minute measurements prior 
to dosing of study medication on Day 1 (Visit 3). 
− Trough FEV1 measurements will be the pre-dose FEV1 measures on Days 29, 57 and 
85 calculated as the average of the -45 and -15 minute measurements prior to dosing 
of study medication. 
− If a public health emergency prevents FEV1 data from being measured at site then 
information on the reasons for the missing assessments will be recorded in the CRF 
If either of the two pre-dose FEV1 measures is missing, the baseline/trough will be set to the 
value of the remaining non-missing measure. If both pre-dose values are missing then the 
baseline/trough will be set to missing. 


 
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If no baseline can be calculated for the subject, then the change from baseline values will be 
recorded as missing. Change in FEV1 is calculated as the Trough FEV1 – Baseline FEV1 
difference such that a positive change indicates improvement. 
The absolute values and the change from baseline trough FEV1 will be summarized by 
treatment group and visit using summary statistics for continuous data. 
4.10.2.1 Primary Analysis 
The analysis of the primary endpoint will be based on a mixed model repeated measures 
(MMRM) analysis including changes from baseline trough FEV1 measurements on Days 29, 
57 and 85 as the dependent variable. The model will include independent fixed-effect terms 
for concomitant LABA use, reversibility to ipratropium, smoking status, age, sex, treatment 
and baseline FEV1 as a covariate. A time effect (visit) and its interaction terms with treatment 
and baseline FEV1 will be included. The variance estimation will be based on an unstructured 
covariance matrix. The Kenward-Roger method for approximating the denominator degrees 
of freedom will be used.   
The primary analysis of the primary efficacy endpoint will be based on the Full Analysis Set 
(FAS) population and includes all randomized subjects who received at least one dose of 
study drug and have at least one recorded post-baseline FEV1 assessment. Available data for 
a subject prior to discontinuing study treatment will be used in the MMRM analysis. Missing 
data is assumed as missing at random (MAR). The robustness of the conclusions to this 
assumption will be assessed with a missing data sensitivity analysis. 
The difference between revefenacin and placebo on Day 85 will be estimated from the least 
squares means (LS means) along with the 95% confidence interval (CI) and associated 2-
sided p-values. As a supportive analysis, the primary efficacy analysis will be performed 
using the Per-Protocol (PP) Analysis Set.  
4.10.2.2 Primary Endpoint Sensitivity Analysis 
Sensitivity analyses using missing data imputation methods are included to assess the 
robustness of the primary estimate with regard to missing data.  
Multiple Imputation (MI) Tipping Point Analysis 
A sensitivity analysis using a two-dimensional tipping point imputation method will be 
applied to the MMRM analysis (FAS population) to assess the robustness of the conclusions 
to the assumption that missing data is MAR. In the tipping point analysis a succession of 
delta adjustments via multiple imputation methods will be used to impute the missing 
revefenacin and placebo trough FEV1 values at each timepoint.  The tipping point is denoted 
as the mean trough FEV1 value that would have to be imputed to overturn a statistically 
significant result.  Clinical judgement will be applied to the plausibility of the tipping point.  
The detail of this imputation method and example SAS code is given in Appendix.   
Single Imputation Last-Observation-Carried-Forward (LOCF) Approach 
The LOCF method described in Section 4.10.1.3 will be used for subjects with missing 
trough FEV1 data on Day 85. Change from baseline trough FEV1 at Day 85 will be analyzed 


 
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using an analysis of covariance (ANCOVA) using the FAS population. The model will 
include treatment, and concomitant LABA use, bronchodilator reversibility to ipratropium, 
smoking status, age, sex, baseline FEV1 as covariates.   
Least squares means for Day 85 will be derived for both treatment groups. The difference 
between revefenacin and placebo on Day 85 will be estimated from the LS means along with 
the 95% CI and associated 2-sided p-values. 
4.10.2.3 Primary Endpoint Subgroup Analysis 
An assessment of whether the effect of treatment on the primary endpoint is modified by each 
Subgroup of Interest (see Section 4.10.1.5) will be made by fitting separate MMRM models, 
identical to the model described for the primary analysis, but including additional terms for 
the subgroup and treatment by subgroup interaction.   
Based on this MMRM model, LS means and standard errors for treatment within subgroup 
and LS means and two-sided 95% CIs for treatment differences within subgroup will be 
provided.  
LS mean differences between groups (calculated as Revefenacin – placebo) and associated CI 
will also be presented by Forest Plot for each subgroup and categories within the subgroup.  
The number of subjects in each treatment group and subgroup will be reviewed. Subgroups 
may need to be regrouped or excluded from analyses where insufficient numbers exist. The 
reasons why subgroup analyses are not performed will be documented.   
4.10.3 Secondary Efficacy Variables 
In all the secondary efficacy analyses the FAS population will be used and missing data will 
not be imputed and will be assumed to be missing at random (MAR) unless otherwise stated. 
If a public health emergency prevents data from being measured or requires data to be 
assessed remotely via a virtual visit, then information on the reasons and the data impacted 
will be recorded in the CRF. 
4.10.3.1 CBL Trough FEV1 and FVC 
The changes from baseline trough FEV1 on Days 29 and 57 will be estimated from the 
MMRM analysis used for the primary analysis of the primary endpoint. 
The changes from baseline trough FVC on Days 29, 57 and 85 will be analyzed using the 
same MMRM analysis described for the primary analysis of the primary endpoint.  The 
baseline FEV1 covariate will be replaced with the baseline trough FVC recorded on Day 1.   
4.10.3.2 CBL to Peak FEV1 (0-2h) on Days 1 and 85 
Lung function assessments will be made after study treatments (5, 15, and 30 minutes, and 1, 
1.5, and 2 hours) on Day 1 and Day 85. Peak FEV1 is defined as the highest post-dose FEV1 
value within 2 hours after the dosing on Day 1.  
Peak FEV1 on Day 1 and Day 85 will be summarized by treatment group for the actual value 
and for the change from baseline on Day 1.  


 
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An ANCOVA model will be used to assess the difference between treatment groups for the 
change from baseline to Peak FEV1 after the first dose on Day 1.  The ANCOVA model will 
include treatment, and concomitant LABA use, reversibility to ipratropium, smoking status, 
age, sex, baseline FEV1 as covariates.   
The difference between revefenacin and placebo on Day 1 will be estimated from the LS 
means along with the 95% CI and associated 2-sided p-values. 
A separate analysis will be performed for Peak FEV1 on Day 85 using the same ANCOVA 
model. 
4.10.3.3 CBL in Weighted Mean FEV1 (0-2h) on Days 1 and 85 
The area under the curve (AUC) [0 to 2] hours will be calculated using the trapezoidal rule, 
including observed data points from the pre-dose (0 hour) through to the 2 hour observation.  
For all observations the nominal time of the observation should be used.  For the calculation 
of AUC, the first (0 hour), last (2 hour) and at least one time point between first and last must 
be available.  Otherwise, the AUC is set to missing. The Baseline FEV1 on Day 1 and Trough 
FEV1 on Day 85 will be used as the 0 hour data point to calculate the AUC for Day 1 and 
Day 85, respectively. 
The weighted mean (WM) FEV1 is derived from dividing AUC by the total time (nominally 2 
hours). 
An ANCOVA model will be used to assess the difference between treatment groups for 
change from baseline in WM FEV1 after the first dose on Day 1.  The ANCOVA model will 
include treatment, and concomitant LABA use, reversibility to ipratropium, smoking status, 
age, sex, baseline FEV1 as covariates.   
The difference between revefenacin and placebo on Day 1 will be estimated from the 
LSmeans along with the 95% CI and associated 2-sided p-values. 
A separate analysis will be performed for WM FEV1 on Day 85. 
4.10.3.4 CBL SGRQ Total Score on Day 85 
The SGRQ total score and 3 component scores, including symptoms, activity, and impacts, 
will be derived.  Baseline SGRQ endpoints will be those recorded on Day 1 (Visit 3). The 
baseline and Day 85 absolute values and the change from baseline in SGRQ total score and 3 
component scores will be summarized by treatment group (continuous data).    
An ANCOVA model will be used to assess the difference between treatment groups for 
change from baseline SGRQ total score on Day 85.  The ANCOVA model will include 
treatment,  and concomitant LABA use, reversibility to ipratropium, smoking status, age, sex, 
baseline SGRQ total score as covariates.  For subjects who discontinue study treatment, the 
data from the SGRQ completed at the Early Termination (ET) visit will be carried forward in 
the analyses. 
The difference between revefenacin and placebo on Day 85 will be estimated from the 
LSmeans along with the 95% CI and associated 2-sided p-values. 


 
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The three SGRQ components will be similarly analyzed. 
4.10.3.5 Number (%) of SGRQ Responders (Total Score ≥4 Units) on Day 85 
A decrease from baseline of 4 units in SGRQ total score is considered clinically meaningful 
and will be defined as a responder.    
The number and percentage of responders on Day 85 in each treatment group will be 
summarized. A comparison between revefenacin and placebo will be evaluated with the odds 
ratio (OR) and corresponding 95% confidence interval from a logistic regression model. The 
model will include fixed-effect terms for concomitant LABA use, reversibility to 
ipratropium, smoking status, age, sex, treatment and baseline SGRQ total score as a 
covariate. 
For subjects who discontinue study treatment, the SGRQ completed at the Early Termination 
(ET) visit will be carried forward and used to derive a responder. 
4.10.3.6 TDI Focal Score on Days 29, 57 and 85 
The BDI and TDI focal scores and associated components will be listed and summarized by 
treatment and visit using summary statistics.  Baseline BDI scores will be recorded on Day 1 
(Visit 3). The TDI questionnaire represents changes from baseline and will be recorded on 
Days 29, 57 and 85.  
The BDI/TDI scores include three components: functional impairment, magnitude of task, 
and magnitude of effort. For BDI scores, each domain can be rated from Grade 0 (very 
severe) to 4 (no impairment). For TDI scores, each domain can be rated from Grade -3 (major 
deterioration) to + 3 (major improvement). The focal score is the sum of the three 
components (ie BDI ranges from 0 to 12 and TDI ranges from -9 to +9). 
The TDI focal score will be analyzed using the same MMRM analysis described for the 
primary analysis of the primary endpoint.  The baseline FEV1 covariate will be replaced with 
the BDI focal score.  Estimates for TDI on Days 29, 57 and 85 will be derived from the 
model. 
The difference between revefenacin and placebo on Days 29, 57 and 85 will be estimated 
from the LSmeans along with the 95% CI and associated 2-sided p-values. 
The three TDI components will be analyzed in a similar way. 
Details of BDI/TDI are further described in Section 6.6. 
4.10.3.7 Number (%) of TDI Responders (Focal Score ≥1) on Days 29, 57 and 85 
A TDI focal score of 1 unit is considered clinically meaningful and will be defined as a 
responder.  
The number and percentage of responders on Days 29, 57 and 85 in each treatment group will 
be summarized. A comparison between revefenacin and placebo will be evaluated with the 
odds ratio (OR) and corresponding 95% confidence interval from a logistic regression model 


 
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including the proportion of responders at each visit (Days 29, 57 and 85) as the dependent 
variable. The MMRM logistic (binomial distribution with logit link function) model will 
include the same independent fixed-effect terms as for the primary analysis of the primary 
endpoint.  The baseline FEV1 covariate will be replaced with the BDI focal score as a 
covariate.  Estimates for the proportion of TDI responders on Days 29, 57 and 85 will be 
derived from the model.   
4.10.3.8 Average Count of Salbutamol Puffs Per Day (Days 1-85) 
Use of salbutamol as a rescue medication will be documented in a medication diary and 
recorded in the eCRF.   Rescue medication use should be recorded as the number of doses per 
day, where each puff of salbutamol is one dose. 
The average count of rescue salbutamol puffs per day will be calculated for each monthly 
interval by dividing the total salbutamol puff counts for each of the 3 monthly intervals by the 
total number of days on study for that month.  
Average count of rescue salbutamol puffs per day = Total salbutamol puff counts / 
Number of non-missing days during each defined interval  
where the “number of non-missing days” is the actual number of days in the interval whilst 
receiving study treatment. 
If a subject withdraws from study treatment early, only the number of days on treatment in 
the interval will be included in the count of non-missing days and rescue medication 
information collected after withdrawal will not be included in the calculations.  
The baseline average count of rescue salbutamol puffs per day will be calculated using the 
last 7 daily entries recorded within 14 days prior to randomization on Day 1. 
The average count of salbutamol puffs per day will be analyzed using the same MMRM 
analysis described for the primary analysis of the primary endpoint with the time variable 
Month (1, 2, 3) replacing Visit.    
The average count of salbutamol puffs per day for the study (Days 1-85) will be estimated 
from the model-derived average of each of the 3 months using an appropriate estimate 
statement as well as the LS mean differences, 95% CI and associated 2-sided p-values.  
Estimates for each one month period (Months 1, 2 and 3) will also be reported. 
4.10.3.9 Percentage of Salbutamol Rescue Free 24h Periods (Days 1-85) 
A 24h rescue-free period is defined as a day without a “yes” for rescue use per the daily 
diary.   
The percentage of salbutamol rescue free 24h periods will be calculated for each monthly 
interval by dividing the number of 24h rescue-free periods for each of the 3 monthly intervals 
by the total number of days on study for that month. 


 
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Percentage of salbutamol rescue free 24h periods = Number of 24h rescue-free 
periods / Number of non-missing days, and multiplying by 100 during each defined 
interval, 
where the “number of non-missing days” is the actual number of days in the interval whilst 
receiving study treatment. 
If a subject withdraws from study treatment early, only the number of days on treatment in 
the interval will be included in the count of non-missing days and rescue medication 
information collected after withdrawal will not be included in the calculations.  
The baseline percentage of salbutamol rescue free 24h periods will be calculated using the 
last 7 daily entries recorded within 14 days prior to randomization on Day 1. 
The percentage of salbutamol rescue free 24h periods will be analyzed using the same 
MMRM analysis described for the primary analysis of the primary endpoint with the time 
variable Month (1, 2, 3) replacing Visit.    
The average percentage of salbutamol rescue free 24h periods for the study (Days 1-85) will 
be estimated from the model-derived average of each of the 3 months using an appropriate 
estimate statement as well as the LSmean differences, 95% CI and associated 2-sided p-
values. 
Estimates for each one month period (Months 1, 2 and 3) will also be reported. 
4.11 Safety Evaluation 
Safety analyses include extent of exposure, adverse event (AE), laboratory test, vital signs, 
electrocardiogram (ECG) and physical examination. 
Safety endpoints will be summarized using the Safety Analysis Set (SS) population.  All 
safety analyses will be presented by treatment group. 
There are no planned statistical analyses for the comparison of treatments for the safety 
endpoints. 
4.11.1 Extent of Exposure  
Descriptive summaries (mean, SD, median, min, max) will be presented for the number of 
vials taken and the study drug exposure by treatment group (Safety Set).   
Study drug exposure will be calculated as the number of days from first to last dose date of 
study drug for the treatment period. 
Study drug exposure (Days) = Date of last dose – Date of first dose + 1 
For subjects who early withdraw, and for whom the last dose date from the End of Treatment 
eCRF page is unknown, the date of last available in-clinic dosing, date of withdrawal, and/or 
dosing recorded via the diary will be used, whichever is later. 
All data for study drug exposure will be listed. 


 
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4.11.2 Adverse Events 
All AEs that occur after the first dose of double-blind study medication to 30 days after the 
last dose of study medication will be considered to be treatment-emergent adverse events 
(TEAEs).  
Where dates are missing or partially missing, adverse events will be assumed to be treatment-
emergent, unless there is clear evidence (through comparison of partial dates) to suggest that 
the adverse event started prior to the first dose of study medication or more than 30 days after 
the last dose of study medication.   
The MedDRA will be used to code the primary SOC and the PT of the AEs. The MedDRA 
version used for reporting the study will be described in relevant table and listing footnotes. 
There are three categories of AE severity: Mild, Moderate and Severe. For adverse events 
with missing intensity, they are counted in the most conservative way as Severe in the 
summary by intensity.  
There are five categories of AE Relationship to study treatment: Definite, Probable, Possible, 
Unlikely, Unrelated/Not Related. An adverse event is considered related to the study 
treatment if the relationship to the study treatment is considered “Definite”, “Probably 
Related”, “Probable” or ‘Possible’. 
All AEs and all TEAEs will be listed by subject.   
All AE tables will be restricted to treatment-emergent AEs unless otherwise specified.  Each 
subject will be counted only once within each PT or SOC. If a subject experiences more than 
one AE within a PT or SOC, only the AE with the strongest relationship or the worst severity, 
as appropriate, will be included in the summaries of relationship and severity. AEs with 
missing classifications regarding relationship to study treatment will be considered as related 
to study drug. 
TEAEs will be sorted in descending order of frequency (total column) by SOC and by PT 
within each SOC, unless otherwise stated, alphabetical order will be used for same frequency 
of SOC or PT.  
An overall summary of TEAEs for both the subjects with at least one AE and the total 
number of AEs in following categories are planned to be displayed: any TEAE, any serious 
TEAE, TEAE by relationship (related, not related), TEAE by severity, TEAE leading to 
treatment discontinuation, and any TEAEs related to a public health emergency. 
The following summaries of the total number of TEAEs and the number and percentage of 
subjects with at least one TEAE will be provided.  These will also be presented by primary 
SOC and PT for each treatment group: 
− All TEAEs by SOC and PT 
− All TEAEs by PT 
− TEAEs occurring in more than 1% of study population by SOC and PT  
− All TEAEs by SOC, PT and Severity 
− Moderate to severe TEAEs by SOC and PT 


 
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− Drug-related TEAEs by SOC and PT 
− Drug-related TEAEs by SOC, PT and Severity 
− Drug-related moderate to severe TEAEs by SOC and PT 
− Public health emergency related TEAEs by SOC and PT 
AECOPD events as defined in the protocol will be captured as AEs with a Preferred Term of 
“COPD”. AECOPD data will be summarized for All Exacerbations; Moderate to Severe 
Exacerbations; and Severe Exacerbations.   
Antimuscarinic TEAEs are of interest as a common event in the LAMA drug class. The 
preferred terms for TEAEs considered antimuscarinic are constipation, dry mouth, dysuria, 
worsening of urinary retention, and worsening of narrow-angle glaucoma. The incidence of 
these events in this study will be presented. 
4.11.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
The following summaries of the total number of TEAEs and the number and percentage of 
subjects with at least one TEAE will be provided.  These will also be presented by primary 
SOC and PT for each treatment group: 
− All serious TEAEs by SOC and PT 
− Drug-related serious TEAEs by SOC and PT 
− TEAEs leading to drug discontinuation 
− Serious TEAEs leading to drug discontinuation 
− TEAEs leading to drug interruption 
− TEAEs leading to death 
4.11.4 Clinical Laboratory Evaluation 
Clinical laboratory tests will be performed at times defined in the study schedule.  Any 
clinically significant changes in laboratory safety data should be recorded as an AE.  
Hematology, chemistry and urinalysis will be collected. Laboratory data will be summarized 
in terms of observed values and changes from baseline and will be tabulated at each 
scheduled time point by treatment group and overall. 
Hematology, chemistry and urinalysis data will be presented in tables as changes from 
baseline relative to normal ranges (e.g. shifts from normal to abnormal). 
All hematology, serum chemistry and urinalysis data will be listed with values flagged if 
outside of the normal range.  
4.11.5 Vital Signs, Physical Findings and Other Observations Related to Safety 
Vital Signs 
Supine or semi-recumbent systolic blood pressure (SBP), diastolic blood pressure (DBP) and 
pulse rate (PR) will be measured at screening and pre-dose and 1 hour post-dose on Day 1 
and 85. 


 
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SBP, DBP and pulse rate will be listed and descriptively summarized by treatment group and 
visit. Change from baseline values will be similarly summarized.  
All data related to vital signs will be listed. 
Physical Findings 
Physical Examination, including body system of respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological system, lymph node, skin, extremities, head, ears, eyes, nose, 
thyroid gland, will be measured at screening and Day 85. Clinically significant conditions at 
Screening will be reported in the Medical History. If conditions have worsened since 
randomization, changes should be captured as AE/SAEs as appropriate.  
Screening measurements will be listed and summarized by treatment group and visit. Shift 
from baseline results will be similarly summarized. 
All data related to physical examination will be listed. 
Electrocardiogram 
Twelve-lead ECG measurements will be measured from a single recording at screening and 
pre-dose and at 1 hour post-dose on Day 1 and 85. 
Baseline and change from baseline for QT, QTcF, HR, QRS, RR and PR will be summarized 
using descriptive statistics by treatment group and visit.   
For QTcF a classification of absolute values and increases from baseline will be performed. 
The number of subjects with maximum absolute QTcF <450 msec, 450 msec ≤QTcF 
<480 msec, 480 msec ≤QTcF <500 msec and QTcF values ≥500 msec will be tabulated by 
treatment and visit. The number of subjects with maximum increase from baseline QTcF 
<30 msec, 30 msec ≤QTcF <60 msec and QTcF ≥60 msec will be tabulated by treatment and 
visit. 
when multiple assessments of ECG taken at a post-baseline timepoint, for the continues 
variables, the average of results at the same timepoint will be used, for the categorical 
variables, the worst ECG finding at that timepoint will be used. 
All recorded values for the ECG parameters will be listed by subject.  A separate listing of 
subjects with values of QTcF ≥500 msec or an increase ≥60 msec will be provided, as 
necessary. 
4.12 Determination of Sample Size 
The objective of this study is to confirm the efficacy of 12 weeks treatment with revefenacin 
175 mcg compared with placebo administered once-daily in subjects with moderate to very 
severe COPD.  The primary endpoint is change from baseline trough FEV1 at Day 85.  The 
comparison of interest for the primary analysis is revefenacin 175 mcg versus placebo. 
For each test on each efficacy endpoint, the null hypothesis is that there is no difference 
between the treatment groups. 


 
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H0:  μrev – μpbo = 0 
The alternative hypothesis is that there is a difference. 
H1:  μrev – μpbo ≠ 0 
The estimate for the difference in mean change from baseline trough FEV1 at Day 85 and the 
common standard deviation are based on the sample size assumptions for the revefenacin US 
pivotal studies (0126 and 0127) in a Western population and the GLOW7 study - a similarly 
designed study in a predominantly Chinese population (Wang et al., 2015). 
A sample size of 256 evaluable subjects (128:128; a 1:1 ratio of revefenacin to placebo) is 
required to provide at least 90% power to detect a difference between revefenacin and 
placebo of 100 mL in the analysis of the change from baseline trough FEV1 at Day 85 
assuming a standard deviation of 245 mL and a two-sided 5% significance level. 
To allow for a 20% dropout rate, approximately 320 subjects in total will be randomized. In 
the event of a public health emergency such as COVID-19, the Sponsor may consider 
increasing enrollment to overcome any additional loss of information for the primary 
endpoint due to the inability of subjects to attend for scheduled clinic visits. The maximum 
number of subjects to be randomized under such circumstances will be limited to 428 (an 
additional 20% increase in enrollment). 
4.13 Changes in the Conduct of the Study or Planned Analysis 
A final SAP (version 1.0) will be available after the clinical protocol is approved and a Case 
Report Form (CRF) is available, but before the first dry run or blinded data review is 
performed. 
The finalization of the SAP (version 2.0) will be completed prior to the database lock. Any 
modifications to the planned analyses after that time will be documented within the Clinical 
Study Report (CSR). 
The below clarifications to the wordings of the secondary efficacy variables used in protocol 
(version 2.0):  
Wordings used in Protocol 
Wordings used in SAP 
Rational 
Peak FEV1 (0-2h) on Day 1 
CBL to Peak FEV1 (0-2h) on 
Day 85 
to reflect the estimates for 
the analyses 
SGRQ responders (total 
score 4 units) on Day 85 
Number (%) of SGRQ 
responders (total score 4 
units) on Day 85 
to reflect the estimates for 
the analyses 
BDI/TDI on Day 85 
TDI on Day 85 
BDI is measured only on 
Day 1 
Trough FEV1 on Days 29 
and 57 
CBL Trough FEV1 on Days 
29 and 57 
to reflect the estimates for 
the analyses 
BDI/TDI on Days 29 and 57 
TDI on Days 29 and 57 
BDI is measured only on 
Day 1 


 
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Weighted Mean FEV1 (0-2h) 
on Day 1 and Day 85 
CBL in Weighted Mean FEV1 
(0-2h) on Day 1 and Day 85 
to reflect the estimates for 
the analyses 
Trough FVC on Days 29, 57 
and 85 
CBL Trough FVC on Days 
29, 57, and 85 
to reflect the estimates for 
the analyses 
TDI responders (focal score 
1) on Days 29, 57 and 85 
Number (%) of TDI 
responders (focal score ≥1) on 
Days 29, 57 and 85 
to reflect the estimates for 
the analyses 
 
5 
REFERENCES 
[1] Global initiative for chronic obstructive lung disease (GOLD). Global strategy for the  
diagnosis, management and prevention of chronic obstructive pulmonary disease. 2019. 
Available at: http://goldcopd.org 
[2] Jones Paul W, Forde Y. St George’s Repiratory Questionnaire Manual. 2009 June, Version 
2.3. 
 
 


 
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6 
Appendix 
6.1 
Sample SAS code for MMRM 
6.2 
Sample SAS code for ANCOVA 
6.3 
Tipping-Point Multiple Imputation Method 
Multiple imputation can be performed in SAS using a general three-step approach.  
1) Imputation Step  
The efficacy data will need to be transformed so that for each subject there is a separate 
column variable for the efficacy value (change from baseline FEV1) at each visit (e.g. 
SUBJID BASE CHG4 CHG8 CHG12). 
PROC MI is applied to an input dataset containing some missing values, which results in 
creation of multiple copies of this dataset. All copies contain identical values of the non-
missing data items, but different values imputed for missing items. 
a. PROC MI distinguishes two types of missingness patterns: non-monotone and 
monotone.  
b. In all analyses non-monotone missing data will be assumed to be missing at random 
Non-monotone missing data will first be imputed using PROC MI code similar to that 
shown below: 
Monotone missing data will then be imputed for a Tipping Point Analysis with incremental 
shifts (k) of +50 mL for the revefenacin arm and -50 mL for the placebo arm in 50 mL 
increments.  This is illustrated by the example PROC MI code shown below: 


 
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2) Analysis Step 
The data from the imputed datasets will then need to be transformed back prior to analysis 
so that for each subject at each visit a separate record is available (eg SUBJID VISIT CHG).   
The following SAS code is an example of code used to summarize the primary analysis 
model on each of the imputed datasets: 
 
3) Pooling Step 
Results from all imputed datasets are then combined together for overall inference using 
PROC MIANALYZE. 
The following SAS code is an example of code used to combine the individual model 
estimates for each imputed dataset by shift parameter: 


 
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P-values from the analyses will be presented in a two-dimensional table as illustrated in 
Table 7: 
Table 7: Two-Dimensional Tipping Point Analysis Results (p-values) 
 
 
Shift Parameters for Missing Data on Revefenacin (mL) 
0 
-50 
-100 
-150 
-200 
-250 
-300 
-350 
-400 
-450 
-500 
Shift 
Parameters 
for 
Missing 
Data on 
Placebo 
(mL) 
0 
 
 
 
 
 
 
 
 
 
 
 
50 
 
 
 
 
 
 
 
 
 
 
 
100 
 
 
 
 
 
 
 
 
 
 
 
150 
 
 
 
 
 
 
 
 
 
 
 
200 
 
 
 
 
 
 
 
 
 
 
 
250 
 
 
 
 
 
 
 
 
 
 
 
300 
 
 
 
 
 
 
 
 
 
 
 
350 
 
 
 
 
 
 
 
 
 
 
 
400 
 
 
 
 
 
 
 
 
 
 
 
450 
 
 
 
 
 
 
 
 
 
 
 
500 
 
 
 
 
 
 
 
 
 
 
 
6.4 
Sample SAS code for Logistic Regression Model 
6.5 
Sample SAS code for MMRM logistic model: 
6.6 
BDI/TDI Component Score and Focal Score 
Dyspnea Index (BDI) measures the severity of dyspnea at the beginning of the trial and the 
Transition Dyspnea Index (TDI) evaluates changes from this baseline (transition period). 
The BDI as well as the TDI are composed of the three categories: Functional Impairment, 
Magnitude of Task, Magnitude of Effort.  
The BDI includes five grades of severity from zero (very severe impairment) to four (no 
impairment) and the categories are summed to create the focal score (zero to twelve).  


 
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The TDI ranges from minus three (major deterioration) to plus three (major improvement) 
including a zero score to indicate “no change”. Also for the TDI the three categories are added 
to obtain a focal score ranging from minus nine, including zero, to plus nine. Provision is made 
for circumstances when dyspnea cannot be rated: in the BDI, score “X” if no information on 
the severity can be obtained, “W” if there is generally insufficient information, or “Y” if the 
patient’s capacity is compromised by factors other than respiratory. In the TDI, score “Z” if 
reduction of activities, effort or functional impairment is caused by reasons other than 
respiratory. 
If a component score is missing or scored W, X , Y, Z then the focal score will be set to missing. 
6.7 
SGRQ Component Score and Total Score 
The SGRQ is designed to measure health impairment in patients with asthma and COPD. It is 
in two parts. Part 1 (Question 1 to 8) produces the Symptoms score, and Part 2 (Question 9 to 
16) the Activity and Impacts scores. A Total score is also calculated which summarises the 
impact of the disease on overall health status. Scores are expressed as a percentage of overall 
impairment where 100 represents worst possible health status and 0 indicates best possible 
health status. 
6.7.1 Item Weights 
Questions 
Answers 
Weights 
Part 1 
Question 1 
Most 
80.6 
 
Several 
63.2 
 
A few 
29.3 
 
Only 
28.1 
 
Not 
0.0 
Question 2 
Most 
76.8 
 
Several 
60.0 
 
A few 
34.0 
 
Only 
30.2 
 
Not 
0.0 
Question 3 
Most 
87.2 
 
Several 
71.4 
 
A few 
43.7 
 
Only 
35.7 
 
Not 
0.0 
Question 4 
Most 
86.2 
 
Several 
71.0 
 
A few 
45.6 
 
Only 
36.4 
 
Not 
0.0 
Question 5 
More than three 
86.7 
 
3 attacks 
60.3 
 
2 attacks 
29.3 
 
1 attack 
44.2 


 
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None 
0.0 
Question 6 
a week or more 
89.7 
 
3 or more days 
73.5 
 
1 or 2 days 
58.8 
 
less than a day 
41.9 
Question 7 
None 
93.3 
 
1 or 2 
76.6 
 
3 or 4 
61.5 
 
nearly every day 
15.4 
 
every day 
0.0 
Question 8 
No 
0.0 
 
Yes 
62.0 
Part 2 
Question 9 
The most important problem I have 
83.2 
 
Causes me quite a lot of problems 
82.5 
 
Causes me a few problems 
34.6 
 
Causes no problem 
0.0 
Question 10 
My chest trouble made me stop work 
88.9 
 
My chest trouble interferes with my work or 
made me change my work 
77.6 
 
My chest trouble does not affect my work 
0.0 
Question 11 
Sitting or lying still 
90.6 
 
Getting washed or dressed 
82.8 
 
Walking around the home 
80.2 
 
Walking outside on the level 
81.4 
 
Walking up a flight of stairs 
76.1 
 
Walking up hills 
75.1 
 
Playing sports or games 
72.1 
Question 12 
My cough hurts 
81.1 
 
My cough makes me tired 
79.1 
 
I get breathless when I talk 
84.5 
 
I get breathless when I bend over 
76.8 
 
My cough or breathing disturbs my sleep 
87.9 
 
I get exhausted easily 
84.0 
Question 13 
My cough or breathing is embarrassing in 
public 
74.1 
 
My chest trouble is a nuisance to my family, 
friends or neighbours 
79.1 
 
I get afraid or panic when I cannot get my 
breath 
87.7 
 
I feel that I am not in control of my chest 
problem 
90.1 
 
I do not expect my chest to get any better 
82.3 
 
I have become frail or an invalid because of 
my chest 
89.9 


 
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Exercise is not safe for me 
75.7 
 
Everything seems too much of an effort 
84.5 
Question 14 
My medication does not help me very much 
88.2 
 
I get embarrassed using my medication in 
public 
53.9 
 
I have unpleasant side effects from my 
medication 
81.1 
 
My medication interferes with my life a lot 
70.3 
Question 15 
I take a long time to get washed or dressed 
74.2 
 
I cannot take a bath or shower, or I take a long 
time 
81.0 
 
I walk more slowly than other people, or I stop 
for rests 
71.7 
 
Jobs such as housework take a long time, or I 
have to stop for rests 
70.6 
 
If I walk up one flight of stairs, I have to go 
slowly or stop 
71.6 
 
If I hurry or walk fast, I have to stop or slow 
down 
72.3 
 
My breathing makes it difficult to do things 
such as walk up hills, carry things up stairs, 
light gardening such as weeding, dance, play 
bowls or play golf 
74.5 
 
My breathing makes it difficult to do things 
such as carry heavy loads, dig the garden or 
shovel snow, jog or walk at 5 miles per hour, 
play tennis or swim 
71.4 
 
My breathing makes it difficult to do things 
such as very heavy manual work, run, cycle, 
swim fast or play competitive sports 
63.5 
Question 16 
I cannot play sports or games 
64.8 
 
I cannot go out for entertainment or recreation 
79.8 
 
I cannot go out of the house to do the 
shopping 
81.0 
 
I cannot do housework 
79.1 
 
I cannot move far from my bed or chair 
94.0 
Question 17 
It does not stop me doing anything I would 
like to do  
0.0 
 
It stops me doing one or two things I would 
like to do 
42.0 
 
It stops me doing most of the things I would 
like to do 
84.2 
 
It stops me doing everything I would like to 
96.7 
6.7.2 Scoring Algorithm 
Each component of the questionnaire is scored separately in three steps: 


 
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i. The weights for all items with a positive responses are summed. 
ii The weights for missed items are deducted from the maximum possible weight for each 
component. The weights for all missed items are deducted from the maximum possible weight 
for the Total score. 
iii. The score is calculated by dividing the summed weights by the adjusted maximum possible 
weight for that component and expressing the result as a percentage: 
𝑆𝑐𝑜𝑟𝑒= 100 × Summed weights from positive items in that component
Sum of weights for all items in that component
 
 
The Total score is calculated in similar way: 
𝑆𝑐𝑜𝑟𝑒= 100 × Summed weights from positive items in the questionnaire
Sum of weights for all items in the questionnaire
 
Sum of maximum possible weights for each component and Total: Symptoms 662.5, Activity 
1209.1, Impacts 2117.8, Total 3989.4 
It will be noted that the questionnaire requests a single response to questions 1-7, 9-10 and 17. 
If multiple responses are given to one of these questions then averaging the weights for the 
positive responses for that question will be applied.  
Symptoms component is calculated from the summed weights for the positive responses to 
questions 1-8. Activity component is calculated from the summed weights for the positive 
responses to questions 11 and 15. Impacts component is calculated from the summed weights 
for the positive responses to questions 9-10, 12-14 and 16-17. 
The Total score is calculated by summing all positive responses in the questionnaire and 
expressing the result as a percentage of the total weight for the questionnaire. 
6.7.3 Handling Missed Items 
The Symptoms component will tolerate a maximum of 2 missed items. The weight for the 
missed item is subtracted from the total possible weight for the Symptoms component (662.5) 
and from the Total weight (3989.4). 
The Activity component will tolerate a maximum of 4 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Activity component (1209.1) and from 
the Total weight (3989.4). 
The Impacts component will tolerate a maximum of 6 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Impacts component (2117.8) and from 
the Total weight (3989.4). 


 
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6.8 
Best Test Result (BTR)  
The BTR process is designed to deselect any unacceptable efforts that are being used to 
represent the Best value for a particular measurement or reselect good quality efforts that 
were deselected by the Principal Investigator. If the Principal Investigator did not disregard 
the unacceptable efforts, the Best value could be influenced due to the fact that the 
MasterScope will report the highest value for FEV1 and FVC per measurement as the Best 
value regardless of the quality efforts. 
The Best value definition in Forced Spirometry is the highest values of FEV1 and FVC of the 
efforts submitted by the investigative site. The goal for BTR is to ensure that only acceptable 
efforts are used to determine these Best values. The data submitted to the sponsor after BTR 
will include the highest value (FEV1 or FVC) reported from acceptable efforts. If there are no 
acceptable efforts available for a measurement then the data submitted will be unacceptable 
quality for that measurement. 


 
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