Clinical trial NCT03095456
Conditions: Chronic Obstructive Pulmonary Disease, COPD Low Peak Inspiratory Flow Rate (PIFR)
Keywords: Chronic Obstructive Pulmonary Disease, COPD Low Peak Inspiratory Flow Rate (PIFR)
Sponsor: Mylan Inc.
Start date: 2017-03-27; Completion date: 2017-11-25
Enrollment: 207 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a randomized, double-blind, double-dummy, parallel group study to compare once daily nebulized Revefenacin with Spiriva once daily delivered via the HandiHaler® on lung function in subjects with COPD and a Low Peak Inspiratory Flow Rate.

Detailed description:

Arms: arm 1: Active Revefenacin and placebo (in place of Spiriva Handihaler®) arm 2: Active Spiriva Handihaler® and placebo (in place of Revefenacin)
Interventions: intervention 1: Revefenacin intervention 2: Spiriva Handihaler® intervention 3: Placebo for Revefenacin intervention 4: Placebo for Spiriva Handihaler®
Intervention descriptions: intervention 1: Revefenacin administered via nebulization. intervention 2: Spiriva Handihaler® contains Spiriva (also known as Tiotropium) and is administered via HandiHaler® device. intervention 3: Placebo administered as double blind, double dummy via nebulization. intervention 4: Placebo administered as double blind, double dummy via Spiriva HandiHaler®.

Protocol documents:
Prot_001.pdf: 










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PROTOCOL SYNOPSIS (CONTINUED) 
 
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Inclusion Criteria  
1. Subject is a male or female subject 40 years of age or older with a diagnosis of COPD. 
2. Subject has <60 L/min of PIFR as measured by 
 device with resistance set 
to 
 at screening at Visit 1B. 
3. Subject is capable of performing reproducible spirometry maneuvers as described by 
current American Thoracic Society (ATS) Guidelines and has a post-ipratropium 
FEV1/FVC ratio <0.7 and post-ipratropium predicted FEV1 < 80% at screening and 
FEV1 >400mL. 
4. Subject has a current or past cigarette smoking history (or equivalent for cigar or pipe 
smoking history) of at least 10 pack-years. 
5. Subject is willing and able to provide signed and dated written informed consent to 
participate prior to initiation of any study related procedures.  
6. Subject is willing and able to adhere to all study assessments/procedures 
7. Women of either non-child bearing potential or child bearing potential, provided that: 
• 
All female subjects of childbearing potential must agree to use a highly effective 
method of birth control during the study and for at least 1 month after completion of 
study drug dosing.  
o A highly effective method of birth control is defined as one that results in a low 
failure rate (i.e. <1% per year) when used consistently and correctly, such as 
condom + diaphragm, condom + spermicide, diaphragm + spermicide, or 
intrauterine device [IUD] with documented failure rate of <1% per year, or 
oral/injectable/implanted hormonal contraceptives used in combination with an 
additional barrier method.  
(Women are considered to be not of childbearing potential if they have had a total 
hysterectomy and/or bilateral tubal ligation (documentation for either must be 
provided before enrollment) or are at least 2 years postmenopausal.)  
8. Subject (or caregiver) based on the investigator’s assessment is able to properly 
prepare and administer study medication administered either by nebulizer or 
. 
Exclusion Criteria: 
1. Subject has a concurrent disease or condition that, in the opinion of the investigator, 
would interfere with continued study participation or confound the evaluation of safety 
and tolerability of the study drug. 
2. Subject has a history of reactions or hypersensitivity to inhaled or nebulized 
anticholinergics  
3. 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. 
4. A clinically significant abnormal lab for any of the following tests that, in the 
investigators opinion, would likely interfere with the successful completion of the study.  








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SCHEDULE OF STUDY PROCEDURES 
 
Table 1: 
Schedule of Study Procedures 
Procedures 
Screeninga 
Randomization 
Day 1 
(Visit 2) 
Treatment 
Period 
(29 days) 
Day 29 
(Visit 3) 
± 5 days 
Follow-Up/ 
Phone call 
7 days after last 
visit 
± 2 days 
Early 
Termination/ 
Withdrawal 
(Visit 1A) 
(Visit 1B) 
Informed Consent 
■ 
 
 
 
 
 
 
Medication and 
Medical History 
■ 
 
 
 
 
 
 
Washout of COPD 
Medications 
(as required) 
■ 
 
 
 
 
 
 
Physical examination 
 
■ 
 
 
■ 
 
■ 
Height and Weight 
 
■ 
 
 
 
 
 
Vital Signs 
 
■ 
 
 
■ 
 
■ 
Inclusion/Exclusion 
Criteria Review 
■ 
■ 
■ 
 
 
 
 
Urine Pregnancy 
Test (Female 
subjects)b 
■ 
 
■ 
 
■ 
 
■ 
Ipratropium 
Reversibility c 
 
■ 
 
 
 
 
 
Subject training on 
the maneuver for 
MIP 
 
■ 
 
 
 
 
 
Randomization 
 
 
■ 
 
 
 
 
Collect and review 
Daily Diary 
 
■ 
■ 
 
■ 
 
■ 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
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Table 1: 
Schedule of Study Procedures 
Procedures 
Screeninga 
Randomization 
Day 1 
(Visit 2) 
Treatment 
Period 
(29 days) 
Day 29 
(Visit 3) 
± 5 days 
Follow-Up/ 
Phone call 
7 days after last 
visit 
± 2 days 
Early 
Termination/ 
Withdrawal 
(Visit 1A) 
(Visit 1B) 
Dispense study med 
 
 
■ 
 
 
 
 
Collect and reconcile 
returned study drug 
(with compliance 
assessment), and 
rescue medication 
 
 
 
 
■ 
 
■ 
Con Meds 
 
■ 
■ 
 
■ 
■ 
■ 
AEs 
 
■ 
■ 
 
■ 
■ 
■ 
Dispense Rescue 
Medication and 
training on use  
■  
 
■ 
 
 
 
 
Dispense Daily diary 
and train on use 
■ 
■ 
■ 
 
 
 
 
Local lab tests for 
creatinine and 
hematocrit (if 
historical tests within 
the last 3 months are 
not available) 
■ 
 
 
 
 
 
 
BDI d and mMRC 
 
 
■ 
 
 
 
 
TDI d 
 
 
 
 
■ 
 
■ 
PIFR 
■e 
■e 
 
 
 ■e 
 
    ■f, g 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
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Table 1: 
Schedule of Study Procedures 
Procedures 
Screeninga 
Randomization 
Day 1 
(Visit 2) 
Treatment 
Period 
(29 days) 
Day 29 
(Visit 3) 
± 5 days 
Follow-Up/ 
Phone call 
7 days after last 
visit 
± 2 days 
Early 
Termination/ 
Withdrawal 
(Visit 1A) 
(Visit 1B) 
Predose Spirometry 
(FEV1, FVC) at 45 
and 15 minutes 
predose 
 
 
■ 
 
■ 
 
    ■f, g 
IC measured with a 
SVC maneuver at 
45 minutes predoseg 
 
 
■ 
 
■ 
 
 ■ 
MIPh 
 
 
■ 
 
■ 
 
  ■f 
LABA dosing 
(if applicable) 
 
 
■ 
■ 
■ 
 
 
Training on the use 
of the 
 
and nebulizer 
devices by watching 
a training video 
 
 
■ 
 
 
 
 
In-Clinic study drug 
dosing 
 
 
■ 
 
■ 
 
 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
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Table 1: 
Schedule of Study Procedures 
Procedures 
Screeninga 
Randomization 
Day 1 
(Visit 2) 
Treatment 
Period 
(29 days) 
Day 29 
(Visit 3) 
± 5 days 
Follow-Up/ 
Phone call 
7 days after last 
visit 
± 2 days 
Early 
Termination/ 
Withdrawal 
(Visit 1A) 
(Visit 1B) 
Record Study Drug 
Use and Rescue 
Med Use on Daily 
diary 
 
 
■ 
■ 
■ 
 
 
Postdose Spirometry 
(FEV1, FVC,)  at 1, 2, 
and 4 hours 
postdose 
 
 
■ 
 
■ 
 
 
a Visit 1A and 1B will be conducted as one visit unless a washout is required in which case they will be conducted as separate visits. 
b A repeat urine pregnancy test is required at randomization (Visit 2) if visit is > 7 days after visit 1A urine pregnancy test. 
c  Spirometry measurements predose and 45 min postdose for ipratropium reversibility. 
d BDI (Baseline Dyspnea Index), TDI (Transitional Dyspnea Index). 
e PIFR will be measured at Visit 1A, only set to
 resistance. PIFR will be measured at V1B set to 
 and 
 resistance and also at 
day 29 and early term visits. Subjects requiring a LAMA washout with ≥75 L/min set at
 resistance will be excluded per exclusion criteria #5 at Visit 
1A.  Subjects not requiring a LAMA washout with ≥60 L/min set at 
 resistance will be excluded (per exclusion criteria #6) at Visit 1A.  PIFR will be 
measured again at Visit 1B for inclusion criteria #2. 
f 
Measurements will be done if subject is willing. 
g IC will be measured by a separate slow vital capacity (SVC) maneuver performed immediately after the FVC maneuver at -45 minutes only on Day 1 and 
Day 29 only.  Similarly, at an ET visit where an FVC maneuver is done 30 minutes apart, the SVC will only be performed immediately after the first FVC. 
h MIP will be performed immediately after the SVC maneuver at -45 minutes only on Day 1 and Day 29 only. 
 


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TABLE OF CONTENTS 
 
PAGE 
 
PROTOCOL SYNOPSIS ....................................................................................................... 2 
SCHEDULE OF STUDY PROCEDURES ............................................................................ 10 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................ 18 
1 
INTRODUCTION ..................................................................................................... 20 
1.1 
Background and Rationale ........................................................................... 20 
1.2 
Nonclinical Profile ......................................................................................... 21 
1.2.1 
Pharmacology................................................................................... 21 
1.2.2 
Toxicology ........................................................................................ 21 
1.3 
Clinical Experience ....................................................................................... 21 
1.4 
Risks and Benefits ....................................................................................... 24 
2 
OBJECTIVES .......................................................................................................... 27 
3 
STUDY DESIGN ...................................................................................................... 28 
3.1 
Overview ...................................................................................................... 28 
3.2 
Rationale for Study Design ........................................................................... 29 
3.3 
Selection of Doses and Duration of Treatment ............................................. 29 
3.4 
Study Endpoints ........................................................................................... 30 
3.4.1 
Minimization of Bias .......................................................................... 30 
3.4.2 
Blinding............................................................................................. 30 
3.4.3 
Treatment Assignment ...................................................................... 31 
4 
STUDY POPULATION ............................................................................................ 32 
4.1 
Inclusion Criteria .......................................................................................... 32 
4.2 
Exclusion Criteria ......................................................................................... 33 
5 
STUDY DRUGS ...................................................................................................... 34 
5.1 
Description of Study Drugs ........................................................................... 34 
5.1.1 
Revefenacin ..................................................................................... 34 
5.1.2 
Tiotropium ........................................................................................ 34 
5.2 
Dose Administration ..................................................................................... 35 
5.2.1 
Revefenacin ..................................................................................... 35 
5.2.2 
Tiotropium ........................................................................................ 35 
5.2.3 
Agents Used for Rescue Medication ................................................. 36 
5.2.3.1 
Albuterol .......................................................................... 36 
5.3 
Treatment Compliance ................................................................................. 36 
5.4 
Drug Accountability and Reconciliation ........................................................ 36 
6 
STUDY PROCEDURES .......................................................................................... 38 
6.1 
Schedule of Study Procedures ..................................................................... 38 
6.2 
Procedures by Visit ...................................................................................... 38 
6.2.1 
Screening ......................................................................................... 38 
6.2.1.1 
Visit 1A (Screening Visit) – (performed up to 7 days 
before Visit 1B) ................................................................ 40 
6.2.1.2 
Visit 1B – (if a washout is not required Visit 1A and 
1B may be conducted as one visit) .................................. 41 
6.2.2 
Treatment and Follow-up Period ....................................................... 41 
6.2.2.1 
Visit 2 (Randomization Visit) ............................................ 41 


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6.2.2.2 
Visit 3 (Day 29) ................................................................ 43 
6.2.2.3 
Visit 4 (Telephone Follow-up) (7 Days ± 2 days 
after Visit 3) ..................................................................... 44 
6.2.3 
Early Termination/Withdrawal Visit ................................................... 44 
6.2.4 
Unscheduled Visits ........................................................................... 45 
6.3 
Description of Study Assessments ............................................................... 45 
6.3.1 
Demographic and Screening Assessments ...................................... 45 
6.3.2 
Efficacy Assessments ....................................................................... 45 
6.3.2.1 
Spirometry ....................................................................... 45 
6.3.3 
Safety Assessments ......................................................................... 46 
6.3.3.1 
Adverse Events ............................................................... 46 
6.3.3.2 
Medical History ................................................................ 46 
6.3.3.3 
Physical Examination ...................................................... 46 
6.3.3.4 
Vital Signs ....................................................................... 47 
6.3.3.5 
Pregnancy ....................................................................... 47 
6.4 
Concomitant Medications ............................................................................. 47 
6.5 
Restrictions .................................................................................................. 50 
6.6 
Discontinuation ............................................................................................ 51 
6.6.1 
Subject Discontinuation .................................................................... 51 
6.6.2 
Subject Replacement ........................................................................ 52 
6.6.3 
Study Discontinuation ....................................................................... 52 
6.7 
Pregnancy .................................................................................................... 52 
6.8 
COPD Exacerbation ..................................................................................... 53 
7 
ADVERSE EVENTS ................................................................................................ 54 
7.1 
Regulatory Definition of an Adverse Event ................................................... 54 
7.2 
Adverse Event Definition for the Purposes of This Study .............................. 54 
7.3 
Assessment of Adverse Events .................................................................... 55 
7.4 
Serious Adverse Events ............................................................................... 55 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events ............................................ 56 
7.6 
Serious Adverse Event Reporting ................................................................ 57 
7.7 
Adverse Event Follow-up ............................................................................. 58 
8 
STATISTICAL CONSIDERATIONS ......................................................................... 59 
8.1 
General Considerations ................................................................................ 59 
8.2 
Sample Size and Power ............................................................................... 59 
8.2.1 
Randomization Strata ....................................................................... 59 
8.3 
Analysis Sets and Subgroups....................................................................... 60 
8.3.1 
Analysis Sets .................................................................................... 60 
8.3.2 
Examination of Subgroups ................................................................ 60 
8.3.3 
Major Protocol Deviations ................................................................. 61 
8.4 
General Analyses ......................................................................................... 61 
8.4.1 
Demographics and Other Baseline Characteristics ........................... 61 
8.4.2 
Screening and Baseline Spirometry .................................................. 61 
8.4.3 
COPD Clinical History and Smoking History ..................................... 61 
8.4.4 
Select Medical History ...................................................................... 61 
8.4.5 
Reversibility ...................................................................................... 61 


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8.5 
Efficacy Analyses ......................................................................................... 61 
8.5.1 
Efficacy Endpoints ............................................................................ 62 
8.5.2 
Primary Efficacy Evaluation .............................................................. 62 
8.5.3 
Secondary Efficacy Endpoints .......................................................... 63 
8.5.3.1 
Trough FVC and IC ......................................................... 63 
8.5.3.2 
Peak FEV1 and FVC ........................................................ 63 
8.5.3.3 
Rescue Medication Endpoints ......................................... 63 
8.5.3.4 
Clinical Outcomes Assessments ..................................... 63 
8.5.3.5 
MIP ................................................................................. 64 
8.5.4 
Impact of Rescue Medication Use on Spirometry Data ..................... 64 
8.5.5 
Multiplicity Adjustment ...................................................................... 64 
8.6 
Safety Analyses ........................................................................................... 65 
8.6.1 
Extent of Exposure ........................................................................... 65 
8.6.2 
Adverse Event Data .......................................................................... 65 
8.6.2.1 
Adverse Events ............................................................... 65 
8.6.3 
Concomitant Medications ................................................................. 65 
8.6.4 
Vital Signs Data ................................................................................ 66 
8.7 
Missing Data Handling ................................................................................. 66 
8.8 
Data Monitoring Committee .......................................................................... 66 
9 
STUDY ADMINISTRATION ..................................................................................... 67 
9.1 
Principal Investigator Responsibilities .......................................................... 67 
9.2 
Institutional Review Board/Independent Ethics Committee ........................... 68 
9.3 
Informed Consent ......................................................................................... 68 
9.4 
Data Recording and Quality Assurance ........................................................ 69 
9.5 
Document Retention .................................................................................... 70 
9.6 
Confidentiality .............................................................................................. 70 
9.7 
Access to Data and Documents ................................................................... 71 
9.8 
Quality Control: Study Monitoring and Auditing ............................................ 71 
9.9 
Publication ................................................................................................... 72 
10 
REFERENCES ........................................................................................................ 73 
PROTOCOL SIGNATURE FORM ....................................................................................... 75 
 


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LIST OF TABLES 
 
Table 1: 
Schedule of Study Procedures ......................................................... 10 
 
 
 
Table 3: 
Outlier Threshold for Vital Signs ....................................................... 66 
 
LIST OF FIGURES 
 
Figure 1: 
Study Design Schema ...................................................................... 28 
Figure 2: 
Statistical Testing Hierarchy (difference between treatment 
groups) ............................................................................................. 64 
 
LIST OF APPENDICES 
 
Appendix 1: 
Signature Page ................................................................................. 74 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
ACh 
Acetylcholine 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under concentration curve 
BDI/TDI 
Baseline Dyspnea Index / Transitional Dyspnea Index 
BP 
blood pressure 
COPD 
chronic obstructive pulmonary disease 
CRF 
case report form 
DPI 
dry powder inhaler 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HR 
heart rate 
IB 
Investigator's Brochure 
IC 
Inspiratory capacity 
ICF 
informed consent form 
ICH 
International Conference on Harmonization (Technical Requirements for 
Registration of Pharmaceuticals for Human Use) 
ICS 
Inhaled Corticosteroids 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LABA 
long-acting beta2 agonist 
LAMA 
long-acting muscarinic antagonist 
LTOT 
Long Term Oxygen Therapy 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
MDI 
Metered-dose inhaler 
MIP 
Maximal Inspiratory Pressures 
mMRC 
Modified Medical Research Council Questionnaire 
M1 
muscarinic receptor 1 (subtype) 
M2 
muscarinic receptor 2 (subtype) 
M3 
muscarinic receptor 3 (subtype) 


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Abbreviation 
Description 
M4 
muscarinic receptor 4 (subtype) 
M5 
muscarinic receptor 5 (subtype) 
NEB 
nebulizer 
PIFR 
Peak Inspiratory Flow Rate 
PRN 
Administration as needed 
SVC 
Slow Vital Capacity 
 




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1.2 
Nonclinical Profile  
Revefenacin is a long-acting, anti-muscarinic agent being developed as an inhalation 
solution for administration via standard jet nebulizer for the treatment of COPD.  A review of 
the nonclinical profile of revefenacin can be found in the current version of the revefenacin 
Investigator’s Brochure (IB). The following is a brief summary of the pertinent findings. 
1.2.1 Pharmacology 
 
 
 
 
 
 
 
 
 Overall, the pharmacology of revefenacin, 
when administered into the lungs, is consistent with that of a long-acting muscarinic 
antagonist and demonstrates good selectivity for lung versus systemic effects.  
Safety pharmacology studies for revefenacin included assessments of potential effects on 
cardiovascular and respiratory function and for potential neurobehavioral effects. These 
studies are summarized in the Investigator’s Brochure. 
1.2.2 Toxicology 
The toxicology assessment of revefenacin included single-dose toxicity, repeated-dose 
toxicity, genotoxicity, reproductive and developmental toxicity, and local tolerance studies. 
The results of these studies are summarized in the Investigator’s Brochure. 
1.3 
Clinical Experience 
 
 
 
 
 


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1.4 
Risks and Benefits 
Subjects participating in this study may be at risk of experiencing adverse events related to 
muscarinic antagonism, including headache, mouth dryness, constipation, blurred vision, 
dizziness and urinary retention.  


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Subjects participating in this study may experience discomfort due to repeated blood 
sampling.  
During the single dose study in which revefenacin was administered as a dry powder, the 
most common adverse events were dysgeusia and headache.  
In Study 
 a single nebulized dose (350 or 700 mcg) of revefenacin was administered to 
COPD subjects according to a crossover design. The study also involved ipratropium and 
placebo. Adverse events were generally mild and occurred with similar frequencies in all 
periods of the study – including the placebo period. The most common adverse events were 
headache and dyspnea. In Study 
 subjects with COPD received doses ranging 
between 22 and 700 mcg (or placebo) once daily for 7 days. Each subject was assigned to 
5 different treatment periods with a 2-week washout between each period. A range of 
adverse events occurred in this population most of which were consistent with the 
underlying disease state (COPD) and not unanticipated in a study of this duration. There 
were no deaths in this study. 
 
. Other adverse 
events were generally mild and occurred with similar frequencies in all treatment periods 
including the placebo period. The most common adverse events reported in this study were 
headache, cough and dyspnea. 
In Study 
 the most common adverse event was dyspnea. There was one serious 
adverse event, a death, in the study. 
 
 
 
 
 
 
 
The investigator assessed the event as unrelated to 
study medication.  
 
 
 


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Clinically significant bronchodilation has been observed in each of the study populations of 
COPD subjects thus far in the development program, however revefenacin is an 
investigational drug and its benefits and risks continue to be evaluated in phase 3. Two 
replicate phase 3 studies have demonstrated that the 88 mcg and 175 mcg doses of 
revefenacin were generally well-tolerated, with comparable rates of adverse events and 
serious adverse events across all treatment groups (active and placebo). The most 
commonly reported adverse events, across both trials and across all treatment groups were 
exacerbations, cough, dyspnea and headache. There were no reports of blurred vision, 
narrow-angle glaucoma or worsening of urinary retention, all of which are commonly 
reported adverse events for this class of medication, and in addition,
 
 


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2 
OBJECTIVES 
The primary objective of the study is as follows: 
• 
To characterize the relative efficacy on trough FEV1 of revefenacin administered once 
daily via nebulization compared to tiotropium administered once daily via 
 in 
a population of subjects with moderate to very severe COPD and suboptimal PIFR. 
The secondary objectives of the study are as follows: 
• 
Characterize relative efficacy of Trough FVC and IC post 28th dose on Day 29  
• 
Characterize relative efficacy of Peak FEV1, FVC and IC on Day 29 (0-4 hours) 
• 
Characterize relative efficacy of Peak FEV1, FVC and IC on Day 1 (0-4 hours) 
• 
Characterize relative use of rescue albuterol use 
 




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3.2 
Rationale for Study Design 
This is a Phase 3b study to assess revefenacin at a dose of 175 mcg administered 
once-daily for 29 days using the jet nebulizer that was utilized in the earlier studies of the 
program. This study is intended to provide data in patients with moderate to severe COPD 
who have sub-optimal PIFR, where nebulized delivery of revefenacin could provide more 
benefit, as measured by spirometry and dyspnea symptoms than a DPI 
 to 
support the use in this demographic as a bronchodilator for the treatment of subjects with 
COPD. The 175 mcg dose selected from the Phase 3 studies has an optimal benefit:risk 
ratio to further characterize the use in this specific patient population. 
The study is designed as a double blinded, double-dummy, parallel-group study, with 
100 subjects randomized to each treatment group 
 
 Randomization allows for an unbiased assessment 
of treatment effects across revefenacin and tiotropium. The duration of treatment is limited, 
and all subjects will have study specific rescue medication (albuterol via MDI or via 
nebulization) provided for the full duration of the study, including during the screening 
(via MDI only) and follow-up periods. Subjects who have an exacerbation that requires 
treatment (other than increased use of study supplied albuterol) during the study period will 
be discontinued.  
Subjects will be required to meet the standard spirometry definitions for moderate to very 
severe COPD (post-bronchodilator FEV1/FVC ratio of <0.7 and a post-bronchodilator 
FEV1<80% of predicted normal and a post-bronchodilator FEV1 >400 mL, [NHANES III]) {5}. 
Subject should meet a PIFR of <60 L/min as measured by I
 device with 
resistance set to 
 at screening at Visit 1B. 
3.3 
Selection of Doses and Duration of Treatment 
The selection of the 175 mcg dose of revefenacin for this study is based on the results of 
two (2) twelve week studies conducted as part of the phase 3 program in the clinical 
development of revefenacin 
 The results of those studies showed 
that revefenacin, administered once daily via a standard jet nebulizer at doses of 88 and 
175 mcg to subjects with moderate to very severe COPD, demonstrated clinically and 
statistically significant improvements in trough FEV1, over the entire treatment period. 
Revefenacin at 175 mcg demonstrated and replicated consistently greater improvements in 


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FEV1 across both studies, in concomitant LABA subjects and in more severe subjects than 
revefenacin at 88 mcg. Most common AEs, across all treatment groups, were exacerbations, 
cough, dyspnea, and headache. The AE profile did not differ from the expected 
safety/tolerability profile to date for revefenacin or other LAMAs. Revefenacin appears to be 
safe and well tolerated in the population of subjects in these studies. 
3.4 
Study Endpoints 
The primary study endpoint is trough FEV1 on Day 29.  
The secondary endpoints are: 
• 
Trough FVC  and IC post 28th dose on Day 29 
• 
Peak FEV1, and FVC on Day 29 (0-4 hours) 
• 
Rescue albuterol use (incidence of albuterol use) 
 
 
 
 
  
 
The safety endpoints are: 
• 
Adverse events 
• 
Vital signs 
• 
Concomitant medications 
3.4.1 Minimization of Bias 
Bias will be minimized through the use of randomization and a double-blind double-dummy 
study design.   
3.4.2 Blinding 
All study subjects, study investigators and their staff, and the Sponsor’s staff involved in the 
conduct of the study will be blinded to treatment assignment with regard to revefenacin and 
the tiotropium comparator arm.  Subjects will be assigned in random order to tiotropium or 
revefenacin according to the randomization schedule. The only personnel who will have 
access to the randomization schedule before database lock are: 
• 
The nominated personnel at the Contract Research Organization responsible for 
generation of the randomization schedule. 
In the event of an untoward safety observation, the investigator may unblind a subject’s 
treatment assignment using the IWRS. If possible, the investigator should first contact the 


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Theravance Clinical Study Director before unblinding. The blind should be broken only if 
knowledge of the subject’s study medication would affect subsequent treatment and such 
knowledge is required for the clinical management of the subject. Any investigator 
unblinding will be documented within the appropriate section of the subject’s case report 
from (CRF) and will be captured in the IWRS.  
Unblinding of individual study subjects or site staff on the basis of results from the study 
procedures (i.e. self-unblinding) is not considered to be either an expected or likely event.  
3.4.3 Treatment Assignment 
After a subject is screened and the investigator determines that the subject is eligible for 
enrollment, the subject will be randomized to one of the two treatment groups using IWRS 
(Day 1 visit) with the following stratification factors: 
 
 
 
 
  




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4.2 
Exclusion Criteria 
1. Subject has a concurrent disease or condition that, in the opinion of the investigator, 
would interfere with study participation or confound the evaluation of safety and 
tolerability of the study drug. 
2. Subject has a history of reactions or hypersensitivity to inhaled or nebulized 
anticholinergics.  
3. 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. 
4. A clinically significant abnormal lab for any of the following tests that, in the investigators 
opinion, would likely interfere with the successful completion of the study.  Historical labs 
performed within the last 90 days are acceptable; if not available, then labs for these 
tests will be performed at Visit 1A. 
• 
creatinine 
• 
hematocrit 
5. For subjects requiring a washout of a LAMA, Subject has ≥75 L/min of PIFR as 
measured by
 device with resistance set to 
 at screening at Visit 1A 
6. For subjects not requiring a washout of a LAMA, Subject has ≥60 L/min of PIFR as 
measured by 
 with resistance set to 
 at screening at Visit 1A   
7. Subject has been hospitalized for COPD or pneumonia within 8 weeks prior to Visit 1A. 
8. Subject has a COPD exacerbation requiring treatment (other than increased use of 
study supplied albuterol) during the screening period. 
9. Subject has used systemic corticosteroids within 8 weeks prior to Visit 1A. 
10. Subject has used antibiotics for respiratory tract infections within 8 weeks prior to 
Visit 1A. 


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5 
STUDY DRUGS  
All study drugs supplied by the Sponsor must be stored in a secure location accessible only 
to designated study personnel. The assignment of subjects to one of the treatment groups 
will be accomplished by randomizing the subject through the IWRS. Each drug kit will 
contain a unique kit number which will be provided by the IWRS on Day 1 to identify the 
study drug kits to dispense to a particular subject.  
More information regarding study drug dispensing, administration, handling and storage are 
provided in a separate Pharmacy Manual. 
5.1 
Description of Study Drugs 
5.1.1 Revefenacin 
Revefenacin has a molecular weight of 
. It is a 
 
 
 
 
  
Revefenacin and its placebo must be stored in a secure location accessible only to 
designated study personnel, at temperatures stated in the Pharmacy Manual.   
Detailed instructions for administration will be provided separately and provided to the study 
subject.  
5.1.2 Tiotropium 
Tiotropium will be provided in blister cards which consists of 
 dry powder capsules 
or matching placebo administered using the 
 device.  
Tiotropium and its placebo should be stored in a secure location at room temperature 
(15°C to 30°C or 59°C to 86°F). 
Detailed instructions for administration will be provided in the Pharmacy Manual.  


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5.2 
Dose Administration 
5.2.1 Revefenacin 
Revefenacin will be administered on the morning of Day 1 in the clinic. The subject will take 
the jet nebulizer, compressor and study drug home where dosing will occur every morning at 
approximately the same time and will be within the window of 6 am and 11 am.  
Revefenacin will be administered immediately after tiotropium each day. 
Training on the home use of the nebulizer will take place after the subject is randomized on 
Visit 2 prior to discharge from the clinic. Subjects will be trained to administer the study drug 
until nebulization of the study drug solution is complete, which takes approximately 
10 minutes and is evidenced by “spluttering” of the nebulizer. Administration will be once 
daily in the morning at approximately the same time each day and the time of administration 
will be recorded by the subject in their diary. This time will be chosen based on convenience 
for the subject and will remain the same for the duration of the study. The subject may 
receive additional instruction at the site based on the judgment of the investigator. Additional 
information on the training of the subject on home nebulization is contained in the Pharmacy 
Manual. 
5.2.2 Tiotropium 
Tiotropium will be administered on the morning of Day 1 in the clinic.  Tiotropium will be 
administered immediately prior to revefenacin on Day 1 and on each day at home. 
The subject will take the 
 device and the tiotropium dry powder capsules home 
where dosing will occur every morning at approximately the same time. This time will be 
chosen based on convenience for the study subject and will be within the window of 6 am 
and 11 am. The time of administration will be recorded by the subject in their diary. At each 
of the remaining study visits subjects will be required to bring their
 device and 
unused tiotropium capsules back to the clinic for in-clinic dosing on visit days. At each study 
visit subjects will be dispensed sufficient tiotropium capsules for home dosing until the time 
the subject returns for their next study visit. 
Training on the home use of the 
 device will take place at Visit 2 after the 
subject is randomized. The subject may receive additional instruction at the site based on 
the judgment of the investigator. Additional information on the training of the subject on the 
use of the 
 device is contained in the Package Insert.  


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5.2.3 Agents Used for Rescue Medication 
5.2.3.1 Albuterol 
Albuterol will be provided as a MDI or as a solution for nebulization for rescue medication on 
an as-needed basis and administered at a dosage of 90 mcg per puff or via nebulization at a 
dosage of 2.5 mg every 6-8 hours.  Subjects will be provided with one MDI at Visit 1A.  At 
Visit 2 (Day 1) subjects must decide whether to receive albuterol via MDI or nebulization for 
the remainder of the study.  This method of administration must remain the same until the 
subject completes the study.  If the subject chooses albuterol via nebulization at Visit 2 then 
the MDI dispensed at Visit 1A should be retrieved.  If the subject chooses to continue with 
albuterol via MDI, then the MDI at Visit 1A may be kept.  Please see package insert for 
further information. 
5.3 
Treatment Compliance 
Compliance will be assessed in study subjects when accountability is performed as 
described in the next section. 
 
 
 
 
 
 
5.4 
Drug Accountability and Reconciliation 
The investigator or designee is responsible for maintaining accountability records for all 
study drug(s) received from the Sponsor, in accordance with applicable government 
regulations and study procedures. The accountability record will include entries for receipt, 
distribution or dispensing, and the on-site destruction or return of the material(s) as specified 
by the sponsor. Unused and expired study drugs will be disposed of in accordance with 
written instructions from Sponsor. 
Study drug accountability will be performed at Visit 3 (Day 29) to document compliance with 
the dosing regimen. Subjects will be instructed to bring back all remaining study drug and all 
study drug packaging at each study visit for drug accountability. 
 
 


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Albuterol use will be captured using the dose counter on the albuterol inhaler.  If a subject 
forgets to return the albuterol inhaler at a study visit, the study coordinator should contact 
the subject by telephone after the subject returns home to obtain the value of the counter as 
reported by the subject. 




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screening visit.  As part of the screening visit, the investigator should review subjects’ most 
recent lab work (within the previous 3 months) to ensure that subjects are stable and to 
confirm that creatinine and hematocrit values are normal and/or not clinically significant.  If 
historical lab tests containing these tests have not been performed within 3 months, then 
local labs should be performed at Visit 1A.  The local lab results (either historical or 
performed at Visit 1A) must be present in the source documents. 
Subjects on LABAs (e.g. salmeterol, indacaterol, vilanterol, formoterol, arformoterol, 
olodaterol) either alone or in combination with an ICS (e.g. fluticasone propionate, 
fluticasone fuorate, budesonide, ciclesonide, beclomethasone) will not need to be washed 
out before enrolling in the study and will be allowed to be randomized on this background 
therapy.  
The first visit will be Screening Visit 1A.  Informed consent will be obtained and the subject’s 
existing COPD medication will be assessed to decide whether any adjustments are required 
to comply with the requirements of the protocol. If required, subjects will start a washout 
period only after signing the informed consent form. After completing the necessary washout 
period (if required) subjects will return for Screening Visit 1B within 7 days. 
If a washout period is not required then the first two screening visits (Visit 1A and Visit 1B) 
may be conducted as one visit.  The time period from Visit 1B (whether this is combined with 
Visit 1A or not) to randomization at Visit 2 will be 3 to 7 days.  Review of the spirometry at 
Visit 1B by the central spirometry vendor will take approximately 2 business days and must 
be completed to determine if the spirometry meets the eligibility criteria before the subject 
can be randomized. 
If a subject does not meet the eligibility criteria for reasons of a failed screening test due to a 
properly administered procedure, this test or procedure will not be allowed to be repeated 
and the subject should be screen failed. This includes spirometry, i.e. if a subject fails to 
meet any spirometry related criteria after the first attempt the subject should be screen 
failed.  Repeat screening spirometry will only be considered if there is a technical issue 
(e.g. with the spirometer or with the software) or if the spirometry was not performed 
properly due to site error.  


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6.2.1.1 Visit 1A (Screening Visit) – (performed up to 7 days before Visit 1B) 
Subjects should not have taken their LABA for approximately 12 hours (if on BID therapy) or 
approximately 24 hours (if on QD therapy) prior to performing the measurement for PIFR at 
Visit 1A.  Additionally, subjects should not have taken albuterol or any other short acting 
bronchodilator for approximately 6 hours prior to the PIFR measurements.  If this has 
occurred subjects may still be consented however should return to have Visit 1A performed 
on a separate day. 
The following procedures will be performed at this visit: 
• 
Written informed consent after the nature of the study has been explained and before 
any study procedure is performed 
• 
Concomitant and previous relevant medication and medical history including an 
assessment of the subject’s COPD medication 
• 
Review of inclusion and exclusion criteria 
• 
If required, based on the washout periods specified in Table 2, subject will begin their 
washout. If subject is receiving a combination COPD medication containing an inhaled 
steroid this may include changing this medication to an inhaled steroid monotherapy. 
• 
Subject will be dispensed one albuterol MDI as a rescue bronchodilator   
• 
PIFR – subjects requiring a washout of a LAMA with ≥75 L/min of PIFR as measured by 
 device with resistance set to
 will be screen failed at Visit 1A 
• 
PIFR – subjects not requiring a washout of a LAMA with ≥60 L/min of PIFR as measured 
by
 device with resistance set to 
 will be screen failed at Visit 1A  
• 
A urine pregnancy test will be done for females of childbearing potential 
• 
Subject will be trained on and dispensed the diaries  
• 
Local lab tests for creatinine and hematocrit if historical local labs within 3 months of 
Visit 1A are not available 




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to accomplish this requirement). Such adjustments will not be considered protocol 
deviations as long as the appropriate reason is documented in the source documents. 
The sequence of events for the subject to follow at home will be as follows:  recording the 
start time of study drug (i.e. use of 
) in the paper diary, then administering the  
 first, followed immediately by nebulized revefenacin.  
Subject should not have taken their LABA for approximately 12 hours (if on BID therapy) or 
approximately 24 hours (if on QD therapy) prior to taking it in the clinic. Additionally, subjects 
should have refrained from taking their short acting bronchodilators (study supplied 
albuterol) for 6 hours prior to spirometry assessments. They should further refrain from using 
albuterol throughout the study visit. 
It is important at study visits that the trough FEV1 is done before receiving study drug (and 
before taking LABA if applicable). If the subject is taking a LABA this must be taken 
immediately before the study drug.  For subjects that are taking a LABA, the sequence will 
be LABA, followed immediately by tiotropium/placebo (
; then nebulized 
revefenacin/placebo. The following procedures will be performed at the Randomization Visit: 
• 
Review of inclusion and exclusion criteria 
• 
Urine pregnancy test if visit is > 7 days after visit 1A 
• 
Randomization (subject eligibility must be confirmed by investigator before randomizing 
subject) 
• 
Collect Daily Diary and reconcile rescue medication as appropriate.  Dispense Daily 
Diary 
• 
Concomitant medications 
• 
Adverse events 
• 
Subjects will be given the choice to receive rescue albuterol either as an MDI or as 
nebules for nebulization for the remainder of the study.  This will be assigned in IWRS 
and dispensed accordingly and subjects will be trained on their administration.  (If the 
subject chooses to receive nebules at this visit, the MDI dispensed at Visit 1A should be 
retrieved.)   
• 
Dispense study drug (IWRS will assign 1 kit of each drug) 
• 
Administer BDI 
• 
Complete modified Medical Research Council Questionnaire (mMRC) 
• 
Predose FEV1, FVC via spirometry to be done 45 minutes and 15 minutes prior to the 
start of study drug dosing 


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• 
Predose IC via spirometry to be done 45 minutes prior to the start of study drug dosing 
post the FVC maneuver 
• 
MIP 
• 
If appropriate, Administer LABA containing product (for those on existing 
LABA-containing therapy) 
• 
Study drug dosing via 
 (tiotropium or placebo) followed immediately by 
study drug dosing via nebulizer (revefenacin or placebo). Training on the specific 
devices will be performed before the first dose is administered and as part of receiving 
the first dose. 
• 
Postdose Spirometry (FEV1, FVC) at 1, 2, and 4 hours postdose 
• 
Record Study Drug use and any in-clinic rescue medication use 
6.2.2.2 Visit 3 (Day 29) 
Subject should not have taken their LABA for approximately 12 hours (if on BID therapy) or 
approximately 24 hours (if on QD therapy) prior to taking it in the clinic. Additionally, subjects 
should have refrained from taking their albuterol for at least 6 hours prior to their spirometry. 
They should further refrain from using albuterol throughout the study visit. 
It is important at study visits that the trough FEV1 is done before receiving study drug (or and 
before taking LABA if applicable). If the subject is taking a LABA this must be taken 
immediately before the study drug. 
The following procedures will be performed at Visit 3: 
• 
Physical Exam 
• 
Vital signs (BP and HR) - subjects need to be resting in a semi-recumbent position 
approximately 5 minutes prior to assessment of vital signs. 
• 
Urine pregnancy test 
• 
Collect and review Daily Diary 
• 
Collect and reconcile returned study drug and assess compliance 
• 
Concomitant medications 
• 
Adverse events 
• 
Complete TDI 
• 
Predose FEV1, and FVC, via spirometry to be done 45 minutes and 15 minutes predose. 
• 
Predose IC via spirometry to be done 45 minutes predose and immediately post the FVC 
maneuver. 
• 
MIP – to be done immediately post the IC measurement 




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(In the instance of a subject terminating early due to an adverse event a telephone follow-up 
visit will be conducted 30 days afterwards to review concomitant medications and adverse 
events.) 
6.2.4 Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to 
assess for or follow-up on adverse events, at the subject’s request, or as deemed necessary 
by the investigator. The date and reason for the unscheduled visit should be recorded in the 
source documentation. The following activities may be completed at unscheduled visits as 
required or medically indicated: 
• 
Medical history update 
• 
Vital Signs 
• 
Physical Exam 
• 
Record concomitant medications 
• 
Record adverse events 
• 
Spirometry 
• 
PIFR 
• 
MIP 
6.3 
Description of Study Assessments 
6.3.1 Demographic and Screening Assessments 
After obtaining informed consent, each subject will be asked to provide a relevant medical 
history including medication history, concomitant medications, and demographic information 
including date of birth, sex, race, and ethnicity.  The subject will also undergo a physical 
examination including vital signs, height, and weight and also will have the following 
assessments measured;  PIFR,  FEV1, FVC (as part of spirometry for ipratropium 
reversibility),  and a urine pregnancy test for  females of child-bearing potential. 
6.3.2 Efficacy Assessments 
6.3.2.1 Spirometry 
Spirometry, using a flow-volume loop for all respiratory flow measurements, will be 
completed as follows during the course of the study. Measurements will be done according 
to methods described separately in the Spirometry Manual; this Manual is based on ATS 
Guidelines. 


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• 
At Visit 1B (as part of ipratropium reversibility) 
• 
At Visits 2 and 3  
The time window for the 45 and 15 minute predose spirometry will be ± 10 minutes, which 
applies to the end time of the session.  The time window for the 1, 2 and 4 hour postdose 
spirometry will be ± 10 minutes, which applies to the start time of the session.  IC will be 
measured by a separate slow vital capacity maneuver and only be performed immediately 
after the 45 minute predose FVC maneuver at Visit 2 and 3. 
A central spirometry vendor will be used to provide standardized training on spirometry, 
qualification of the spirometry technician, and quality control of the spirometry throughout 
the study. 
PIFR and MIP will be measured at time points shown in the schedule of procedures using 
methods described in the Spirometry Manual.  As PIFR will be measured with a device that 
involves taking a visual reading using a graduated scale, a second person at the site will be 
asked to verify the reading and this verification will be noted in the source documents.  
6.3.3 Safety Assessments  
6.3.3.1 Adverse Events 
Adverse events will be reviewed and recorded from the time of first dose of study medication 
through the last day of the follow-up visit. Adverse events may be observed by the site study 
personnel or spontaneously reported by the subject. Subjects will be reminded to call the 
site to report AEs that occur between visits. 
6.3.3.2 Medical History 
Complete medical history at screening will include evaluation for past and present 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, 
lymphatic, hematologic, immunologic, dermatologic, psychiatric, genitourinary, substance 
abuse, surgical history, or any other diseases or disorders. 
6.3.3.3 Physical Examination 
Physical examinations will include examination of the following:  general appearance; head, 
ears, eyes, nose, and throat; neck, skin, cardiovascular system, respiratory system, 
abdominal system, lymphatic system, dermatologic system, musculoskeletal system, and 
nervous system.  


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6.3.3.4 Vital Signs 
Blood pressure (BP), and heart rate (HR), will be recorded only once in the eCRF for each 
protocol specified time point; at screening only, a second measurement may be obtained to 
rule out sustained elevation/decrease of either systolic or diastolic blood pressure. BP will 
be measured manually using a mercury sphygmomanometer or calibrated automatic blood 
pressure device. HR will be measured by palpation of the radial pulse over a 60-second 
period or by the automated blood pressure device.  
6.3.3.5 Pregnancy 
Urine pregnancy tests will be performed in women of child bearing potential. A positive urine 
pregnancy test will be confirmed with a second urine test. If the subject is an early 
termination or withdrawal, a urine pregnancy test will also be performed at the early 
termination visit.  
6.4 
Concomitant Medications 
Inhaled maintenance steroid therapy will be continued at the allowed maintenance dose 
throughout the treatment and washout periods. Albuterol will be allowed as required 
(or “PRN”) during the study. Albuterol should be withheld for at least 6 hours before the first 
spirometry performed at each study visit until all spirometry is completed.  Only study 
supplied albuterol should be used during the subject’s participation in the study. 
If subjects have used albuterol within 6 hours of the spirometry measurement the visit must 
be rescheduled. Use of albuterol as a rescue inhaler will be documented in a medication 
diary and recorded in the eCRF. 
Subjects who are receiving a LABA or LABA/ICS (either QD or BID) may be enrolled into the 
study provided that the dose has been stable for at least 30 days prior to Screening and the 
steroid component is ≤1000 mcg/day equivalent to fluticasone propionate. Once enrolled it is 
important to standardize administration of the subject’s LABA or LABA/ICS together with the 
study drug.  These subjects should administer their LABA or LABA/ICS in the morning 
immediately prior to the administration of study drugs. This administration should be 
documented in the source documents on study visit days and subjects should be instructed 
to follow the same procedure while at home between study visits. If subjects have used their 
LABA or LABA/ICS on the morning prior to their in-clinic visit instead of taking it immediately 


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prior to study drug at Visit 2, this visit will be rescheduled and the subject will be trained on 
the importance of not taking this the morning of the study visit. 
LABA and LABA/ICS drugs include the following examples:   
• 
fluticasone propionate/salmeterol combination product  
• 
budesonide/formoterol fumarate dihydrate combination product  
• 
fluticasone furoate/vilanterol combination product 
• 
mometasone/formoterol 
The initiation of new treatment for COPD during this study is strictly prohibited. If the subject 
experiences worsening of symptoms that requires additional therapy other than increased 
use of study supplied albuterol (i.e. an exacerbation of their COPD) they should be 
withdrawn from the study and, if the event qualifies, report this event as a serious adverse 
event. 
Table 2 lists the medications that require washout prior to Randomization. These 
medications are also prohibited throughout the study. Subjects will be permitted to restart 
their routine medications after the completion of Visit 3. 


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6.5 
Restrictions 
Subjects are to observe the following restrictions from Screening through to Day 29: 
• 
Use of recreational drugs 
• 
Medicinal marijuana 
• 
Excessive alcohol during the study period 
• 
Participation in another investigational drug study 
• 
Donation of ≥500 mL blood (or equivalent) 
During study visits (i.e. when the subject is in clinic), smoking, exercise, or caffeine intake or 
large meals should be restricted (further details provided in the 0149 Study Manual). 


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6.6 
Discontinuation 
6.6.1 Subject Discontinuation 
Any subject (or his or her legally authorized representative) may withdraw their consent to 
participate in the study at any time without prejudice. The investigator must withdraw from 
the study any subject who requests to be withdrawn. A subject’s participation in the study 
may be discontinued at any time at the discretion of the investigator and in accordance with 
his or her clinical judgment. When possible, the tests and evaluations listed for the 
termination visit should be carried out. If a subject withdraws before completing the study, 
the reason for withdrawal is to be documented on the CRF. All efforts should be made 
however to minimize discontinuations from the study.  If a subject withdraws consent from 
participation in the study, the sponsor retains the right to use the subject’s data through to 
the date the subject withdraws consent. 
Exacerbations of COPD as part of the disease under study should not be recorded as 
adverse events unless they are Serious Adverse Events (e.g. they are life threatening, 
require or prolong hospitalization, etc.). 
Reasons for which the investigator or the Sponsor may withdraw a subject from the study or 
a subject may choose to terminate participation before completion of the study include, but 
are not limited to, the following: 
• 
Adverse event 
• 
COPD Exacerbation requiring treatment (other than increased use of study supplied 
albuterol)  
• 
Subject choice (i.e. withdrew consent) 
• 
Major deviation of the protocol 
• 
Lost to follow-up 
• 
Termination of the study by the Sponsor 
• 
Other 
Subjects who discontinue study drug early because of an adverse reaction should be 
encouraged to continue their participation in the follow-up safety assessments. A telephone 
follow-up visit will be conducted 30 days after discontinuation to review concomitant 
medications and adverse events if the discontinuation was due to an AE. If a subject fails to 
return for scheduled visits, a documented effort must be made to determine the reason. This 
will consist of at least 3 telephone calls followed by a registered letter to the subject.  


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6.6.2 Subject Replacement 
 
 
  
6.6.3 Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. 
Certain circumstances may require the premature termination of the study, if the principal 
investigator and the Sponsor feel that the type, number and/or severity of AEs justify 
discontinuation of the trial, as for example, when several cases of similar SAEs (SUSARs) 
considered related by both the investigator and the Sponsor occurs. The Sponsor reserves 
the right to discontinue this study at any time for any reason.  
6.7 
Pregnancy 
If a female subject becomes pregnant during the study, the clinical study director 
(or designee) must be notified immediately and the subject discontinued from the study.  
The Investigator must report this to the Sponsor using the Pregnancy Reporting Form 
within 24 hours of becoming aware of the pregnancy. 
If not all information requested on the Pregnancy Reporting Form is available at the time 
of the initial report, follow-up reports must be completed and submitted within 24 hours of 
the Investigator’s becoming aware of any new information. The Investigator is required to 
follow up on the pregnancy until it has completed.  
If the female partner of a male subject becomes pregnant, the Investigator must attempt to 
obtain consent to collect pregnancy information (including the status of the newborn, if 
applicable). 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required. The outcome of the pregnancy and the status of the newborn 
(if applicable) will be reported on the Pregnancy Reporting Form within 24 hours of the 
Investigator’s becoming aware of that information. 


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6.8 
COPD Exacerbation 
Exacerbations of COPD requiring treatment other than increased use of study supplied 
albuterol are cause for withdrawal from the study and will be captured as a reason for study 
termination.  


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7 
ADVERSE EVENTS 
7.1 
Regulatory Definition of an Adverse Event 
In the International Conference on Harmonization (ICH) E6 Guideline for Good Clinical 
Practice, Section 1.2 defines an adverse event (AE) as any untoward medical occurrence in 
a subject or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product. 
7.2 
Adverse Event Definition for the Purposes of This Study 
For the purposes of this clinical study, adverse events will be defined as follows:  
An adverse event (AE) is any untoward medical occurrence in a clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with the study treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease, whether or not considered related to the 
study drug (investigational product). 
Preexisting events that increase in frequency or severity or change in nature during or as a 
consequence of participation in clinical studies will also be considered as adverse events. 
An AE may also include pre- or post-treatment complications that occur as a result of a 
protocol-mandated procedure (such as a biopsy). 
Any medical condition or clinically significant laboratory abnormality with an onset date prior 
to the first dose of study medication is considered to be preexisting and should be 
documented in the medical history CRF, if applicable for the study. 
Whenever possible, the diagnosis (rather than a series of terms related to a diagnosis) 
should be recorded as the AE term. 
An AE does not include the following: 
• 
COPD Exacerbation as that is the disease under study, unless such exacerbation 
qualifies as an SAE. (See SAE below) 
• 
Medical or surgical procedures (such as surgery, endoscopy, tooth extraction, or 
transfusion); the condition that leads to the procedure is an adverse event 


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• 
Preexisting diseases or conditions present or detected before to first dose of study 
medication that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (such as 
hospitalization for elective surgery or social and/or convenience admissions) 
• 
Overdose of either study drug or concomitant medication without any signs or 
symptoms, unless the subject is hospitalized for observation 
7.3 
Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded in the case report form, including 
the dates of onset and resolution, severity, relationship to study drug, outcome, and action 
taken with study medication. 
Clinical severity should be recorded and graded using mild, moderate or severe as 
described below. 
Mild 
= Awareness of signs or symptoms, but easily tolerated 
Moderate 
= Discomfort sufficient to cause interference with usual activities 
Severe 
= Incapacitation with inability to work or perform usual activities 
The relationship to study drug therapy should be assessed using the following definitions: 
• 
Not Related:  Evidence exists that the adverse event has an etiology other than the 
study drug (such as a preexisting condition, underlying disease, intercurrent illness, or 
concomitant medication). 
• 
Possibly/Probably Related: A temporal relationship exists between the event onset 
and administration of the study drug. It cannot be readily explained by the subject’s 
clinical state or concomitant therapies and appears with some degree of certainty to be 
related based on the known therapeutic and pharmacologic actions of the drug. In case 
of cessation or reduction of the dose, the event abates or resolves and reappears upon 
rechallenge. It should be emphasized that ineffective treatment should not be considered 
as causally related in the context of adverse event reporting. 
These criteria in addition to good clinical judgment should be used as a guide for 
determining the causal assessment. If it is felt that the event is not related to study drug 
therapy, then an alternative explanation should be provided. 
7.4 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any adverse drug experience occurring at any 
dose that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening situation (subject is at immediate risk of death) 


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• 
In-patient-hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other 
serious events) 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Congenital anomaly/birth defect in the offspring of a subject who received study drug 
• 
Other: Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such events are as follows: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
Additional Considerations for Serious Adverse Events 
• 
Death is an outcome of an adverse event and not an adverse event in itself. In reports of 
death due to disease progression, where no other information is provided, the death will 
be assumed to have resulted from progression of the disease being treated with the 
study drug(s). 
• 
All deaths, regardless of cause, must be reported for subjects if the death occurs while 
the subject is participating in the study. 
• 
“Occurring at any dose” does not imply that the subject is receiving study drug at the 
time of the event; dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE, but may have contributed to the event. 
• 
“Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death, if it had 
occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is an SAE. 
• 
“In-patient-hospitalization” means the subject has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department. 
• 
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Abnormal assessments (such as vital signs) that are associated with signs and/or symptoms 
or are considered clinically significant in the judgment of the investigator must be recorded 
as AEs or SAEs if they meet the definition of an adverse event (or serious adverse event), 




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documenting the notification, as required by local regulatory authorities and in accordance 
with the local institutional policy. 
7.7 
Adverse Event Follow-up 
A subject experiencing an AE or SAE will be followed by the investigator or his/her trained 
delegate(s) through the follow-up visit or until the investigator and/or the Sponsor has 
determined that the AE or SAE has resolved or a stable clinical endpoint is reached, 
whichever is longer. The Sponsor may request follow-up of certain adverse events until 
resolution and documentation of assessments made during this period. 
The investigator must take all therapeutic measures necessary for resolution of an SAE. Any 
medications necessary for treatment of the SAE must be recorded in the concomitant 
medication section of the case report form. 


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8 
STATISTICAL CONSIDERATIONS 
8.1 
General Considerations 
All individual data will be listed as measured. All statistical summaries and analyses will be 
performed using SAS software (SAS Institute, Cary, North Carolina, USA).  
Continuous data will be summarized using 
 
 
 
  
Categorical data will be summarized using the
 
 
Any changes to the protocol-specified analyses will be pre-specified in the Statistical 
Analysis Plan prior to data lock. 
8.2 
Sample Size and Power 
 
 
 
 
 approximately 100 subjects will be 
randomized per treatment group (N=200 subjects in total). 
 
 
 
 
A total of 50 or more subjects with GOLD grade 4 will be enrolled. 
8.2.1 Randomization Strata 
Randomization will be conducted using the following stratum to ensure balance in subjects: 
• 
Concomitant LABA use 
) 
• 
Baseline PIFR set to 
 resistance 
 
• 
GOLD airway limitation grade (
) 




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8.3.3 Major Protocol Deviations 
The following protocol deviations are defined as major and would be considered to have an 
impact on the analysis of efficacy data. 
 
 
 
 
 
 
 
8.4 
General Analyses 
8.4.1 Demographics and Other Baseline Characteristics 
Demographics (including age, sex, race, ethnicity, height, weight, and BMI) and baseline 
characteristics (concomitant LABA use) will be summarized for the Safety analysis set. 
8.4.2 Screening and Baseline Spirometry 
A summary of pulmonary function at screening, including reversibility, and at baseline using 
the ITT analysis set will be provided. 
8.4.3 COPD Clinical History and Smoking History 
A summary of the COPD clinical characteristics/history and smoking history using the ITT 
analysis set will be provided. 
8.4.4 Select Medical History 
A summary of select medical history/characteristics using the Safety analysis set will be 
provided characterizing co-morbidities and disease severity. 
8.4.5 Reversibility 
Reversibility to ipratropium is defined as a post-bronchodilator increase of 12% and at least 
a 200 mL increase in FEV1 relative to the pre-bronchodilator response at the relative 
screening visit. 
8.5 
Efficacy Analyses 
For efficacy analyses, the ITT population will be used. In select analyses, the PP and 
subgroup examination sets may be used. 


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8.5.1 Efficacy Endpoints 
The primary study endpoint is trough FEV1 post the 28th dose on Day 29. 
The secondary endpoints are: 
• 
Trough FVC  and IC post 28th dose on Day 29 
• 
Peak FEV1 and FVC on Day 29 (0-4 hours) 
• 
Rescue albuterol use (incidence of albuterol use) 
 
 
 
 
s FEV1, FVC (0-4 hours) on Days 1 and 29  
• 
TDI on Day 29 
8.5.2 Primary Efficacy Evaluation 
 
 
 
 
  
The following hypothesis testing schema will be employed to assess the primary endpoint: 
the null hypothesis for the treatment comparison will be that there is no difference between 
the mean responses at a given dose level of revefenacin and the mean response on the 
tiotropium treatment in trough FEV1. The alternative hypothesis will be that there is a 
difference. 
 
 
 
 
 
 
 
 
 
 


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. 
8.5.3 Secondary Efficacy Endpoints 
8.5.3.1 Trough FVC and IC  
 
  
8.5.3.2 Peak FEV1 and FVC   
Peak pulmonary functions will be summarized 
 
 
8.5.3.3 Rescue Medication Endpoints 
Rescue medication endpoints will be summarized using a similar methodology as the 
primary endpoint where
 
 
8.5.3.4 Clinical Outcomes Assessments 
 
 
 
 
 
 
 
 




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8.6 
Safety Analyses 
For all safety analyses, the safety analysis set will be used. 
Safety variables to be summarized include vital signs and adverse events. Vital signs will be 
summarized in terms of observed values and changes from baseline. 
8.6.1 Extent of Exposure 
A subject’s data for the extent of exposure to study drug will be generated from study drug 
accountability. Dosing information for individual subjects will be listed. 
 
 
 
8.6.2 Adverse Event Data 
8.6.2.1 Adverse Events 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will present by system organ class (SOC), preferred term 
(PT) and severity, the frequency and percentage of subjects reporting each observed event. 
A treatment-emergent adverse event (TEAE) will be defined as any AE that 
 
 
AEs observed during the period from obtaining 
informed consent to the first dose of study drug are to be captured as medical history. 
All AEs and all TEAEs will be listed by subject. The frequency of subjects who experience 
TEAEs will be summarized overall and by treatment group. AEs will also be summarized by 
relationship to treatment (study drug) and severity. 
A listing will be provided for all subjects who experience an SAE. Data listings will also be 
provided for subjects who discontinued the study due to any AE, as well as for a SAE. 
8.6.3 Concomitant Medications 
Medications will be summarized both prior and during the 1-month treatment period. 
Medications will be summarized as COPD bronchodilator, ICS and non-COPD medications. 
 


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8.6.4 Vital Signs Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.7 
Missing Data Handling 
 
 
 
 
8.8 
Data Monitoring Committee 
No data monitoring committee is planned for this study. 
Monitoring of trial data to ensure the safety of subjects will take place by the ongoing 
periodic review of tables and listings of the safety data collected during the conduct of the 
trial.  These meetings will take place approximately monthly once the trial has been initiated. 


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9 
STUDY ADMINISTRATION 
This study will be conducted in compliance with all applicable regulations. 
9.1 
Principal Investigator Responsibilities 
Before beginning the study, the principal investigator (PI) at each site must provide to the 
Sponsor or its designee a fully executed and signed Form FDA 1572 and, if applicable, a 
financial disclosure form. For applicable studies, financial disclosure forms must also be 
completed for all sub-investigators who will be directly involved in the treatment or 
evaluation of research subjects in this study. (A sub-investigator is defined in ICH E6 as any 
individual member of the clinical study team designated and supervised by the investigator 
at a study site to perform critical study-related procedures and/or to make important 
study-related decisions [e.g. associates, residents, research fellows].) 
The PI will ensure the following: 
• 
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the Sponsor, except when necessary 
to protect the safety, rights, or welfare of subjects. 
• 
He or she will personally conduct or supervise the study. 
• 
He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional 
review board (IRB) review and approval in 21 CFR Part 56 are met.  
• 
He or she will report to the Sponsor adverse experiences that occur in the course of the 
investigation in accordance with 21 CFR 312.64. 
• 
He or she has read and understands the information in the revefenacin Investigator’s 
Brochure, including potential risks and side effects of the drug. 
• 
His or her staff and all persons who assist in the conduct of the study are informed about 
their obligations in meeting the above commitments 
• 
He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• 
He or she will ensure that the IRB/IEC complies with the requirements of 
21 CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human subjects or others are 
reported to the IRB/IEC. Additionally, he or she will not make any changes in the 
research without IRB/IEC approval, except where necessary to eliminate apparent 
immediate hazards to human subjects. 
• 
He or she agrees to comply with all other requirements regarding the obligations of 
clinical investigators and all other pertinent requirements in 21 CFR Part 312. 


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9.2 
Institutional Review Board/Independent Ethics Committee 
Before beginning study-specific research, the investigator will obtain written confirmation 
that the IRB, IEC, or Research Ethics Board (REB) is properly constituted and compliant 
with ICH and GCP requirements, applicable laws, and local regulations. A copy of the 
confirmation from the IRB/IEC/REB will be provided to the Sponsor or its designee. The 
protocol, informed consent form (ICF), IB, and any other appropriate written information 
provided to the subjects that the IRB/IEC/REB may require to fulfill its responsibilities will be 
submitted to the IRB/IEC/REB in advance of the study. The Sponsor or its designee must 
approve the ICF and all subject recruitment materials before they are submitted to the 
IRB/IEC/REB. The study will not proceed until appropriate documents from the IRB/IEC/REB 
confirming unconditional approval of the protocol and the ICF are obtained by the 
investigator and copies are received by the Sponsor or its designee. If possible, the 
approval document should refer to the study by study protocol title and the Sponsor study 
number, identify the documents reviewed, and include the date of the review and approval. 
The written approval of the IRB/IEC/REB will be retained as part of the study file. The study 
may proceed before approval of consent forms and other study documents translated to a 
language other than the native language of the clinical site, provided that written 
IRB/IEC/REB approval of the translated documents is obtained before they are used. Any 
amendments to the protocol should be reviewed promptly. 
The investigator must provide the appropriate periodic reports on the progress of the study 
to the IRB/IEC/REB and the Sponsor in accordance with local IRB/IEC/REB requirements 
and applicable governmental regulations, whichever is strictest. 
9.3 
Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (GCP Guideline, 
Section 4.8), 21 CFR §50, and other applicable local regulations, will be obtained for each 
subject before enrollment of the subject into the study. The investigator will prepare the ICF 
or revise the template ICF and provide the documents to the Sponsor (or designee) for 
approval before submission to the IRB/IEC/REB. The Sponsor and the IRB/IEC/REB must 
approve the documents before they are implemented. 
The investigator will provide copies of the signed ICF to each subject (or the subject’s legally 
authorized representative) and will maintain the original in the subject’s record file. 


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9.4 
Data Recording and Quality Assurance 
As used in this protocol, the term case report form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used. 
Electronic data capture (EDC) technology will be used for this study. All clinical information 
requested in this protocol will be recorded on the electronic case report forms approved by 
the Sponsor, or via other data collection methods, e.g. electronic laboratory data transfer. 
Study site personnel will enter (in English) study data into the CRFs for each randomized 
subject. Training on the EDC application will be completed and documented before access 
to the EDC system is given. 
In the event of a CRF data change (e.g. correction of an error or addition of new 
information), corrections will be made to the CRF. Corrections to the CRFs, including the 
reason for change, will be automatically documented through the EDC system’s audit trail. 
The investigator is responsible for reviewing all CRFs, verifying them for accuracy, and 
approving them via an electronic signature. The investigator is designated as the signatory 
coordinating investigator. 
An electronic copy of the CRF casebooks will be sent to the site for retention with other 
study documents after full completion of the study, i.e. after database lock. 
The investigator is responsible for maintaining accurate, authentic, complete, and up-to-date 
records for each subject. The investigator is also responsible for ensuring the availability of 
any original source documentation related to the study (including any films, tracings, 
computer discs, tapes, and worksheets). In most cases the source is the subject’s medical 
record. Data collected on the CRFs must match the source documents. 
In some cases, the CRF may also serve as the source document. In these cases, a 
document should be available at the investigator’s site and clearly identify those data that 
will be recorded in the CRF and for which the CRF will stand as the source document. 
 


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9.5 
Document Retention 
Until otherwise notified by the Sponsor, an investigative site must retain in a controlled 
manner all study documents required by the Sponsor and by the applicable regulations. The 
investigative site must take measures to prevent accidental or premature destruction of 
essential documents, that is, documents that individually and collectively permit evaluation 
of the conduct of a study and the quality of the data produced, including paper copies of 
study records (e.g. subject charts) and any original source documents that are electronic, as 
required by applicable regulations. 
The investigator must consult the Sponsor representative before disposal of any study 
records and must notify the Sponsor of any change in the location or disposition of the study 
files. If an investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study documents, custody must be transferred to a person who 
will accept the responsibility. The Sponsor must be notified in writing of the name and 
address of the new custodian and must approve this transfer of responsibility. 
9.6 
Confidentiality 
The investigator or designee must explain to each subject, before enrollment into the study, 
that, for evaluation of study results, the subject’s confidential medical information obtained 
during the study may be shared with the study sponsor, the study sponsor's designated 
service providers, regulatory agencies, and the institutional review board (IRB) or 
independent ethics committee (IEC). Suppliers used in the study will also have access to 
some of the subjects’ medical information as part of providing their services in the study 
(e.g. central spirometry). The investigator (or designee) is responsible for obtaining written 
permission to use confidential medical information in accordance with country-specific 
regulations (such as the Health Insurance Portability and Accountability Act in the 
United States) from each subject or, if appropriate, the subject’s legally authorized 
representative. If permission to use confidential medical information is withdrawn, the 
investigator is responsible for documenting that no further data from the subject will be 
collected. 
Subject medical information obtained during this study is confidential, and disclosure to 
unauthorized third parties is prohibited. The pertinent sections of data protection laws will be 
complied with in full. Study records containing subject information will only be identified by 


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the subject identification number, subject initials, date of birth, and study number, and not by 
the subject’s full name, except the subject consent form, which is archived at the study 
center only. The subject’s name will not be used in any public report of the study. 
During the course of the study, a confidential subject identification list will be maintained by 
the investigator and archived at the investigative site. 
Before and during the conduct of the study, no study-related details may be disclosed, 
i.e. placed on the internet, published, or otherwise publicized, or provided to a third party 
without prior written permission from the Sponsor. The policy for publication of data after 
completion of the study is described in Section 9.9 (Publication). 
9.7 
Access to Data and Documents 
Upon receipt of the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare. 
Study data recorded on the CRFs must be verifiable to the source data. All original 
recordings, laboratory reports, and subject records generated by this study must be 
available to the Sponsor, representatives of the Sponsor, the IRB/IEC/REB, and applicable 
regulatory authorities, and they may be used for submission to regulatory authorities. In 
addition, all source data should be attributable (signed and dated), consistent with local 
medical practice. The investigator must therefore agree to allow direct access to all source 
data. Subjects (or their legally authorized representatives) must also allow access to their 
medical records, and subjects will be informed of this and will confirm their agreement when 
giving informed consent. 
9.8 
Quality Control: Study Monitoring and Auditing 
Qualified individuals designated by the Sponsor will monitor all aspects of the study 
according to GCP and standard operating procedures (SOPs) for compliance with 
applicable government regulations. The investigator agrees to allow these monitors direct 
access to the clinical data and supplies, dispensing, and storage areas and, if requested, 
agrees to assist the monitors. The investigator and staff are responsible for being present or 
available for consultation during routinely scheduled site visits conducted by the Sponsor or 
its designees. 


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


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10 
REFERENCES 
The following references are available upon request. 
1. Global initiative for chronic obstructive lung disease (GOLD). Global strategy for the 
diagnosis, management and prevention of chronic obstructive pulmonary disease. 
2017. Available at: http://goldcopd.com 
2. Martonen TB, Katz IM. Deposition patterns of aerosolized drugs within human lungs: 
effects of ventilatory parameters. Pharm Res. 1993 Jun;10(6):871-8 
3. Seheult JN, Costello S, Tee KC, Bholah T, Al Bannai H, Sulaiman I, Costello RW. 
Investigating the relationship between peak inspiratory flow rate and volume of 
inhalation from a 
 Inhaler and baseline spirometric parameters: a 
cross-sectional study. Springerplus. 2014 Sep 2;3:496. doi: 10.1186/2193-1801-3-
496. eCollection 2014 
4. Mahler DA, Waterman LA, Ward J, Gifford AH. Comparison of dry powder versus 
nebulized beta-agonist in patients with COPD who have suboptimal peak inspiratory 
flow rate. J Aerosol Med Pulm Drug Deliv. 2014 Apr;27(2):103-9. doi: 
10.1089/jamp.2013.1038. Epub 2013 Jun 8 
5. Al-Showair RA, Tarsin WY, Assi KH, Pearson SB, Chrystyn H. Can all patients with 
COPD use the correct inhalation flow with all inhalers and does training help? Respir 
Med. 2007 Nov;101(11):2395-401. Epub 2007 Jul 12 
6. Jarvis S, Ind PW, Shiner RJ. Inhaled therapy in elderly COPD patients; time for 
re-evaluation? Age Ageing. 2007 Mar;36(2):213-8 
7. Mahler DA, Waterman LA, Gifford AH. Prevalence and COPD phenotype for a 
suboptimal peak inspiratory flow rate against the simulated resistance of the 
 
dry powder inhaler. J Aerosol Med Pulm Drug Deliv. 2013 Jun;26(3):174-9. doi: 
10.1089/jamp.2012.0987. Epub 2012 Oct 1 
8. Chee Hong Loh, MD; Tina Lovings, RCP; Jill Ohar, MD. Long Acting Nebulized 
Agents Decrease Readmissions in Patients With Suboptimal Peak Inspiratory Flow. 
Chest. 2016;150(4_S):925A. doi:10.1016/j.chest.2016.08.1025 


Protocol 0149, Amendment 2 
Version 1.0, 04APR2017 
TD-4208 
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Appendix 1: 
Signature Page 


Protocol 0149, Amendment 2 
Version 1.0, 04APR2017 
TD-4208 
Page 75 
 
Confidential – Property of Theravance Biopharma, Inc. 
Protocol Signature Form 
 
 
 
 
 
Title: 
A Phase 3b, Randomized, Double-Blind, Double-Dummy, Parallel-Group, 
Study to Compare Once Daily Nebulized Revefenacin with Spiriva Once Daily 
Delivered via the 
on Lung Function in Subjects with Chronic 
Obstructive Pulmonary Disease and a Low Peak Inspiratory Flow Rate 
 
Study No.: 
0149 
 
 
Date: 
04 April 2017 
 
 
 
 
 
 
I have read the forgoing protocol and agree to conduct this study in accordance with the 
current protocol. I also agree to conduct the study in compliance with all applicable 
regulations. 
 
 
 
______________________________________________ 
Investigator’s Name (print) 
 
 
 
______________________________________________ 
______________________ 
Investigator’s Signature 
Date 

SAP_000.pdf: 
 
Statistical Analysis Plan 
Study 0149 
 
Final Version, 27NOV2017 
revefenacin 
 
Page 1 
 
  
STATISTICAL ANALYSIS PLAN 
Compound: 
revefenacin 
Study Number: 
Study 0149 
Study Title: 
A Phase 3b, Randomized, Double-Blind, Double-Dummy, 
Parallel-Group, Study to Compare Once Daily Nebulized 
Revefenacin with Spiriva Once Daily Delivered via the 
HandiHaler® on Lung Function in Subjects with Chronic 
Obstructive Pulmonary Disease and a Low Peak Inspiratory Flow 
Rate 
Protocol Version: 
 
Sponsor: 
Theravance Biopharma R&D, Inc. 
c/o Theravance Biopharma US, Inc. 
901 Gateway Boulevard 
South San Francisco, CA  94080 
Plan Version: 
27 November 2017 – Version 1.0 
Plan History: 
No prior versions 
Plan Prepared by: 
 
 
Theravance Biopharma US, Inc. 
 
 
CONFIDENTIAL 
This document is confidential and the property of Theravance Biopharma, Inc. It may not be 
copied or provided to any other party without the express written consent of 
Theravance Biopharma, Inc. 
© Theravance Biopharma (Unpublished Work). All rights reserved. 
 




 
 
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TABLE OF CONTENTS 
 
PAGE 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................. 6 
1 
INTRODUCTION ....................................................................................................... 8 
2 
STUDY OBJECTIVES ............................................................................................... 8 
2.1 
Primary Objective ........................................................................................... 8 
 
 
3 
OVERVIEW OF STUDY DESIGN .............................................................................. 9 
4 
SAMPLE SIZE AND POWER .................................................................................. 11 
5 
STUDY ENDPOINTS ............................................................................................... 11 
5.1 
General Endpoints ....................................................................................... 12 
5.2 
Efficacy Endpoints ........................................................................................ 13 
5.3 
Safety Endpoints .......................................................................................... 14 
6 
GENERAL ANALYSIS CONSIDERATIONS ............................................................ 15 
6.1 
Global Definitions and Conventions.............................................................. 15 
6.1.1 
Baseline Definition ............................................................................ 15 
6.1.2 
Analysis Windows ............................................................................. 15 
6.1.3 
Missing Data ..................................................................................... 16 
6.2 
Adverse Events ............................................................................................ 18 
6.3 
Medications .................................................................................................. 18 
6.4 
Medical History ............................................................................................ 18 
6.5 
General Considerations for Summaries ........................................................ 18 
6.6 
Tables, Figures and Listings (TFLs) ............................................................. 20 
7 
ANALYSIS SETS ..................................................................................................... 21 
7.1 
Safety ........................................................................................................... 21 
7.2 
Intent-to-Treat .............................................................................................. 21 
7.3 
Per-Protocol ................................................................................................. 21 
7.4 
Examination of Subgroups ........................................................................... 22 
7.4.1 
Study-Specific Subgroups ................................................................ 22 
7.5 
Major Analysis Protocol Deviations .............................................................. 22 
8 
DEFINITION OF ANALYSIS VARIABLES ............................................................... 23 
8.1 
General Variables ........................................................................................ 23 
8.2 
Efficacy Variables ......................................................................................... 25 
8.3 
Safety Variables ........................................................................................... 27 
9 
ANALYSES.............................................................................................................. 27 
9.1 
General Analyses ......................................................................................... 28 
9.1.1 
Subject Disposition ........................................................................... 28 
9.1.2 
Demographics and Baseline Characteristics ..................................... 28 
9.1.3 
Reversibility Summaries ................................................................... 28 
9.1.4 
Screening and Baseline Spirometry Summaries ............................... 29 


 
 
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9.1.5 
Baseline Clinical Characteristics Summaries .................................... 30 
9.1.6 
GOLD Category Summary ................................................................ 30 
9.1.7 
Key Demographic and Baseline Characteristics Summary ............... 31 
9.2 
Efficacy Analysis .......................................................................................... 32 
9.2.1 
General Considerations for Efficacy Analyses .................................. 32 
9.2.2 
Primary Efficacy Evaluation: Trough FEV1 ....................................... 32 
9.2.2.1 
Sensitivity Analyses of the Efficacy Endpoint: Trough 
FEV1 ................................................................................. 33 
9.2.3 
Secondary Efficacy Evaluation: Trough FVC and Trough IC ............. 33 
9.2.3.1 
Sensitivity Analyses of the Efficacy Endpoint: Trough FVC 
and Trough IC on Day 29 .................................................. 34 
9.2.4 
Secondary Efficacy Evaluation: Peak FEV1 and Peak FVC 
(0−4 hours) ....................................................................................... 34 
9.2.5 
Secondary Efficacy Evaluation: Rescue Medication Puffs/Day ......... 36 
9.2.6 
Exploratory Efficacy Evaluation: Weighted Mean FEV1 and 
Weighted Mean FVC (0-4 hours) ...................................................... 36 
9.2.7 
Exploratory Efficacy Evaluation: TDI Scores ..................................... 37 
9.2.8 
Exploratory Efficacy Evaluation: PIFR and MIP ................................ 38 
9.2.9 
Multiplicity Adjustment ...................................................................... 39 
9.3 
Safety Analyses ........................................................................................... 40 
9.3.1 
Extent of Exposure ........................................................................... 41 
9.3.2 
Adverse Events ................................................................................ 41 
9.3.2.1 
Antimuscarinic Adverse Events ......................................... 43 
9.3.3 
Vital Signs ........................................................................................ 43 
9.3.4 
Medical History ................................................................................. 43 
9.3.5 
Prior and Concomitant Medications .................................................. 43 
 
 
 


 
 
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LIST OF FIGURES 
 
Figure 1: 
Study Schematic ............................................................................... 10 
Figure 2: 
Statistical Testing Hierarchy (difference between treatment 
groups) ............................................................................................. 39 
 
LIST OF TABLES 
 
Table 1: 
Efficacy Endpoints ............................................................................ 14 
Table 2: 
Baseline Assessment for Specific Parameters .................................. 15 
Table 3: 
Analysis Windows: Visits .................................................................. 16 
Table 4: 
Analysis Windows: Treatment Emergent Events ............................... 16 
Table 5: 
GOLD Severity of Airflow Limitation Categories ................................ 24 
Table 6: 
GOLD Categories ............................................................................. 24 
Table 7: 
GOLD Grade .................................................................................... 25 
Table 8: 
Vital Signs Outlier Thresholds ........................................................... 43 
 
LIST OF APPENDICES 
 
Appendix 1: 
Reporting Structures for Data Summary ........................................... 44 
Appendix 2: 
Coding Logic for Concomittant Medications and Adverse 
Events of Interest .............................................................................. 45 
Appendix 3: 
BDI Scoring ...................................................................................... 50 
Appendix 4: 
TDI Tool ............................................................................................ 51 
Appendix 5: 
Regular and Truncated Hochberg Procedures .................................. 54 
Appendix 6: 
Summary of TFLs (General, Safety and Efficacy) ............................. 55 
 
 


 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
ABS 
absolute 
ADaM 
Analysis data model 
AE 
adverse event 
ALB 
albuterol 
AUC 
area under the curve 
AR 
autoregressive 
BDI 
Baseline Dyspnea Index 
BID 
twice-daily 
BLQ 
below level of quantification 
BLS MEAN 
Binomial least square mean reporting method 
BMI 
body mass index 
BP 
blood pressure 
CAT 
COPD Assessment Tool 
CCQ 
Clinical COPD Questionnaire 
CEC 
cardiovascular event committee 
CFB 
change from baseline 
CI 
confidence interval 
C 
continuous reporting method 
COPD 
chronic obstructive pulmonary disease 
CRO 
contract research organization 
CSR 
clinical study report 
D 
day(s) 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
ePFM 
electronic peak flow meter 
F 
frequency reporting method 
FVC 
forced vital capacity 
FEV1 
forced expiratory volume in one second 
GERD 
gastrointestinal reflux disease 
GOLD 
Global initiative for chronic obstructive lung disease 
H 
hour(s) 
HR  
heart rate 
ICS 
inhaled corticosteroid 
IPR 
ipratropium 
ITT 
intent-to-treat 
KDE 
kernel density estimation 
KM 
Kaplan Meier reporting method 


 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
LABA 
long-acting beta agonist 
LAMA 
long-acting muscarinic antagonist 
LS 
least-square 
MAR 
missing at random 
MDI 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIP 
maximum inspiratory pressure 
MF 
multiple frequency reporting method 
mL 
milliliters 
mMRC 
Modified Medical Research Council Dyspnea Scale 
MNAR 
missing not at random 
NC 
non-calculable 
NLS MEAN 
normal least square mean reporting method 
NQ 
non-quantifiable 
PD 
pre-dose 
PIFR 
peak inspiratory flow rate 
PK 
pharmacokinetic 
PP 
per-protocol 
QD 
once-daily 
REV 
revefenacin 
RMMM 
repeated measures mixed effect model 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCR 
screening 
SOC 
system organ class 
TDI 
Transitional Dyspnea Index 
TEAE 
treatment-emergent adverse event 
UN 
unstructured 
WM 
weighted mean 
WHODD 
World Health Organization Drug dictionary 
 


 
 
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1 
INTRODUCTION 
This document outlines the initial plan for the summarization and analysis of clinical data 
collected in the Phase 3b Study 0149 for revefenacin. This document describes the a priori 
plan for analysis.  Once the analysis is in progress, it may become apparent from the data 
that the planned analysis should be modified.  Any substantive modification to the original 
analysis plan will be identified in the clinical study report (CSR). 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• 
To characterize the relative efficacy on trough FEV1 of revefenacin administered once 
daily via nebulization compared to tiotropium administered once daily via
 in 
a population of subjects with moderate to very severe COPD and suboptimal PIFR. 
2.2 
Exploratory Objectives 
The exploratory objectives of the study are: 
  
 
 
 
 
 
 
 
 
 


 
 
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3 
OVERVIEW OF STUDY DESIGN 
This is a randomized, double-blind, double-dummy, parallel group study.  
Each subject will receive study treatment once daily in the morning for the length of study 
duration, up to 29 days and all subjects will be allowed to continue on their current regimen 
of concomitant ICS/LABA therapy of their choice, either QD or BID administration. There will 
be two treatment groups (revefenacin 175 mcg and tiotropium 18 mcg). Revefenacin 
solution for inhalation (3 mL) will be administered using the 
 jet nebulizer. 
Tiotropium will be administered using the 
 device with the drug and placebo 
capsules blinded using precedent blinding methods. 
Subjects will be assessed during screening for low PIFR using the 
 device to 
measure PIFR set to 
 resistance for inclusion to the study and set to the 
 resistance for descriptive purposes. Subjects with PIFR lower than 60 L/min 
set to the 
 resistance defined in this study as suboptimal PIFR, and who meet all 
eligibility criteria will be randomized. 
Once screening criteria have been met, subjects will have baseline characteristics and 
medical history collected.  At Visit 1B reversibility to ipratropium will be evaluated and PIFR 
measurements will be collected set to both the 
 and to Handihaler® resistance. 
At Visit 2 (Day 1), eligible subjects will be randomized to one of two groups in the study.   
Spirometry, including FVC and FEV1, will be assessed at baseline (-45 and -15 minutes 
predose), 1 hour, 2 hour, and 4 hour post dosing. Hyperinflation, as measured by inspiratory 
capacity (IC) will also be assessed at -45 mins predose. This will be done by a Slow Vital 
Capacity (SVC) maneuver immediately after the FVC maneuver. Maximal Inspiratory 
Pressure (MIP) will be performed following the SVC.   
At Visit 3 (Day 29), subjects will return for final in-clinic dosing and spirometry assessments. 
Safety assessments, including collection of adverse events will be performed at every visit. 
A supply of rescue medication (albuterol MDI or nebulized) for use in the study and a 28-day 
supply of study medication will be provided for each subject. 


 
 
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Figure 1: 
Study Schematic 
Visit 1A 
Visit 1B 
Visit 2 
Randomization 
Treatment Period 
(29 days) 
Visit 3 
(Day 29) 
Follow-Up 
Phone Call 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
PIFR 
 
PIFR  
ipratropium 
Reversibility 
Spirometry  
 
Randomization 
Baseline 
Measures 
revefenacin 
active 
tiotropium 
Placebo 
revefenacin 
Placebo  
tiotropium 
active 
ConMeds 
 
AEs 
 
Study 
Medication 
Daily Diary 
ConMeds 
Adverse 
Events 
Washout 
(Up to 48 hours) 
No 
Exacerbations 
Study 
Medication 
Daily Diary 
ConMeds 
Adverse 
Events 
TDI  
Spirometry 
PIFR 
MIP 


 
 
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4 
SAMPLE SIZE AND POWER 
 
 
 
 
 approximately 100 subjects will be 
randomized per treatment group (N=200 subjects in total). 
 
 
 
 
A total of 50 or more subjects with GOLD airflow limitation category 4 will be enrolled. 
5 
STUDY ENDPOINTS 
All study endpoints and/or assessments include an evaluation type, i.e., absolute value, 
change from baseline, an ADAM Type, either derived from raw data or raw data, i.e., CRF or 
Lab-type data, an evaluation window, i.e., screening, Day 1, Days 1-29, and a summary 
type, i.e., continuous, frequency, normal least squares.  
The primary study endpoint is trough FEV1 post the 28th dose on Day 29 
The secondary endpoints are: 
• 
Trough FVC  and IC post 28th dose on Day 29 
• 
Peak FEV1, FVC on Day 29 (0-4 hours) 
• 
Rescue albuterol use (incidence of albuterol use) 
The safety endpoints are: 
• 
Exposure 
• 
Adverse events 
• 
Vital signs 
• 
Concomitant medications 
The exploratory endpoints will be characterized:  
 
 
 
  
 
 
 
 


 
 
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5.1 
General Endpoints 
The following general endpoints will be summarized in the following table. 
Endpoint 
Evaluation Type 
ADAM Type 
Reporting 
Window 
age 
 
 
 
sex 
 
 
 
ethnicity 
 
 
 
race 
 
 
 
height 
 
 
 
weight 
 
 
 
BMI 
 
 
 
smoking Status 
 
 
 
Maximum number of packs per day 
 
 
 
Number of years smoked 
 
 
 
Number of pack-years 
 
 
 
Age (≤65, >65) 
 
 
 
concurrent ICS use 
 
 
 
concurrent LABA use 
 
 
 
concurrent QD/BID/NO LABA 
 
 
 
concurrent ICS/LABA use 
 
 
 
Baseline FEV1  
 
 
 
predicted normal FEV1 
 
 
 
percent predicted FEV1 
 
 
 
Baseline FVC 
 
 
 
FEV1 to FVC ratio 
 
 
 
Baseline PIFR 
 
 
 
Baseline IC 
 
 
 
Baseline MIP 
 
 
 
duration of COPD 
 
 
 
subjects with a history of 
supplemental oxygen 
 
 
 
Cardiovascular risk factor 
 
 
 
GOLD category 
 
 
 
GOLD severity of airflow limitation 
 
 
 
Indicator: mMRC score ≥2 
 
 
 


 
 
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Endpoint 
Evaluation Type 
ADAM Type 
Reporting 
Window 
primary reason for study drug 
discontinuation 
 
 
 
subject disposition 
 
 
 
subjects in Safety Group 
 
 
 
subjects in ITT Group 
 
 
 
subjects in PP Group 
 
 
1 
Note: D: day, PD: pre-dose, SCR: screening, ABS: absolute value, EOS: end of study 
 
5.2 
Efficacy Endpoints 
The efficacy endpoints will be summarized in Table 1. 


 
 
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Table 1: 
Efficacy Endpoints 
Endpoint 
Evaluation 
Type 
ADAM Type 
Reporting 
Window 
Summary 
Type(s) 
trough FEV1 
ABS, CFB 
derived 
D29 
NLS 
MEAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: D: day, CFB: change from baseline, ABS: absolute value 
Note: For summary types, see Appendix 1) 
 
5.3 
Safety Endpoints 
Safety variables to be summarized include exposures, vital signs, and adverse events. Vital 
signs will be summarized in terms of observed values and changes from baseline. 


 
 
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6 
GENERAL ANALYSIS CONSIDERATIONS 
6.1 
Global Definitions and Conventions 
All data from scheduled and unscheduled visits will be presented in the subject listings; 
however, unless noted otherwise, only data from appropriately windowed visits 
(Section 6.1.2) will be included in the summaries, statistical analysis, and calculation of 
derived parameters. 
6.1.1 Baseline Definition 
The Table 2 indicates the timing of the baseline assessment to be used in the analysis of 
specific parameters. 
Table 2: 
Baseline Assessment for Specific Parameters 
Parameter 
No 
Baseline 
Visit 
1B 
Visit 2 
(Day 1-PD) 
PIFR 
 
X 
 
FEV1  
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
 
 
X 
1 mean of -45 and -15 min PD assessments; PD: pre-dose 
6.1.2 Analysis Windows 
All assessments will be summarized using analysis windows.  
All data (scheduled and unscheduled visits) will be presented in the subject listings; 
however, unless noted otherwise, only data from appropriately windowed visits will be 
included in the summaries, statistical analysis, and calculation of derived parameters. 
The following visit windows will be used in the summary of clinical data. 


 
 
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Table 3: 
Analysis Windows: Visits  
Nominal Visit 
Nominal Day 
Start (days) 
Stop (days) 
2 
1 
1 
1 
3 
29 
14 
44 
Safety Endpoints 
The following windows summarize the definition of treatment-emergent. 
Table 4: 
Analysis Windows: Treatment Emergent Events  
Window 
Start 
Stop 
Adverse events 
Signing of ICF 
Maximum of Follow-up visit or 
Last dose + 7 days 
Treatment-emergent Adverse events 
Post first dose 
Last dose + 7 days 
General Selection Process for Multiple Records in an Analysis Window 
In general, if multiple, valid, non-missing observations exist at a visit or collection time point 
then records will be chosen based on the following: 
• 
The record closest to the nominal time point in question, or, 
• 
The later record if the two visits are equidistant from the time point, or, 
• 
The average (arithmetic mean) if there is more than one record at the same time 
point (generally applies to assessments done in triplicate). 
Multiple Spirometry Records 
  
 
6.1.3 Missing Data 
 
 
 
 
 
 


 
 
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Primary Efficacy Endpoints 
 
  
Rescue Medication Use Question 
 
 
Rescue Medication Accountability 
Screening albuterol kits 
No imputation for missing data will be done for albuterol kits dispensed prior to Day 1. 
Post-screening albuterol kits 
For post-screening albuterol kit (i.e., dispensed on or after Day 1) with missing end counts at 
the end of study, the number of puffs used will be imputed as the starting count. 
Albuterol kits dispensed on the day of last dose or early termination visit will not be included 
in summary analyses. 
All Other Efficacy Endpoints 
In general, missing data will not be imputed. If a missing data method is used, it will be fully 
specified in the corresponding efficacy analysis section. 
Adverse Events 
For graded adverse event summaries, subjects with an AE and no grade on the CRF will be 
graded as severe. 
For by relationship adverse event summaries, subjects with an AE and no relatedness on 
the CRF will be graded as “possibly/probably related”. 


 
 
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6.2 
Adverse Events 
Recorded adverse events will be mapped according to the MedDRA thesaurus by the data 
management CRO for this study, with Theravance review and approval of the mappings.  
BioClinica will use MedDRA, version 18.1.  
6.3 
Medications 
Recorded prior and concomitant medication names will be mapped according to the World 
Health Organization Drug Dictionary (WHODD) by the data management CRO for this study 
with Theravance Biopharma review and approval of the mappings.   
For non-concomitant medication eCRFs that contain albuterol use information, e.g., study 
drug administration and in-clinic albuterol dosing forms, mapping will be conducted by 
Theravance Biopharma using the WHODD mapping. 
6.4 
Medical History 
Medical history will be mapped according to MedDRA version 18.1 and will be provided in 
listings. Selected medical history will be summarized.  
6.5 
General Considerations for Summaries 
Analyses and tabulations will generally be prepared using SAS, version 9.4 or later.  
Reporting Structures for Data Summary 
Data will be summarized using the appropriate reporting structure as defined in Appendix 1. 
Presenting Multiple Summaries on Same Table Summary 
In summary tables where multiple single line frequency summaries are being presented, the 
“n line” can be suppressed in the individual summaries and presented at the top of the 
summary a single time. 
Use of Evaluable N Terminology 
The term “evaluable non-missing n” will only be used in summaries derived from 
model-based analyses. 
 
 


 
 
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Ordering of Treatment Headers in Summary Tables 
In summary table treatment headers, reverencing will be abbreviated as REV and will be 
presented in the following order: 
• 
Tiotropium, 
• 
REV 175 mcg, 
• 
Total (Applicable to General Analysis and Exposure summaries). 
In safety summaries by LABA subgroup, treatment groups will be presented in the following 
order: 
• 
Tiotropium, 
• 
REV 175 mcg, 
Rounding 
In general, the convention for rounding is as follows: 
• 
Values greater than or equal to x.x5 are rounded up, 
• 
Values between 0 and less than x.x5 are rounded down, 
• 
Values between –x.x5 and 0 are rounded up, 
• 
Values less than or equal to −x.x5 are rounded down. 
All rounding will occur in the last step of data summarization. 
Significant Digits 
Raw measurements will be reported the same as the data captured electronically or on the 
CRFs. Exceptions will be made for values reported with greater than four significant digits 
(round to four significant digits using a similar criterion as for percentages with the five in the 
last digit). 
The following significant digit convention will be used for the purposes of summarizing 
spirometry data: 
• 
Mean, median: 1 significant digit, 
• 
Standard deviation: 2 significant digits, 


 
 
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• 
Minimum, maximum: 1 significant digit, 
• 
Percentages: 1 decimal place. 
The following significant digit convention will be used for the purposes of summarizing 
non-efficacy data (primarily lab data) data: 
• 
Mean, median: +1 significant digit reported data, 
• 
Standard deviation: +2 significant digits reported data, 
• 
Minimum, maximum: 2 significant digits reported data, 
• 
Percentages: +1 decimal place. 
P-values 
P-values will be reported with four significant digits, e.g., 0.xxxx, except when reporting 
p-values less than 0.0001, reported as <0.0001.  
Colors in Figures 
In figures that only contain the three treatment groups, the following colors will be used: 
• 
Tiotropium (orange), 
• 
revefenacin 175 mcg (dodgerblue- CX1E90FF). 
In figures that contain multiple subgroups in the same figure (e.g., forest plots), no color 
(default black) will be used. 
6.6 
Tables, Figures and Listings (TFLs) 
A line listing of tables, listings, and figures to be generated are in Appendix 6.   
Table titles will be denoted as underlined text in Section 9 of this SAP. 
Unique table, listing or figure mock-ups will be in a separate document. 


 
 
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7 
ANALYSIS SETS 
7.1 
Safety 
The Safety analysis set will include all subjects who  
(1) Were randomized into the study, and, 
(2) Received at least one dose of study drug (revefenacin or tiotropium).  
Treatment assignment will be based on actual treatment. The Safety analysis set is the 
primary analysis set for safety analyses. 
7.2 
Intent-to-Treat 
The Intent-to-treat (ITT) analysis set will include all subjects who  
(1) Were randomized into the study, 
(2) Received at least one dose of study drug (revefenacin or tiotropium), and, 
(3) Have at least one recorded post-baseline FEV1 assessment.  
Treatment assignment will be based on the treatment randomized.
 
 
7.3 
Per-Protocol 
The Per-protocol (PP) analysis set included all subjects in the ITT analysis set with no major 
analysis protocol deviations (Section 7.5).  
Treatment assignment will be based on actual treatment. 


 
 
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7.4 
Examination of Subgroups 
7.4.1 Study-Specific Subgroups 
The following subgroups are pre-defined for the purposes of analyses: 
1. Baseline PIFR baseline PIFR [
 
2. Baseline smoking status: 
 
3. Age: 
 
4. Current LABA or ICS/LABA use: 
 
5. Reversibility to a short-acting bronchodilator:  
 
6. Baseline post bronchodilator % predicted FEV1: 
 
 
7.5 
Major Analysis 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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with major analysis protocol deviations will be identified before the database lock 
and provided in a listing.   
In addition, a listing of all major deviations will be provided whether or not they impact the 
analysis. 


 
 
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8 
DEFINITION OF ANALYSIS VARIABLES 
8.1 
General Variables 
Age 
Age will be calculated as of the date of signing informed consent and truncated to its integer 
value. The following formula is used: 
𝐵𝐵𝐵𝐵𝐵𝐵𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝐴𝐴𝐴𝐴𝐴𝐴= 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓ቀ
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵ℎ
365.25
ቁ. 
BMI 
BMI will be calculated and converted to metric units by the following: 
𝐵𝐵𝐵𝐵𝐵𝐵ቀ𝑘𝑘𝑘𝑘
𝑚𝑚2
ൗ
ቁ=
𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡(𝑘𝑘𝑘𝑘)
൫ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡(𝑚𝑚)൯
2. 
Reversibility to a Short-Acting Bronchodilator 
Reversibility (yes or no), to ipratropium, is defined as a post-bronchodilator (CFB) FEV1 
increase of at least (≥) 12% and at least (≥) a 200 mL increase, relative to the pre-
bronchodilator FEV1, at the relative screening visit. 
Smoking Pack Years 
Maximum number of packs multiplied by years smoked. 
LABA Use and Type of LABA Use 
Two variables will be used in the analysis models to identify if a subject was on a concurrent 
LABA or ICS/LABA medication and whether the concurrent LABA or ICS/LABA was 
administered QD or BID: 
• 
Concurrent LABA: yes (1) or no (0) 
• 
LABA Type: none (0), QD (1) or BID (2) 
LABA flags will be derived using concomitant medication data, i.e., presence or absence of 
a record matching the logic for LABA use, to ensure accuracy. 
 
 
 


 
 
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GOLD Severity of Airflow Limitation Categories 
Table 5: 
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 
Note: Based on post-ipratropium values in patients with post-ipratropium FEV1/ FVC <0.70 
GOLD Categories (2011 Definition) 
Table 6: 
GOLD Categories 
GOLD Category 
GOLD Airflow 
Severity Category 
Exacerbations 
mMRC 
A 
GOLD 1-2 
≤1 
0-1 
B 
GOLD 1-2 
≤1 
≥2 
C 
GOLD 3-4 
≥2 
0-1 
D 
GOLD 3-4 
≥2 
≥2 


 
 
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GOLD Categories (2017 Definition) 
 
Table 7: 
GOLD Grade 
Airflow Limitation  
GOLD Grade 
Exacerbations 
mMRC 
>80 
1, A 
≤1 
0-1 
 
1, B 
≤1 
≥2 
 
1, C 
≥2 
0-1 
 
1, D 
≥2 
≥2 
50-79.9 
2, A 
≤1 
0-1 
 
2, B 
≤1 
≥2 
 
2, C 
≥2 
0-1 
 
2, D 
≥2 
≥2 
30-49.9 
3, A 
≤1 
0-1 
 
3, B 
≤1 
≥2 
 
3, C 
≥2 
0-1 
 
3, D 
≥2 
≥2 
<30 
4, A 
≤1 
0-1 
 
4, B 
≤1 
≥2 
 
4, C 
≥2 
0-1 
 
4, D 
≥2 
≥2 
Screening data will be used to categorize subjects. For the purposes of categorization, 
GOLD categories (using 2011 definition to ensure consistency between the efficacy and 
safety studies in the phase 3 program) will use the GOLD airflow severity category and 
mMRC scores as the primary method to determine GOLD Category.  If GOLD airflow 
severity is missing, then exacerbations will be used.  
In addition, GOLD grade using 2017 definition will also be used for categorizing the 
subjects.  
8.2 
Efficacy Variables 
 
 
 
 
 


 
 
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 𝑅𝑅𝑅𝑅𝑅𝑅𝑢𝑢𝑢𝑢𝑢𝑢𝑝𝑝𝑝𝑝𝑑𝑑
 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑁𝑁𝑠𝑠𝑠𝑠𝑠𝑠𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑖𝑖𝑒𝑒𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑖𝑖𝑖𝑖𝐷𝐷𝐷𝐷𝐷𝐷𝑜𝑜𝑜𝑜𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑠𝑠𝑠𝑠𝑠𝑠𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑒𝑒𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑚𝑚𝐷𝐷𝐷𝐷𝐷𝐷𝑜𝑜𝑜𝑜𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑛𝑛𝑛𝑛𝑛𝑛𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑒𝑒𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑖𝑖𝑘𝑘𝑘𝑘𝑘𝑘𝑤𝑤𝑤𝑤𝑎𝑎𝑎𝑎𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑘𝑘𝑘𝑘𝑘𝑘𝑤𝑤𝑤𝑤𝑎𝑎𝑎𝑎𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑒𝑒𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐
  
 
 
 
 
 
 
  
 
 


 
 
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his analysis plan where the 
weighted mean (WM) is the AUC/total time, nominally, 4 H. 𝑦𝑦𝑖𝑖𝑦𝑦𝑖𝑖𝑡𝑡𝑖𝑖𝑡𝑡𝑖𝑖𝑖𝑖𝑊𝑊𝑡𝑡𝑡𝑡𝑡𝑡
 
 
 
 
  
 
 
 
 
8.3 
Safety Variables 
Adverse Events 
Adverse events (AEs) are recorded from signing of the informed consent form through the 
final follow-up assessment.  Non-treatment-emergent AEs and treatment-emergent AEs 
(defined in Section 9.3.2) will be summarized separately.   
Bronchodilators by Drug Class 
Appendix 2 contains coding logic for determination of specific drug classes for 
bronchodilators. 
9 
ANALYSES 
Table, figures and listing titles are denoted in underlined text. 


 
 
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9.1 
General Analyses 
9.1.1 Subject Disposition 
Subject disposition information will be summarized for all subjects by treatment group.  
Summaries will include the following parameters:  
• 
Number of randomized subjects, 
• 
Number and percentage of subjects randomized and treated with study drug 
(ITT Analysis set), 
• 
Number of subjects randomized, but not dosed 
• 
Number and percentage of subjects completing the study, 
• 
Number and percentage of subjects by reason discontinuing the study drug, 
• 
Number and percentage of subjects by reason discontinuing the study. 
A listing of subject disposition will include the ITT analysis set status, the date of informed 
consent signed, the date of first dose and last dose of study drug, primary reason for subject 
discontinuation of study medication, the date of last visit, study completion status, primary 
reason for study termination, and the date of last contact. 
9.1.2 Demographics and Baseline Characteristics 
Demographics and baseline characteristics (age, sex, race, ethnicity, height, weight, and 
BMI) will be summarized for ITT set. 
A listing of demographics and baseline characteristics will also be provided. 
9.1.3 Reversibility Summaries  
A post-bronchodilator screening reversibility summary taken during screening visits will be 
provided with the following parameters: 
• 
Ipratropium reversibility (mL), 
• 
Ipratropium reversibility (%), 
 
 


 
 
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In addition, a post-bronchodilator screening reversibility categorical summary will be 
provided in a separate summary: 
• 
Not reversible to ipratropium, 
• 
Reversible to ipratropium, 
Separate listings will also be provided. The ITT analysis set will be used for the summaries. 
9.1.4 Screening and Baseline Spirometry Summaries 
A screening spirometry summary will be provided with the following parameters: 
• 
Post-ipratropium predicted Normal FEV1 (mL), 
• 
Post-ipratropium percent predicted FEV1 (%), 
• 
Post-ipratropium FEV1 (mL), 
• 
Post-ipratropium FVC (mL), 
• 
Post-ipratropium FEV1 to FVC (ratio), 
A Baseline spirometry summary will be provided in a separate table with the following 
parameters: 
• 
Baseline FEV1 (mL) 
• 
Baseline FVC (mL) 
• 
Baseline PIFR (L/min) 
• 
Baseline PIFR by Category (≤40, > 40) 
• 
Baseline IC (L) 
• 
Baseline MIP (cm H2O) 
• 
Baseline FEV1 to FVC (ratio) 
• 
Baseline predicted Normal FEV1 (mL) 
• 
Baseline percent predicted FEV1 (mL) 
A single listing that includes screening, baseline and post-baseline spirometry will be 
provided. The ITT analysis set will be used for the summaries. 


 
 
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9.1.5 Baseline Clinical Characteristics Summaries 
A summary of COPD clinical characteristics taken at baseline will be provided with the 
following parameters: 
• 
Proportion of subject with baseline PIFR ≥ 40 L/min 
• 
Proportion of subject ≥65 years of age (%),  
• 
Duration of COPD (years), 
• 
Proportion of subjects with a history of supplemental oxygen use (%), 
A summary of smoking characteristics taken at baseline will be provided with the following 
parameters: 
• 
Smoking history, current and former, (%), 
• 
Number of years smoked (years), 
• 
Maximum number of packs per day (packs), 
• 
Pack years (packs). 
A summary of LABA and ICS use will be provided with the following parameters using coded 
concomitant medication data: 
• 
Concurrent ICS use (%), 
• 
Concurrent LABA use (%), 
• 
Subgroup: Concurrent QD LABA use (%), 
• 
Subgroup: Concurrent BID LABA use (%), 
• 
Concurrent ICS/LABA use (%). 
Three listings will also be provided. The ITT analysis set will be used for the summaries. 
9.1.6 GOLD Category Summary 
A summary of GOLD categories will be provided with the following parameters: 
• 
GOLD Severity of Airflow Limitation groups, 
• 
2011 GOLD Categories, 
• 
2017 GOLD Categories 


 
 
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A listing will be provided. The ITT analysis set will be used for the summary. 
9.1.7 Key Demographic and Baseline Characteristics Summary 
A summary of key demographic and baseline characteristics will include the following with 
the following parameters on a single page: 
• 
Age, mean(SD), 
• 
Sex (male), %, 
• 
Race (white), %, 
• 
BMI, mean (SD), 
• 
Current smoker (yes), %, 
• 
Concurrent ICS use (yes), %, 
• 
Concurrent LABA use (yes), %, 
• 
Concurrent ICS/LABA use (yes), %, 
• 
Post-ipratropium percent predicted FEV1, mean (SD), 
• 
Post-ipratropium FEV1 to FVC (ratio), mean (SD), 
• 
Baseline FEV1 (in mL), mean (SD), 
• 
Baseline FVC , mean (SD), 
• 
Baseline IC, mean(SD) 
• 
Baseline PIFR (L/min), mean (SD), 
• 
Baseline PIFR (≥40 L/min), % 
• 
Baseline MIP (cm H2O), mean (SD) 
• 
Baseline MIP, mean (SD) 
• 
Proportion of subjects with baseline mMRC ≥2, % 
• 
Proportion of subjects with ≤1 exacerbations in prior year, % 
• 
BDI score, LS mean (SE) 


 
 
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For continuous summaries, only the “mean (SD)” will be displayed. As this data is 
summarized in listing format elsewhere, no listing is provided for this summary. The ITT 
analysis set will be used for the summary. 
9.2 
Efficacy Analysis 
9.2.1 General Considerations for Efficacy Analyses 
Analysis Set for Efficacy Analyses 
For all efficacy data analyses, the ITT analyses set will be used unless otherwise specified. 
9.2.2 Primary Efficacy Evaluation: Trough FEV1 
Hypothesis 
The null hypothesis will be that there is no difference between revefenacin (175 mcg) and 
tiotropium (18 µg) in change from baseline trough FEV1 on Day 29.   
Symbolically, this is expressed as follows: 
𝐻𝐻0: 𝜇𝜇𝑅𝑅𝑅𝑅𝑅𝑅= 𝜇𝜇𝑇𝑇𝑇𝑇𝑇𝑇  
𝐻𝐻1: 𝜇𝜇𝑅𝑅𝑅𝑅𝑅𝑅≠𝜇𝜇𝑇𝑇𝑇𝑇𝑇𝑇 
Analysis and Summary Tables 
 
 
 
 
 
 
 
 
  
 
 
 
 
   


 
 
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Figures 
 
 
 
 
 
 
  
 
 
 
 
9.2.3 Secondary Efficacy Evaluation: Trough FVC and Trough IC 
Hypothesis 
The null hypothesis will be that there is no difference between revefenacin (175 mcg) and 
tiotropium (18 µg) in change from baseline trough FVC and trough IC on Day 29, 
respectively.   
Symbolically, this is expressed as follows: 
𝐻𝐻0: 𝜇𝜇𝑅𝑅𝑅𝑅𝑅𝑅= 𝜇𝜇𝑇𝑇𝑇𝑇𝑇𝑇  
𝐻𝐻1: 𝜇𝜇𝑅𝑅𝑅𝑅𝑅𝑅≠𝜇𝜇𝑇𝑇𝑇𝑇𝑇𝑇 
 
 
 


 
 
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Analysis and Summary Tables 
Similar approach used for the primary efficacy endpoint of change from baseline trough 
FEV1 will apply for Trough FVC and trough IC, respectively.  
Similar code used for primary analysis will be used for trough FVC and trough IC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
9.2.4 Secondary Efficacy Evaluation: Peak FEV1 and Peak FVC (0−4 hours) 
Hypothesis 
The null hypothesis will be that there is no difference between revefenacin (175 mcg) and 
tiotropium (18 µg) in change from Baseline peak FEV1 and peak FVC on Day 1 and Day 29.   


 
 
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Analysis and Summary Tables 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 


 
 
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Figures 
 
 
 
 
 
 
  
 
  
 
 
9.2.6 Exploratory Efficacy Evaluation: 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 


 
 
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9.2.7 Exploratory Efficacy Evaluation:
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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A summary of TDI Responders (≥1 units) will include observed counts and proportions 
(using frequency reporting format) and observed least-square proportions and odd ratios on 
the differences between treatment groups (using BLS MEAN format). Nominal p values and 
multiplicity adjusted p values will be reported.  
9.2.8 Exploratory Efficacy Evaluation:
 
 
 
   
 
 
 
  
 
 
 
 
 
 
  
 
 
  


 
 
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9.3 
Safety Analyses 
For all safety analyses, the safety analysis population will be used. 
Safety variables to be summarized include exposures, concomitant medication, vital signs 
and adverse events. Vital signs will be summarized in terms of observed values and 
changes from baseline. 


 
 
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9.3.1 Extent of Exposure 
Study drug exposure (Number of Doses and Days) will be summarized using the eight-point 
descriptive summary by study periods.  The source for exposure data is the drug 
accountability data domain. 
Study drug compliance will be assessed using the following categories using the same 
source as the drug exposure data by study periods: 
• 
100%; 
• 
95%; 
• 
90%; 
• 
80%; 
• 
<80%. 
Study drug administration (date/time and study day) will be provided in a data listing.  The 
source for study drug administration is the diary data domain. 
9.3.2 Adverse Events 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will present by system organ class (SOC), preferred term 
(PT) and severity and/or relatedness, the frequency and percentage of subjects reporting 
each observed event. 
A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or 
after the date of first dose of study drug up to the date of last dose of study drug plus 7 days 
in the follow-up period.  AEs observed during the period from obtaining informed consent to 
the start of administration of study drug will be regarded separately from TEAEs. Treatment-
limiting AEs are defined as any event that leads to permanent or temporary discontinuation 
from treatment. 
Summary of adverse events will be dependent on adverse events observed.  If no adverse 
events meeting a specific table are observed, the summary table will not be completed. 
Blank summary tables will not be utilized.  The following is the list of adverse event tables: 
 
 


 
 
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Overall: 
• 
Overall Summary of Adverse Events 
By preferred term: 
• 
Treatment-emergent Adverse Events by SOC and PT 
• 
Treatment-emergent Adverse Events by PT 
• 
Treatment-emergent Adverse Events by SOC and PT occurring in more than 1% of 
Study population 
• 
Treatment-emergent Adverse Events by SOC, PT and LABA Use 
By severity: 
• 
Treatment-emergent Adverse Events by SOC, PT and Severity 
• 
Moderate or Severe Treatment-emergent Adverse Events by SOC and PT 
• 
Serious Adverse Events 
• 
Deaths during Study 
By relatedness: 
• 
Drug-Related Treatment-emergent Adverse Events by SOC and PT 
• 
Drug-Related Treatment-emergent Adverse Events by SOC, PT and LABA Use 
• 
Drug-Related Treatment-emergent Adverse Events by SOC, PT and Severity 
• 
Moderate or Severe Drug-Related Treatment-emergent Adverse Events by SOC and 
PT 
• 
Drug-related Serious Adverse Events 
Other: 
• 
Adverse Events Leading to Premature Study Drug Discontinuation 
• 
Adverse Events Leading to Temporary Interruption of Study Drug 
 
 


 
 
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The overall summary of adverse events will include the following summary lines, any AE, 
moderate or severe AEs, moderate or severe AEs related to Study Drug, serious AEs, 
serious AEs related to Study Drug, AEs leading to discontinuation, AEs leading to 
interruption, deaths during Study. 
9.3.2.1 Antimuscarinic Adverse Events 
Antimuscarinic TEAEs are of interest as a common event in the drug class and will be 
summarized by preferred terms. The preferred terms for TEAEs considered antimuscarinic 
are as follows: 
• 
Constipation 
• 
Dry mouth 
• 
Dysuria 
• 
Worsening of urinary retention 
• 
Worsening of narrow-angle glaucoma. 
9.3.3 Vital Signs 
For each nominal time point, vital signs will be summarized in terms of observed values and 
changes from Baseline.  Vital signs outliers will be flagged in the listing. 
Table 8: 
Vital Signs Outlier Thresholds 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
<85 
>160 
<45 
>100 
9.3.4 Medical History 
Medical history collected at screening will be provided in a data listing and a summary table. 
9.3.5 Prior and Concomitant Medications 
Prior and concomitant Medications will be listed and summarized separately. Tables and 
listings will be provided for concomitant bronchodilators, concomitant corticosteroids, 
Concomitant NON-COPD medications, Post-treatment Bronchodilators.  Coding logic for 
each group is in Appendix 2. 


 
 
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Appendix 1: 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 


 
 
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Appendix 3: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix 4: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Study 0149 
 
Final Version, 27NOV2017 
revefenacin 
 
Page 52 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Study 0149 
 
Final Version, 27NOV2017 
revefenacin 
 
Page 53 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Study 0149 
Final Version, 27NOV2017 
revefenacin 
Page 54 
 
Confidential – Property of Theravance Biopharma, Inc. 
Appendix 5: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Study 0149 
Final Version, 27NOV2017 
revefenacin 
Page 55 
 
Confidential – Property of Theravance Biopharma, Inc. 
Appendix 6: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Study 0149 
Final Version, 27NOV2017 
revefenacin 
Page 56 
 
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Type 
Number 
Table Title 
Randomized 
Safety 
ITT 
PP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Study 0149 
Final Version, 27NOV2017 
revefenacin 
Page 57 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Study 0149 
Final Version, 27NOV2017 
revefenacin 
Page 58 
 
Confidential – Property of Theravance Biopharma, Inc. 
Listings 
Nu
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Study 0149 
Final Version, 27NOV2017 
revefenacin 
Page 59 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Study 0149 
Final Version, 27NOV2017 
revefenacin 
Page 60 
 
Confidential – Property of Theravance Biopharma, Inc.