Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: Chronic Obstructive Pulmonary Disease, COPD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1060
Healthy volunteers: no

Brief summary:
The purpose of this study is to measure the safety and tolerability of TD 4208, an investigational drug being developed to treat people with moderate to very severe COPD, compared to tiotropium.

Detailed description:

Arms:
arm 1: 88 mcg arm 2: 175 mcg arm 3: 18 mcg

Interventions: intervention 1: TD-4208 intervention 2: Tiotropium
Intervention descriptions: intervention 1: Subjects receiving TD-4208 are blinded to one of two doses of 4208. intervention 2: There is not a placebo, there is an active comparator (Tiotropium) arm.

Protocol document:
Prot_001.pdf: 
Protocol 0128, Amendment 3 
Version 1.0, 21JAN2016 
TD-4208 
Page 1 
 
  
CLINICAL STUDY PROTOCOL 
 
Study Title: 
A Phase 3, 52-week, Randomized, Active-Controlled Parallel 
Group Study to Evaluate the Safety and Tolerability of 
Nebulized TD-4208 in Subjects with Chronic Obstructive 
Pulmonary Disease 
Study Short Title: 
A 52-Week Parallel Group Safety Study of TD-4208 in COPD 
Sponsor Study No.: 
0128 
Date: 
21 January 2016, 
 
Test Product: 
TD-4208  
US IND: 
 
Sponsor: 
Theravance Biopharma R&D, Inc. 
c/o Theravance Biopharma US, Inc. 
901 Gateway Boulevard 
South San Francisco, California  94080 
 
Telephone: 
 
 
Facsimile: 
 
 
 
Clinical Study Director: 
 
Theravance Biopharma US, Inc. 
 
Telephone: 
 
 
 
This study will be conducted according to the principles of Good Clinical Practice. 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma, Inc. It may not be 
copied or provided to any other party without the express written consent of 
Theravance Biopharma, Inc. 
© Theravance Biopharma (Unpublished Work). All rights reserved. 


Protocol 0128, Amendment 3 
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Confidential – Property of Theravance Biopharma, Inc. 
PROTOCOL SYNOPSIS 
 
Study Number and Title: Study TD-4208-0128: A Phase 3, 52-week, Randomized, 
Active-Controlled Parallel-Group Study to Evaluate the Safety and Tolerability of Nebulized 
TD-4208 in Subjects with Chronic Obstructive Pulmonary Disease  
Study Short Title: A 52-Week Parallel Group Safety Study of TD-4208 in COPD 
Estimated Number of Study Centers and Countries or Regions:  Approximately 
 in the United States  
Background and Rationale:
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  


Protocol 0128, Amendment 3 
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Page 3 
 
PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
Objectives:  The primary objective of the study is as follows: 
• 
To characterize the safety and tolerability of TD-4208 administered once daily for 
52 weeks in a population of patients with moderate to very severe COPD 
The exploratory objectives of the study are: 
 
 
 
 
 
 
Study Design:  This is a randomized, active-controlled, parallel-group study.  
Each subject will receive treatment once daily for a total of 52 weeks. There will be three 
treatment groups (TD-4208 88 μg, TD-4208 175 μg and tiotropium 18 μg). TD-4208 will be 
administered as a 3 mL solution by inhalation using the 
 jet nebulizer and 
tiotropium will be administered as a dry powder capsule with the 
 device. The 
study will be double-blind with respect to the TD-4208 dose arms, and open-label with 
respect to the tiotropium control arm. 
Subjects who are currently using LABA-containing products (LABA monotherapy or 
LABA/ICS fixed dose combination) will be permitted to continue the use of these 
concomitant medications throughout the course of the study. 
 
 Subjects that are 
not on a LABA-containing therapy when they enter the study and require a 
LABA-containing therapy to treat a COPD exacerbation (either temporarily or from that 
point onwards) during the treatment phase of the study will be allowed to remain in the 
study.  
Screening will involve either one or two visits, depending on whether a washout period is 
required. The first visit will be an Initial Screening Visit (Visit 1A) when 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. The 
subject will start a washout period only after signing the informed consent form.  
After completing the washout (if required) the subject will return for further screening 
assessments, including an Ipratropium Reversibility Visit (Visit 1B) and baseline blood 
tests, ECG and vitals. It is only necessary to conduct the Initial Screening Visit (Visit 1A) 
and Ipratropium Reversibility Visit (Visit 1B) as separate visits if a washout period or a 
stable ICS/LABA run-in period (at least 30 days) is required. If a washout period is not 
required, these two visits may be performed as one visit.  
If a washout period is required, the time from the Initial Screening Visit (Visit 1A) to Visit 1B 
will be no longer than 45 days.  
At the Ipratropium Reversibility Visit (Visit 1B), the FEV1 response to a nebulized dose of 
ipratropium (500 μg) will be tested to confirm the subject’s COPD status and GOLD 
Stage {1}.  
 
 


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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
 A paper diary will be used for the recording of concomitant 
medications and adverse events.  
All remaining inclusion and exclusion criteria will be reviewed at this Visit 1B 
 
 
 
 
On Visit 2 (Day 1 of dosing), eligible subjects will be randomized to one of three treatment 
groups in the study.
 
The treatment period will involve 6 visits: 
• 
Visit 2 (Day 1) 
• 
Visit 3 (Day 29) 
• 
Visit 4 (Day 92) 
• 
Visit 5 (Day 183) 
• 
Visit 6 (Day 274)  
• 
Visit 7 (Day 365) 
All visits will have a visit window of ±5 days with the exception of Day 1. On these visit 
days, subjects will attend the clinic for assessment of pre-dose vital signs and ECG, trough 
(pre-dose) FEV1, review of diary card for AEs and concomitant medications. Subjects will 
administer study medication under supervision at all clinic visits (with the exception of Visit 
7) to assess nebulizer technique and to correct and retrain as required. PIFR (Peak 
Inspiratory Flow Rate) will be measured using the In-check Dial device for all subjects on 
Visit 2 prior to any assessments. ECG and vitals will be measured 60 minutes pre-dose 
and 10 minutes post-dose at these visits. On all visits with the exception of Visit 3, subjects 
will return the used vials of study medication and the study-specific rescue medication they 
have been issued. On all visits with the exception of Visit 7 (12 month visit), subjects will be 
issued sufficient study medication and rescue medication albuterol MDI to use for at least 
3 months until the time of their next clinic visit.  
Subjects with a concomitant LABA will dose the LABA or LABA/ICS immediately prior to 
nebulization with TD-4208 (or administration of tiotropium for those subjects in the 
tiotropium control arm) on all treatment visit days (Visit 2-7).  
A diary will be used for recording study medication dosing times, study-specific rescue 
medication use, concomitant medications, and adverse events throughout the 52-week 
dosing period and the 1-week follow-up period
 
 
A follow-up visit (Visit 8) by telephone will be performed 7 days after the final dose of study 
drug.  
 


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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
In a subset of subjects at specific sites (n=150 in total), subjects will undergo 24-hour 
Holter (Ambulatory ECG monitor) monitoring at Visit 1B, Visit 3 (1 month) and Visit 5 
(6 months). 
Subjects who experience 1 or 2 moderate or severe acute exacerbations of COPD 
(AECOPD) will be allowed to continue study drug throughout the exacerbation and will not 
be withdrawn from the study. All patients will be offered appropriate therapy for their 
AECOPD, including oral steroids, and/or antibiotics for a period of up to 14 days. Subjects 
will also be allowed to initiate LABA with or without inhaled corticosteroids (ICS) at the 
investigator’s discretion in accordance with current COPD guidelines or to have their 
existing dose of ICS increased in response to the AECOPD. Subjects who experience 
>2 AECOPD episodes (each separated by more than 1 month to confirm that they are 
separate events) will be withdrawn from the study and treated appropriately.  
An independent external Clinical Events Committee (CEC) will perform ongoing blinded 
review and adjudication of pre-specified cardiovascular (CV) events of interest collected in 
the electronic case report forms and other pre-specified subject-level source documents 
during the conduct of the study. 
Duration of Study Participation: The screening period will be variable in length, 
depending on whether a washout period is required. The minimum duration from Visit 1A to 
Visit 2 is 1 week (7 days) and the maximum duration is 7 weeks (57 days). Randomization 
at Visit 2 will be followed by 12 months of dosing. A follow-up visit by telephone will be 
performed 7 days after the final treatment visit. The total number of days of participation for 
each completed subject therefore may range from a minimum of 54 weeks to a maximum 
of 60 weeks.  
Number of Subjects per Group: Approximately 350 subjects will be enrolled in each of 
3 treatment groups in a blinded 1:1:1 fashion (total of 1050 subjects).  
Subjects who experience 1 or 2 moderate or severe acute exacerbations during the study 
will be treated as appropriate but will be permitted to continue in the study. 


Protocol 0128, Amendment 3 
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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
Study Population: 
Patients with moderate to very severe COPD who meet the criteria for study enrollment.  
Inclusion Criteria  
1. Subject is a male or female subject 40 years of age or older (age at Visit 1A). 
2. Subject is willing and able to provide signed and dated written informed consent to 
participate at Visit 1A prior to initiation of any study related procedures.  
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 at Visit 1B.  
4. Subject has moderate-to-very severe stable COPD with a post-ipratropium FEV1 less 
than 80% of predicted normal at Visit 1B and a post-ipratropium FEV1 >700 mL at 
Visit 1B. 
5. Subject has a current or past cigarette smoking history (or equivalent for cigar or pipe 
smoking history) of at least 10 pack-years. 
6. Subject must be willing and able to attend study visits according to the visit schedule. 
7. Women of either child bearing potential or non-child bearing potential as follows: 
• 
Women of childbearing potential must have documentation of a negative urine 
pregnancy test at Visit 1B and Visit 2 (prior to randomization). If a urine pregnancy 
test is positive, it must be confirmed via a second urine pregnancy test. 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.  
o 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 care giver) based on the investigator’s assessment is able to properly 
prepare and administer study medication administered either by nebulizer or 
 


Protocol 0128, Amendment 3 
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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
Exclusion Criteria: 
1. Females who are pregnant, lactating, breastfeeding or planning to become pregnant 
during the study. 
2. Subject has a significant respiratory disease or disorder other than COPD that, in the 
opinion of the investigator, would affect the interpretation of data from this study, 
including but not limited to restrictive lung disorders, benign or malignant tumors of the 
lung, chronic pulmonary infections such as tuberculosis, occupational lung disease 
such as silicosis or asbestosis, inflammatory disorders of the lung, alpha-1-antitrypsin 
deficiency, and/or abnormalities of the chest wall or musculature (e.g., scoliosis, 
myasthenia gravis, phrenic nerve palsy).  
3. Subject has a history of cancer of any organ, treated or untreated in the 5 years prior to 
Visit 1A (excludes localized basal cell or squamous cell carcinoma of the skin; localized 
prostate cancer in situ of grade 1; localized cervical cancer in situ of grade 0). 
4. 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, tolerability, 
or pharmacokinetics of the study drug. 
5. Subject has a history of reactions or hypersensitivity to inhaled or nebulized 
anticholinergics or short-acting beta-agonists. 
6. 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. 
7. Subject has a significantly increased risk of cardiovascular events, as indicated by a 
history at Visit 1A of myocardial infarction or unstable angina within the last 6 months, 
unstable or life threatening cardiac arrhythmia requiring intervention in the last 
3 months, or New York Heart Association (NYHA) Class IV heart failure.  
8. Subjects with clinically significant and uncontrolled hypertension, hypercholesterolemia 
or Type II diabetes mellitus. 
9. Subject has been hospitalized for COPD or pneumonia within 8 weeks prior to Visit 1B. 
10. Subject has used systemic corticosteroids within 6 weeks of Visit 1B. 
11. Subject has used antibiotics for respiratory tract infections within 6 weeks of Visit 1B. 
12. Subject has undergone lung volume reduction surgery or lobectomy within 12 months 
prior to Visit 1B 
13. Subject has an abnormal and clinically significant 12-lead ECG findings at Visit 1B 
according to the following criteria: 
• 
atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute 
• 
sustained or nonsustained ventricular tachycardia (VT) 
• 
second degree heart block Mobitz type II 
• 
third degree heart block (unless pacemaker or defibrillator had been 
inserted) 
• 
QT interval corrected for heart rate (QTcF) ≥500 milliseconds (msec)  
 


Protocol 0128, Amendment 3 
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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
14. Subject is unwilling or unable to stop the use of prohibited medications during the 
washout (if required) and treatment period and follow-up period of the study. 
15. Subject has participated in a previous TD-4208 study.  
16. Subject has used any other investigational medication within 30 days or five drug 
half-lives (whichever is longer) of screening. 
17. Subject has a history of known or suspected alcohol or drug abuse within 2 years prior 
to screening, at the discretion of the investigator.  
18. Subject is affiliated with the investigator site (e.g., investigator, study coordinator, site 
employee, etc.).  
19. Subject requires long-term oxygen therapy (>15 hours a day) on a daily basis for 
chronic hypoxemia. 
20. Subjects who are participating in the initiation phase of a supervised pulmonary 
rehabilitation program (subjects in the maintenance phase will be eligible). 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:   
• 
TD-4208 solution for inhalation by jet nebulizer. Daily (QD) administration every 
morning for 52 weeks (dose 88 µg or 175 µg). 
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of 
Treatment: 
• 
Tiotropium dry powder administered using capsules with the 
 device. 
Daily (QD) administration every morning for 52 weeks (dose 18 µg). 
Statistical Methods  
Sample Size: 
Sample size (n=350 per group) is based on meeting ICH regulatory requirements for 
long-term safety for chronic use in this indication. 
 
 
 
Study Endpoints: 
The primary endpoint(s) of this study assess the long-term safety and tolerability of 
TD-4208 in the treatment of COPD: 
• 
Frequency and severity of adverse events, including exacerbations 
• 
Vital signs 
• 
Clinical laboratory evaluations 
• 
12-lead ECG changes from baseline 
 
 


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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
In addition, the following exploratory endpoints will be characterized: 
 
 
 
   
 
 
 
 
 
Analysis: 
All safety data will be presented in listings. Descriptive summary tables will be provided for 
treatment-emergent adverse events, laboratory evaluations, vital signs, 12-lead ECG 
parameters, and concomitant medications.  
 
 
 
 
 
 
 
 
 
 


Protocol 0128, Amendment 3 
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Confidential – Property of Theravance Biopharma, Inc. 
SCHEDULE OF STUDY PROCEDURES 
 
Table 1: 
Schedule of Study Procedures 
Procedure 
Screening 
Treatment Period 
Early 
termination/ 
Withdrawal* 
Telephone 
Follow-up 
Visit 
1Aa 
Visit 
1Ba 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
 
 
Day 1 
Day 29 
Day 92 
Day 183 
Day 274 
Day 365 
7±2 days 
after Visit 7 or 
early 
termination 
(±5)  
(±5)  
(±5)  
(±5)  
(±5)  
Informed Consent 
■ 
Medication and Medical History 
■ 
 
 
 
 
 
 
 
 
 
Washout of COPD Medications 
(as required) 
■ 
 
 
 
 
 
 
 
 
 
Physical examination 
 
■ 
 
 
 
■ 
 
■ 
■ 
 
Height and Weight 
 
■ 
 
 
 
 
 
■ 
■ 
 
PIFR 
 
 
■ 
 
 
 
 
 
 
 
Vital Signsb 
 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
 
ECG (12-lead)b 
 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
 
24 hour Holter monitor (substudy 
subjects only) c 
 
■ 
 
■ 
 
■ 
 
 
 
 
Ipratropium Reversibilityd 
 
■ 
 
 
 
 
 
 
 
 
Hematology, Serum Chemistry, 
Urinalysis 
 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
 
Urine Pregnancy Teste 
 
■ 
■e 
■ 
■ 
■ 
■ 
■ 
■ 
 
 
 
Review Inclusion/Exclusion Criteria 
■ 
■ 
■ 
 
 
 
 
 
 
 
Randomization 
 
 
■ 
 
 
 
 
 
 
 
Baseline 
 
Spirometry
 
 
LABA Dosing (as appropriate) 
 
 
■ 
■ 
■ 
■ 
■ 
■ 
 
 
Study Drug Dosingh 
 
 
■ 
■ 
■ 
■ 
■ 
 
 
 
 
 
 
Concomitant Medications 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
Table 1: 
Schedule of Study Procedures 
Procedure 
Screening 
Treatment Period 
Early 
termination/ 
Withdrawal* 
Telephone 
Follow-up 
Visit 
1Aa 
Visit 
1Ba 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
 
 
Day 1 
Day 29 
Day 92 
Day 183 
Day 274 
Day 365 
7±2 days 
after Visit 7 or 
early 
termination 
(±5)  
(±5)  
(±5)  
(±5)  
(±5)  
Adverse Events 
 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
Dispensing of study drug for home 
use 
 
 
■ 
■ 
■ 
■ 
■ 
 
 
 
Collect and reconcile returned study 
drug 
 
 
 
■ 
■ 
■ 
■ 
■ 
■ 
 
Dispense Rescue Medication as 
needed   
■ 
 
■ 
■ 
■ 
■ 
■ 
 
 
 
Collect and reconcile returned 
rescue medication (as appropriate) 
 
 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
 
Training on use of Diaries 
 
■ 
 
 
 
 
 
 
 
 
Dispense Diariesk 
 
■ 
 
 
 
 
 
 
 
 
Review/Collect Diaries 
 
 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
 
Assess compliance 
 
 
 
■ 
■ 
■ 
■ 
■ 
■ 
 
Demonstrate proper use of nebulizer 
or 
 and retrain as 
necessary 
 
 
■ 
■ 
■ 
■ 
■ 
 
 
 
a The duration of each of the screening visits is approximately 1 hour for Visit 1A and 4 hours for Visit 1B. Visit 1A and 1B may be conducted on the same day if 
a washout period is not required. 
b Vital signs and ECG performed at approximately 60 min pre-dose and at 10 minutes post dose. Subjects need to be resting in a semi-recumbent position 
approximately 5 minutes prior to assessment of vital signs and ECG. The sequence of performing these procedures at each visit is vital signs, then ECG 
followed by spirometry. ECG and Vitals done at the screening visit (1B) will be done once, prior to the ipratropium reversibility testing, and once at Visit 7. 
c The 24 hour Holter will be performed at selected sites as a substudy. 
d Spirometry will be performed pre-dose and 45 min post-dose for ipratropium reversibility. 
e Urine pregnancy test performed prior to randomization (as applicable).  
f 
A Treatment Satisfaction Questionnaire will be performed by the subject to determine baseline characteristics related to preferences for drug administration 
and, at the end of the study to determine
 with study drug. 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
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g Spirometry measurements will be performed 45 and 15 minutes pre-dose. At Visit 7 spirometry will be performed as a trough measurement, however study 
drug will not be administered.   
h Study drug dosing will be in-clinic on study visit days. The last dose of study drug will be at home the day before on Day 364. 
i 
 
  
 
 
k Diaries will be used to collect timing of study drug dosing,
, concomitant medications, and adverse events. 
 
* All Subjects who terminate early, regardless of reason, will have a 12 month follow-up telephone call to determine vital status.  
 


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TABLE OF CONTENTS 
 
PAGE 
 
PROTOCOL SYNOPSIS ....................................................................................................... 2 
SCHEDULE OF STUDY PROCEDURES ............................................................................ 10 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................ 17 
1 
INTRODUCTION ..................................................................................................... 19 
 
Background and Rationale ........................................................................... 19 
1.1
 
Nonclinical Profile ......................................................................................... 20 
1.2
1.2.1 
Pharmacology................................................................................... 20 
1.2.2 
Toxicology ........................................................................................ 20 
1.2.3 
Pharmacokinetics ............................................................................. 20 
 
Clinical Experience ....................................................................................... 21 
1.3
 
Risks and Benefits ....................................................................................... 22 
1.4
2 
OBJECTIVES .......................................................................................................... 25 
3 
STUDY DESIGN ...................................................................................................... 26 
 
Overview ...................................................................................................... 26 
3.1
 
Rationale for Study Design ........................................................................... 28 
3.2
 
Selection of Doses and Duration of Treatment ............................................. 29 
3.3
 
Study Endpoints ........................................................................................... 30 
3.4
 
Minimization of Bias ..................................................................................... 31 
3.5
3.5.1 
Blinding............................................................................................. 31 
3.5.2 
Treatment Assignment ...................................................................... 31 
4 
STUDY POPULATION ............................................................................................ 32 
 
Inclusion Criteria .......................................................................................... 32 
4.1
 
Exclusion Criteria ......................................................................................... 33 
4.2
5 
STUDY DRUGS ...................................................................................................... 35 
 
Description of Study Drugs ........................................................................... 35 
5.1
5.1.1 
TD-4208 ........................................................................................... 35 
5.1.2 
Tiotropium ........................................................................................ 36 
5.1.3 
Agents for Reversibility Testing ........................................................ 36 
5.1.3.1 
Ipratropium ...................................................................... 36 
5.1.4 
Agents for Rescue Therapy .............................................................. 36 
5.1.4.1 
Albuterol .......................................................................... 36 
 
Dose Administration ..................................................................................... 37 
5.2
5.2.1 
TD-4208 ........................................................................................... 37 
5.2.2 
Tiotropium ........................................................................................ 37 
5.2.3 
Agents Used for Reversibility Testing ............................................... 38 
5.2.3.1 
Ipratropium ...................................................................... 38 
5.2.4 
Agents Used for Rescue Medication ................................................. 38 
5.2.4.1 
Albuterol .......................................................................... 38 
 
Treatment Compliance ................................................................................. 38 
5.3
 
Drug Accountability and Reconciliation ........................................................ 38 
5.4
6 
STUDY PROCEDURES .......................................................................................... 40 
 
Schedule of Study Procedures ..................................................................... 40 
6.1
 
Total Blood Volume ...................................................................................... 40 
6.2


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TABLE OF CONTENTS (CONTINUED) 
 
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Procedures by Visit ...................................................................................... 40 
6.3
6.3.1 
Screening ......................................................................................... 40 
6.3.1.1 
Visit 1A (Initial Screening Visit) – (performed up to 
45 days before Visit 1B) .................................................. 42 
6.3.1.2 
Visit 1B (Ipratropium Reversibility Visit) – (if a 
washout or a stable ICS/LABA run-in period (at 
least 30 days) is not required Visit 1A and 1B may 
be conducted as one visit) ............................................... 42 
6.3.2 
Treatment and Follow-up Period ....................................................... 43 
6.3.2.1 
Visit 2 .............................................................................. 43 
6.3.2.2 
Visits 3, 4, 5, 6, and 7 ...................................................... 44 
6.3.3 
Visit 8 (Telephone Follow-up) ........................................................... 45 
6.3.4 
Early Termination/Withdrawal Visit ................................................... 45 
6.3.5 
Unscheduled Visits ........................................................................... 46 
 
Description of Study Assessments ............................................................... 47 
6.4
6.4.1 
Demographic and Baseline Assessments ......................................... 47 
6.4.2 
Efficacy Assessments ....................................................................... 47 
6.4.2.1 
Spirometry ....................................................................... 47 
6.4.3 
Safety Assessments ......................................................................... 47 
6.4.3.1 
Adverse Events ............................................................... 47 
6.4.3.2 
Medical History ................................................................ 48 
6.4.3.3 
Physical Examination ...................................................... 48 
6.4.3.4 
Vital Signs ....................................................................... 48 
6.4.3.5 
Laboratory Tests ............................................................. 48 
6.4.3.6 
ECG – 12-lead ................................................................ 49 
6.4.3.7 
24-hour Holter Substudy.................................................. 49 
 
Concomitant Medications ............................................................................. 50 
6.5
 
Restrictions .................................................................................................. 53 
6.6
 
Discontinuation ............................................................................................ 54 
6.7
6.7.1 
Subject Discontinuation .................................................................... 54 
6.7.2 
Subject Replacement ........................................................................ 56 
6.7.3 
Study Discontinuation ....................................................................... 56 
 
Pregnancy .................................................................................................... 56 
6.8
7 
ADVERSE EVENTS ................................................................................................ 57 
 
Regulatory Definition of an Adverse Event ................................................... 57 
7.1
 
Adverse Event Definition for the Purposes of This Study .............................. 57 
7.2
 
Assessment of Adverse Events .................................................................... 58 
7.3
 
Serious Adverse Events ............................................................................... 58 
7.4
 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
7.5
as Adverse Events or Serious Adverse Events ............................................ 59 
 
Serious Adverse Event Reporting ................................................................ 60 
7.6
 
Adverse Event Follow-up ............................................................................. 61 
7.7
8 
STATISTICAL CONSIDERATIONS ......................................................................... 62 
 
General Considerations ................................................................................ 62 
8.1
 
Sample Size and Power ............................................................................... 62 
8.2
 
Analysis Sets ............................................................................................... 62 
8.3


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8.3.1 
Analysis Sets .................................................................................... 62 
8.3.2 
Examination of Subgroups ................................................................ 63 
8.3.3 
Major Protocol Deviations ................................................................. 63 
 
General Analyses ......................................................................................... 63 
8.4
8.4.1 
Demographics and Other Baseline Characteristics ........................... 63 
8.4.2 
Screening and Baseline Spirometry .................................................. 64 
8.4.3 
COPD Clinical History and Smoking History ..................................... 64 
8.4.4 
Select Medical History ...................................................................... 64 
 
Safety Analyses ........................................................................................... 64 
8.5
8.5.1 
Extent of Exposure ........................................................................... 64 
8.5.2 
Adverse Event Data .......................................................................... 65 
8.5.2.1 
Adverse Events ............................................................... 65 
8.5.2.2 
Administration-Related Bronchoconstriction .................... 65 
8.5.2.3 
Exacerbations ................................................................. 66 
8.5.2.4 
Cardiovascular Events of Interest .................................... 66 
8.5.3 
Concomitant Medications ................................................................. 66 
8.5.4 
Laboratory Data ................................................................................ 66 
8.5.5 
Vital Signs Data ................................................................................ 67 
8.5.6 
ECG Data ......................................................................................... 67 
8.5.7 
Holter ECGs ..................................................................................... 68 
 
Efficacy Analyses ......................................................................................... 68 
8.6
8.6.1 
Efficacy Endpoints ............................................................................ 68 
 
 
 
 
 
 
 
Treatment Satisfaction Questionnaires ......................................................... 71 
8.7
 
Missing Data Handling ................................................................................. 71 
8.8
 
Clinical Events Committee ........................................................................... 71 
8.9
 
Data Monitoring Committee .......................................................................... 71 
8.10
9 
STUDY ADMINISTRATION ..................................................................................... 72 
 
Principal Investigator Responsibilities .......................................................... 72 
9.1
 
Institutional Review Board/Independent Ethics Committee ........................... 73 
9.2
 
Informed Consent ......................................................................................... 73 
9.3
 
Data Recording and Quality Assurance ........................................................ 74 
9.4
 
Document Retention .................................................................................... 75 
9.5
 
Confidentiality .............................................................................................. 75 
9.6
 
Access to Data and Documents ................................................................... 76 
9.7
 
Quality Control: Study Monitoring and Auditing ............................................ 76 
9.8
 
Publication ................................................................................................... 77 
9.9
10 
REFERENCES ........................................................................................................ 78 
PROTOCOL SIGNATURE FORM ....................................................................................... 80 
 


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LIST OF TABLES 
 
Table 1: 
Schedule of Study Procedures ......................................................... 10 
 
 
 
Table 3: 
Severity Criteria for COPD Exacerbations ........................................ 55 
Table 4: 
Outlier Threshold for Vital Signs ....................................................... 67 
Table 5: 
ECG Test Outlier Thresholds ............................................................ 67 
 
LIST OF FIGURES 
 
Figure 1: 
Study Design Schematic ................................................................... 27 
 
LIST OF APPENDICES 
 
Appendix 1: 
Signature Page ................................................................................. 79 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
ACh 
Acetylcholine 
AE 
adverse event 
AECOPD 
acute exacerbations of chronic obstructive pulmonary disease 
ALT 
alanine aminotransferase 
ASM 
airway smooth muscle 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under concentration curve 
AUC0-t 
area under the concentration-versus-time curve calculated from time zero to the 
last detectable time point 
BDI/TDI 
Baseline Dyspnea Index / Transitional Dyspnea Index 
BP 
blood pressure 
CLr 
renal clearance calculated as Ae/AUC0-t 
Cmax 
observed maximum concentration 
CEC 
Clinical Events Committee  
CAT 
COPD Assessment Test 
CCQ  
Clinical COPD Questionnaire  
COA 
Clinical outcome assessment 
COPD 
chronic obstructive pulmonary disease 
CRF 
case report form 
CRU 
clinical research unit 
DPI 
dry powder inhaler 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EXACT 
Exacerbations in COPD Tool 
FEV1 
forced expiratory volume in 1 second 
FPM 
fine particle mass 
FTIH 
first time in human 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
hERG 
human ether-à-go-go-related gene 
HR 
heart rate 
IB 
Investigator's Brochure 
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 
IH 
Inhalation 


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Abbreviation 
Description 
IRB 
Institutional Review Board 
LABA 
long-acting beta2 agonist 
LAMA 
long-acting muscarinic antagonist 
LTOT 
Long Term Oxygen Therapy 
mAChR 
muscarinic acetylcholine receptor 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
MDI 
Metered-dose inhaler 
mMRC 
Modified Medical Research Council Dyspnea Index 
M1 
muscarinic receptor 1 (subtype) 
M2 
muscarinic receptor 2 (subtype) 
M3 
muscarinic receptor 3 (subtype) 
M4 
muscarinic receptor 4 (subtype) 
M5 
muscarinic receptor 5 (subtype) 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PIFR 
Peak Inspiratory Flow Rate 
PFM 
peak flow meter 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PRO 
Patient Reported Outcome 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
RR 
respiratory rate 
SABA 
short-acting beta2 agonist 
SAE 
serious adverse event 
SGRQ 
St. George’s Respiratory Questionnaire 
SOP 
standard operating procedure 
t1/2 
terminal half-life, estimated as ln 2/λz where λz is the terminal elimination rate 
constant determined by the slope of the terminal phase of the plasma 
concentration-versus-time curve 
Tmax 
time to maximum concentration 
 


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1 
INTRODUCTION 
Pharmacologic treatment of chronic obstructive pulmonary disease (COPD) with 
bronchodilators is central to the management of both the symptoms and the long term risks 
of the condition. Long-acting inhaled bronchodilators are convenient and may be more 
effective for long-term symptom relief than short-acting bronchodilators; accordingly, 
widely-accepted treatment guidelines such as those produced by the Global Initiative for the 
Treatment of Obstructive Lung Disease (GOLD) recommend the use of long-acting 
muscarinic antagonist (LAMA) bronchodilators as first-line therapies for subjects with 
persistent COPD symptoms {1}. For some patients, bronchodilator therapy is most 
effectively provided using a nebulizer device. TD-4208 is designed as a once-daily agent to 
be administered using a standard jet nebulizer.  
 
Background and Rationale 
1.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Nonclinical Profile 
1.2
A review of the nonclinical profile of TD-4208 can be found in the current version of the 
TD-4208 Investigator’s Brochure (IB). The following is a brief summary of the pertinent 
findings. 
1.2.1 Pharmacology 
 
 
 
 
 
 
 
 
 Overall, the pharmacology of TD-4208, 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 TD-4208 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 TD-4208 included single-dose, repeated-dose and genetic 
toxicity studies. The results of these studies are summarized in the Investigator’s Brochure.  
1.2.3 Pharmacokinetics 
The nonclinical pharmacokinetic assessment of TD-4208 included single and repeat-dose 
pharmacokinetic studies in animals and an evaluation of the metabolic fate and drug-drug 
interaction potential of TD-4208. TD-4208 PK is characterized by high selectivity for lung 
tissue and low systemic plasma concentrations after inhaled administration. There is a low 
potential for drug-drug interactions. The results of these studies are summarized in the 
Investigator’s Brochure.  


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Clinical Experience 
1.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Risks and Benefits 
1.4
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.  
Subjects participating in this study may experience discomfort due to repeated blood 
sampling.  
During the single dose study in which TD-4208 was administered as a dry powder, the most 
common adverse events were dysgeusia and headache.  
In Study
 a single nebulized dose (350 or 700 μg) of TD-4208 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 μg (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 


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underlying disease state (COPD) and not unanticipated in a study of this duration. There 
were no deaths. There were three SAEs (pneumonia, transient ischemic attack and chest 
pain (non-ischemic); none of which were attributed to study drug. 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. This event occurred in a 57 year old female subject 
during the washout period following completion of the 7-day 175 μg dosing period. Prior to 
the subject being discharged from the unit after the routine 24-hour in-patient stay on Day 7, 
the investigator had obtained a history, performed a physical examination and obtained an 
ECG on the subject. There were no abnormalities observed at the time of these evaluations. 
An autopsy was performed and reported 95% and 70% occlusion of the left and right 
coronary artery respectively. The coroner reported the cause of death as coronary artery 
insufficiency due to atherosclerosis. The investigator assessed the event as unrelated to 
study medication.  
Administration of placebo in study
 resulted in asymptomatic declines in FEV1 of >15% 
in 42.2% of patients, and this result was also observed following the evening dose of 
placebo in the 175 µg QD dosing arm. No administration-related bronchospasm was 
reported in the study. The phenomenon appeared to be short-lived following administration, 
resolved within one hour of dosing and was blunted or ablated by the presence of TD-4208. 
The immediate postdose transient decline in FEV1 that was observed with TD-4208 appears 
to be similar to what has been observed with other nebulized products that use nebulized 
citrate-buffered 0.9% saline as a vehicle. This effect is consistent with evidence in patients 
with COPD of a transient decrease in FEV1 following inhalation of normal (0.9%) saline 
despite the pre-administration of a short-acting bronchodilator, such as albuterol. 
In Study 
, the most common adverse events were dyspnea, cough, chronic obstructive 
pulmonary disease, back pain, and oropharyngeal pain. There were 4 SAEs reported in the 
study. These included (worsening) hypertension (175 μg), intestinal obstruction (350 μg), 
and unstable angina (175 μg); all were considered unrelated to study drug by the blinded 
Investigator on the basis of previous medical history and timing of the event. The fourth 
event, supraventricular tachycardia (44 μg), was considered possibly related by the blinded 


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Investigator; subsequent, review of all the available cardiovascular data including the 
pre-randomization Holter record by an independent cardiologist concluded that the 
supraventricular tachycardia (SVTs) were not likely to represent a study drug-induced 
change and represented only a slight worsening of pre-existing SVTs. 
Clinically significant bronchodilation has been observed in each of the study populations of 
COPD subjects thus far in the development program, however TD-4208 is an investigational 
drug and its benefits and risks continue to be evaluated in phase 3.  


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2 
OBJECTIVES 
The primary objective of the study is: 
• 
To characterize the safety and tolerability of TD-4208 administered once daily for 
52 weeks in a population of patients with moderate to very severe COPD 
The exploratory objectives of the study are: 
 
 
 
 
 
 


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3 
STUDY DESIGN 
 
Overview 
3.1
This is a randomized, active-controlled, parallel-group study. Each subject will receive 
treatment once daily in the morning for a total of 52 weeks. There will be three treatment 
groups (TD-4208 88 μg, TD-4208 175 μg, and tiotropium 18 μg). TD-4208 will be 
administered as a 3 mL solution by inhalation using the
 jet nebulizer and 
tiotropium as a dry powder capsules with the
 device. The study will be 
double-blind with respect to the TD-4208 dose arms, and open-label with respect to the 
tiotropium control arm. 
There will be 1050 subjects randomized 
 
 Screening will ensure that 
subjects are eligible for inclusion in the study. Subjects will undergo washout from prohibited 
medications as appropriate, including all products containing long-acting antimuscarinics 
[LAMA] (either in combination or alone). Patients who are currently on long-acting 
beta-agonists [LABA] (with or without inhaled corticosteroids) will be permitted to be enrolled 
in the study. Subjects that are not on a LABA or LABA / ICS when they enter the study and 
require a LABA or LABA/ICS to treat a COPD exacerbation at the discretion of the 
investigator in accordance with COPD guidelines will be allowed to remain in the study. 
 
  
The study will consist of 1 or 2 screening visits, depending on whether a washout period is 
required and 6 treatment period visits and a telephone follow-up visit as shown in the study 
design schematic (Figure 1).  
 


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The procedures for each study visit are specified in the Schedule of Study Procedures and 
described in Section 6 Study Procedures.  
 
Rationale for Study Design 
3.2
This is a Phase 3 study to assess long term safety and tolerability of two doses (88 and 
175 μg) of TD-4208 administered once-daily for 52 weeks. The active control group will be 
treated with tiotropium to allow comparisons to a LAMA that is commercially available.
 
 
 
The two doses were selected from the Phase 2 studies as 
appropriate doses with an optimal benefit:risk ratio to further characterize the safety and 
efficacy of TD-4208 in phase 3.  
The study is designed as an active-controlled parallel-group study, with 350 subjects 
randomized to each treatment group
 
. This study increases the experience of TD-4208 dosing 
with a longer term treatment period compared to the Phase 2 studies. A parallel group 
design is suitable and practical to meet the objectives of the study. Study medication will be 
identical in appearance for each of the two doses of TD-4208, and both the study subjects 
and investigative site staff will remain blinded to the dose of TD-4208, however the 
tiotropium will be administered as an open-label treatment. Randomization allows for an 
unbiased assessment of treatment effects across the doses of TD-4208 tested, and 
provides for comparisons with open-label tiotropium. The duration of treatment is limited, 
and all subjects will have study-specific rescue medication (albuterol via MDI) provided for 
the full duration of the study, including during the screening and follow-up periods. Subjects 
who experience 1 or 2 moderate or severe acute exacerbations of COPD (AECOPD) will be 
allowed to continue study drug throughout the exacerbation and will not be withdrawn from 
the study. Any subjects who experience more than 2 exacerbations will be withdrawn and 
placed on appropriate therapy.  
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 >700 mL, [NHANES III]) {5}. 
Subjects will be eligible for enrollment regardless of the improvement in their FEV1 following 
ipratropium administration at screening. The inclusion of both highly responsive and poorly 


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responsive subjects from a broad range of disease severities in Phase 3 is intended to 
reflect the same population that was used in Phase 2 as well as the intended population if 
TD-4208 is approved. Patients who are already on a background of LABA-containing 
therapy (LABA alone or LABA/ICS) will be included and allowed to continue their 
concomitant LABA-containing therapy, to represent the concomitant therapies that subjects 
may be using if TD-4208 is approved. 
Assessments of subject status and safety laboratory evaluations are designed to ensure 
subject safety and compliance with medication during the course of the 52 week period of 
dosing. 
 
Selection of Doses and Duration of Treatment 
3.3
The doses selected for this study have been chosen on the basis of experience with 
TD-4208 in 4 previously conducted studies where study drug was administered via nebulizer 
– studies 0059, 0091, 0116, and 0117. 
Study 0059 examined single doses of 350 and 700 μg and Study 0091 examined doses of 
22, 44, 88, 175, 350 and 700 μg once daily in a 7 day placebo controlled crossover design. 
Twenty four hours after the last (Day 7) dose in each period, the FEV1 for each of the doses 
of TD-4208 was statistically greater than that following placebo, although 22 and 44 μg 
produced sub-therapeutic effects. At doses from 88-350 μg there was a greater increase in 
lung function (both trough and weighted mean). There appeared to be no additional benefit 
of dosing with 700 μg compared with 350 µg.  
All doses were well tolerated in Study 0091, adverse events were infrequent throughout the 
study and there was no evidence of a dose response relationship for TD-4208 or even an 
excess of AEs in any of treatment arms in relation to the observed adverse event rates in 
the placebo arm. 
Study 0117 was a definitive dose-ranging study and evaluated the doses of 44, 88, 175 and 
350 µg once daily over 28 days in a randomized, placebo-controlled parallel group design. 
The lowest and highest doses in this range represented the upper and lower parts of the 
dose response curve on which to assess the 88 and 175 µg treatment effects. TD-4208 was 
generally well tolerated and 88 µg was confirmed as the minimally effective dose. The 44 µg 
dose was subeffective and was not statistically significant compared to placebo. The fourth 
study was a mechanistic study to assess dose interval and tested doses of 175 µg QD and 


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44 µg BID in a randomized, placebo-controlled crossover study. The study confirmed QD 
dosing as the appropriate dose frequency for TD-4208, with no advantage observed with 
dosing a lower total daily dose given in divided intervals (44 µg BID). 
The study will evaluateTD-4208 QD at the two doses 88 µg and 175 µg in COPD. These 
doses were selected from the Phase 2B dose-ranging study (Study 0117) as the two doses 
having the optimal benefit:risk ratio in terms of efficacy and safety to move forward and 
further investigate in the Phase 3 program.  
 
Study Endpoints 
3.4
The primary endpoint(s) of this study assess the long-term safety and tolerability of TD-4208 
in the treatment of COPD: 
• 
Frequency and severity of adverse events, including exacerbations 
• 
Vital signs 
• 
Clinical laboratory evaluations 
• 
12-lead ECG changes from baseline 
In addition, the following exploratory endpoints will be characterized: 
• 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Minimization of Bias 
3.5
Bias will be minimized through the use of randomization and blinding (with regard to 
TD-4208 dose).  
3.5.1 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 dose of TD-4208. 
The tiotropium comparator arm will be open-label, and subjects will be assigned in random 
order to tiotropium or TD-4208 according to the randomization schedule. The only personnel 
who will have access to the randomization schedule before database lock are: 
• 
The nominated statistician 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 
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.  
3.5.2 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 three treatment groups using IWRS 
(Day 1 visit). 
  
 
 
 
 
 


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4 
STUDY POPULATION 
The following inclusion and exclusion criteria must be satisfied before subjects are entered 
into the study: 
 
Inclusion Criteria 
4.1
1. Subject is a male or female subject 40 years of age or older (age at Visit 1A). 
2. Subject is willing and able to provide signed and dated written informed consent to 
participate at Visit 1A prior to initiation of any study related procedures.  
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 at Visit 1B.  
4. Subject has moderate to very severe stable COPD with a post-ipratropium FEV1 less 
than 80% of predicted normal at Visit 1B and a post-ipratropium FEV1 >700 mL at Visit 
1B. 
5. Subject has a current or past cigarette smoking history (or equivalent for cigar or pipe 
smoking history) of at least 10 pack-years. 
6. Subject must be willing and able to attend study visits according to the visit schedule. 
7. Women of either child bearing potential or non-child bearing potential as follows: 
• 
Women of childbearing potential must have documentation of a negative urine 
pregnancy test at Visit 1B and Visit 2 (prior to randomization). If a urine pregnancy 
test is positive, it must be confirmed via a second urine pregnancy test. 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 care giver) based on the investigator’s assessment is able to properly 
prepare and administer study medication administered either by nebulizer or 
.  


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Exclusion Criteria 
4.2
1. Females who are pregnant, lactating, breastfeeding or planning to become pregnant 
during the study. 
2. Subject has a significant respiratory disease or disorder other than COPD that, in the 
opinion of the investigator, would affect the interpretation of data from this study, 
including but not limited to restrictive lung disorders, benign or malignant tumors of the 
lung, chronic pulmonary infections such as tuberculosis, occupational lung disease such 
as silicosis or asbestosis, inflammatory disorders of the lung, alpha-1-antitrypsin 
deficiency, and/or abnormalities of the chest wall or musculature (e.g., scoliosis, 
myasthenia gravis, phrenic nerve palsy).  
3. Subject has a history of cancer of any organ, treated or untreated in the 5 years prior to 
Visit 1A (excludes localized basal cell or squamous cell carcinoma of the skin; localized 
prostate cancer in situ of grade 1; localized cervical cancer in situ of grade 0). 
4. 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, tolerability, 
or pharmacokinetics of the study drug. 
5. Subject has a history of reactions or hypersensitivity to inhaled or nebulized 
anticholinergics or short-acting beta-agonists. 
6. 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. 
7. Subject has a significantly increased risk of cardiovascular events, as indicated by a 
history at Visit 1A of myocardial infarction or unstable angina within the last 6 months, 
unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months, 
or New York Heart Association (NYHA) Class IV heart failure.  
8. Subjects with clinically significant and uncontrolled hypertension, hypercholesterolemia 
or Type II diabetes mellitus. 
9. Subject has been hospitalized for COPD or pneumonia within 8 weeks prior to Visit 1B. 
10. Subject has used systemic corticosteroids within 6 weeks of Visit 1B. 
11. Subject has used antibiotics for respiratory tract infections within 6 weeks of Visit 1B. 
12. Subject has undergone lung volume reduction surgery or lobectomy within 12 months 
prior to Visit 1B. 
13. Subject has an abnormal and clinically significant 12-lead ECG findings at Visit 1B 
according to the following criteria: 
• 
atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute 
• 
sustained or nonsustained ventricular tachycardia (VT) 
• 
second degree heart block Mobitz type II 
• 
third degree heart block (unless pacemaker or defibrillator had been inserted) 
• 
QT interval corrected for heart rate (QTcF) ≥500 milliseconds (msec).  
14. Subject is unwilling or unable to stop the use of prohibited medications during the 
washout (if required) and treatment period and follow-up period of the study. 
15. Subject has participated in a previous TD-4208 study.  


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16. Subject has used any other investigational medication within 30 days or five drug 
half-lives (whichever is longer) of screening. 
17. Subject has a history of known or suspected alcohol or drug abuse within 2 years prior to 
screening, at the discretion of the investigator.  
18. Subject is affiliated with the investigator site (e.g., investigator, study coordinator, site 
employee, etc.).  
19. Subject requires long-term oxygen therapy (>15 hours a day) on a daily basis for chronic 
hypoxemia. 
20. Subjects who are participating in the initiation phase of a supervised pulmonary 
rehabilitation program (subjects in the maintenance phase will be eligible). 


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5 
STUDY DRUGS  
All study drug supplied by the Sponsor must be stored in a secure refrigerated 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 and at 
each of the study visits thereafter to identify the study drug kits to dispense to a particular 
subject.  
Study drug will be administered to the subjects under supervision at the clinic during study 
visits on the morning of Day 1, Day 29, Day 92, Day 183, and Day 274. Study drug will not 
be administered at the last study visit on Day 365 as the last dose of study drug will be at 
home the day before on Day 364. Subjects will be dispensed study drug to take home with 
them on Day 1 for home administration each morning on Day 2 through 28, and similarly at 
each study visit thereafter to provide a sufficient supply for home administration in between 
study visits. The time window for study drug administration will be between 6 am and 11 am. 
All subjects must return all used and unused study drug on each of the study visits where 
this applies.  
More information regarding study drug dispensing, administration, handling and storage are 
provided in a separate Pharmacy Manual. 
 
Description of Study Drugs 
5.1
5.1.1 TD-4208 
TD-4208 free base has a molecular weight of 
  It is a 
 
 
 
 
  
TD-4208 and its placebo must be stored
 
accessible only to designated study personnel. On days in which the study medication is 
administered in the clinic on the day it is dispensed,
 
 


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Detailed instructions for administration will be provided separately and provided to the study 
subject.  
5.1.2 Tiotropium 
Tiotropium will be provided in the commercially available presentation which consists of 
 dry powder capsules administered using the 
 device. The drug should 
be stored at 25°C (77°F) with excursions permitted to 15°C to 30°C (59°C to 86°F). 
Detailed instructions for administration will be provided in the Package Insert.  
5.1.3 Agents for Reversibility Testing 
5.1.3.1 
Ipratropium 
Ipratropium will be provided as a solution for administration via jet nebulizer for reversibility 
testing during screening, at a dose of 500 µg. Refer to the package insert for further 
information.  
5.1.4 Agents for Rescue Therapy 
5.1.4.1 
Albuterol 
Subjects who are randomized to the study will return the study-specific rescue medication 
they used during screening at Visit 2 and will be issued with a new study-specific rescue 
medication albuterol MDI.  
Subjects will be dispensed rescue medication as needed on each of the remaining study 
visits to ensure they have adequate access to rescue medication throughout the study. It is 
important to dispense a sufficient quantity of albuterol MDI so that the subject does not run 
out of albuterol in between study visits based on the subject’s normal usage. Subjects will 
bring all rescue medication they have been dispensed as they return for each study visit for 
reconciliation.  
Refer to the package insert for further information. 


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Dose Administration 
5.2
5.2.1 TD-4208 
TD-4208 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. This time will be chosen based on convenience for the study 
subject and will be within the window of 6 am and 11 am. At each of the remaining study 
visits subjects will be required to bring their nebulizer and compressor back to the clinic for 
in-clinic dosing on visit days. If a subject has taken their dose of study drug in the morning 
prior to their in-clinic visit, this visit will be rescheduled. At each study visit subjects will be 
dispensed sufficient study drug for home dosing until the time the subject returns for their 
next study visit. 
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 eDiary. 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 (Visit 2) in the clinic. 
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 eDiary. 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. 


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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.  
5.2.3 Agents Used for Reversibility Testing 
5.2.3.1 
Ipratropium 
Ipratropium will be provided as 2.5 mL vials containing a solution of 500 µg to be 
administered via nebulizer. See package insert for further information.  
5.2.4 Agents Used for Rescue Medication 
5.2.4.1 
Albuterol 
Albuterol will be provided as a MDI for rescue medication on an as-needed basis and 
administered at a dosage of 90 µg per puff. See package insert for further information. 
 
Treatment Compliance 
5.3
Compliance will be assessed in study subjects when accountability is performed as 
described in the next section. Compliance will be defined as subjects who are considered to 
have received 80% of the total number of doses that should have been administered in 
between study visits. 
The eDiaries will be used to record the timing of dosing by the subject (or caregiver).  
 
Drug Accountability and Reconciliation 
5.4
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 every study visit following Day 1 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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Treatment compliance will be assessed by counting the empty foil pouches from the used 
study drug and the unused vials (for TD-4208) and used and unused blister cards 
(for tiotropium). If a subject does not return the foil pouches, the unused vials or blister cards 
it will be assumed that the subject did not administer the study drug. If a subject misses 
recording any dose of study drug based on the subject’s eDiary the site should discuss the 
missing entries to determine if the missing entries are due to not recording the 
administration in the eDiary and remind the subject of the importance of recording this in 
their diary. Discrepancies between the subject’s eDiary and the count of returned study drug 
should be documented in the source documents. 
Subjects will record their use of study-specific rescue medication (albuterol) in their diaries, 
recording any use (or not) in each 24 hour period in the study including the screening and 
follow-up period.  


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6 
STUDY PROCEDURES 
 
Schedule of Study Procedures 
6.1
The schedule of study procedures is summarized in Table 1.  
Throughout the study investigators should conduct the order of the assessments for each 
study visit as indicated in the study procedures and strive to maintain consistency in this 
order. With the exception of Screening Visit 1, all study procedures for a visit must be 
completed on the same day. Any missed visits, test not done, or procedures that are not 
conducted must be reported as such on the electronic case report forms (eCRFs).  
The scheduling of Visits 3, 4, 5, 6, and 7, are based on the date of occurrence of Visit 2 
(Day 1 of the treatment period when the subject is randomized). If a visit does not occur on 
schedule, the following visits should still occur relative to when the Day 1 visit occurred. The 
Day 29 Visit will be allowed to have a visit window of 5 days on either side of the assigned 
date if scheduling does not allow for the subject to be seen on the assigned day. The visits 
thereafter (Visits 4, 5, 6, and 7) will also have a visit window of 5 days on either side of the 
assigned date. The follow-up visit should be scheduled 7 days after Visit 7, with a 2 day visit 
window on either side of the assigned date. 
 
Total Blood Volume 
6.2
The total volume of blood to be drawn from each subject for safety laboratory assessments 
for the entire period of the study is approximately 105 mL. Additional samples may be drawn 
for safety laboratory testing as considered necessary by the investigator. 
 
Procedures by Visit 
6.3
6.3.1 Screening 
Screening assessments and study procedures outlined in this section can only be performed 
after obtaining informed consent. Importantly, this includes any washout of a subject’s 
current medication for the purpose of participation in the study or changing a subject’s 
combination medication containing an inhaled steroid to inhaled steroid monotherapy 
(see Table 2 for specific washout periods required).  
 


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Participants in this study who, at the time of screening are taking COPD medications 
requiring a washout will have two screening visits (1A and 1B). Long acting bronchodilators 
requiring a washout include LAMAs (tiotropium (
), glycopyrronium bromide, 
aclidinium (
, umeclidinium (
 or any other approved LAMA); combination 
LAMA/LABA products including 
, olodaterol/tiotropium or any other approved 
combination LAMA/LABA; and roflumilast (Table 2). The effects of the long acting agent will 
be washed out between Visits 1A and 1B and this washout period will be no longer than 
45 days. Subjects not taking these long acting bronchodilators, or other COPD medications 
requiring a washout, at screening will need only one screening visit (1A/B). 
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 Visit 1A (Initial Screening Visit) when 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. The subject will 
start a washout period only after signing the informed consent form. After completing the 
washout (if required) the subject will return for Visit 1B (Ipratropium Reversibility Visit). It is 
only necessary to conduct Visit 1A and 1B as separate visits if a washout period is required. 
If a washout period is not required these two visits may be performed as one visit. 
If a washout period or a stable ICS/LABA run-in period (at least 30 days) is required the time 
from the Initial Screening Visit to Visit 1B will be no longer than 45 days. If a washout period 
or a stable ICS/LABA run-in period (at least 30 days) is not required then the two screening 
visits (Visit 1A and Visit 1B) may be conducted as one visit. The time period from Visit 1B 
(i.e., the Ipratropium Reversibility Visit, whether this is combined with Visit 1A or not) until 
Day 1 of dosing (Visit 2), will be 7 to 12 days.  
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 


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meet any spirometry related criteria after the first attempt the subject should similarly be 
screen failed.  
6.3.1.1 
Visit 1A (Initial Screening Visit) – (performed up to 45 days before Visit 1B) 
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 
• 
Complete Treatment Satisfaction Questionnaire 
• 
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 1 inhaler of albuterol as rescue medication.   
6.3.1.2 
Visit 1B (Ipratropium Reversibility Visit) – (if a washout or a stable 
ICS/LABA run-in period (at least 30 days) is not required Visit 1A and 1B 
may be conducted as one visit) 
The following procedures will be performed at this visit: 
• 
Pre-dose of ipratropium 
o Vital signs. Subjects need to be resting in a semi-recumbent position 
approximately 5 minutes prior to assessment of vital signs and ECG. 
o ECG (12 lead)  
o Complete physical examination 
o Height and weight 
• 
Spirometry reversibility testing pre- and post-dose ipratropium after withholding 
bronchodilators as specified in Table 2. Spirometry will be performed pre-dose and 
45 minutes post-dose. 
• 
Blood collection 
o Hematology 
o Serum chemistry 
• 
Urine collection 
o Urinalysis (microscopy not required) 
o Urine pregnancy test in women of child bearing potential 
• 
Review of inclusion and exclusion criteria   
• 
Subject will be trained on and dispensed the diaries  


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• 
Concomitant medications 
• 
Adverse events  
• 
 
• 
Dispense diaries 
• 
24-hour Holter monitor applied (substudy subjects only) 
NOTE:  Substudy subjects will be asked to return to the clinic the following day to have 
the Holter Monitor removed 
6.3.2 Treatment and Follow-up Period 
6.3.2.1 
Visit 2  
The following procedures will be performed at Visit 2. The timing of procedures pre-dose 
study drug administration is relative to the start of nebulization. The timing of procedures 
post-dose study drug administration is relative to the completion of nebulization. 
Prior to any assessments on Visit 2, randomized subjects will measure their Peak Inspiratory 
Flow Rate (PIFR) using the In-check Dial device. This procedure will be performed by 
trained site staff. Subjects will perform three attempts with resistance dialed to 
 
and three attempts without any resistance. The highest value of the three attempts for each 
setting will be recorded.  
Procedures performed at the same timepoints will be performed in the following sequence - 
vital signs, then ECG, followed by spirometry. All attempts should be made to perform the 
spirometry at the required timepoints (i.e., the spirometry procedure will take priority over 
other procedures and if necessary the timing of the other procedures are approximate and 
may be adjusted 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 in the 
eDiary whether albuterol was used or not in the last 24 hours and the start time of study 
drug nebulization, then administering study drug. It is important at study visits that the trough 
FEV1 be done before receiving study drug (or LABA if applicable). If the subject is taking a 
LABA this must be taken immediately before the study drug. 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. 


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• 
 
• 
Vital signs (approximately 60 min pre-dose and 10 minutes post dose).  
• 
12-lead ECG (approximately 60 minutes pre-dose and 10 minutes post dose) 
• 
Blood collection 
o Hematology 
o Serum chemistry 
• 
Urine collection 
o Urinalysis (microscopy not required) 
o Urine pregnancy test in women of child bearing potential 
• 
Review of inclusion and exclusion criteria 
• 
Randomization (subject eligibility must be confirmed by investigator before randomizing 
subject)  
• 
  
• 
Administer LABA containing product (as appropriate for those on existing 
LABA-containing therapy) 
• 
Study drug dosing via nebulizer (if randomized to TD-4208) or the 
 
(if randomized to tiotropium). Training on the specific device will be performed as part of 
the first dose administered.  
• 
Concomitant medications  
• 
Adverse events 
• 
Dispense study drug (IWRS will assign 1 kit) 
• 
Collect and reconcile rescue medication as appropriate  
• 
Dispense new rescue medication as needed (IWRS can assign 1 to 4 inhalers); the 
rescue medication used in screening will be collected 
6.3.2.2 
Visits 3, 4, 5, 6, and 7 
The following procedures will be performed at these visits: 
• 
 
 
• 
Vital signs (approximately 60 minutes pre-dose and 10 minutes post dose)  
• 
12-lead ECG (approximately 60 minutes pre-dose and 10 minutes post dose)  
• 
Physical exam (at Visits 5 and 7 only) 
• 
Weight (at Visit 7 only) 
• 
Blood collection  
o Hematology 


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o Serum chemistry 
• 
Urine collection 
o Urinalysis (microscopy not required) 
o Urine pregnancy test in women of child bearing potential 
• 
Review of diary   
• 
  
• 
Administer LABA containing product (as appropriate for those on existing 
LABA-containing therapy) 
• 
Study drug dosing via nebulizer or 
 (as applicable) and retraining as 
necessary (at Visit 3, 4, 5, and 6 only) 
• 
24-hour Holter monitor applied (substudy subjects only) (Visits 3 & 5 only) 
NOTE:  Substudy subjects will be asked to return to the clinic the following day to have 
the Holter Monitor removed 
• 
Concomitant medications 
• 
Adverse events 
• 
Dispense study drug for home use (IWRS will assign kits at each visit as needed) 
(at Visit 3, 4, 5, and 6 only)  
• 
Dispense rescue medication as needed 
• 
Collect and reconcile returned study drug 
• 
Collect and reconcile rescue medication as appropriate 
• 
 
• 
Assess Compliance 
6.3.3 Visit 8 (Telephone Follow-up) 
The following reviews with the subject will take place via telephone.  
• 
Concomitant medications 
• 
Adverse events  
6.3.4 Early Termination/Withdrawal Visit 
• 
 
 
 
• 
Vital signs 
• 
Weight 
• 
ECG 
• 
Physical Exam 
• 
Blood collection 


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o Hematology 
o Serum chemistry 
• 
Urine collection 
o Urinalysis (microscopy not required) 
o Urine pregnancy test in women of child bearing potential 
• 
Review of diary 
•
 
• 
Concomitant medications 
• 
Adverse events 
• 
Collect and reconcile returned study drug 
• 
Collect and reconcile rescue medication as appropriate 
• 
 
• 
Assess Compliance 
(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.) 
All subjects who terminate early, regardless of the reason, will have a follow-up telephone 
call at 12 months from Day 1 (randomization) to determine their vital status. 
6.3.5 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 
medically indicated: 
• 
Medical history update 
• 
Vital signs 
• 
12-lead ECG 
• 
Laboratory assessment (hematology and chemistry to be performed by a central lab) 
• 
Physical examination 
• 
Record concomitant medications 
• 
Record adverse events 


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Description of Study Assessments 
6.4
6.4.1 Demographic and Baseline 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, ECG, laboratory evaluations including 
hematology, serum chemistry, urinalysis, FEV1 measurements (pre- and post-ipratropium 
inhalation and on a separate screening visit pre- and post-albuterol inhalation), and a urine 
pregnancy test for females of child-bearing potential. 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
6.4.3 Safety Assessments  
6.4.3.1 
Adverse Events 
Adverse events will be reviewed and recorded from the signing of the informed consent form 
through the last day of the follow-up visit. Adverse events may be observed by the site study 


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personnel or spontaneously reported by the subject. Subjects will be reminded to call the 
site to report AEs that occur between visits. 
6.4.3.2 
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. 
Any changes that occur following the subject signing the informed consent form will be 
captured as adverse events.  
6.4.3.3 
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.  
6.4.3.4 
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.  
Vital signs (HR and BP) will be monitored at 60 minutes pre-dose and at 10 minutes post 
dose.  
6.4.3.5 
Laboratory Tests 
A central lab will be used for all laboratory assessments. Specimen collections times are 
specified in the Schedule of Study Procedures and all assessments will be performed 
non-fasting.  


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6.4.3.5.1 Hematology  
Hematocrit and hemoglobin, red blood cell count, white blood cell count, including 
differential count of total neutrophils, eosinophils, basophils, monocytes, lymphocytes; mean 
corpuscular volume; mean corpuscular hemoglobin; and mean corpuscular hemoglobin 
concentration, and platelet count. 
6.4.3.5.2 Serum Chemistry  
Sodium, potassium, chloride, bicarbonate (if available), BUN, creatinine, magnesium, 
calcium, phosphate, total bilirubin, direct and indirect bilirubin, alkaline phosphatase, lactate 
dehydrogenase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transferase, and GFR (derived from serum creatinine). 
6.4.3.5.3 Urinalysis  
Urinalysis includes determination of pH; specific gravity; presence of blood, glucose, protein, 
ketones, bilirubin, urobilinogen, nitrite, and leukocytes.  
6.4.3.5.4 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.  
6.4.3.6 
ECG – 12-lead 
ECGs will be done singly following a 5-minute semi-recumbent rest at Screening Visit 1B 
and 60 minutes pre-dose and 10 minutes post dose at Visits 2 – 6. 
6.4.3.7 
24-hour Holter Substudy 
A substudy will be conducted at selected sites where subjects will perform a 24-hour Holter 
monitor recording at Visit 1B, Visit 3 (1 month), and Visit 5 (6 months). Subjects will return to 
the site from 1 to 4 days after the visit so that the Holter monitor may be retrieved by the 
site. If the recording is incomplete (either missing or < 6 hours duration) then another 
24-hour Holter should be performed.   


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All subjects will be asked to participate in the substudy at these sites until enrollment in the 
substudy is complete at approximately 150 subjects. Once enrollment is complete in the 
substudy, these sites can continue to enroll subjects into the main study. 
 
Concomitant Medications 
6.5
Prior to the ipratropium reversibility testing during screening, short acting bronchodilators 
must be withheld for at least 6 hours.  
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 6 hours before the first 
spirometry performed at each study visit until all spirometry is completed. 
If subjects have used albuterol within 6 hours of the spirometry measurement on Visit 1B or 
Visit 2 the visit must be rescheduled. If subjects have used albuterol within 6 hours of the 
spirometry measurement at Visits 3, 4, 5, 6 or 7 then the visit should still be performed as 
scheduled. Use of albuterol as a rescue inhaler will be documented in a medication eDiary 
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 Visit 1B and the 
steroid component is ≤1000 μg/day equivalent to fluticasone propionate. For reversibility 
testing at screening, subjects who are on a QD regimen should not have had their last dose 
within approximately the last 24 hours and for BID subjects not within approximately the last 
12 hours, prior to the reversibility test. Once enrolled it is important to standardize 
administration of the subject’s LABA or LABA/ICS together with the study drug, as the 
spirometry will be measuring the combined effect of receiving the LABA and the study drug. 
These subjects should administer their LABA or LABA/ICS in the morning immediately prior 
to the nebulization of study drug. This administration should be documented in the source 
documents on study visit days and subjects should be instructed to follow the same 
procedure while at home between study visits. If subjects have used their LABA or 
LABA/ICS on the morning prior to their in-clinic visit instead of taking it immediately prior to 
study drug nebulization at Visit 2, this visit will be rescheduled. During any of the other 
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their in-clinic visit instead of taking it immediately prior to study drug nebulization the visit 
should still be performed as scheduled.   
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 
LABA (with or without ICS) may be started for the treatment of an exacerbation for those 
subjects who were not previously on LABA-containing therapy and may be continued after 
the exacerbation is resolved for the remainder of the study at the investigator’s discretion in 
accordance with COPD guidelines. During treatment for the exacerbation, study drug may 
be discontinued for no longer than 14 days. When an exacerbation occurs the symptoms 
must be resolved completely before their in-clinic visit. If prescribed for treatment of 
exacerbation, subjects should also complete their steroids and antibiotics regimen before 
they schedule their in-clinic visit. 
Albuterol use (whether there has been any use in the last 24 hours) will be recorded in the 
subject’s eDiary every day.  
Table 2 lists the medications that require washout prior to Visit 1B. These medications are 
also prohibited throughout the study from Visit 1B to Visit 8 (24 hours after the last dose of 
study drug) inclusive. Subjects will be permitted to restart their routine medications after the 
completion of Visit 8.  


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Restrictions 
6.6
Subjects are to observe the following restrictions from Screening through to Day 365: 
• 
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) 


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During study visits (i.e., when the subject is in clinic), excessive smoking, exercise, or 
caffeine intake or large meals should be restricted (further details provided in the 
Study 0128 Spirometry Manual). 
 
Discontinuation 
6.7
6.7.1 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. 
Exacerbations of COPD will be classified as mild, moderate, or severe according to the 
below criteria. Subjects who experience 1 or 2 moderate or severe acute exacerbations of 
COPD (AECOPD) will be allowed to continue study drug throughout the exacerbation and 
will not be withdrawn from the study. Any subjects who experience more than 
2 exacerbations (each separated by more than 1 month to confirm that they are separate 
events) will be withdrawn and placed on appropriate therapy. Subjects that are not on a 
LABA-containing therapy when they enter the study and require a LABA-containing therapy 
(either LABA alone or LABA/ICS) to treat a COPD exacerbation (either temporarily or from 
that point onwards at the discretion of the investigator in accordance with COPD guidelines) 
during the treatment phase of the study will be allowed to remain in the study. During 
treatment for the exacerbation, study drug may be discontinued for no longer than 14 days. 


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Table 3: 
Severity Criteria for COPD Exacerbations 
COPD exacerbation is defined as a complex of respiratory symptoms (increase or new 
onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest 
tightness with a duration of at least 3 days requiring treatment with SABAs, antibiotics, 
systemic steroids, or hospitalization. 
 
Severity of COPD exacerbation 
Criteria 
Mild 
A deterioration of COPD symptoms, in the 
judgment of the investigator, managed with 
an increased use of SABA but not requiring 
the use of antibiotics or oral or systemic 
corticosteroids. 
Moderate 
A deterioration of COPD symptoms, in the 
judgment of the investigator, based on any 
one of the following criteria: 
• 
An acute change in symptoms with 
purulent sputum requiring treatment 
with a course of antibiotics for lower 
airway disease 
• 
An acute change in symptoms 
requiring treatment with a course of 
oral steroid for lower airway disease 
• 
Subjects meeting the above criteria 
may receive treatment in a hospital 
setting as long as the duration of the 
visit is <1 day 
Severe 
A deterioration of COPD symptoms that 
results in hospitalization for emergency 
treatment of the COPD and the duration of 
the visit is ≥1 day.  
The Sponsor will be notified of all subject withdrawals. 
Reasons for which the investigator or the Sponsor may withdraw a subject from the study or 
a subject may choose to terminate participation before completion of the study include, but 
are not limited to, the following: 
• 
Adverse event 
• 
Subject choice 
• 
Major deviation of the protocol 
• 
Termination of the study by the Sponsor 
• 
Other 


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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.  
All subjects who terminate early, regardless of the reason, will have a follow-up telephone 
call at 12 months from Day 1 (randomization) to determine their vital status. 
6.7.2 Subject Replacement 
 
 
 
  
6.7.3 Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. 
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.  
 
Pregnancy 
6.8
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. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required. 


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7 
ADVERSE EVENTS 
 
Regulatory Definition of an Adverse Event 
7.1
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. 
 
Adverse Event Definition for the Purposes of This Study 
7.2
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 subject who has signed an 
informed consent form and is participating in a clinical investigation. 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 time the subject signed the informed consent form 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: 
• 
Medical or surgical procedures (such as surgery, endoscopy, tooth extraction, or 
transfusion); the condition that leads to the procedure is an adverse event 
• 
Preexisting diseases or conditions present or detected before signing an informed 
consent form that do not worsen 


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• 
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 
 
Assessment of Adverse Events 
7.3
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. 
 
Serious Adverse Events 
7.4
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-subject-hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other 
serious events) 
• 
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-subject-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. 
 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
7.5
Adverse Events or Serious Adverse Events 
Abnormal laboratory findings (such as clinical chemistry, hematology, or urinalysis) or other 
abnormal assessments (such as electrocardiograms [ECGs], X-rays, or vital signs) that are 
associated with signs and/or symptoms or are considered clinically significant in the 
judgment of the investigator must be recorded as AEs or SAEs if they meet the definition of 


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an adverse event (or serious adverse event), as described in Sections 7.2 (Adverse Event 
Definition for the Purposes of This Study) and 7.4 (Serious Adverse Events). 
If there are any AE questions, the investigator is encouraged to contact the Sponsor to 
discuss. 
 
Serious Adverse Event Reporting 
7.6
Any SAE that occurs after a subject signs an informed consent form through the follow-up 
visit (or at the time a subject is determined to be ineligible for the study or who does not 
enroll in the study), regardless of causal relationship, must be reported to the Sponsor within 
24 hours of the investigator’s knowledge of the event. To report an SAE, complete and fax 
the Serious Adverse Event Report Form to the following: 
Theravance Clinical Drug Safety 
Fax: 
 
For medical questions regarding an SAE, contact the medical monitor by telephone as 
follows: 
Sponsor Medical Monitor Contact Information: 
  
 
Telephone: 
 
Email: 
 
As an alternate, contact: 
 
Telephone: 
 
Email: 
 
For fatal or life-threatening events, also fax copies of hospital case reports, autopsy reports, 
and other documents when requested. Additional information may be requested from the 
investigator to ensure the timely completion of accurate safety reports. 
An SAE may qualify for reporting to regulatory authorities if the SAE is possibly attributable 
to the study drug and is unexpected/unlisted based on the current TD-4208 Investigator’s 
Brochure. In this case, all investigators will receive notification of the event. The investigator 
is responsible for notifying the Institutional Review Board or Ethics Committee and 


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documenting the notification, as required by local regulatory authorities and in accordance 
with the local institutional policy. 
 
Adverse Event Follow-up 
7.7
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 
 
General Considerations 
8.1
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. 
 
Sample Size and Power 
8.2
Sample size (n=350 per group) is based on meeting ICH regulatory requirements for 
long-term safety for chronic use in this indication.
 
 
 
 
 
Analysis Sets 
8.3
8.3.1 Analysis Sets 
The Safety (Safety) analysis set will include all subjects receiving at least one dose of study 
drug summarized by actual drug received. The Safety analysis set will be the primary 
analysis for General and Safety analyses. 
The Intent-to-Treat (ITT) analysis set will include all randomized subjects receiving at least 
one dose of study drug and at least one post-baseline FEV1 assessment. The ITT analysis 
set will be the primary analysis set for the summarization of efficacy analyses. 
The modified Intent-to-Treat (mITT) analysis set will include all ITT subjects with no switch in 
maintenance bronchodilator therapy (e.g. addition of a LABA therapy) during the study. 


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The Per-protocol (PP) analysis set will include all subjects in the ITT analysis set with no 
major protocol deviations 
8.3.2 Examination of Subgroups 
The following subgroups are pre-defined at baseline: 
• 
Baseline smoking status 
 
• 
Age 
 
• 
Current ICS use [
 
• 
Reversibility to ipratropium, 
• 
Baseline post bronchodilator % predicted FEV1 
 
 
• 
Baseline use of a LABA-containing therapy 
Selected efficacy analyses, as defined in the statistical analysis plan (SAP), will be 
conducted using the subgroup examination sets. Additional subgroups may be defined in 
the SAP. 
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. 
 
 
 
 
 
 
Additional criteria may be specified in the SAP. 
 
General Analyses 
8.4
8.4.1 Demographics and Other Baseline Characteristics 
Demographics (including age, sex, race, ethnicity, height, weight, and BMI) and baseline 
characteristics (concomitant LABA and ICS use) will be summarized for the Safety analysis 
set. 


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8.4.2 Screening and Baseline Spirometry 
A summary of pulmonary function at screening, including reversibility, and at baseline using 
the Safety analysis set will be provided. 
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. 
8.4.3 COPD Clinical History and Smoking History 
A summary of the COPD clinical characteristics/history and smoking history using the Safety 
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. 
 
Safety Analyses 
8.5
For all safety analyses, the safety analysis set will be used. 
Safety variables to be summarized include vital signs, adverse events, clinical laboratory 
results (hematology, chemistry, and urinalysis), corrected QT interval (QTc, from standard 
safety digital ECGs) and exacerbation data. Vital signs will be summarized in terms of 
observed values and changes from baseline. 
8.5.1 Extent of Exposure 
A subject’s data for the extent of exposure to study drug will be generated from the study 
drug administration page of the CRF. Dosing information for individual subjects will be listed. 
Using drug administration data, estimates of exposure to TD-4208 will be summarized. Dose 
discontinuations and reasons for study drug discontinuation will be listed and summarized. 


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8.5.2 Adverse Event Data 
8.5.2.1 
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 begins on or 
after the date of first dose of study drug up to the date of last dose of study drug plus the 
number of 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. 
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. 
8.5.2.2 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.5.2.3 
Exacerbations  
Exacerbations will be summarized descriptively using both exacerbations reported as 
adverse events and 
 in separate summaries. 
Exacerbation data will be summarized for the following categories: a) All exacerbations, 
b) Moderate and severe exacerbations, and c) Severe exacerbations. 
The rate of exacerbations per subject per year over the treatment period will be analyzed 
using a 
 
  
The time to first exacerbation will be analyzed using 
 
. 
Additional exacerbation analyses may be specified in the SAP. 
8.5.2.4 
Cardiovascular Events of Interest 
Adjudicated CV events will be presented by CV events categories, showing number (%) of 
patients with at least 1 adjudicated treatment emergent CV events, sorted by alphabetical 
order. Listings will be provided for all adjudicated treatment emergent CV events by 
treatment group and patient. 
8.5.3 Concomitant Medications 
Medications will be summarized both prior and during the 12-month treatment period. 
Medications will be summarized as COPD bronchodilator, ICS and non-COPD medications. 
8.5.4 Laboratory Data 
Laboratory data will be summarized in terms of observed values, changes from baseline, 
values relative to normal ranges, and changes from baseline relative to normal ranges. 
Listings will flag laboratory values that are outside of normal range. 
Clinical laboratory test results will be listed by subject. Reference ranges provided by the 
laboratory for each parameter will be used to evaluate the clinical significance of laboratory 
test results. Values falling outside of the relevant reference range will be flagged, as 
appropriate, in the data listings. Abnormalities in clinical laboratory test results will be listed 
in a separate listing.  


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8.5.5 Vital Signs Data 
Vital Signs data will be summarized in terms of observed values (by time point), changes 
from baseline (by time point), and counts and percentages within appropriately defined 
categories (Table 4). 
Table 4: 
Outlier Threshold for Vital Signs 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
<85 
>160 
<45 
>100 
8.5.6 ECG Data 
The QTcF, PR interval, QRS duration, and HR from standard digital ECGs will be 
summarized in terms of observed values, changes from baseline, and counts and 
percentages within appropriately defined categories (Table 5). 
Table 5: 
ECG Test Outlier Thresholds  
Heart 
Rate 
(bpm) 
Heart Rate 
Change From 
Baseline 
(bpm) 
PR  
Interval 
(msec) 
PR % 
Change  
From 
Baseline 
(%) 
QRS  
Interval 
(msec) 
QTcF 
(msec) 
QTcF  
Change 
From 
Baseline 
(msec) 
>120 
≥20 
≥200 
≥15 
≥120 
≤450 
≤30 
>130 
≥30 
≥220 
≥25 
 
>450, ≤480 
>30, ≤60 
 
 
 
 
 
>480, ≤500 
>60 
 
 
 
 
 
>500 
 
Treatment emergent ECG abnormalities are defined as those not present at baseline, or 
those that worsened after treatment, e.g., borderline at baseline, but were prolonged after 
treatment. QTcF will also be summarized by the following categories, Normal (males <430, 
females <450), Borderline (males (≥430, <450); females (≥450, <470)) and Prolonged 
(males ≥450, females ≥470). 
When multiple values exist for the same nominal time point (e.g., triplicate reading), the 
average of the readings taken for ECG parameters will be used in the data analysis, 
including the outlier analysis stated below. 


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All recorded values for the ECG parameters will be presented in a by-subject listing. A 
separate listing of subjects with values of QTcF >500 msec or an increase >60 msec will be 
provided, as necessary. 
Cumulative distribution plots will be provided for maximum change in QTcF by visit. 
8.5.7 Holter ECGs 
Results of Holter interpretation will provide the following heart rate (HR) variables in units of 
bpm: maximum (max) HR, minimum (min) HR, and mean HR for the entire recording, and 
count of supraventricular premature beats (PACs) singles and, separately, couplets, and 
ventricular premature beats (VPCs) singles and, separately, couplets normalized for 
24 hours.  
Holter interpretation will provide numbers of episodes of arrhythmia including pauses, 
supraventricular couplets, supraventricular runs, supraventricular tachycardia, atrial 
fibrillation or flutter, ventricular couplets, ventricular runs and ventricular tachycardia; and 
episodes of other diagnostic findings including, e.g., abnormal ST segments, junctional 
rhythm and atrioventricular block. 
 
Efficacy Analyses 
8.6
 
 
8.6.1 Efficacy Endpoints 
The exploratory efficacy endpoints are: 
• 
 
 
   
 
 
 
 
 
Endpoints will be reported as nominal p-value without control for multiplicity. 


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8.6.2 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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8.6.3 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment Satisfaction Questionnaires 
. 
 
Missing Data Handling 
8.8
  
. 
 
Clinical Events Committee 
8.9
An independent external Clinical Events Committee (CEC) will perform ongoing blinded 
review and adjudication of pre-specified CV events of interest collected in the electronic 
case report forms and other pre-specified subject-level source documents during the 
conduct of the study. Further information on the composition and processes followed by the 
CEC can be found in the CEC Charter. 
 
Data Monitoring Committee 
8.10
No data monitoring committee is planned for this study. 


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9 
STUDY ADMINISTRATION 
This study will be conducted in compliance with all applicable regulations. 
 
Principal Investigator Responsibilities 
9.1
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 subinvestigators who will be directly involved in the treatment or evaluation 
of research subjects in this study. (A subinvestigator is defined in ICH E6 as any individual 
member of the clinical study team designated and supervised by the investigator at a study 
site to perform critical study-related procedures and/or to make important study-related 
decisions [e.g., associates, residents, research fellows].) 
The 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 TD-4208 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. 


Protocol 0128, Amendment 3 
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Institutional Review Board/Independent Ethics Committee 
9.2
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. 
 
Informed Consent 
9.3
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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Confidential – Property of Theravance Biopharma, Inc. 
 
Data Recording and Quality Assurance 
9.4
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. 


Protocol 0128, Amendment 3 
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Confidential – Property of Theravance Biopharma, Inc. 
 
Document Retention 
9.5
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. 
 
Confidentiality 
9.6
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 lab and 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 


Protocol 0128, Amendment 3 
Version 1.0, 21JAN2016 
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Page 76 
 
Confidential – Property of Theravance Biopharma, Inc. 
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). 
 
Access to Data and Documents 
9.7
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. 
 
Quality Control: Study Monitoring and Auditing 
9.8
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. 


Protocol 0128, Amendment 3 
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Confidential – Property of Theravance Biopharma, Inc. 
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. 
 
Publication 
9.9
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. 


Protocol 0128, Amendment 3 
Version 1.0, 21JAN2016 
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Page 78 
 
Confidential – Property of Theravance Biopharma, Inc. 
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. 
Updated 2011. Available at: http://goldcopd.com. 
2. Beckett WS, McDonnell WF, Horstman DH, House DE. Role of the parasympathetic 
nervous system in acute lung response to ozone. J Appl Physiol. 1985 
Dec;59(6):1879-85. 
3. Belmonte KE. Cholinergic pathways in the lungs and anticholinergic therapy for 
chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(4):297-304; 
discussion 311-2. 
4. Fryer AD, Adamko DJ, Yost BL, Jacoby DB. Effects of inflammatory cells on neuronal 
M2 muscarinic receptor function in the lung. Life Sci. 1999; 64(6-7):449-55.  
5. Miller, MR, Hankinson, J, Brusasco, V, Burgos, F, Casaburi, R, Coates, A, & Wanger. 
Standardisation of spirometry. Eur Respir J, 2005:26(2), 319-38. 


Protocol 0128, Amendment 3 
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Appendix 1: 
Signature Page 


Protocol 0128, Amendment 3 
Version 1.0, 21JAN2016 
TD-4208 
Page 80 
 
Confidential – Property of Theravance Biopharma, Inc. 
Protocol Signature Form 
 
 
 
 
 
Title: 
Study TD-4208-0128: A Phase 3, 52-week, Randomized, 
Active−Controlled Parallel Group Study to Evaluate the Safety and 
Tolerability of Nebulized TD−4208 in Subjects with Chronic Obstructive 
Pulmonary Disease 
 
 
Study No.: 
0128 
 
 
Date: 
21 January 2016 
 
 
 
 
 
 
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 0128 
 
Version 1.0, 13MAR2017 
revefenacin 
 
Page 1 
 
  
STATISTICAL ANALYSIS PLAN 
Compound: 
revefenacin (TD-4208) 
Study Number: 
Study 0128 
Study Title: 
A Phase 3, 52-week, Randomized, Active-Controlled Parallel 
Group Study to Evaluate the Safety and Tolerability of Nebulized 
TD-4208 in Subjects with Chronic Obstructive Pulmonary 
Disease 
Protocol Version: 
Version 1.0, 
 
Sponsor: 
Theravance Biopharma R&D, Inc. 
c/o Theravance Biopharma US, Inc. 
901 Gateway Boulevard 
South San Francisco, CA  94080 
Plan Version: 
Version 1.0, 13 March 2017 
Plan History: 
No prior versions 
Plan Prepared by: 
 
, Biostatistics 
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. 
 


Study 0128 
revefenacin 
STATISTICAL ANALYSIS PLAN 
revefenacin, Study 0128 
Statistical Analysis Plan 
Version 1.0, 13MAR2017 
Page 2 
A Phase 3, 52-week, Randomized, Active-Controlled Parallel-Group Study to Evaluate the 
Safety and Tolerability of Nebulized TD-4208 in Subjects with Chronic Obstructive 
Pulmonary Disease 
Plan Version: 
Reviewed: 
Author: 
Biostatistics 
Reviewer: 
Clinical 
Developmen
Reviewer: 
Version 1.0, 13 March 2017 
21 March 2017 
 
 
Theravance Biopharma US, Inc. 
 
 
Theravance Biopharma US, Inc. 
 
Theravance Biopharma US, Inc. 
Confidential - Property of Theravance Biopharma, Inc. 
Date 
Date 


 
 
Statistical Analysis Plan 
Study 0128 
 
Version 1.0, 13MAR2017 
revefenacin 
 
Page 3 
 
Confidential – Property of Theravance Biopharma, Inc. 
TABLE OF CONTENTS 
 
PAGE 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................. 6 
1 
INTRODUCTION ....................................................................................................... 8 
2 
STUDY OBJECTIVES ............................................................................................... 8 
2.1 
Primary Objective ........................................................................................... 8 
2.2 
Exploratory Objectives ................................................................................... 8 
3 
OVERVIEW OF STUDY DESIGN .............................................................................. 9 
4 
SAMPLE SIZE AND POWER .................................................................................. 10 
5 
STUDY ENDPOINTS ............................................................................................... 10 
5.1 
General Endpoints ....................................................................................... 11 
5.2 
Safety Endpoints .......................................................................................... 13 
5.3 
Exploratory Efficacy 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 ........................................................................... 16 
6.1.3 
Evaluable Efficacy Assessment ....................................................... 19 
6.1.4 
Missing Data ................................................................................... 21 
6.2 
Adverse Events ............................................................................................ 23 
6.3 
Medications .................................................................................................. 23 
6.4 
Medical History ............................................................................................ 23 
6.5 
General Considerations for Summaries ........................................................ 23 
6.6 
Tables, Figures and Listings (TFLs) ............................................................. 26 
7 
ANALYSIS SETS ..................................................................................................... 27 
7.1 
Safety ........................................................................................................... 27 
7.2 
Intent-to-Treat .............................................................................................. 27 
7.3 
Per-Protocol ................................................................................................. 27 
7.4 
Examination of Subgroups ........................................................................... 28 
7.4.1 
Study-Specific Subgroups ............................................................... 28 
7.5 
Major Analysis Protocol Deviations .............................................................. 28 
8 
DEFINITION OF ANALYSIS VARIABLES ............................................................... 29 
8.1 
General Variables ........................................................................................ 29 
8.2 
Exploratory Efficacy Variables ...................................................................... 31 
9 
ANALYSES.............................................................................................................. 33 
9.1 
Safety Variables ........................................................................................... 33 
9.2 
General Analyses ......................................................................................... 33 
9.2.1 
Subject Disposition .......................................................................... 33 
9.2.2 
Demographics and Baseline Characteristics ................................... 34 
9.2.3 
Reversibility Summaries .................................................................. 34 


 
 
Statistical Analysis Plan 
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9.2.4 
Screening and Baseline Spirometry Summaries.............................. 34 
9.2.5 
Baseline Clinical Characteristics Summaries ................................... 35 
9.2.6 
GOLD Category Summary .............................................................. 36 
9.2.7 
Key Demographic and Baseline Characteristics Summary .............. 36 
9.3 
Safety Analyses ........................................................................................... 37 
9.3.1 
Extent of Exposure .......................................................................... 37 
9.3.2 
Adverse Events ............................................................................... 38 
9.3.2.1 
Exacerbations ................................................................... 40 
9.3.2.2 
Cardiovascular Events of Interest ..................................... 41 
9.3.2.3 
Antimuscarinic Adverse Events ......................................... 42 
9.3.3 
Vital Signs ....................................................................................... 42 
9.3.4 
ECG ................................................................................................ 43 
9.3.5 
Holter ECGs .................................................................................... 44 
9.3.6 
Clinical Laboratory Results .............................................................. 45 
9.3.7 
Medical History ............................................................................... 45 
9.3.8 
Prior and Concomitant Medications ................................................. 45 
9.3.9 
12-month Vital Status ...................................................................... 45 
9.4 
Exploratory Efficacy Analyses ...................................................................... 46 
9.4.1 
General Considerations for Exploratory Efficacy Analyses .............. 46 
9.4.2 
Exploratory Efficacy Evaluation: Trough FEV1 ................................ 46 
9.4.3 
Sensitivity Analyses of the Efficacy Endpoint: Trough FEV1 ........... 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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TABLE OF CONTENTS (CONTINUED) 
 
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LIST OF FIGURES 
 
Figure 1: 
Study Schematic .................................................................................... 10 
 
LIST OF TABLES 
 
Table 1: 
General Endpoints .................................................................................. 12 
Table 2: 
Additional Safety Endpoints .................................................................... 14 
Table 3: 
Baseline Assessment for Specific Parameters ....................................... 16 
Table 4: 
Analysis Windows: Visits ........................................................................ 17 
Table 5: 
Analysis Windows: Treatment Emergent Events .................................... 18 
Table 6: 
Analysis Windows: Vital Signs and ECGs ............................................... 19 
Table 7: 
Dummy Coding for Concurrent LABA ..................................................... 30 
Table 8: 
GOLD Severity of Airflow Limitation Categories...................................... 30 
Table 9: 
GOLD Categories ................................................................................... 30 
Table 10: 
Vital Signs Outlier Thresholds ................................................................ 43 
Table 11: 
ECG Test Outlier Thresholds .................................................................. 44 
Table 12: 
SGRQ Component and Total Maximum Scores ..................................... 54 
Table 13: 
Maximum Allowable Missing Questions for an Evaluable SGRQ 
Score ...................................................................................................... 54 
Table 14: 
CCQ Subdomains .................................................................................. 60 
 
LIST OF APPENDICES 
 
Appendix 1: 
Reporting Structures for Data Summary ................................................. 63 
 
 
Appendix 3: 
Coding Logic for Concomittant Medications and Adverse Events of 
Interest ................................................................................................... 65 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 14: 
SAS Macros ......................................................................................... 105 
Appendix 15: 
Summary of TFLs (General, Safety and Efficacy) ................................. 129 
 
 


 
 
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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 
LOD 
limit of detection 
LS 
least-square 
MAR 
missing at random 
MDI 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
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 
OTE 
overall treatment effect 
PD 
pre-dose 
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 
SGRQ 
Saint Georges Respiratory Questionnaire 
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 3 Study 0128 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 
The primary objective of the study is: 
• 
To characterize the safety and tolerability of TD-4208 administered once daily for 
52 weeks in a population of subjects with moderate to very severe COPD. 
2.2 
Exploratory Objectives 
 
 
  
 
  
 
 
 
 
 


 
 
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3 
OVERVIEW OF STUDY DESIGN 
Studies 0128 is a randomized, active-controlled, parallel-group study. Each subject will 
receive treatment once daily in the morning for a total of 52 weeks. There will be three 
treatment groups (TD-4208 88 μg, TD-4208 175 μg, and tiotropium 18 μg). TD-4208 will be 
administered as a 3 mL solution by inhalation using the 
 jet nebulizer and 
tiotropium as a dry powder capsules with the
 device. The study will be 
double-blind with respect to the TD-4208 dose arms, and open-label with respect to the 
tiotropium control arm. There will be 1050 subjects randomized with the intention to obtain 
data on the final day of the treatment period (Day 365) from 
 Screening 
will ensure that subjects are eligible for inclusion in the study. Subjects will undergo washout 
from prohibited medications as appropriate, including all products containing long-acting 
antimuscarinics [LAMA] (either in combination or alone). Patients who are currently on 
long-acting beta-agonists [LABA] (with or without inhaled corticosteroids) will be permitted to 
be enrolled in the study. Subjects that are not on a LABA or LABA / ICS when they enter the 
study and require a LABA or LABA/ICS to treat a COPD exacerbation at the discretion of the 
investigator in accordance with COPD guidelines will be allowed to remain in the study.  
Screening will ensure that subjects are eligible for inclusion in the study. Subjects will 
undergo washout from prohibited medications as appropriate, including all products 
containing long-acting antimuscarinics [LAMA] (either in combination or alone). Patients who 
are currently on long-acting beta-agonists [LABA] (with or without inhaled corticosteroids) 
will be permitted to be enrolled in the study. Subjects that are not on a LABA or LABA / ICS 
when they enter the study and require a LABA or LABA/ICS to treat a COPD exacerbation 
at the discretion of the investigator in accordance with COPD guidelines will be allowed to 
remain in the study.   
 
  
The study will consist of 1 or 2 screening visits, depending on whether a washout period is 
required and 6 treatment period visits and a telephone follow-up visit as shown in the study 
design schematic (Figure 1). 
 


 
 
Statistical Analysis Plan 
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Figure 1: 
Study Schematic 
 
 
4 
SAMPLE SIZE AND POWER 
Sample size (n=350 per group) is based on meeting ICH regulatory requirements for 
long-term safety for chronic use in this indication.
 
 
 
 
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 1-365, and a summary 
type, i.e., continuous, frequency, normal least squares.  
The primary endpoint(s) of this study assess the long-term safety and tolerability of TD-4208 
in the treatment of COPD:  
• 
Frequency and severity of adverse events, including exacerbations  
• 
Vital signs  


 
 
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• 
Clinical laboratory evaluations  
• 
12-lead ECG changes from baseline  
The exploratory endpoints will be characterized:  
• 
 
 
  
 
 
  
 
  
5.1 
General Endpoints 
The following general endpoints will be summarized in Table 1. 
 


 
 
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Table 1: 
General Endpoints 
Endpoint 
Evaluation Type 
ADAM Type 
Reporting 
Window 
Summary 
Type(s) 
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 
duration of COPD 
number of exacerbations in last 12 
months 
number of hospitalization for 
exacerbation in last 12 months 
subjects with a history of respiratory 
infections 
subjects with a history of supplemental 
oxygen 
subjects with a history of diabetes 
mellitus 
subjects with a history of pulmonary 
hypertension 


 
 
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Table 1: 
General Endpoints 
Endpoint 
Evaluation Type 
ADAM Type 
Reporting 
Window 
Summary 
Type(s) 
subjects with a history of ischemic heart 
disease 
subjects with a history of GERD 
subjects with cardiovascular risk factors 
GOLD category 
GOLD severity of airflow limitation 
Indicator: Baseline CAT Score: CAT 
≥10 
Indicator: mMRC score ≥2 
primary reason for study drug 
discontinuation 
subject disposition 
subjects in Safety Group 
subjects in ITT Group 
subjects in PP Group 
Note: D: day, PD: pre-dose, SCR: screening, ABS: absolute value, EOS: end of study 
Note: For summary types, see Appendix 1 
 
5.2 
Safety Endpoints 
Safety variables to be summarized include vital signs, adverse events, clinical laboratory 
results (hematology, chemistry, and urinalysis), corrected QT interval (QTc, from standard 
safety digital ECGs) and exacerbation data. Vital signs will be summarized in terms of 
observed values and changes from baseline. 
Cardiovascular events of interest will be specified in a separate CEC charter. 
In addition, the rate of exacerbations through adverse events and 
 will be 
summarized. 


 
 
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Table 2: 
Additional Safety Endpoints 
Endpoint 
Evaluation Type 
ADaM 
Type 
Reporting 
Window 
Summary 
Type(s) 
Time to first exacerbation_AE 
OBS 
derived 
D1-365 
KM 
 
 
 
 
 
 
5.3 
Exploratory Efficacy Endpoints 
Endpoint 
Evaluation Type 
ADAM 
Type 
Reporting 
Window 
Summary 
Type(s) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Endpoint 
Evaluation Type 
ADAM 
Type 
Reporting 
Window 
Summary 
Type(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 3 indicates the timing of the baseline assessment to be used in the analysis of 
specific parameters. 


 
 
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Table 3: 
Baseline Assessment for Specific Parameters 
Parameter 
No 
Baseline 
Visit 
1B 
Visit 2 
(Day 1-PD) 
PD of each visit 
Laboratory safety tests 
 
X 
 
 
Vital signs and ECG 
 
 
X 
 
Holter ECG 
 
X 
 
 
FEV1  
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 mean of -45 and -15 min PD assessments 
6.1.2 Analysis Windows 
All assessments will be summarized using analysis windows.  
Instances may occur where a subject is administered pre-dose assessments, e.g., PROs, on 
planned Day 1 [Visit 2] but then the subject does not dose due to various reasons. Since the 
subject will dose at an eventual later date, the current date would be assigned a study day 
<1 since study days are relative to first dose.  The subject will, in general, not repeat the 
PRO assessments.  These assessments (study day <1) will be windowed into study day 1 
[Visit 2] for analysis and summary purposes. 
In the instance where the PROs are repeated, the study day <1 will be windowed as 
unscheduled and the Study Day 1 will be windowed as Study Day 1. 
All data (scheduled and unscheduled visits) will be presented in the subject listings; 
however, unless noted otherwise, only data from assessments within analysis windows 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 4: 
Analysis Windows: Visits 
Nominal Visit 
Nominal Day 
Start (days) 
Stop (days) 
2 
1 
1 
1 
3 
29 
19 
39 
4 
92 
72 
112 
5 
183 
153 
213 
6 
274 
244 
304 
7 
365 
335 
395 
8 
NA 
V7+5 
V7+9 
 
 


 
 
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Safety Endpoints 
The following windows summarize the definition of treatment-emergent. 
Table 5: 
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, ECGs 
and Labs 
Post first dose 
Last dose + 7 days 


 
 
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Table 6: 
Analysis Windows: Vital Signs and ECGs 
Amendment 
Window 
Start 
Stop 
Amendment 3 
“60 minutes pre-dose” / “pre-dose” 
-90 
-30 
Amendment 3 
“10 min post dose” 
5 
40 
 
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 time point 
(generally applies to assessments done in triplicate). 
Multiple Spirometry Records 
If multiple spirometry non-NULL records exist, the later record by date/time will be selected.  
Spirometry records with a NULL value will be excluded from analyses. 
6.1.3 Evaluable Efficacy Assessment 
Potential Confounders to Efficacy Assessment 
There’s no formal statistical comparison on exploratory efficacy assessment between 
revefenacin and tiotropium in this safety study.  
Additional concomitant short acting bronchodilators or restricted long-acting muscarinic 
antagonists or beta agonists, taken immediately prior to or during efficacy assessments will 
confound the assessment of a treatment effect attributed to revefenacin relative to 
tiotropium. In addition, the lack of administration of study drug, e.g., subjects who have 
discontinued study drug prior to an assessment or subjects who did not dose on the study 
day, will confound the assessment of the treatment effect of revefenacin relative to 
tiotropium.   
 
 
 


 
 
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6.1.4 Missing Data 
In general, it is not anticipated that there will be considerable missing data.  In general, 
missing data will not be imputed.  Missing data for the following specific endpoints will be 
handled as follows: 
Exploratory Efficacy Endpoint 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Adverse Events 
For graded adverse event summaries, subjects with an AE and no grade on the CRF will be 
graded as severe. 
For graded adverse event summaries, subjects with an AE and no relatedness on the CRF 
will be graded as “possibly/probably related”. 
Concomitant Medications 
Missing dates and times will be handled as follows: 
• 
Missing start date (no month or year) will be considered as taken on the first dose 
date;   
• 
Missing start day will be taken as the first day of the month;  
• 
Missing start month will be taken as January;   
• 
Missing stop date will be considered as taken during the entire remaining study 
period. 
• 
If a start or stop time is missing, the start time is imputed as 1 minute after a.m. 
midnight (12:01) and stop time is imputed to be 1 min before p.m. midnight (23:59).  
Laboratory Data 
For non-efficacy laboratory data, a missing baseline value will be replaced with the last 
available assessment, generally the screening assessment.  A retest value will be used if 
the first test is invalidated, e.g., specimen hemolyzed.   
Laboratory data that are continuous in nature but are less than the lower limit of 
quantitation/limit of detection (LOD) will be, in general, imputed as follows: 
• 
A value that is 1 unit less than the LOD will be used for calculation of descriptive 
statistics if the data are reported in the form of “<x” (x is considered as the LOD).  
More specifically, x−1 is used for data summarization if the data are reported in the 
form of “<x”; and x.e where e = d−1, will be used for analysis if the data are reported 
in the form of “<x.d”. 
• 
The LOD will be used for calculation of descriptive statistics if the data is reported in 
the form of “≤x” or “≥x”. 


 
 
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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.  
 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.  The CRO will use the 
September 2015 version of the WHODD. 
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 for salbutamol. 
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 88 mcg, 
• 
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, 
• 
Tiotropium + ICS/LABA and/or LABA 
• 
REV 88 mcg, 
• 
REV 88 mcg + ICS/LABA and/or LABA 
• 
REV 175 mcg, 
• 
REV 175 mcg + ICS/LABA and/or LABA. 
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. 
 
 


 
 
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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 
efficacy data: 
• 
Mean, median: 1 significant digit, 
• 
Standard deviation: 2 significant digits, 
• 
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 0.001, reported as <0.001.  
Colors in Figures 
In figures that only contain the three treatment groups, the following colors will be used: 
• 
Tiotropium (orange), 
• 
revefenacin 88 mcg (steelblue – CX4682B4), 
• 
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. 


 
 
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6.6 
Tables, Figures and Listings (TFLs) 
A line listing of tables, listings, and figures to be generated are in Appendix 15.   
Table titles will be denoted as underlined text in the SAP. 
Selected 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 smoking status: 
 
2. Age: 
 
3. Current ICS use: [
; 
4. Reversibility to a short-acting bronchodilator:  
 
5. 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: 
𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 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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Table 7: 
Dummy Coding for Concurrent LABA 
LABA group 
Concurrent LABA 
LABA Type 
No concurrent LABA 
0 
0 
Concurrent QD LABA 
1 
1 
Concurrent BID LABA 
1 
2 
GOLD Severity of Airflow Limitation Categories 
Table 8: 
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 
Screening data will be used to categorize subjects. 
GOLD Categories (2011 Definition) 
Table 9: 
GOLD Categories 
Category 
Characteristic 
GOLD Airflow 
Severity Category 
Exacerbations 
mMRC 
CAT 
A 
Low Risk 
Less Symptoms 
GOLD 1-2 
≤1 
0-1 
<10 
B 
Low Risk 
More Symptoms 
GOLD 1-2 
≤1 
≥2 
≥10 
C 
High Risk 
Less Symptoms 
GOLD 3-4 
≥2 
0-1 
<10 
D 
High Risk 
More Symptoms 
GOLD 3-4 
≥2 
≥2 
≥10 
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 CAT 
scores as the primary method to determine GOLD Category.  If GOLD airflow severity is 
missing, then exacerbations will be used.  If CAT score is missing, then mMRC score will be 
used. 


 
 
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8.2 
Exploratory Efficacy Variables 
 
 
 
 
 
 
 
 
 𝑅𝑅𝑅𝑅𝑅𝑅𝑢𝑢𝑢𝑢𝑢𝑢𝑝𝑝𝑝𝑝𝑑𝑑𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑘𝑘𝑘𝑘𝑘𝑘𝑤𝑤𝑤𝑤𝑎𝑎𝑎𝑎𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑒𝑒𝑒𝑒𝑒𝑒𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
 
 
 
 
 
 
 
 
 


 
 
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 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑛𝑛𝑛𝑛𝑛𝑛𝑖𝑖𝑛𝑛
 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑛𝑛𝑛𝑛𝑛𝑛𝑖𝑖𝑛𝑛
 𝒏𝒏𝒏𝒏𝒏𝒏𝒏𝒏
 
 
 
 
 
 


 
 
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9 
ANALYSES 
Table, figures and listing titles are denoted in underlined text. 
9.1 
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 will 
be summarized separately.   
Bronchodilators by Drug Class 
Appendix 3 contains coding logic for determination of specific drug classes for 
bronchodilators. 
  
 
 
 
9.2 
General Analyses 
9.2.1 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. 
 


 
 
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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. 
9.2.2 Demographics and Baseline Characteristics 
Demographics and baseline characteristics (age, sex, race, ethnicity, height, weight, and 
BMI) will be summarized for the safety analysis set. 
A listing of demographics and baseline characteristics will also be provided. 
9.2.3 Reversibility Summaries  
A post-bronchodilator screening reversibility summary taken during screening visits will be 
provided with the following parameters: 
• 
Ipratropium reversibility (mL), 
• 
Ipratropium reversibility (%), 
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. 
9.2.4 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), 
 
 


 
 
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A Baseline spirometry summary will be provided in a separate table with the following 
parameters: 
• 
Baseline FEV1 (mL), 
• 
Baseline FVC (mL), 
• 
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. 
9.2.5 Baseline Clinical Characteristics Summaries 
A summary of COPD clinical characteristics taken at baseline will be provided with the 
following parameters: 
• 
Proportion of subject ≥65 years of age (%),  
• 
Duration of COPD (years), 
• 
Number of exacerbations in past 12 months (%), 
• 
Number of hospitalizations for an exacerbation in past 12 months (%), 
• 
Proportion of subjects with a history of respiratory infections (%), 
• 
Proportion of subjects with a history of supplemental oxygen use (%), 
• 
Proportion of subjects with diabetes mellitus (%), 
• 
Proportion of subjects with a history of pulmonary hypertension (%), 
• 
Proportion of subjects with a history of ischemic heart disease (%), 
• 
Proportion of subjects with a history of GERD (%), 
• 
Proportion of subjects with a cardiovascular risk factor (%). 
 
 


 
 
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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. 
9.2.6 GOLD Category Summary 
A summary of GOLD categories will be provided with the following parameters: 
• 
GOLD Severity of Airflow Limitation groups, 
• 
GOLD Categories. 
A listing will be provided. The ITT analysis set will be used for the summary. 
9.2.7 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), 


 
 
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• 
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), 
• 
Proportion of subjects with baseline mMRC ≥2, % 
• 
Proportion of subjects with baseline CAT ≥10,% 
• 
Proportion of subjects with ≤1 exacerbations in prior year, % 
• 
GOLD C/B categories, n % 
• 
BDI score, LS mean (SE) 
For continuous summaries, only the “mean (SD)” will be displayed. As this data is 
summarized in list format elsewhere, no listing is provided for this summary. The ITT 
analysis set will be used for the summary. 
9.3 
Safety Analyses 
For all safety analyses, the safety analysis population will be used. 
Safety variables to be summarized include vital signs, adverse events, clinical laboratory 
results (hematology, chemistry, and urinalysis), corrected QT interval (QTc, from standard 
safety digital ECGs) and exacerbation data. Vital signs will be summarized in terms of 
observed values and changes from baseline. 
9.3.1 Extent of Exposure 
Study drug exposure (Number of doses) will be summarized using the eight-point descriptive 
summary by study periods.  The source for exposure data is the drug accountability data 
domain. 


 
 
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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%. 
Compliance will be calculated overall (months 1-12), months 9-12, months 6-9, months 3-6 
and months 1-3. 
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 the 
number of 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, or a reduction in the treatment dose. 
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: 
Overall: 
• 
Overall Summary of Adverse Events 


 
 
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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 
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. 


 
 
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9.3.2.1 Exacerbations 
Exacerbations will be summarized using both exacerbations reported as adverse events 
 
 
Exacerbations Reported as Adverse Events 
A summary of COPD exacerbations, as defined in the protocol, and reported with an AE PT 
of COPD will be summarized descriptively by severity. Exacerbation data will be 
summarized for the following categories using counts and percentages: a) All exacerbations, 
b) Moderate or severe exacerbations, and c) Severe exacerbations. 
In addition, a negative binomial model will be fit to assess the exacerbation rate per year 
and relative risk using the same categories.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In addition, time to first exacerbation will be summarized using Kaplan-Meier methodology. 
 
 


 
 
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9.3.2.2 Cardiovascular Events of Interest 
Adjudication Summary of Treatment-Emergent Cardiovascular Adverse Events by 
Cardiovascular Category will summarize, by CEC class categories, adjudicated events: 
• 
All-cause Death 
• 
Cardiovascular death 
• 
Non-cardiovascular death 
• 
Myocardial infarction/Unstable Angina 
• 
Stroke/TIA 
• 
Heart Failure 
• 
Cardiac Arrhythmia 
• 
Atrial arrhythmia 
• 
Ventricular arrhythmia 


 
 
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9.3.2.3 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. 
 


 
 
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Table 10: 
Vital Signs Outlier Thresholds 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
<85 
>160 
<45 
>100 
 
9.3.4 ECG 
A summary of ECG parameters, parameters reported separately QTcF, PR interval, QT 
interval, QRS duration, RR, and HR, will be summarized in terms of observed values and 
change from baseline.  
Subjects without post-baseline measurement for a given treatment period will be excluded 
from the summary statistic (e.g., denominator of the summary statistic) for that time point.   
All recorded values by central reader at ECG core lab for the standard 12-lead 
electrocardiogram parameters will be presented in a by-subject listing.   
Outlier Analysis 
The number of subjects with absolute ECG values and change from baseline in the ranges 
shown in Table 11 will be presented in Electrocardiogram Outlier Summary by Visit and 
Time Point. 
In addition in the same summary, QTcF will also be summarized by the following categories, 
Normal (males <430, females ≤450), Borderline (males (>430, ≤450); females (>450, ≤470)) 
and Prolonged (males >450, females >470). 
Individual ECG data collected during the study will be presented in a listing. A separate 
listing of subjects with values of QTcF >500 msec or an increase >60 msec will be provided, 
as necessary. 
Figures 
Cumulative distribution plots will be provided for maximum change in QTcF by day. 
 


 
 
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Investigator Assessment of ECG Readings 
The investigators’ assessment of ECGs as normal, abnormal and clinically significant, or 
abnormal but not clinically significant will be summarized for baseline and for each visit. 
Table 11: 
ECG Test Outlier Thresholds 
Heart 
Rate 
(bpm) 
Heart Rate 
Change from 
Baseline (bpm) 
PR 
 Interval 
(msec) 
PR Percentage 
Change From 
Baseline (%) 
QRS 
 Interval 
(msec) 
QTcF 
(msec) 
QTcF change 
from Baseline 
(msec) 
>120 
>20 
>200 
>15 
>120 
Males: 
≤30 
>130 
>30 
>220 
>25 
 
≤430 
>30, ≤60 
 
 
 
 
 
>430 
>60 
 
 
 
 
 
>450 
 
 
 
 
 
 
>470 
 
 
 
 
 
 
>480 
 
 
 
 
 
 
>500 
 
 
 
 
 
 
Females: 
 
 
 
 
 
 
≤450 
 
 
 
 
 
 
>450 
 
 
 
 
 
 
>470 
 
 
 
 
 
 
>480 
 
 
 
 
 
 
>500 
 
 
9.3.5 Holter ECGs 
Descriptive statistics will be provided to the results of Holter interpretation which will include 
the following heart rate (HR) variables:  
• 
Maximum (max), minimum (min) and mean HR, for the entire recording, 
• 
Supraventricular premature beats (PACs) singles and couplets, 
• 
Ventricular premature beats (VPCs) singles and couplets normalized for 24 hours, 
Subjects without post-baseline measurement for a given treatment period will be excluded 
from the summary statistic (e.g., denominator of the summary statistic) for that time point.   
All the Holter ECG variables will be presented in a by-subject listing.  


 
 
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The detailed analysis plan for Holter’s ECG data will be detailed in a separate document.   
9.3.6 Clinical Laboratory Results 
Laboratory data, hematology, serum chemistry and urinalysis, will be summarized in terms 
of observed values, changes from baseline for each period.  In addition, changes from 
baseline for each period relative to normal ranges (e.g., shifts from normal to abnormal 
high/low) will be summarized in hematology: shift from baseline, serum chemistry: shift from 
baseline and urinalysis: shift from baseline.   
Listings will flag laboratory values that are outside of normal range. 
Listings of all abnormal lab values for each of the Laboratory sets will be provided. 
9.3.7 Medical History 
Medical history collected at screening will be provided in a data listing and a summary table. 
9.3.8 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 3. 
9.3.9 12-month Vital Status 
All subjects were followed for vital status at 12-months.  Subjects who discontinued were 
contacted around their expected Day 365 visit to collect vital status. A Vital Status Summary 
will estimate the probability of being alive at 12-months using a Kaplan-Meier estimate to 
account for subjects who were lost to follow-up. 
 


 
 
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9.4 
Exploratory Efficacy Analyses 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 𝑖𝑖𝑖𝑖𝑖𝑖
  
 𝑖𝑖𝑖𝑖𝑖𝑖
 
 
 
 
 
 


 
 
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Statistical Analysis Plan 
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 𝑖𝑖𝑖𝑖𝑖𝑖
 𝑖𝑖
𝑖𝑖𝑖𝑖 
 
 
 
 
 
 
 
  
 
 
 
 


 
 
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 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑤𝑤𝑤𝑤𝑤𝑤𝑡𝑡𝑡𝑡𝑓𝑓𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑖𝑖𝑖𝑖𝑒𝑒𝑒𝑒𝑒𝑒𝑤𝑤𝑤𝑤𝑖𝑖𝑖𝑖𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑤𝑤𝑤𝑤𝑤𝑤𝑡𝑡𝑡𝑡𝑓𝑓𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑠𝑠𝑠𝑠𝑠𝑠𝑜𝑜𝑜𝑜𝑤𝑤𝑤𝑤𝑤𝑤𝑡𝑡𝑡𝑡𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖


 
 
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9.4.9 Exploratory Efficacy Evaluation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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9.4.10 Exploratory Efficacy Evaluation: 
 
 
 
 
 
 
 


 
 
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9.4.12 Multiplicity Adjustment 
No multiplicity adjustment of p-values for the efficacy endpoints will be made.  
 


 
 
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Appendix 1: 
Reporting Structures for Data Summary 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 


 
 
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  𝑅𝑅𝑅𝑅𝑅𝑅𝑢𝑢𝑢𝑢𝑢𝑢𝑝𝑝𝑝𝑝𝑑𝑑𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑎𝑎𝑎𝑎𝑁𝑁
   
 𝑅𝑅𝑅𝑅𝑅𝑅𝑢𝑢𝑢𝑢𝑢𝑢𝑝𝑝𝑝𝑝𝑑𝑑𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
 
 
Appendix 3: 
Coding Logic for Concomittant Medications and Adverse Events of 
Interest 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
Study 0128 
Version 1.0, 13MAR2017 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
Study 0128 
Version 1.0, 13MAR2017 
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Statistical Analysis Plan 
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Version 1.0, 13MAR2017 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
Study 0128 
Version 1.0, 13MAR2017 
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Appendix 14: 
SAS Macros 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
 
       


 
Statistical Analysis Plan 
Study 0128 
Version 1.0, 13MAR2017 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Version 1.0, 13MAR2017 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
Study 0128 
Version 1.0, 13MAR2017 
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Statistical Analysis Plan 
Study 0128 
Version 1.0, 13MAR2017 
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Appendix 15: 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Version 1.0, 13MAR2017 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Version 1.0, 13MAR2017 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Figures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Study 0128 
Version 1.0, 13MAR2017 
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