Clinical trial NCT02867761
Conditions: COPD (Chronic Obstructive Pulmonary Disease)
Keywords: COPD Chronic Obstructive Pulmonary Disease Pulmonary Function Tests Current Smoker Former Smoker Chronic Obstructive Airway Disease Respiratory Symptoms
Sponsor: University of Michigan
Start date: 2017-08-29; Completion date: 2021-07-07
Enrollment: 780 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study hypothesis is that symptomatic current and former smokers with spirometric values within the normal range (post-bronchodilator FEV1/FVC≥0.70 and post-BD FVC ≥ 70% predicted will still derive symptomatic benefit from long-acting bronchodilator therapy even though they are excluded from current GOLD guideline recommendations.

Detailed description:
RETHINC is a 12-week multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily in symptomatic current and former smokers with respiratory symptoms despite preserved spirometry as defined by CAT ≥ 10 and post-bronchodilator FEV1/FVC ratio ≥0.70, respectively.

Arms: arm 1: indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks arm 2: Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks
Interventions: intervention 1: Indacaterol/Glycopyrrolate intervention 2: Placebo
Intervention descriptions: intervention 1: 27.5/15.6 mcg active indacaterol/glycopyrrolate intervention 2: 27.5/15.6 mcg placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
RETHINC: REdefining Early THerapy IN COPD 
 
 
 
IRB Approval Date: July 27, 2020 
NCT02867761 
 
 


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RETHINC 
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RETHINC:  REdefining Therapy IN early COPD  
VERSION 4.2   
 
Study Sponsor(s): 
National Institutes of Health 
 
PROTOCOL CHAIRS 
 
MeiLan K. Han, MD MS 
University of Michigan 
1500 E Medical Ctr Drive 
Ann Arbor, MI 481092 
Phone: 734-936-5201 
Fax:  734-936-5048 
E-mail: mrking@umich.edu 
 
 
 
 
 
 
 
 
 
Prescott Woodruff, MD MPH 
513 Parnassus Ave., Box 0130 
San Francisco, CA  94143 
University of California, SF 
Phone: 415-514-2061 
Fax: 415-502-7814 
E-mail: Prescott.woodruff@ucsf.edu 
 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of the 
Protocol Chairs. 
 
 
 


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INVESTIGATOR SIGNATURE PAGE 
Protocol: 
  
Version/Date:  
  
Site Principal Investigator ( Each site investigator must complete a signature page): [Insert na
  
Title:   RETHINC:  REdefining Therapy IN early COPD 
  
Study Sponsor: National Institutes of Health 
 
INSTRUCTIONS: The site Principal Investigator should print, sign, and date at the indicated 
location below.  A copy should be kept for your records and the original signature page sent. 
After signature, please return the original of this form by surface mail to:  
[Insert Name/Title and Address] 
 
I confirm that I have read the above protocol in the latest version.  I understand it, and I will 
work according to the principles of Good Clinical Practice (GCP) as described in the United 
States Code of Federal Regulations (CFR) – 45 CFR part 46 and 21 CFR parts 50, 56, and 
312, and in the International Conference on Harmonization (ICH) document Guidance for 
Industry: E6 Good Clinical Practice: Consolidated Guidance dated April 1996.  Further, I will 
conduct the study in keeping with local legal and regulatory requirements. 
As the site Principal Investigator, I agree to carry out the study by the criteria written in the 
protocol and understand that no changes can be made to this protocol without the written 
permission of the Data Coordinating Center, the Protocol Chairs and the IRB. 
 
____________________________________     
Site Principal Investigator  (Print) 
 
____________________________________                                      _________________ 
Site Principal Investigator (Signature)                                                          Date 


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Summary of Amendment #4 changes 
Protocol 
Version 
Page* # 
Location 
Revision, Insertions, Deletions  
Rationale for Change 
4.2 
36 
Schedule of 
Events for 
Participants 
Requiring 
Washout 
 
Clarified washout for 30 days or more instead of <-4 
week period.  
Administrative change 
4.1 
11, 24, 25 Protocol Synopsis, 
Study Hypothesis/ 
Objectives, Study 
Design 
Addition of a secondary endpoint: improvement in both 
BDI/TDI and SGRQ 
Improvement in both metrics is 
clinically meaningful and well powered. 
4.0 (2/2018) 
p. 1, TOC 
and 
footers 
N/A 
Updated protocol number and date and page numbers. 
Administrative change. 
4.0 (2/2018) 
p. 11 and 
26 
Protocol Synopsis 
and Selection of 
Participants and 
Clinical sites 
Reduce smoking pack years required for enrollment from 
20 to 10. 
The original protocol was based on 
preliminary data generated from the 
SPIROMICS trial (NEJM 2016; 
374:1811) where we demonstrated a 
high rate of respiratory exacerbations 
and CT airway wall thickening among 
individuals with CAT≥10 and smoking 
history ≥ 20 pack years but normal 
spirometry. Twenty pack years was an 
inclusion criteria for Spiromics. Our 


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hypothesis is that these individuals have 
airways disease not detectable by 
spirometry but responsive to a 
bronchodilator. Since then, data 
published by Dr. Wedzicha in AJRCCM 
demonstrates that at a threshold of  ≥10 
pack-years smoking history, respiratory 
symptoms begin to increase and lung 
function starts to decline suggesting 
airway pathology begins at this smoking 
threshold (AJRCCM 2017;196:1021 & 
AJRCCM 2016;193:662).  Further, 
subgroup analyses of the COPDGene 
cohort (similar to SPIROMICS but 
different inclusion criteria) isolating to 
subjects with 10-20 pack years smoking 
history demonstrates similar statistically 
significant elevations in exacerbation 
rates and CT airway wall thickening in 
symptomatic GOLD 0 subjects as was 
seen in the SPIROMICS NEJM 
publication. These data support that a 10 
pack year smoking history will be 
sufficient to identify the patient 
population of interest. 
4 (2/2018) 
p. 15, 27 
and 30 
Protocol Synopsis, 
Study Hypothesis 
and Exclusion 
Criteria 
Reduce FVC requirement from 80% to 70% predicted 
Our choice to exclude patients with 
FVC<80% was based on inclusion 
criteria for the SPIROMICS study. Our 
goal was to exclude patients with other 
significant lung diseases, however we 


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have found that the use of 80% is overly 
strict and excluding some patients, for 
instance, who are overweight.  In 
secondary analyses of the COPDGene 
cohort (similar to SPIROMICS but 
different inclusion criteria), isolating to 
subjects with FVC between 70-80% 
predicted demonstrates similar 
statistically significant elevations in 
exacerbation rates and CT airway wall 
thickening in symptomatic GOLD 0 
subjects as was seen in the SPIROMICS 
NEJM publication. Therefore we 
propose to drop to 70% which we feel is 
still adequate to exclude significant 
interstitial lung disease. 
4/2018 
p. 31 
Table 4.3-1 
Ease restrictions on prohibited medications 
Our original prohibited medications list 
was based on the FLIGHT 1 and 2 study 
protocol documents provided to us by 
Novartis.  FLIGHT 1 and 2 were 
performed in order to obtain FDA 
approval for our study drug (Utibron: 
indacaterol/glycopyrrolate) in a COPD 
patient population.  Since the protocol 
was written, however, the drug was 
approved by the FDA and the package 
insert with guidance regarding drug 
interactions is now available.  Several of 
the drugs prohibited by the Novartis 
studies are no longer included in the 


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package insert.  These include anti-
psychotics, varenicline, mast cell 
stabilizers, and leukotriene antagonists.  
None of these medications are listed on 
the Utibron package insert and therefore 
allowing such medications should not 
increase risk for participants, but should 
improve our ability to recruit.  We 
already have restrictions in place in the 
protocol to exclude patients who would 
not be appropriate for the study such as 
active psychosis or asthma and therefore 
do not believe that easing these 
restrictions will result in inclusion of 
patients inappropriate for the study. 
4/2018 
p. 35-37 
and p. 38-
39 
Screening/ 
Enrollment and 
Schedule of events 
Reduce post-BD time from 30 minutes to 15 minutes 
The choice of 30 minutes was based on 
the SPIROMICS protocol which also 
included administration of an anti-
cholinergic. However, here we are using 
albuterol alone.  We note that the other 
PTC studies are using 15 minutes and 
therefore we propose to change this to 
reduce coordinator confusion and 
conform to the other PTC studies.  The 
ATS/ERS task force on standardization 
of spirometry (ERJ 2005;26:319) 
recommends 15 minutes for 
bronchodilator testing after a short-
acting beta agonist. 


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4/2018 
p.29 
Survey Instruments 
to be Used 
Clarified name of test as “BDI/TDI” as opposed to just 
“TDI” 
Clarification to reduce confusion 
4/2018 
p.29 
Stratification, 
Randomization, 
and 
Blinding/Masking 
Clarified text regarding drug resupply as this process 
has been modified since the protocol was written. 
Clarification to clarify process 
4/2018 
p. 30 
Securing Blinding 
and Randomization 
Clarified text regarding blinding and randomization 
Clarify process 
4/2018 
p. 31 
Table 4.3-2 
Clarified title of Table 4.3-2 from “Prohibited COPD-
related Medications” to “Prohibited COPD-related 
Medications Requiring Washout Period of 30 days” 
Clarify that prohibited medications can 
be washed out 
4/2018 
p. 35-39 
Pre-Screening and 
Screening/ 
Enrollment 
Updated details regarding how to screen, schedule of 
events for bringing subjects in who require washout, and 
clarification of the rescreening process 
Increased detail provided in protocol 
4/2018 
p. 40 
Visit Windows 
Added that if a delay in Visit 2 causes subject to run out 
of study drug, study site should contact DCC for further 
instructions to determine whether drug supply would 
allow more drug to be dispensed. 
Process clarification 
4/2018 
p.41 
Special 
consideration for 
treatment failure 
subjects 
Provided enhanced detail regarding pulmonary function 
testing to be performed on treatment failure subjects. 
Process clarification 
 
Summary of Amendment #3 changes 
 


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3.0 (09/2017) p. 27, 28 
7.5 & 7.6 – 
Schedule of Events 
for both Non-
Washout and 
Washout 
Participants 
New Text:  Baseline Medical History 
Previous Text: Medical History 
Clarification of which medical history 
information is being collected. 
3.0 (09/2017) p. 27, 28 
7.5 & 7.6 Schedule 
of Events for both 
Non-Washout and 
Washout 
Participants 
New Text: FEV1, FVC, SVC and IC before 
administration of study drug and FEV1 and FVC 
every hour after administration of study drug for a 
total of three hours (i.e. a trough and an AUC0-3 
measurement). 
 
Previous Text: FEV1, FVC, SVC and IC before and 
every hour after administration of study drug for three 
hours (i.e. a trough and an AUC0-3 measurement). 
Consistency in description of AUC0-3 
process throughout protocol.  
3.0 (09/2017) p. 27, 28 
7.5 & 7.6 – 
Schedule of Events 
for both Non-
Washout and 
Washout 
Participants 
Addition of footnote and corresponding superscript 
“End of Study3”: “3. Should a subject terminate early, 
the subject will be brought in to complete all 
assessments included at the Week 12 End of Study 
visit.” 
Clarification of process to follow for 
subjects who terminate early from the 
study.  
3.0 (09/2017) p. 30 
7.9 Discontinuation
of study treatments 
Addition of ‘Discretion of site primary investigator’ to 
circumstances  for study treatment discontinuation 
 
Confirmation that site investigator may 
discontinue patients per their discretion. 
3.0 (09/2017) p. 30 
7.9.1 Special 
Considerations for 
Added section to provide specific instructions on drug 
discontinuation for subjects who meet treatment failure 
endpoint. 
Provide clarification on how to handle a 
subset of study participants who may 


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Treatment Failure 
Subjects 
have a specific experience during study 
participation. 
3.0 (09/2017) p. 31 
7.9.2 Special 
Considerations for 
subjects who start a
prohibited 
medication 
Added section to provide specific instructions for 
subjects who begin using prohibited medication during 
the course of their participation in the study.  
Provide clarification on how to handle a 
subset of study participants who may 
have a specific experience during study 
participation. 
 
 
3.0 (09/2017) p. 31 
7.9.3 Special 
Considerations for 
subjects who 
experience an 
AE/SAE requiring 
study drug 
interruption 
Added section to provide specific instructions for 
subjects who experience a safety event requiring drug 
interruption 
Provide clarification on how to handle a 
subset of study participants who may 
have a specific experience during study 
participation. 
3.0 (09/2017) p. 32 
8.2.3 Serious 
Adverse Event 
(SAE) 
Removed previous definitions of SAE to align with those 
of the PTC.  
Consistency between PTC and PLG in 
regards to safety reporting. 
3.0 (09/2017) p. 34 
8.3.2 Attribution of 
Adverse Events 
Modified entire table to align with PTC.  
Consistency between PTC and PLG in 
regards to safety reporting. 
3.0 (09/2017) p.35  
8.5.2 Reporting to 
Health Authority 
New Text: After an adverse event requiring 24 hour 
reporting (per Section 8.5.1, Reporting of Serious 
Adverse Events), the event will be submitted by the 
site investigator and assessed by protocol chairs and 
the DCC per local regulations.  Although this 
protocol was submitted to the FDA and received an 
IND exemption, MedWatch forms will be completed 
Addition of additional reporting for the 
DCC to Sunovion Pharmaceuticals. 


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for applicable Serious Adverse Events and 
forwarded to Sunovion Pharmaceuticals (global 
oversight for the study) for further reporting to the 
FDA.  
 
Previous Text: After an adverse event requiring 24 hour 
reporting (per Section 8.5.1, Reporting of Serious 
Adverse Events), the event will be submitted by the site 
investigator and assessed by protocol chairs and the 
DCC per local regulations.  This protocol was submitted 
to the FDA and received an IND exemption.  
 
  
 
 
 


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Protocol Synopsis 
Title 
Redefining Therapy in early COPD: RETHINC 
Short Title 
RETHINC 
Clinical Phase 
Phase III 
Study Objectives 
A 12-week multicenter, randomized, double-blind, placebo-
controlled, parallel-group study to assess the efficacy and 
safety of indacaterol/glycopyrrolate  27.5/15.6 mcg inhaled 
twice daily in symptomatic current and former smokers with 
respiratory symptoms despite preserved spirometry as 
defined by CAT ≥ 10 and post-bronchodilator FEV1/FVC ratio 
≥0.70, respectively. 
Study Design 
Double-blinded, placebo-controlled, parallel-group 
Primary Endpoint(s) 
• 
Proportion of individuals who experience a 4 unit 
improvement in SGRQ at 12 weeks and do not meet 
criteria for treatment failure during the 12 week 
treatment period. 
Secondary Endpoint(s)  
• 
Proportion of individuals with a 2 unit improvement in 
CAT without treatment failure 
• 
Proportion of individuals with a 1 unit improvement in 
the BDI/TDI without treatment failure 
• 
Proportion of individuals with both a 4 unit 
improvement in SGRQ and a 1 unit improvement in 
BDI/TDI without treatment failure 
• 
Mean change in SGRQ 
• 
Mean change in CAT 
• 
Mean change in BDI/TDI 
• 
AUC0-3h for FEV1 
• 
Change from baseline in 12 hour trough FEV1 
(absolute value and % predicted) 
• 
Change from baseline in 12 hour trough inspiratory 
capacity, FEF25-75% and iso-volume FEF25-75%  
(absolute value and % predicted) 
• 
Mean change in symptoms and rescue medication 
use based on daily diary 
• 
Treatment failure defined by increase in lower 
respiratory symptoms necessitating treatment with 
active, long-acting inhaled bronchodilator, 
corticosteroids or antibiotics 
 


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Accrual Objective 
580 subjects 
Study Duration 
36 months 
Treatment Description  
Indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily 
vs. placebo 
Inclusion Criteria 
1. Subject must be able to understand and provide informed 
consent 
2. Age 40-80 
3. ≥10 pack-year smoking history 
4. Post-bronchodilator FEV1/FVC ratio ≥0.70 
5. Baseline CAT≥10 
Exclusion Criteria 
1. Inability or unwillingness of a participant to give written 
informed consent or comply with study protocol. 
2. Subject is pregnant, breast-feeding, or plans to become 
pregnant. 
3. Active pulmonary infection or prior pulmonary infection 
where antibiotic and/or steroid treatment was completed ≤4 
weeks prior to enrollment. 
4. Post-BD  FVC < 70% predicted 
5. A primary diagnosis of asthma established by each study 
investigator based on ATS/ERS criteria as previously 
implemented in the MACRO clinical trial (1). 
6. Known concomitant lung disease, pulmonary tuberculosis 
(unless confirmed by chest x-ray to be no longer active), or 
clinically significant bronchiectasis. 
7.  History (or family history) of long QT syndrome. 
8.  History of paroxysmal (intermittent) atrial fibrillation will be 
considered an exclusion.  Patients with persistent atrial 
fibrillation as defined by continuous atrial fibrillation for at 
least 6 months and controlled with a rate control strategy (i.e., 
selective beta blocker, calcium channel blocker, pacemaker 
placement, digoxin or ablation therapy) for at least 6 months 
may be considered for inclusion. In such patients, heart rate 
at enrollment must be < 100/min.   
9.  Patients with BMI < 15 or more than 40 kg/m2. 
10. Patients with diabetes Type I or uncontrolled diabetes 
Type II. 
11.  Patients who, in the judgment of the investigator, have a 
clinically relevant laboratory abnormality or a clinically 
significant condition such as (but not limited to) significant 


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renal disease, psychiatric disease, gastrointestinal disease, 
unstable ischemic heart disease, arrhythmia (excluding 
chronic stable atrial fibrillation), uncontrolled hypertension or 
any other condition which in the opinion of investigator might 
compromise patient safety or compliance, interfere with 
evaluation, or preclude completion of the study. 
12. Patients with any history of lung cancer. 
 
 
13.  Patients with narrow-angle glaucoma, symptomatic  
benign prostatic  hyperplasia  or bladder-neck obstruction or 
severe renal impairment or urinary retention. Benign Prostatic 
Hyperplasia (BPH) patients who are stable on treatment can 
be considered. 
 
14.  Any other past or current medical problems or findings 
from physical examination or laboratory testing that are not 
listed above, which, in the opinion of the investigator, may 
pose additional risks from participation in the study, may 
interfere with the participant’s ability to comply with study 
requirements or that may impact the quality or interpretation 
of the data obtained from the study. 
15. Patients with a history of hypersensitivity to any of the 
study drugs or to drugs from similar chemical classification, 
including untoward reactions to sympathomimetic amines 
or inhaled medication or any component thereof. 
 
16. Patients unable to successfully use a dry powder inhaler 
device or perform spirometry measurements. 
 
17.  Use of other investigational drugs at the time of 
enrollment or within 30 days or 5 half-lives of enrollment, 
whichever is longer. 
18. Patients receiving any prohibited medications in the 
classes or groups listed in Table 4.3-1. 
 
19. Patients receiving any prohibited COPD related 
medications in the classes or groups in Table 4.3-2 must 
undergo the required washout period prior to Visit 1. 
 
Statistical Considerations 
Sample size should provide at least 90% power to detect a 
difference in proportion of subjects who have a 4 unit 
improvement in SGRQ without treatment failure at 12 weeks 
in treatment versus placebo arms. 
 
 
 


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Table of Contents 
Glossary of Abbreviations .................................................................................................................................................. 18 
1. Background and Rationale ........................................................................................................................................ 20 
1.1 Critical Knowledge pertinent to the lung disease and intervention ................................................................ 20 
1.2 Rationale for Selection of Investigational Agent ............................................................................................... 20 
1.3 Prior Clinical Studies ............................................................................................................................................. 21 
1.4 Rationale for Study Population ............................................................................................................................ 22 
1.5 Feasibility of the Intervention in the Target Population ................................................................................... 23 
2.  Study Hypotheses/Objectives .................................................................................................................................. 24 
2.1 Hypotheses ............................................................................................................................................................... 24 
2.2 Primary Objective .................................................................................................................................................. 24 
2.3 Secondary Objectives ........................................................................................................................................... 24 
2.4   Anticipated Short and Long Term Impact of the Intervention ......................................................................... 24 
3 Study Design ............................................................................................................................................................... 24 
3.1 Description of Study Design ................................................................................................................................ 24 
3.2 Primary Endpoint(s)/Outcome(s) ........................................................................................................................ 25 
3.3 Secondary Endpoint(s)/Outcome(s) ................................................................................................................... 25 
3.4 Survey Instruments to be Used ............................................................................................................................. 25 
3.5 Stratification, Randomization, and Blinding/Masking ......................................................................................... 26 
3.5.1 
Procedure for Unblinding/Unmasking ..................................................................................................... 26 
3.5.2 
 Securing Blinding and Randomization Information .............................................................................. 27 
4 Selection of Participants and Clinical Sites/Laboratories ..................................................................................... 27 
4.1 Inclusion Criteria .................................................................................................................................................... 27 
4.2 Exclusion Criteria .................................................................................................................................................. 27 
4.3 Prohibited Medication ............................................................................................................................................. 28 
4.4 Recruitment and Retention .................................................................................................................................... 29 
4.5 Training of Clinical Centers .................................................................................................................................... 29 
5.  Known and Potential Risks and Benefits to Participants ..................................................................................... 29 
5.1 Risks of Investigational Product or Intervention ............................................................................................... 29 
Table 5.1-1 Adverse Events with Indacaterol/glycopyrrolate greater than or equal to 1% incidence and 
higher than placebo in COPD patients .................................................................................................................... 30 


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5.2 Risks of Other Protocol Specified Medications ................................................................................................. 30 
5.3 Risks of Study Procedures .................................................................................................................................. 30 
5.4 Potential Benefits .................................................................................................................................................. 31 
6.   Investigational Agent/Device/Intervention ............................................................................................................ 31 
6.1 Investigational Agent/Device.................................................................................................................................. 31 
6.2 Drug Accountability ............................................................................................................................................... 31 
6.3 Assessment of Adherence to the Investigational Agent .................................................................................. 32 
7.   Study Procedures ..................................................................................................................................................... 32 
7.1 Pre-screening Phone Call All Subjects ................................................................................................................ 32 
7.2 Screening/Enrollment  (non washout subjects, Visit 1) ..................................................................................... 32 
7.3 Washout visit (washout subjects only, Visit 0) .................................................................................................... 33 
7.4 Phone Call (washout subjects only, Week 3) ...................................................................................................... 33 
7.5 Screening/Enrollment (washout subjects only, Visit 1) ...................................................................................... 34 
7.6 Phone Call (all subjects, Week 4) ......................................................................................................................... 34 
7.7 End of Study  (all subjects, Visit 2) ....................................................................................................................... 34 
7.8 Schedule of Events for Participants Requiring No Medication Washout ........................................................ 35 
7.9 Schedule of Events for Participants Requiring Washout ................................................................................... 36 
7.10 Unscheduled Visits ................................................................................................................................................ 37 
7.11 Visit Windows ......................................................................................................................................................... 37 
7.12 Discontinuation of study treatments ................................................................................................................... 37 
7.13 Special Consideration(s) for Treatment Failure Subjects ............................................................................... 38 
7.13.1 Special Consideration(s) for subjects who start a prohibited medication (Table 4.3-1) ...................... 38 
7.13.2 Special Consideration(s) for subjects who experience an AE/SAE requiring study drug interruption
....................................................................................................................................................................................... 38 
8. Safety Monitoring and Reporting .............................................................................................................................. 38 
8.1 Overview ................................................................................................................................................................... 38 
8.2 Definitions ................................................................................................................................................................. 38 
8.2.1 Adverse Event (AE).......................................................................................................................................... 39 
8.2.2 Unexpected Adverse Event ............................................................................................................................ 39 
8.2.3 Serious Adverse Event (SAE) ........................................................................................................................ 39 
8.3 Grading and Attribution of Adverse Events ......................................................................................................... 40 
8.3.1 Grading Criteria ................................................................................................................................................ 40 
8.3.2 Attribution Definitions ....................................................................................................................................... 40 


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8.4 Collection and Recording of Adverse Events ...................................................................................................... 40 
8.4.1 Collection Period .............................................................................................................................................. 40 
8.4.2 Collecting Adverse Events .............................................................................................................................. 41 
8.4.3 Recording Adverse Events ............................................................................................................................. 41 
8.5 Reporting of Serious Adverse Events and Adverse Events .............................................................................. 41 
8.5.1 Reporting of Serious Adverse Events ........................................................................................................... 41 
8.5.2 Reporting to Health Authority ......................................................................................................................... 42 
8.5.3 Reporting of Adverse Events to IRBs/IECs .................................................................................................. 43 
8.6 Reporting of Other Safety Information .................................................................................................................. 43 
8.7 Review of Safety Information ................................................................................................................................. 43 
8.7.1 DCC Adverse Event Review ........................................................................................................................... 43 
8.7.2 DSMB Review ................................................................................................................................................... 43 
9. Statistical Considerations and Analytical Plan ....................................................................................................... 43 
9.1 Overview ................................................................................................................................................................... 43 
9.2 Endpoints/Outcomes ............................................................................................................................................... 44 
9.3 Measures to Minimize Bias .................................................................................................................................. 44 
9.4 Analysis Plan.......................................................................................................................................................... 44 
9.4.1 Analysis Populations. ....................................................................................................................................... 44 
9.4.2 
Primary Analysis of Primary Endpoint(s)/Outcome(s) .......................................................................... 45 
9.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s) ................................................................... 45 
9.4.4 Analyses of Secondary and Other Endpoint(s)/Outcome(s)...................................................................... 46 
9.4.5 Additional Analyses .......................................................................................................................................... 46 
9.5 Interim Analyses .................................................................................................................................................... 46 
9.5.1 
Interim Analysis of Efficacy Data ............................................................................................................. 46 
9.5.2  
Interim Analysis of Safety Data ................................................................................................................ 46 
9.6 Statistical Hypotheses ............................................................................................................................................. 47 
9.7 Sample Size Considerations .................................................................................................................................. 47 
10. 
Identification and Access to Source Data ....................................................................................................... 47 
10.1 Source Data ........................................................................................................................................................... 47 
10.2 Access to Source Data ......................................................................................................................................... 48 
11. 
Protocol Deviations ............................................................................................................................................ 48 
11.1 Protocol Deviation Definitions ............................................................................................................................. 48 
11.2 Reporting and Managing Protocol Deviations .................................................................................................. 48 


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11.3 Ethical Considerations and Compliance with Good Clinical Practice ........................................................... 48 
11.4 Statement of Compliance ..................................................................................................................................... 48 
11.5 Informed Consent Process .................................................................................................................................. 49 
11.6 Privacy and Confidentiality .................................................................................................................................. 49 
References ....................................................................................................................................................................... 50 
 
 


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Glossary of Abbreviations 
BD 
Bronchodilator 
BDI 
Baseline Dyspnea Index 
CAT 
COPD Assessment Test 
CFR 
Code of Federal Regulations 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
IC 
Inspiratory Capacity 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
LABA 
Long Acting Beta Agonist 
LAMA 
Long Acting Muscarinic Antagonist 
MCID 
Minimum Clinically Important Difference 
MI 
Myocardial Infarction 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events 
OHRP 
Office for Human Research Protections 
PI 
[Site] Principal Investigator 
RCT 
Randomized Controlled Trial 
RETHINC 
Redefining Therapy in Early COPD 
SABA 
Short Acting Beta Agonist 
SAE 
Serious Adverse Event 
SAMA 
Short Acting Muscarinic Antagonist 
SAR 
Suspected Adverse Reaction 


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SGRQ 
St. George’s Respiratory Questionnaire 
SPIROMICS 
Subpopulations and Intermediate Outcome Measures in COPD Study 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
TDI 
Transition Dyspnea Index 
UP 
Unanticipated Problem 
 
 
 


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1. Background and Rationale  
1.1 
Critical Knowledge pertinent to the lung disease and intervention 
Currently, COPD is defined by having an FEV1/FVC<0.7. In 2011, the GOLD guidelines were revised, 
recognizing that spirometric staging alone poorly captures disease severity (2). Instead, patients with COPD 
were divided into four GOLD groups (A-D) based on symptom scores (using standardized questionnaires such 
as the CAT) and exacerbation risk. Groups A and B correspond to low exacerbation risk, with few symptoms 
(CAT<10 or mMRC<2) and more symptoms (CAT≥10 or mMRC≥2), respectively. Groups C and D correspond 
to high risk (GOLD stages 3/4, and/or ≥2 exacerbations annually) with few symptoms (GOLD C) or more 
symptoms (GOLD D). The first choice for therapy in group B is LABA or LAMA. However, mounting evidence 
suggests that the spirometric definition of COPD may be insufficient to diagnose COPD at all. Indeed, 
accumulating data suggest that many current and former smokers with a “normal” FEV1/FVC (≥0.7), manifest 
symptoms of COPD, disability due to those symptoms and clinically significant exacerbations (3-5).  When 
carefully studied this group has evidence of occult airflow obstruction consistent with airway disease not 
detected by simple spirometry. These data suggest that many smokers with symptoms despite normal 
FEV1/FVC have chronic obstructive lung disease consistent with COPD, but do not fit current management 
guidelines. Because this population is large, the health burden posed by those with undiagnosed chronic lung 
disease is significant (3). Importantly, whether they would benefit from therapy is entirely unknown. A minority 
of them are already being treated in the community, but without guidance or evidence. The trial proposed 
here will test the following overarching hypothesis: current and former smokers with respiratory 
symptoms despite normal spirometry (FEV1/FVC≥0.7) will derive benefit from inhaled bronchodilator 
therapy, even though they are excluded from the current GOLD guideline recommendations. The 
clinical trial that stems from this hypothesis will provide new fundamental clinical and therapeutic knowledge 
regardless of the outcome. If these people do benefit from symptom-stratified bronchodilator therapy, then 
current guidelines for the management of COPD may require significant reconsideration. Such a result would 
call into question our very definition of COPD, suggesting that our current definition is insufficient to guide basic 
therapy in a large segment of our population. If these smokers with symptoms despite normal spirometry do 
not benefit from symptom-stratified bronchodilator therapy, then this result too will provide important guidance 
for community physicians, given that many patients in this group are already being treated. 
1.2 
Rationale for Selection of Investigational Agent 
The GOLD consensus report (2) and COPD Foundation guidelines (6) currently recommend the use of long-
acting bronchodilators, used either alone or in combination, as treatment for patients with COPD with any 
severity of lung dysfunction who have symptoms based on CAT≥10 or mMRC≥2.  Long-acting bronchodilators 
including the long-acting beta-agonists (indacaterol, formoterol and salmeterol) as well as several long-acting 
muscarinic antagonists (tiotropium, umeclidinium, and aclidinium) which are all currently FDA approved in the 
US as monotherapy for the treatment of COPD).  The FDA has also approved the use of dual bronchodilators 
which combine a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) for 
maintenance therapy in COPD.  These include AnoroTM (umeclidinium/vilanterol) and StioltoTM 
(tiotropium/olodaterol).  Indacaterol/glycopyrrolate is the dualbronchodilator that we propose to test in our 
proposal, and it was recently FDAapproved.  Indacaterol/glycopyrrolate has rapid onset of action with 
sustained bronchodilator effect over a 12-hour period and is administered twice daily. Its indication is the long-
term maintenance treatment of COPD including chronic bronchitis and/or emphysema.  
In clinical studies, both LABAs and LAMAs appear to be effective for improving lung function in terms of FEV1 
although the effects of combination LABA and LAMA are greater than the effects of either drug alone.  In the 
Flight1 and Flight2 studies comparing indacaterol/glycopyrrolate 27.5/15.6 mcg twice daily to indacaterol 27.5 
mcg twice daily, glycopyrrolate 15.6 mcg twice daily or placebo, the improvement in FEV1 area under the curve 
from 0 to 12 hours (AUC0-12h) for the combination was superior to either monocomponent (p<0.001).  In 
addition, symptom improvement based on SGRQ and TDI scores as well as rescue medication use were also 
significantly greater in the combination treatment group as compared both to monocomponents and placebo 
(p<0.001). 


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In addition to the benefit that dual bronchodilators improve 
FEV1 and symptoms more than the monocomponents, there is 
another advantage to the use of dual bronchodilators in the 
COPD patient population. While a correlation between 
bronchodilator responsiveness to a beta-agonist and 
antimuscarinic in individual patients is observed, there are 
clearly individuals who respond preferentially to one of the two 
classes of bronchodilators (Figure 1). This preferential 
response to beta-agonists or antimuscarinics may have a 
biological underpinning, as differential responses have been 
associated with polymorphisms in the β2-adrenergic receptor 
gene (ADRB2) (7). 
   
Hence in choosing a bronchodilator to test in this study, we 
chose a bronchodilator therapy with dual mechanism of action 
which is most likely to produce the greatest bronchodilation and 
symptom improvement in the most number of individuals, 
allowing us to best test the hypothesis that bronchodilation in 
symptomatic smokers will result in respiratory symptom 
improvement. By using maximal bronchodilator therapy we 
have the best chance of proving or disproving our hypothesis. 
1.3 
Prior Clinical Studies  
The core clinical development program for indacaterol/glycopyrrolate (tradename Utibron) is comprised of: 1) 
the recently-published Flight 1 and Flight 2 studies which were two, placebo-controlled, parallel group, 12-week 
randomized studies to characterize the safety and efficacy of indacaterol/glycopyrrolate and 2) Flight 3, a 52-
week placebo-controlled study aimed primarily at establishing long-term safety of indacaterol/glycopyrrolate (8, 
9).  Study populations were male or female greater than 40 years of age with post-bronchodilator 
FEV1/FVC<80% predicted, FEV1 ranging from 30-80% and a minimum of 10 pack-year smoking history. 
Patients were excluded if they had a history of asthma, prolonged QTc interval or history of respiratory 
infection in the past 6 weeks prior to screening.  The primary endpoint for Flight 1 and 2 was FEV1 between 0 
to 12 h (FEV1 AUC0-12h) after 12 weeks of treatment with indacaterol/glycopyrrolate as compared to the 
monocomponents indacaterol and glycopyrrolate.  Secondary endpoints included change in percentage of 
SGRQ responders (defined as individuals experiencing a 4 point drop in SGRQ) in addition to demonstrating 
superiority of indacaterol/glycopyrrolate compared to placebo in terms of FEV1 AUC0-12h, the transition dyspnea 
index (TDI) score, daily rescue medication use and daily symptoms as reported by an e-diary at week 12.  12 
week change in quality of life as assessed by the COPD Assessment Test (CAT) was an exploratory endpoint.  
Pooled data from Flight 1 and 2 demonstrated statistically significant improvement in FEV1 AUC0-12h when 
compared to its respective mono-components in the pooled analysis (treatment difference [Δ] =103 mL and 88 
mL versus indacaterol and glycopyrrolate, respectively, p<0.001).  In addition, indacaterol/glycopyrrolate 
treatment was significantly superior to placebo for FEV1 AUC0-12h (Δ =246 mL, p<0.001).   
 
Patients treated with indacaterol/glycopyrrolate also had statistically and clinically significant improvement in 
their SGRQ total score at Week 12 when compared with placebo (mean 5.0 unit improvement, p<0.001).The 
SGRQ total score also showed a significant reduction with indacaterol/glycopyrrolate treatment compared with 
indacaterol (p=0.019) and glycopyrrolate (p=0.033).  A significantly higher proportion of patients (responders) 
in the indacaterol/glycopyrrolate group also achieved the minimum clinically important difference (MCID) of 4 
units when compared to placebo (odds ratio of 2.5, p<0.001), indacaterol (odds ratio of 1.3, p=0.041) and 
glycopyrrolate (odds ratio of 1.5, p=0.003).  Importantly, the the indacaterol/glycopyrrolate treatment arm also 
had a statistically and clinically significant improvement (defined as ≥1 unit increase) in the TDI total score 
compared with placebo (1.64 unit improvement, p<0.001), and statistical improvements as compared to 
Figure 1 Intraindividual association between β2-
adrenergic response on the x-axis (salmeterol) 
and antimuscarinic response on the y-axis 
(oxytropium) demonstrating while there is a 
correlation, significant intra-individual variation 
exists in FEV1 improvement with beta-agonist 
versus antimuscarinic bronchodilators. 


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indacaterol (0.78 unit improvement, p<0.001) and glycopyrrolate (0.73 unit improvement, p<0.001) at Week 12. 
The proportion of patients with a MCID ≥1unit in the TDI total score was significantly higher with 
indacaterol/glycopyrrolate compared with placebo, indacaterol and glycopyrrolate. For TDI, the odds ratio for 
responder rate (with response defined by 1 unit change from baseline) at 12 weeks was 1.58 (95% CI 0.97, 
2.57) and 2.19 (95% CI 1.33, 3.60).  For SGRQ, the odds ratio for responder rate (with response defined by a 
4 unit change from baseline) was 1.71 (95% CI 1.05, 2.78) and 1.80 (95% CI 1.08, 2.98). There was also a 
significant reduction in mean daily puffs and increase in percentage of days with no rescue medication use with 
indacaterol/glycopyrrolate compared with placebo.  An exploratory endpoint in the Flight studies was the 
change in health-related quality of life assessed by COPD Assessment Test (CAT) at Week 12.  Using pooled 
data, a mean difference of 1.8 (95% CI 1.1, 2.4) units CAT score improvement was seen in the 
indacaterol/glycopyrrolate group as compared to placebo (p<0.001).  The difference between 
indacaterol/glycopyrrolate and monocomponents was also statistically significant at the p<0.05 level. 
 
1.4 
Rationale for Study Population 
For simplicity we will refer to current and former smokers with FEV1/FVC≥0.7 as GOLD 0 subjects. Our 
preliminary data from the NHLBI-funded SPIROMICS study suggest that a significant percentage of GOLD 0 
subjects have symptoms, exacerbations, activity limitation and airway wall thickening consistent with airway 
disease not detected by simple spirometry. The SPIROMICS study is an ongoing longitudinal observational 
study of current and former smokers (≥ 20 pack years) with a 
range of airflow obstruction and never-smoking controls. In 
preliminary data we categorized GOLD 0 smokers and subjects 
with GOLD I/II COPD as symptomatic (CAT≥10) or asymptomatic 
(CAT<10). We used CAT because we have previously shown that 
the mMRC≥2 and CAT≥10 (both used by GOLD for identifying 
symptomatic patients in GOLD I-IV) are not equivalent and that 
the mMRC≥2 is overly stringent (10). We also provide 
corroborating evidence where available from another NHLBI 
study, COPDGene. While CAT was not collected in COPDGene, 
we use SGRQ≥25 which is approximately equivalent to CAT≥10 
(11). 
 
Many GOLD 0 current and former smokers have clinically 
important symptoms of COPD. In SPIROMICS we found that 52% 
of GOLD 0 subjects had CAT≥10 (Figure 1), slightly less than the 
prevalence of CAT≥10 in GOLD 1&2 (65%, p<0.001) but far 
greater than the prevalence in never-smoking controls (16%, 
p<0.001). 
 
Symptomatic GOLD 0 smokers had higher prospective rates of 
exacerbation of respiratory disease and shorter 6 minute walk 
distance (6MWD). In SPIROMICS, whether defined based on use 
of antibiotics, systemic corticosteroids, both medications, any 
health care utilization, or hospitalization/emergency department (ED) visits (severe exacerbations), the 
prospective rate of exacerbations was higher in GOLD 0 smokers with CAT≥10 than in  GOLD 0 with CAT<10 
or healthy never-smoking controls (Figure 2). The 6MWD was also lower in GOLD 0 with CAT≥10 (408±100m) 
as compared to both GOLD 0 with CAT<10 (462±92m) and GOLD 1&2 subjects with CAT<10 (452±101m) (all 
p<0.05).  
 
Figure 1. In SPIROMICS, 52% of GOLD 0 
smokers have elevated symptoms of 
COPD (defined as CAT≥10. 


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In COPDGene, walk distance was similarly reduced 
in symptomatic subjects with normal spirometry vs. 
asymptomatic subjects (402±104m vs 471±102m, 
p<0.001).  
 
Symptomatic GOLD 0 current/former smokers have 
decreased inspiratory capacity, consistent with 
occult airflow obstruction.  In SPIROMICS, we 
found that the post-bronchodilator inspiratory 
capacity (IC) was 2.66±0.74 in symptomatic GOLD 
0 subjects vs 2.88±0.75 in asymptomatic GOLD 0 
subjects, p=0.001). The IC in this group was similar 
to symptomatic GOLD I/II patients (2.67±0.81, 
p=0.48) and worse than asymptomatic GOLD I/II 
patients (2.88±0.84, p=0.004). This decreased IC is 
not explained by emphysema as the percent of lung 
<-950 Hounsfield units (HU) by quantitative chest 
HRCT in symptomatic GOLD 0 subjects was low 
and no different from asymptomatic subjects 
(p=0.99). Instead, symptomatic GOLD 0 subjects 
have a higher Pi10 (a measure of airway wall 
thickness) than asymptomatic GOLD 0 subjects 
(3.73±0.090 vs 3.70±0.090, p<0.05). Hence we hypothesize that these physiologic changes are due to occult 
airway disease. While we could find no studies of bronchodilators in GOLD 0 subjects, several studies in 
GOLD I patients demonstrate the benefit of bronchodilators in terms of improvements in inspiratory capacity, 
functional residual capacity, residual volume, airways resistance, dynamic hyperinflation and work of breathing 
(12-15). 
 
Many symptomatic GOLD 0 current/former smokers are already being treated for COPD, with great variability 
in medication choice. In SPIROMICS, 43% of these subjects were on bronchodilators: 31% SABA and 11% 
SAMA; 31% LAMA and 15% LABA. Finally, 23% were using inhaled corticosteroids. 
 
In the above analyses, all spirometry was post-bronchodilator and all p-values were Bonferroni-corrected for 
multiple comparisons across four groups (symptomatic/GOLD 0, asymptomatic GOLD 0, symptomatic/GOLD 
I&II, and asymptomatic GOLD I&II). Current smoking was more common in symptomatic as compared to 
asymptomatic GOLD 0 subjects (58% vs. 42%, p<0.001), and the BMI was higher (29.8±5.4 vs 27.8±4.7, 
p<0.001). Therefore all of the above analyses were repeated while controlling for current smoking, BMI as well 
as age, gender, race, ethnicity, congestive heart failure, GERD self-report, and any asthma diagnosis, and 
there was no material change in the results in these adjusted models.  
 
Summary of our rationale for the study population: We show that respiratory symptoms are common in 
GOLD 0 current/former smokers (i.e. with FEV1/FVC≥0.7 post-bronchodilator), and that GOLD 0 smokers with 
symptoms have higher rates of respiratory exacerbation, activity limitations, and evidence of occult airflow 
obstruction (decreased inspiratory capacity). Our data also indicate that this is not due to emphysema but is 
instead associated with airway wall thickening, and we hypothesize that this occult airway disease will respond 
to effective bronchodilator therapy.   
  
1.5 
Feasibility of the Intervention in the Target Population 
Indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily is simple to use and should be feasible in terms of 
ease of use and tolerability in the target population for this study (symptomatic smokers with FEV1/FVC≥0.70) 
as it is in the population for which it was developed (symptomatic smokers with FEV1/FVC<0.70).  While an 
RCT of long-acting bronchodilator therapy in symptomatic GOLD 0 smokers (i.e. those with FEV1/FVC≥0.70) 
Figure 2. Increased symptoms (CAT≥10) are associated 
with increased prospective rates of exacerbations in GOLD 
0 subjects. 


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has never been performed, several studies in GOLD I patients demonstrate the benefit of bronchodilators in 
terms of improvements in inspiratory capacity, functional residual capacity, residual volume, airways 
resistance, dynamic hyperinflation and work of breathing (12-15).  As outlined above in 1.2., there is also 
evidence that the degree of FEV1 improvement and symptom improvement defined by percentage of subjects 
with 4 point drop in SGRQ with indacaterol/glycopyrrolate therapy actually increases in parallel with FEV1.  In 
summary these data provide rationale for long-acting bronchodilator therapy in the target population for this 
proposal. 
2.  Study Hypotheses/Objectives 
2.1 Hypotheses 
The study proposed here will test the hypothesis that symptomatic current and former smokers with spirometric 
values within the normal range (post-bronchodilator FEV1/FVC≥0.70 and post-BD FVC ≥ 70% predicted [to 
guard against restrictive lung disease]) will still derive symptomatic benefit from long-acting bronchodilator 
therapy even though they are excluded from current GOLD guideline recommendations.  
2.2 Primary Objective 
Proportion of individuals who experience a 4 unit improvement in SGRQ and do not meet criteria for treatment 
failure during the 12 week study period. 
2.3    Secondary Objectives  
 
• 
Proportion of individuals with 2 unit improvement in CAT without treatment failure 
• 
Proportion of individuals with a 1 unit improvement in BDI/TDI without treatment failure 
• 
Proportion of individuals with both a 4 unit improvement in SGRQ and a 1 unit improvement in BDI/TDI 
without treatment failure 
• 
Mean change in SGRQ 
• 
Mean change in CAT 
• 
AUC0-3h for FEV1 
• 
Change from baseline in trough FEV1 (absolute value and % predicted) 
• 
Change in baseline from trough inspiratory capacity, FEF25-75% and iso-volume FEF25-75% (absolute 
value and % predicted) 
• 
Mean change in level of symptoms and rescue medication use based on daily diary 
• 
Treatment failure defined by increase in lower respiratory symptoms necessitating treatment with 
active, long-acting inhaled bronchodilator, corticosteroids or antibiotics. 
2.4   Anticipated Short and Long Term Impact of the Intervention 
As this is a 12-week interventional trial, we expect the short term impacts of the intervention to be evidenced 
by improvement in the primary outcome measure, specifically improvements in symptoms as measured by 
proportion of individuals experiencing a 4 unit improvement in SGRQ and do not meet criteria for treatment 
failure during the 12 week study period.  We hope that the long term impacts of this study will be to further 
investigation in this population of patients and to influence both how we as a research and medical community 
define and treat COPD.  While this is not a study of smoking cessation, we will be including current and former 
smokers and as such realize this is an opportunity to provide medical information on respiratory health effects 
of smoking.  As part of the study, information on smoking cessation resources will be provided to all currently 
smoking participants at the time of first in-person contact. 
3 Study Design 
3.1 Description of Study Design  


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RETHINC is a Phase III, double-blind, placebo-controlled, parallel-design multi-site study comparing 
indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily vs placebo in subjects with ≥10 pack-years 
smoking history with post-bronchodilator FEV1/FVC ≥0.70 and CAT ≥ 10.  Treatment duration is 12 weeks with 
290 patients in each arm.  SGRQ, CAT, BDI/TDI and spirometry will be performed at baseline and 12 weeks.  
A phone call at 4 weeks will assess for adverse events. 
 
Figure 3.1-1.  Flow Diagram 
 
Prior to 
Enrollment 
 
 
 
 
In-person  
Study Visit 1 
 
Phone Call 
Week 4 
 
 
In-person  
Study Visit 2 
Week 12 
 
3.2 Primary Endpoint(s)/Outcome(s) 
The primary study endpoint will be comparison of the proportion of individuals on treatment versus placebo 
who experience a 4 unit change in SGRQ after 12 weeks and do not meet criteria for treatment failure during 
the 12 week study period. If we meet our primary outcome we will conclude that treatment improves clinical 
status in symptomatic “at risk” smokers even if they do not meet the formal spirometric definition of COPD 
(FEV1/FVC<0.7). 
3.3 Secondary Endpoint(s)/Outcome(s) 
Important secondary endpoints in comparing treatment versus placebo after 12 weeks will be proportion of 
individuals with 2 unit change in CAT without treatment failure; proportion of individuals with a 1 unit change in 
BDI/TDI without treatment failure; proportion of individuals with both a 4 unit improvement in SGRQ and a 1 
unit improvement in BDI/TDI without treatment failure; mean change in SGRQ; mean change in CAT; AUC0-3h 
in FEV1; change from baseline in 12 hour trough FEV1; change from baseline in 12 hour trough inspiratory 
capacity, FEF25-75% and iso-volume FEF25-75% and mean change symptoms and rescue medication use 
based on daily diary; and treatment failure defined by increase in lower respiratory symptoms necessitating 
treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics. 
3.4 Survey Instruments to be Used 
Total N=580:  Obtain informed consent. Screen subjects by criteria. 
Randomize 
Administer Study Product/Intervention 
N=290         
Indacaterol/glycopyrrolate 
N=290 
Placebo 
Assessment of Final Outcome Measures 
Assess for adverse events, reassess symptoms 


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SGRQ  The St. George’s Respiratory Questionnaire (SGRQ) is a validated health status instrument developed 
for COPD that contains 50 items divided into three components: "Symptoms" concerned with respiratory 
symptoms, their frequency and severity; "Activity" concerned with activities that cause or are limited by 
breathlessness; and "Impacts" which covers a range of aspects concerned with social functioning and 
psychological disturbances resulting from airway disease (16). A score will be calculated for each component 
and a "Total" score will also be calculated. In each case the lowest possible value is zero and the highest 100. 
Higher values correspond to greater impairment of quality of life.  The accepted minimal clinically important 
difference (MCID) for SGRQ is a 4 unit change (17). At the 12 week visit, subjects will be instructed to provide 
responses to SGRQ that reflect their health status during the 12 week treatment period. 
CAT The COPD Assessment Test is a validated, short and simple patient completed questionnaire which has 
been developed for use in routine clinical practice to measure the health status of patients with COPD (11, 18). 
The CAT is an 8-item questionnaire suitable for completion by all patients diagnosed with COPD. When 
completing the questionnaire, subjects rate their experience on a scale, ranging from 0 (minimum impairment) 
to 5 (maximum impairment) with a scoring range of 0-40. Higher scores indicate greater disease impact.  The 
accepted MCID for CAT is a 2 unit change (19). 
BDI/TDI Dyspnea will be measured at baseline using the baseline dyspnea index (BDI) and during the 
treatment period using the transition dyspnea index (TDI), which captures changes from baseline.  The BDI 
and TDI were originally developed to assess dyspnea in patients with a variety of respiratory conditions 
including COPD.  Each have three domains; functional impairment, magnitude of task and magnitude of effort. 
The BDI domains are rated from 0 (severe) to 4 (unimpaired) and the rates are summed for the baseline focal 
score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. The TDI domains are rated 
from -3 (major deterioration) to 3 (major improvement) and the rates are summed for the transition focal score 
ranging from -9 to 9; minus scores indicate deterioration.  The accepted MCID for TDI is 1 unit change (20).   
3.5 Stratification, Randomization, and Blinding/Masking 
A permuted block randomization scheme will be created with varying block sizes stratified by clinical center, 
smoking history (current smoker/former smoker) and prior maintenance treatment for COPD requiring washout. 
Once a subject has completed the screening and evaluation for inclusion/exclusion criteria, the randomization 
process will begin. Subjects will be randomized to receive active drug and placebo with equal probability (1:1), 
via Internet with a central interactive response system (IVRS). On the day of randomization, after the subject 
has successfully met all inclusion and exclusion criteria, the investigator or designee will login to the central 
randomization website to obtain the assigned kit randomization number for that subject. One pharmacist at 
each site will be unblinded to treatment group. For resupply of the site, the pharmacy will need to notify the 
NEMO to request the next shipment of drug supply when on-site drug supply is down to one placebo kit or one 
active drug kit. The trial results will be reported according to guidelines specified in the CONSORT statement. 
A flow diagram describing screening, recruitment, randomization, dropout, and vital status will be included in 
the primary manuscript. AEs and efficacy data will be presented by the 2 treatment groups. Adherence, 
dropout, and loss to follow-up will be carefully examined across the 2 treatment groups. Analyses of safety will 
be based on data from all randomized subjects who received at least 1 dose of study drug. 
3.5.1 Procedure for Unblinding/Unmasking 
Unblinding must be approved by the DSMB unless an immediate life threatening condition has developed and 
the Protocol Chairs are not accessible.  In the case of emergent unblinding, the site investigator will notify the 
protocol chairs and the DCC of the unblinding event on the next business day; the protocol chairs and the DCC 


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will then notify the DSMB and FDA. A full account of the event will be recorded, including the date and time of 
the unblinding, the reason for the decision to unblind, and the name of the individual who made the decision 
and the roles of who was notified and unblinded (i.e. coordinator, PI, subject, etc). The reasons for unblinding 
of a participant’s treatment will be included in the final study report. 
3.5.2  Securing Blinding and Randomization Information 
 All subjects, monitors, and study center personnel related to the study, except for the pharmacist (or qualified 
designee) who prepares the study drug and the pharmacy monitor who monitors the pharmacy records and 
procedures, will be blinded to study treatment throughout the study.  A designated statistician will securely 
maintain an unblinded randomization schema.  
4 Selection of Participants and Clinical Sites/Laboratories 
4.1 Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for enrollment as study participants:  
1. Subject must be able to understand and provide informed consent 
2. Age 40-80 
3. ≥10 pack-year smoking history 
4. Post-bronchodilator FEV1/FVC ratio ≥0.70 
5. Baseline CAT≥10 
4.2 Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment as study participants:  
 
1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol. 
2. Subject is pregnant, breast-feeding, or plans to become pregnant. 
3. Active pulmonary infection or prior pulmonary infection where treatment was completed ≤ 4 weeks prior 
to enrollment. 
4. Post-BD FVC < 70% predicted. 
5. A primary diagnosis of asthma established by each study investigator on the basis of the American 
Thoracic Society/European Respiratory Society guidelines as implemented in the MACRO study (1). 
 
In this implementation, physician investigators are asked apply the criteria above and if, after applying 
the these criteria, the clinicians are still unsure about the distinction in a specific patient, then  
bronchodilator testing with inhaled albuterol will be performed and patients with changes in FEV1 > 400 
mL will be excluded. 
 
Clinical Features Differentiating COPD and Asthma  
 
History 
COPD 
Asthma 
Smoker or ex-smoker 
Nearly all 
Possibly 
Symptom onset < 35 yrs 
Rare 
Common 
Chronic productive cough 
Common 
Uncommon 
Breathlessness 
Persistent and 
progressive 
Variable 
Nighttime waking with 
breathlessness and wheeze 
Uncommon 
Common 
Significant diurnal or day-to-day 
variation of symptoms 
Uncommon 
Common 
 


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6. Known concomitant lung disease, pulmonary tuberculosis (unless confirmed by chest x-ray to be no 
longer active), or clinically significant bronchiectasis. 
7.  History (or family history) of long QT syndrome. 
8. History of paroxysmal (intermittent) atrial fibrillation will be considered an exclusion.  Patients with 
persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled 
with a rate control strategy (i.e., selective beta blocker, calcium channel blocker, pacemaker placement, 
digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, 
heart rate at enrollment must be < 100/min.  
9. Patients with BMI < 15 or more than 40 kg/m2. 
10. Patients with diabetes Type I or uncontrolled diabetes Type II. 
11. Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a 
clinically significant condition such as (but not limited to) significant renal disease, psychiatric disease, 
gastrointestinal disease, unstable ischemic heart disease, arrhythmia (excluding chronic stable atrial 
fibrillation), uncontrolled hypertension or any other condition which in the opinion of investigator might 
compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study. 
12. Patients with any history of lung cancer. 
13. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck 
obstruction or severe renal impairment or urinary retention.  Benign Prostatic Hyperplasia (BPH) 
patients who are stable on treatment can be considered. 
14. Any other past or current medical problems or findings from physical examination or laboratory testing 
that are not listed above, which, in the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability to comply with study requirements 
or that may impact the quality or interpretation of the data obtained from the study. 
15. Patients with a history of hypersensitivity to any of the study drugs or to drugs from similar chemical 
classification, including untoward reactions to sympathomimetic amines or inhaled medication or any 
component thereof. 
16. Patients unable to successfully use a dry powder inhaler device or perform spirometry measurements.  
17. Use of other investigational drugs at the time of enrollment or within 30 days or 5 half-lives of 
enrollment, whichever is longer. 
18. Patients receiving any prohibited medications in the classes or groups listed in Table 4.3-1. 
19. Patients receiving any prohibited COPD related medications in the classes or groups in Table 4.3-2 
must undergo the required washout period prior to Visit 1. 
 
The class of medications listed in Table 4.3-1 are not permitted to be taken during the study and are 
considered exclusion criteria.  Medications in Table 4.3-2 are also not permitted but subjects may be washed 
out per protocol, see Section 7. If a patient requires any of these medications and they cannot be safely 
washed out (with permission of the subject’s primary physician) then they should not be included in the study.  
Short acting beta agonists are the only “rescue” medication allowed during the trial.   Each concomitant drug 
must be individually assessed against all exclusion criteria and the tables below to see if it allowed. If in doubt 
you should contact the Protocol Chairs before randomizing a patient or allowing a new medication to be 
started.  
4.3 Prohibited Medication  
Table 4.3-1 Prohibited Medications 
Class of medication 
Cardiac anti-arrhythmics Class Ia 
Cardiac anti-arrhythmics Class III 
Tricyclic antidepressants 
Monoamino-oxidase inhibitors 


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Other investigational drugs  
 
NOTE:  If participant is on a non-potassium sparing diuretic (unless administered as a fixed-dose combination, i.e. all in 
one pill/tablet with a potassium conserving drug or has adequate documentation of concomitant use of a potassium 
conserving drug), we require them to have a serum potassium level check either at the enrollment visit or at a separate 
screening visit and to exclude them if they have a potassium level that is below the lower limit of normal for that 
laboratory. The serum potassium level must be available and reviewed before randomization. If it is desired that a 
patient initiate a non-potassium sparing diuretic (not as part of fixed-dose combination) after the subject has been 
randomized, a potassium level that is above the lower limit of normal for the chosen laboratory should be documented 
if on study drug. 
Table 4.3-2 Prohibited COPD-related Medications Requiring Washout Period of 30 days 
Class of medication 
Minimum washout period prior  
to Visit 1 
Long-acting anticholinergics 
30 days 
Short-acting anticholinergics 
30 days 
Fixed combinations of long-acting beta-agonists and inhaled corticosteroids 
30 days 
Fixed combinations of short acting beta agonists and short-acting 
anticholinergics 
30 days 
Long-acting beta agonists 
 
30 days 
 
4.4 Recruitment and Retention 
A variety of recruitment techniques at each center should be employed as allowed by local IRB’s including 
local advertising aimed at (a) health system patients; (b) smoking cessation groups; (c) general public, 
including social media; (d) review of local databases or patient registries; (e) pulmonary function test database 
and electronic medical record query; (f) screening of pulmonary clinics, (g) lung cancer screening clinics and 
(h) primary care clinics.  The study will also be posted on clinicaltrials.gov.  Due to the short duration of the 
study and low number of study visits, we expect attrition to be low.  However, we will also work with the clinical 
centers to keep logistical burden on subjects to a minimum. 
4.5 Training of Clinical Centers 
At clinical center initiation, the DCC Project Manager will be responsible for training and certification sessions, 
including training on required software and systems, study procedures and eCRFs for study coordinators, PIs, 
and other study staff as needed.  The site training is a critical study milestone necessary before a site can start 
enrolling subjects into the study.  Due to limited budget, instead of onsite visits, webinars will be used to 
conduct site training. A Manual of Operations will be written by the DCC Project Manager, describing detailed 
study procedures that augment the protocol will be posted on the website.  It is updated regularly as changes 
and refinements to the study are taken.   
5.  Known and Potential Risks and Benefits to Participants 
5.1 Risks of Investigational Product or Intervention  
 
Adverse drug reactions 
 


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Data provided from the prescribing information (package insert) approved by the FDA for 
indacaterol/glycopyrrolate is outlined in Table 5.1-1. 
 
 
Table 5.1-1 Adverse Events with Indacaterol/glycopyrrolate greater than or equal to 1% incidence and 
higher than placebo in COPD patients 
 
Indacaterol/glycopyrrolate 
27.5/15.6 mcg BID 
Indacaterol  
27.5 mcg BID 
Glycopyrrolate  
15.6 mcg BID 
Placebo 
Nasopharyngitis 
21 (4.1%) 
13 (2.5%) 
12 (2.3%) 
9 (1.8%) 
Hypertension 
10 (2.0%) 
5 (1.0%) 
3 (0.6%) 
7 (1.4%) 
Back pain 
9 (1.8%) 
7 (1.4%) 
2 (0.4%) 
3 (0.6%) 
Oropharyngeal pain 
8 (1.6%) 
4 (0.8%) 
8 (1.6%) 
6 (1.2%) 
 
Other adverse reactions occurring more frequently with indacaterol/glycopyrrolate than with placebo, but 
with an incidence of less than 1% include dyspepsia, gastroenteritis, chest pain, fatigue, peripheral edema, 
rash/pruritus, insomnia, dizziness, bladder obstruction/urinary retention, atrial fibrillation, palpitations, 
tachycardia.  Additional adverse reactions that were reported in registration trials included upper and lower 
respiratory tract infection, pneumonia, diarrhea, headache, gastroesophageal reflux disease, 
hyperglycemia, rhinitis.   
In addition, indacaterol/glycopyrrolate can produce paradoxical bronchospasm that may be life-threatening. 
Immediate hypersensitivity reactions have been reported after administration of indacaterol or 
glycopyrrolate.  Indacaterol, like other beta2-agonists, can produce a clinically significant cardiovascular 
effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or 
symptoms.  In addition, beta-agonists have been reported to produce ECG changes, such as flattening of 
the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance 
of these findings is unknown.  Indacaterol/glycopyrrolate also has the potential to worsen pre-existing 
chronic conditions including urinary retention and narrow-angle glaucoma.   
Contraindications 
All long acting beta agonists are contraindicated in patients with asthma without the use of long-term 
asthma controller medications. Per protocol, patients with a primary diagnosis of asthma will be excluded 
from participation in this study. 
5.2 Risks of Other Protocol Specified Medications 
Albuterol is an inhaled, short-acting beta-agonist that will be used to perform post-bronchodilator spirometry.  
Dosage of albuterol administered in these scenarios is 90 mcg per actuation or 360 mcg total. In clinical 
studies, at least 3% of patients taking albuterol report headache, tachycardia (increased heart rate), muscle 
pain, dizziness, pharyngitis (sore throat), and rhinitis (runny nose). Less than 3% of patients taking albuterol 
report chest pain, infection, diarrhea, glossitis (swelling of the tongue), anxiety, dyspnea (difficulty breathing), 
ear disorder, ear pain, and urinary tract infection.  In small cumulative dose studies, tremor, nervousness, and 
headache were most frequently reported. 
5.3 Risks of Study Procedures 
Demographic and health status information:  Subjects could experience fatigue or frustration during the 
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Physiologic studies:  Mild respiratory distress, transient desaturation, and lightheadedness can be seen during 
the pulmonary function testing. These are rarely significant if testing is performed by trained personnel such as 
those involved in this study. Participants will be monitored closely during the procedure. 
 
Washout:  For subjects requiring washout of an inhaled respiratory medication, participants could experience 
increased respiratory distress.  If significant symptoms are experienced during the washout period, the 
subjects will not be enrolled in the study. 
 
Research Lab/Venipuncture: The risk associated with blood draws can include but is not limited to pain, 
bruising, or superficial phlebitis. The vein in which the needle has been inserted to draw blood may become 
sore and red. A temporary “black and blue mark” may develop, and rarely fainting may occur. 
5.4 Potential Benefits 
Participating subjects may benefit from the intervention in terms of a reduction in respiratory symptoms 
including shortness of breath, wheezing and cough.  This study may also benefit society in demonstrating 
treatment efficacy of long acting bronchodilator therapy in patients currently not included in COPD treatment 
guidelines.   
6.   Investigational Agent/Device/Intervention 
6.1 Investigational Agent/Device 
The investigational agent is indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily.  This drug has been 
extensively studied in COPD and is FDA approved for treatment of COPD in the US.  Administration of this 
medication involves removing capsule from a blister pack, placing the capsule in the Neohaler device, 
puncturing the capsule with the device and inhaling via the mouthpiece, see Figure 6.1-1. 
 
Figure 6.1-1.  Neohaler. 
 
6.2 
Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator will maintain adequate 
records of the disposition of the investigational agent, including the date and quantity of the drug received, to 
whom the drug was dispensed (participant-by-participant accounting), and a detailed accounting of any drug 
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Records for receipt, storage, use, and disposition will be maintained by the study site.  A drug-dispensing log 
will be kept current for each participant.  This log will contain the identification of each participant and the date 
and quantity of drug dispensed. 
All records regarding the disposition of the investigational product will be available for inspection. 
Indacaterol/glycopyrrolate will be dispensed to the sites by the DCC or designee.    
6.3 
Assessment of Adherence to the Investigational Agent  
Compliance will be assessed through indacaterol/glycopyrrolate capsule counts at the final study visit. 
7.   Study Procedures 
7.1 Pre-screening Phone Call All Subjects 
Subjects will be evaluated by pre-screening phone call prior to the screening and enrollment visit (Visit 1). 
During the pre-screening phone call, study staff will review the inclusion and exclusion criteria with the subject 
to determine their eligibility.  This will include administration of the CAT questionnaire by phone to determine 
whether score meets enrollment criteria of ≥ 10.  If subject is eligible a  screen/enrollment visit will be 
scheduled.  If subject is ineligible due to factors that may be subject to change over time (e.g. BMI drops or a 
prohibited medication has been discontinued for clinical reasons), subjects may be undergo phone call re-
screening.  Even subjects who are brought in for a Visit 1 may be re-screened (see 7.2).  
 
If the subject is currently taking a prohibited COPD medication from Table 4.3-2, the subject may be brought in 
for an additional on-site screening visit (visit 0) to be consented and the COPD medication discontinued, after 
seeking agreement from the subject’s primary provider.  Subjects will be strictly instructed that if they cannot 
tolerate being off of their COPD medication, then they should restart their COPD medication and notify us.  The 
subject will be called 3 weeks after the COPD medication discontinued to see if they are tolerating washout 
and if so, be brought back for Visit 1, 30 days after the initial on-site screening visit.   
7.2 Screening/Enrollment  (non washout subjects, Visit 1) 
A subject number will be assigned at this time of signed informed consent. The required order of completion of 
these assessments will be further outlined in the Manual of Procedures. 
• 
Inclusion/exclusion criteria assessment 
• 
Demographics information including date of birth, sex, race and ethnicity, height, weight 
• 
Relevant medical history including smoking status and history, documented history of respiratory 
infection treated in the past 30 days with antibiotics or steroids and asthma diagnosis (see exclusion 
criteria). 
• 
Current concomitant medications (See Note).   
• 
Current and prior COPD medication history used in the 12 months prior to Visit 
• 
Physical Exam and vital signs 
• 
Completion of questionnaires including SGRQ, CAT and BDI 
• 
FEV1, FVC, SVC and IC before and 15 mins after 4 puffs of albuterol  
• 
Pregnancy test is required for females of child bearing potential prior to randomization. 
• 
Distribution of diary cards and study drug. 
• 
Education on the benefits of smoking cessation and resources for help with smoking cessation 
 
NOTE:  If participant is on a non-potassium sparing diuretic (unless administered as a fixed-dose combination, 
i.e. all in one pill/tablet with a potassium conserving drug, or has adequate documentation of concomitant use 


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of a potassium conserving drug), we require them to have a serum potassium level check either at the 
enrollment visit or at a separate screening visit and to exclude them if they have a potassium level that is below 
the lower limit of normal for that laboratory. The serum potassium level must be available and reviewed before 
randomization.  If the level is checked and is above the lower limit of normal for the chosen laboratory, the 
subject may be enrolled into the study.  If it is desired that a patient initiate a non-potassium sparing diuretic 
(not as part of fixed-dose combination) after the subject has been randomized, a potassium level that is above 
the lower limit of normal for the chosen laboratory should be documented if on study drug. 
 
Subjects who meet enrollment criteria will be randomized to indacaterol/glycopyrrolate versus placebo at this 
visit.  If at this visit the subject is determined to be taking a prohibited COPD medication from Table 4.3-2, the 
patient may still be enrolled after a 30 day wash-out at which point the subject would be brought back for a 
Visit 1 (follow Schedule of Events for Washout Subjects).  At this visit, every patient will be encouraged to 
increase physical activity during the study period. 
 
Subjects who do not meet enrollment criteria at Visit 1 may be brought back to repeat Visit 1 for potential 
enrollment.  Rationale to rescreen includes factors that may be subject to change over time (e.g. BMI drops or 
a prohibited medication has been discontinued for clinical reasons).  In such cases, all Visit 1 procedures will 
be repeated. 
7.3 Washout visit (washout subjects only, Visit 0) 
Subjects taking medications in Table 4.3-2 will require medication washout prior to enrollment.  For these 
subjects, see 7.9 for schedule of events for participants requiring wash-out.  For these subjects, an additional 
on-site washout visit will be performed.  Note during this visit a shortened, post-bronchodilator only spirometry 
will be performed.  The subsequent medication washout period is 30 days.  A phone call performed one week 
prior to enrollment (Visit 1) will be performed to determine if subject tolerated the wash-out.  Subjects who 
tolerate wash-out may proceed to enrollment.  See 7.9 for schedule of events for the enrollment visit for 
washout subjects. 
 
Assessments conducted during this visit will include: 
• 
Inclusion/exclusion criteria assessment 
• 
Demographics information including date of birth, sex, race and ethnicity, height, weight 
• 
Relevant medical history including smoking status and history, documented history of respiratory 
infection treated in the past 30 days with antibiotics or steroids and asthma diagnosis (see exclusion 
criteria). 
• 
Current concomitant medications (See Note).   
• 
Current and prior COPD medication history used in the 12 months prior to Visit 
• 
Physical Exam and vital signs 
• 
Completion of CAT 
• 
FEV1 and FVC 15 mins after 4 puffs of albuterol 
 
7.4 Phone Call (washout subjects only, Week 3) 
• 
Current concomitant medications (See Note).   
• 
Interim medical history including need for antibiotics and/or steroids for a respiratory event including 
review of smoking status. 
 


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7.5 Screening/Enrollment (washout subjects only, Visit 1) 
 
Assessments conducted during this visit will include: 
• 
inclusion/exclusion criteria assessment 
• 
FEV1, FVC, SVC and IC before and 15 mins after 4 puffs of albuterol  
• 
Pregnancy test is required for females of child bearing potential prior to randomization. 
• 
Distribution of diary cards and study drug. 
• 
Interim medical history including need for antibiotics and/or steroids for a respiratory event including 
review of smoking status. 
• 
Physical Exam and vital signs 
• 
Completion of questionnaires including SGRQ, CAT and BDI 
• 
Review of concomitant medications (See Note). 
 
NOTE:  If participant is on a non-potassium sparing diuretic (unless administered as a fixed-dose combination, 
i.e. all in one pill/tablet with a potassium conserving drug, or has adequate documentation of concomitant use 
of a potassium conserving drug), we require them to have a serum potassium level check either at the 
enrollment visit or at a separate screening visit and to exclude them if they have a potassium level that is below 
the lower limit of normal for that laboratory. The serum potassium level must be available and reviewed before 
randomization.  If the level is checked and is above the lower limit of normal for the chosen laboratory, the 
subject may be enrolled into the study.  If it is desired that a patient initiate a non-potassium sparing diuretic 
(not as part of fixed-dose combination) after the subject has been randomized, a potassium level that is above 
the lower limit of normal for the chosen laboratory should be documented if on study drug. 
 
Washout subjects who do not meet enrollment criteria at Visit 1 may be rescreened if their primary care 
physician allows them to maintain the washout. In such instances, washout subjects would be brought back to 
repeat Visit 1.  Rationale to rescreen includes factors that may be subject to change over time (e.g. BMI drops 
or a prohibited medication has been discontinued for clinical reasons).  In such cases, all Visit 1 procedures 
will be repeated. 
7.6 Phone Call (all subjects, Week 4) 
Subjects will be contacted by phone at 4 weeks after enrollment (Phone call).  Assessments conducted during 
this visit include: 
• 
Interim medical history including need for antibiotics and/or steroids for a respiratory event including 
review of smoking status. 
• 
Concomitant medications (See Note). 
• 
Assessment of medication side effects 
• 
Evaluate for interim acute exacerbation 
 
7.7 End of Study  (all subjects, Visit 2) 
Subjects will be brought in to the clinical center for their second study visit at week 12  Assessments conducted 
during this visit will include: 
• 
Concomitant medications. 
• 
Interim medical history including need for antibiotics and/or steroids for a respiratory event and review 
of smoking status. 
• 
Current and prior COPD medication history used in the 12 weeks since Visit 1 


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• 
Physical Exam and vital signs 
• 
Completion of questionnaires including SGRQ, CAT and TDI 
• 
FEV1, FVC, SVC and IC before administration of study drug and FEV1 and FVC every hour after 
administration of study drug for a total of three hours (i.e. a trough and an AUC0-3 measurement).  
• 
Evaluate for interim acute exacerbation 
• 
Indacaterol/glycopyrrolate capsule counts 
• 
Collection of diary cards 
• 
 
7.8 Schedule of Events for Participants Requiring No Medication Washout 
 
Pre-Screen 
Phone Visit 
Screen/ 
Enrollment 
Visit 1 
Phone  
Call 
 
End of 
Study3  
Visit 2 
Study Week 
≤ - 4 
0 
4 
12 
Study Day 
-30 to -1 
0 
28 
84 
Window (in days) 
 
0 
±7 
±7 
Informed consent  
 
X 
 
 
Review of inclusion and exclusion criteria 
X 
X 
 
 
Demographics 
 
X 
 
 
Baseline Medical history 
 
X 
 
 
Smoking history/status 
X 
X 
X 
X 
Physical exam including HR and BP 
 
X 
 
X 
FEV1, FVC, SVC and IC before and 15 mins 
after 4 puffs of albuterol 
 
X 
 
 
FEV1, FVC, SVC and IC before administration 
of study drug and FEV1 and FVC every hour 
after administration of study drug for a total of 
three hours (i.e. a trough and an AUC0-3 
measurement). 
 
 
 
X 
Research Labs - Pregnancy test1, Potassium 
Level Check4 
 
X 
 
 
CAT 
X 
X 
 
X 
SGRQ 
 
X 
 
X 
BDI/TDI 2 
 
X 
 
X 
Review interim medical history 
 
 
X 
X 
Review concomitant meds 
X 
X 
X 
X 
Distribution of daily diary 
 
X 
 
 
Collection of daily diary 
 
 
 
X 
Drug distribution 
 
X 
 
 


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7.9 Schedule of Events for Participants Requiring Washout 
Smoking cessation education 
 
X5 
 
 
Capsule counts 
 
 
 
X 
1. 
Females of childbearing potential are required to have a negative pregnancy test prior to randomization. 
2. 
BDI done at Screening /Enrollment visit, TDI done at Visit 2. 
3. 
Should a subject terminate early, the subject will be brought in to complete all assessments included at the Week 12 End of Study visit.   
4. 
Serum potassium level check either at the enrollment visit or at a separate screening visit.  The serum potassium level must be available and 
reviewed before randomization. 
5. 
Current smokers only 
 
Pre-
Screen 
Phone 
Call 
On-Site 
Wash-
out 
Visit 0 
Phone  
Call  
Screen/ 
Enroll-
ment 
Visit 1 
Phone  
Call 
 
End of 
Study3 
Visit 2 
Study Week 
-8 to -4 
 
≤ -1 
0 
4 
12 
Study Day 
-60 to -31 
-30 or 
more 
-7 to -1 
0 
28 
84 
Window (in days) 
 
 
 
 
±7 
±7 
Informed consent  
 
X 
 
  
 
 
Review of inclusion and exclusion criteria 
X 
X 
 
X 
 
 
Demographics 
 
X 
 
 
 
 
Baseline Medical history 
 
X 
 
 
 
 
Smoking history/status 
X 
X 
 
X 
X 
X 
Physical exam including HR and BP 
 
X 
 
X 
 
X 
FEV1 and FVC 15 mins after 4 puffs of albuterol 
 
X 
 
 
 
 
FEV1, FVC, SVC and IC before and 15 mins after 4 
puffs of albuterol 
 
 
 
X 
 
 
FEV1, FVC, SVC and IC before administration of 
study drug and FEV1 and FVC every hour after 
administration of study drug for a total of three hours 
(i.e. a trough and an AUC0-3 measurement). 
 
 
 
 
 
X 
Research Labs - Pregnancy test1,  
Potassium Level Check4 
 
 
 
X 
 
 
CAT 
X 
X 
 
X 
 
X 
SGRQ 
 
 
 
X 
 
X 
BDI/TD2 
 
 
 
X 
 
X 
Review interim medical history 
 
 
X 
X 
X 
X 
Review concomitant meds 
X 
X 
X 
X 
X 
X 


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7.10 Unscheduled Visits 
If disease activity increases or other concerns arise between regularly scheduled visits, participants should be 
instructed to contact study personnel and may be asked to return to the study site for an “unscheduled” visit. 
For individuals who are considered a “treatment failure” defined by increase in lower respiratory symptoms 
necessitating treatment with active, long-acting inhaled bronchodilator, inhaled or oral corticosteroids, or 
antibiotics, every effort will be made to bring the individual back for a study visit at the time of treatment failure 
to assess safety and for a final study visit as close to 12 weeks as possible.  
7.11 Visit Windows 
Study visits should take place within +/- 7 days of the schedule outlined in the schedule of events. If an acute 
exacerbation of COPD delays visit 2, then this visit may occur after clinical stabilization and beyond 7 days.  If 
the delay causes subject to run out of study medication, contact the DCC for further instructions. 
7.12 Discontinuation of study treatments 
Patients may voluntarily withdraw from the study for any reason at any time. They may be considered 
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to follow-up for any other 
reason.  If premature withdrawal occurs for any reason, the investigator must make every effort to determine 
the primary reason for a patient’s premature withdrawal from the study and record this information on the Study 
Completion eCRF.  Patients who discontinue study drug before completing the study, and those who 
prematurely withdraw from the study for any reason, an attempt should be made to schedule the subjects for a 
final visit as close to 12 weeks as possible. 
Study treatment must be discontinued and the patient withdrawn from the trial under the following 
circumstances: 
a.  Withdrawal of informed consent 
b.  Pregnancy 
c.  Any other protocol deviation that results in a significant risk to the patient’s safety 
d.  For patients who are lost to follow-up (i.e. those patients whose status is unclear because they fail to 
appear for study visits without stating an intention to withdraw), the investigator should show "due 
diligence" by documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. 
e. Patients who are prematurely withdrawn from the study will not be replaced by an equal number of 
newly enrolled patients. 
Distribution of daily diary 
 
 
 
X 
 
 
Collection of daily diary 
 
 
 
 
 
X 
Drug distribution 
 
 
 
X 
 
 
Smoking cessation education 
 
X5 
 
 
 
 
Capsule counts 
 
 
 
 
 
X 
1. 
Females of childbearing potential are required to have a negative pregnancy test prior to randomization. 
2. 
BDI done at Screening/ Enrollment visit, TDI done at Visit 2. 
3. 
Should a subject terminate early, the subject will be brought in to complete all assessments included at the Week 12 End of Study visit.   
4. 
Serum potassium level check either at the enrollment visit or at a separate screening visit.  The serum potassium level must be available and reviewed 
before randomization. 
5. 
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f. Discretion of the site primary investigator. 
7.13 Special Consideration(s) for Treatment Failure Subjects  
Treatment failure is defined as an increase in lower respiratory symptoms necessitating treatment with long 
acting bronchodilator, corticosteroids or antibiotics. 
If any new inhaled respiratory medication (other than Albuterol), antibiotic, or oral steroid was started for lower 
respiratory symptoms (NOT sinusitis), patient has met treatment failure endpoint. The subject should be 
encouraged to remain in the study and on study drug, unless started on an open label long-acting 
bronchodilator.  For treatment failure subjects where study medication is discontinued, the full End of Study 
Spirometry 0-3 AUC should NOT be performed.  Rather only one pre-BD FEV1, FVC, SVC and IC should be 
performed. 
ALL subjects who experience treatment failure should continue with the study through to completion. Subjects 
who require treatment with a prohibited COPD medication (Table 4.3-2) shall discontinue study drug and NOT 
re-start study drug.   
Subjects who meet treatment failure AND who discontinue drug will perform a modified pulmonary function 
assessment at the end of study visit (Week 12).  Refer to the study Manual of Operations for further details.  
7.13.1 Special Consideration(s) for subjects who start a prohibited medication (Table 4.3-1) 
Subjects who begin treatment with a prohibited medication (Table 4.3-1) shall discontinue study drug and NOT 
re-start study drug.  These subjects will perform a modified pulmonary function assessment at the end of study 
visit (Week 12).  Refer to the study Manual of Operations for further details. 
7.13.2 Special Consideration(s) for subjects who experience an AE/SAE requiring study drug 
interruption 
Subjects that have stopped taking study drug due to an adverse event may re-start taking study drug after 
recovery. In all instances the timing of re-starting study drug is left to the discretion of the site Primary 
Investigator. 
  
Note that adverse events requiring treatment with a COPD-prohibited medication (4.3.2) meet the definition for 
treatment failure.  These individuals shall not restart study drug.  
 
Additionally, these subjects will perform a modified pulmonary function assessment at the end of study visit 
(Week 12).  Refer to the study Manual of Operations for further details. 
8. Safety Monitoring and Reporting 
8.1 Overview 
This section defines the types of safety data that will be collected under this protocol and outlines the 
procedures for appropriately collecting, grading, recording, and reporting those data. Adverse events that are 
classified as serious according to the definition of health authorities must be reported promptly (per Section 
12.5, Reporting of Serious Adverse Events and Adverse Events).  Appropriate notifications will also be made to 
site principal investigators, Institutional Review Boards (IRBs) and DCC. Information in this section complies 
with ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
ICH Guideline E-6: Guideline for Good Clinical Practice, 21CFR Parts 312 and 320, and applies the standards 
set forth in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE) : 
http://ctep.cancer.gov/reporting/ctc.html. 
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8.2.1 Adverse Event (AE) 
Any untoward or unfavorable medical occurrence associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research (modified from the definition of 
adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical 
Practice) (from OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to 
Subjects or Others and Adverse Events (1/15/07)" http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2 )  
For this study, an adverse event will include any untoward or unfavorable medical occurrence associated with:   
• 
Study therapy regimen: Occurring within one week of use of indacaterol/glycopyrrolate. 
• 
Study mandated procedures: Any event occurring within one day of a mandated study procedure will be 
considered a possible adverse event of these procedures and will be evaluated further for any relationship. 
These procedures include spirometry. 
For the procedures below, clinical situations are listed that are considered to be outside the normal range of 
outcomes and will be recorded as Adverse Events.  These situations do not limit an investigator from recording 
and reporting any other events, associated or not with these procedures as AEs. 
Pulmonary Function Testing  
• Wheezing, shortness of breath or chest tightness requiring treatment with bronchodilators within 30 
minutes from the procedure 
• Coughing requiring treatment with bronchodilators within 30 minutes from the procedure 
 
8.2.1.1 Suspected Adverse Reaction (SAR)  
Any adverse event for which there is a reasonable possibility that the investigational drug caused the adverse 
event. For the purposes of safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug 
(21 CFR 312.32(a)). 
8.2.2 Unexpected Adverse Event  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the package 
insert or is not listed at the specificity, severity or rate of occurrence that has been observed; or is not 
consistent with the risk information described in the protocol. 
8.2.3 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of the investigator it 
results in any of the following outcomes (21 CFR 312.32(a)): 
1. Results in death;  
2. Is life-threatening  i.e. places a participant at immediate risk of death from the event as it occurred;  
3. Requires inpatient hospitalization or prolongation of existing hospitalization;  
4. Results in a persistent or significant disability/incapacity;  
5. Results in a congenital anomaly/birth defect; OR  
6. Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
participant’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition (e.g. allergic bronchospasm requiring intensive treatment in the 
emergency room or at home).  
 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol mandated procedures 
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8.3 Grading and Attribution of Adverse Events 
8.3.1 Grading Criteria 
The study site will grade the severity of adverse events experienced by the study participants according 
to the criteria set forth in the National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (CTCAE, Version 4.0) This document (referred to herein as the NCI-CTCAE manual) provides a 
common language to describe levels of severity, to analyze and interpret data, and to articulate the 
clinical significance of all adverse events. The NCI-CTCAE has been reviewed by the Protocol Chairs 
and has been deemed appropriate for the subject population to be studied in this protocol. 
Grade 1 = mild adverse event. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 
Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
 
Events of grade 2 or higher will be recorded on the appropriate electronic AE case report form for this 
study. If a specific event or result from a given clinical evaluation is not included in the NCI-CTCAE 
manual, then an abnormal result would be considered an adverse event if changes in therapy or 
monitoring are implemented as a result of the event/result. 
8.3.2 Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study procedure(s) 
will initially be determined by the site investigator and recorded on the appropriate AE eCRF.  The 
relationship of an adverse event to study therapy regimen or procedures will be determined using the 
descriptors and definitions provided in Table 8.3.2.  
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE 
web site: http://ctep.cancer.gov/reporting/ctc.html. 
Table 8.3.2 Attribution of Adverse Events 
Code 
Descriptor 
Relationship (to primary investigational 
product and/or other concurrent mandated 
study therapy or study procedure) 
 RELATED CATEGORIES 
1 
Definitely 
The adverse event is clearly related. 
2 
Probably 
There is evidence to suggest a probable causal 
relationship. 
3 
Possibly 
The adverse event has a reasonable possibility to 
be related; there is evidence to suggest a causal 
relationship. 
UNRELATED CATEGORY 
4 
Not related 
The adverse event is clearly not related. 
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Adverse events will be collected from the time of consent until a subject completes study participation or until 
30 days after he/she prematurely withdraws (without withdrawing consent) or is withdrawn from the study. 
8.4.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the subject. 
• 
Interviewing the subject [e.g., using a checklist, structured questioning, diary, etc.]  . 
• 
Receiving an unsolicited complaint from the subject. 
• 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an 
adverse event, as defined in Section 8.3, Grading and Attribution of Adverse Events. 
8.4.3 Recording Adverse Events 
Throughout the study, the investigator will record adverse events and serious adverse events as described 
previously (Section 8.2, Definitions) on the appropriate eCRF regardless of the relationship to study therapy 
regimen or study procedure. 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the end of study 
participation, or until 30 days after the subject prematurely withdraws (without withdrawing consent)/or is 
withdrawn from the study, whichever occurs first. 
8.5 Reporting of Serious Adverse Events and Adverse Events 
8.5.1 Reporting of Serious Adverse Events  
Each adverse event is to be classified by the investigator as serious (see Section 8.2.3, Serious Adverse 
Event) or non-serious.  This classification determines the reporting procedures to be followed.  If a serious 
adverse event occurs, expedited reporting to local regulatory bodies will follow local regulations as appropriate. 
The site investigator will report to protocol chairs and the DCC all serious adverse events (see Section 8.2.3, 
Serious Adverse Event), regardless of relationship to study drug or expectedness within 24 hours of 
discovering the event.    
SAEs are reportable from the time that the subject provides informed consent, which is obtained prior to the 
subject’s participation in the clinical trial, i.e., prior to undergoing any trial-related procedure and/or receiving 
investigational product, until a subject completes study participation or until he/she prematurely withdraws or is 
withdrawn from the study.    
 
For serious adverse events, all requested information on the AE/SAE eCRF should be provided. In particular, if 
the serious adverse event is fatal or life-threatening, notification to the DCC must occur immediately.  This 
timeframe also applies to additional new information (follow-up) on previously forwarded serious adverse event 
reports. In the event that the investigator does not become aware of the occurrence of a serious adverse event 
immediately (e.g., if an outpatient trial subject initially seeks treatment elsewhere), the investigator is to report 
the event within 24 hours after learning of it and document the time of his/her first awareness of the adverse 
event.  As additional details become available, the AE/SAE eCRF will be updated and submitted. When an 
SAE report is sent it will include the PIs assessment of the adverse event and assignment of a relationship to 
any specific aspect of the study.  In addition, an investigator may be requested to obtain specific additional 
follow-up information in an expedited fashion.  This information may be more detailed than that captured on the 
adverse event case report form.  In general, this will include a description of the adverse event in sufficient 
detail to allow for a complete medical assessment of the case and independent determination of possible 
causality.  Information on other possible causes of the event, such as concomitant medications and illnesses 
must be provided.  In the case of a subject death, a summary of available autopsy findings must be submitted 
as soon as possible to the DCC or its designated representative. The investigator’s assessment of causality 
must be provided.  An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an adverse event.  If the 


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investigator's causality assessment is "unknown but not related to study drug", this should be clearly 
documented on study records.  In addition, if the investigator determines the adverse event is associated with 
trial procedures, the investigator must record this causal relationship in the source documents and eCRF, as 
appropriate.  
8.5.2 Reporting to Health Authority 
After an adverse event requiring 24 hour reporting (per Section 8.5.1, Reporting of Serious Adverse Events), 
the event will be submitted by the site investigator and assessed by protocol chairs and the DCC per local 
regulations.  Although this protocol was submitted to the FDA and received an IND exemption, MedWatch 
forms will be completed for applicable Serious Adverse Events and forwarded to Sunovion Pharmaceuticals 
(global oversight for the study) for further reporting to the FDA.  
8.5.2.1 Annual Reporting 
The investigator will include in the annual study report to local regulatory authorities all adverse events 
classified as: 
• 
Serious and unexpected suspected adverse reaction (see Section 8.2.1.1, Suspected Adverse 
Reaction, and Section 8.2.2, Unexpected Adverse Event). 
• 
Serious adverse reaction  that is not suspected to be related to the treatment (see Section 8.2.2, 
Suspected Adverse Reaction). 
Pregnancies are not reported as serious adverse events.  
The DCC will receive a copy of the annual study report submitted by the investigator to the local regulatory 
authorities. The investigator shall also summarize safety data at the end of the study and periodically 
throughout the study for the DSMB. These reports may include (but are not limited to) masked summaries and 
listings of AEs, SAEs, events requiring discontinuation of a study-mandated procedure for individual subjects 
and protocol deviations. All adverse events (not just those requiring 24-hour reporting) will be reported by the 
protocol chairs and the DCC to the DSMB. 
8.5.2.2 Expedited Safety Reporting  
Serious and unexpected suspected adverse reaction [SUSAR] (see Section 8.2.1.1, Suspected Adverse 
Reaction and Section 8.2, Unexpected Adverse Event and 21 CFR 312.32(c)(1)i).  
The investigator shall report any suspected adverse reaction that is both serious and unexpected.  The 
investigator shall report an adverse event as a suspected adverse reaction only if there is evidence to suggest 
a causal relationship between the study drug and the adverse event, such as: 
1. A single occurrence of an event that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, or Stevens-Johnson Syndrome); 
2. One or more occurrences of an event that is not commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
3. An aggregate analysis of specific events observed in a clinical trial (such as known consequences of 
the underlying disease or condition under investigation or other events that commonly occur in the 
study population independent of drug therapy) that indicates those events occur more frequently in the 
drug treatment group than in a concurrent or historical control group. 
 
SAEs that are unexpected will be reported to the DSMB by the protocol chairs and the DCC within 15 calendar 
days of their notification of the event.  If a death or life-threatening event occurs that is believed by the site 
investigator to be study drug related, notification to the DSMB by the protocol chairs and the DCC will occur 


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within 7 calendar days after their initial notification of the event. Copies of the Expedited Safety Report will also 
be provided to the site investigators. 
8.5.3 Reporting of Adverse Events to IRBs/IECs 
The investigator shall report adverse events, including expedited reports, in a timely fashion to their respective 
IRBs/IECs in accordance with applicable local regulations and guidelines. 
8.6 Reporting of Other Safety Information 
An investigator shall promptly notify the site IRB as well as the DCC when an “unanticipated problem involving 
risks to participants or others” is identified, which is not otherwise reportable as an adverse event. 
8.7 Review of Safety Information 
8.7.1 DCC Adverse Event Review 
The DCC shall receive annual reports from the protocol investigator compiling new and accumulating 
information on AEs, SAEs, and pregnancies recorded by the study site on appropriate eCRFs.  The Protocol 
Chairs will also review SAE and pregnancy reports in real time. 
8.7.2 DSMB Review  
8.7.2.1 Planned DSMB Reviews  
The Data and Safety Monitoring Board (DSMB) shall review safety data at least yearly during planned DSMB 
Data Review Meetings. Data for the planned safety reviews will include, at a minimum, a listing of all reported 
AEs and SAEs.  The DSMB will be informed of any Expedited Safety Reports in a timely manner.  Reports will 
be prepared by the DCC and will be sent to the DSMB for their regular scheduled meetings. Tables showing 
study progress will be presented by clinical center and overall. These will minimally include recruitment, 
protocol deviations, adherence, attrition, adverse events, data quality, descriptive characteristics of the study 
sample, and efficacy.  All AEs will be reported as described above.  
8.7.2.2 Ad hoc DSMB Reviews  
In addition to the pre-scheduled data reviews and planned safety monitoring that will be coordinated by the 
DCC, the DSMB may be called upon for ad hoc reviews. The DSMB will review any event that potentially 
impacts safety at the request of the Protocol Chairs or the DCC.  In addition, the following events will trigger an 
ad hoc comprehensive DSMB Safety Review:  
• 
Any death that occurs in the study, which is possibly or definitely related to study treatment regimen. 
• 
The occurrence of a Grade 3 or higher related and unexpected SAE in any study participants who have 
received a study treatment. 
After review of the data, the SMC will make recommendations regarding study conduct and/or continuation. 
8.7.2.2.1 Temporary Suspension of enrollment for ad hoc DSMB Safety Review  
A temporary halt in enrollment will be implemented if an ad hoc DSMB safety review is required. No new 
participants will be enrolled until the DSMB has met and discussed the eCRFs. 
9. Statistical Considerations and Analytical Plan 
9.1 Overview  
The scientific objective of this study is to determine whether the combination of long-acting beta agonist, 
indacaterol, and the long-acting muscarinic antagonist, glycopyrrolate, provides symptom relief and improves 


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clinical status in symptomatic smokers with post-BD FEV1/FVC≥0.70, a group of patients that has not 
previously been objectively evaluated in a placebo-controlled trial.  The study design is a two-visit study of 580, 
symptomatic current or former smokers who will be randomized in a double-blind, placebo-controlled fashion to 
indacaterol/glycopyrrolate versus placebo.  “Symptomatic” for the purposes of this study will be defined as CAT 
score≥10.  During the first visit, baseline SGRQ score will be established and the subject assigned to drug 
versus placebo.  SGRQ score will be reassessed at the second in-person visit. Treatment failure during the 
study period will be defined by increase in lower respiratory symptoms necessitating treatment with active, 
long-acting inhaled bronchodilator, inhaled or oral corticosteroids, or antibiotics. 
9.2 Endpoints/Outcomes 
The primary scientific endpoint of this study is the proportion of subjects who experience a four point drop in 
SGRQ in the treatment versus placebo groups and do not meet criteria for treatment failure during the 12 week 
treatment period. The rationale for this composite definition of “success” with respect to the primary outcome is 
that differential treatment failure in the two arms could bias the observed change in SGRQ at 12 weeks if 
subjects who are randomized to placebo fail inordinately and are more likely to receive a long-acting 
bronchodilator or corticosteroid and cease study medication during the 12 week treatment period. In other 
words, we will not consider participants who have treatment failure during the study as eligible for “success” at 
the end of the study. Instead, they will be considered a “failure” with respect to the primary outcome regardless 
of their SGRQ score at 12 weeks. This will also allow us to avoid a major source of non-ignorable missing data 
due to “drop outs” and lack of data on SGRQ score at 12 weeks. If those drop outs occurred because of 
treatment failure, then they will still add to our primary outcome because they will meet criteria for “failure”.  
Key Secondary endpoints include: 
a. Proportion of subjects in the treatment versus placebo groups who experience a two point improvement 
in CAT score without treatment failure. 
b. Proportion of subjects in the treatment versus placebo groups who experience a one unit improvement 
in BDI/TDI score without treatment failure. 
c. Mean change in SGRQ 
d. Mean change in CAT 
e. Mean change in BDI/TDI 
f. AUC0-3h for FEV1 
g. Mean 12-week change in trough FEV1 between treatment and placebo groups (absolute and % 
predicted). 
h. Mean 12-week change in trough Inspiratory Capacity, FEF25-75% and iso-volume FEF25-75%between 
treatment and placebo groups (absolute and % predicted). 
i. 
Mean change in symptoms and rescue medication use based on daily diary. 
j. 
Treatment failure defined by increase in respiratory symptoms necessitating treatment with active, long-
acting inhaled bronchodilator and/or corticosteroid (inhaled or oral). 
 
9.3 
Measures to Minimize Bias  
A stratified, randomized block procedure will be used where strata are defined by clinical center, smoking 
status and history of prior treatment with COPD maintenance medication. 
9.4 
Analysis Plan 
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9.4.1.1 Safety Population 
The Safety Population is defined as all subjects who have consented to participate.  The Safety Population will 
be used for all safety analyses.  Subjects will be analyzed by treatment received.  If subjects inadvertently 
receive both active drug and placebo, they will be included in the indacaterol/glycopyrrolate group. 
9.4.1.2 Efficacy Populations 
The primary outcome will be based on intention-to-treat population for the SGRQ measurement which will be 
supplemented by blinded assessment of treatment failure in a composite endpoint. For individuals who do not 
complete 12 weeks of treatment, every effort will be made to bring them back at 12 weeks for SGRQ and other 
symptom and physiologic assessments.  For those who drop out of the study and decline any further visits, we 
will compare baseline values to those who complete the 12 week assessments and note any differences that 
could impact the analysis.  
9.4.1.3 Effect of drop outs on the Efficacy population 
Our composite primary endpoint definition will allow us to avoid a major source of missing data due to “drop 
outs” and lack of data on SGRQ score at 12 weeks. If those drop outs occurred because of treatment failure 
(which may be disease-related and intervention-related), then they will still be “informative” in that they add to 
our primary outcome because they will meet criteria for “treatment failure”. There will remain some drop outs 
that are “non-informative” because they are due to factors other than treatment failure. This number should be 
small given our relatively short study and should be due to random causes that are unrelated to the disease or 
the intervention. Subjects with non-informative missing measures at 12 weeks will not be included in the 
analysis.  
9.4.2 Primary Analysis of Primary Endpoint(s)/Outcome(s)   
The primary analysis will be conducted via GEE regression with logit link to compare the proportion of subjects 
who experience improvement with treatment defined as a four point drop in SGRQ and absence of treatment 
failure in the treatment versus placebo groups, adjusted for clinical center of recruitment, change of smoking 
status between baseline and 12 weeks, prior maintenance treatment for COPD requiring washout, and BMI at 
baseline.   No formal statistical analysis for efficacy will be conducted until the end of the study given the 
interest in obtaining follow-up for multiple endpoints of interest. Change of Smoking status will be modeled as a 
categorical variable with four categories reflecting the four potential types of changes patients might 
experience (persistent smoker, persistent former smoker, smoker quit smoking during the trial, former smoker 
restarts smoking during the trial). Baseline BMI will be included as a continuous variable.  
 
Denote ∆ SGRQij be the change of SGRG between baseline and 12 weeks for subject j (j=1,2,3,..ni) from site I 
(i=1, 2,3…, m).   
 
If ∆ SGRQij ≥4 and no trt failure, let Yij=1, otherwise Yij=0. The model we will use is as the following: 
 
logit{Pr(Yij=1)}= β1+β2Treatmentij+β3Change of Smoking Statusij+β4Washoutij+β5BMIij 
Within site association among the response will be modeled by exchangeable correlation structure.  
 
9.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s)  
To address the potential heterogeneity our study population, additional planned supportive analyses will be to 
examine the primary endpoint in specific subgroups based on smoking status (current smoker yes/no), long-
term respiratory medication use prior to entering the study requiring washout and baseline bronchodilator 


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responsiveness and BMI (males with BMI >30kg/m2, males with BMI ≤30kg/m2, females with BMI >30kg/m2, 
females with BMI ≤30kg/m2).  Additional exploratory subgroup analyses will also include gender (male/female), 
age (<65 years/≥65 years), baseline FEV1% predicted baseline IC (< median for all randomized subjects / ≥ 
median for all randomized subjects), presence of chronic bronchitis, Interactions between these covariates and 
treatment will be tested to study whether treatment effect on primary outcome differs between corresponding 
subgroups. If interaction term is found to be significant, additional analysis will be done to study treatment 
effect within each subgroups.  Each covariate will be tested one at a time.  
9.4.4 Analyses of Secondary and Other Endpoint(s)/Outcome(s) 
As outlined for analysis of the primary endpoint, a similar GEE regression will be conducted to compare the 
proportion of subjects who experience a 2 point drop in CAT without treatment failure, a 1 point drop in TDI 
without treatment failure and treatment failure alone in the treatment versus placebo groups adjusted for 
clinical center and smoking status. For analysis of continuous measures including 12-week change in trough 
FEV1, trough Inspiratory Capacity, FEF25-75% and iso-volume FEF25-75% and AUC0-3h, analysis will be 
conducted with linear mixed models to adjust for center effect. No adjustment for multiplicity will be made.   
9.4.5 Additional Analyses 
Regression models with multivariable will also be used to adjust the secondary endpoints for baseline 
covariates of interest including age, gender, smoking status, 12-hour trough FEV1%, 12-hour trough IC, 
bronchodilator responsiveness, BMI and history of long-term respiratory medication use.   
9.5 
Interim Analyses  
9.5.1 Interim Analysis of Efficacy Data 
None 
9.5.2  Interim Analysis of Safety Data 
 
Safety Analyses 
Safety analyses will be performed on the Safety Population biannually or when 100 patients have completed 
12 weeks of follow-up, whichever is sooner.   
Safety Assessments 
The following assessments will be used to monitor safety: 
• 
Adverse events (AEs) and serious adverse events (SAEs) 
• 
Changes in FEV1 between baseline and twelve weeks for all randomized study subjects. 
 
Planned Method of Analysis 
Safety data will be summarized descriptively overall and separately for the active treatment group, placebo 
group, and consented but not randomized subjects. Individual subject listings will be prepared for all safety 
data. 
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Frequencies (number and percentage) of subjects with one or more treatment emergent AEs will be 
summarized by treatment group, by system organ class and preferred term according to the Medical Dictionary 
for Regulatory Activities (MedDRA™) terminology.  All treatment emergent AEs, all treatment emergent AEs 
potentially related to study drug, all treatment emergent SAEs and all treatment emergent SAEs potentially 
related to study drug will be summarized.  Specific AEs of special interest, particularly respiratory system 
related AEs, will be outlined in the SAP and summarized.   
The incidence of AEs, and their severity, as well as the incidence of subjects who withdraw due to an AE will 
be tabulated.  A subject listing of all treatment emergent AEs, and AEs causing study discontinuation will be 
presented.  
Changes in FEV1 
Summary statistics (mean, standard deviation, minimum, and maximum) in changes in FEV1 will be tabulated 
for the overall randomized population and by treatment group (labeled as ‘A’ and ‘B’).  
9.6 Statistical Hypotheses  
The superiority of indacaterol/glycopyrrolate over placebo will be evaluated by testing the following 
null hypothesis (Ho) versus the alternative hypothesis (Ha): 
 
Ho: There is no difference in the proportion of individuals with a 4 point drop in SGRQ after 12 weeks of 
treatment for patients with symptomatic, smokers with post-BD FEV1/FVC ≥0.70 treated with 
indacaterol/glycopyrrolate compared to placebo. 
 
Ha: There is a difference in in the proportion of individuals with a 4 point drop in SGRQ after 12 weeks of 
treatment for patients with symptomatic, smokers with post-BD FEV1/FVC ≥0.70 treated with 
indacaterol/glycopyrrolate compared to placebo. 
9.7 Sample Size Considerations  
Sample size estimations were performed using preliminary data from the Novartis FDA development program 
studies. At week 12, using Flight 1 where the effect on SGRQ was slightly smaller than Flight 2, 57% of 
subjects taking indacaterol/glycopyrrolate vs 39% of subjects taking placebo had a ≥4 unit decrease in SGRQ.  
Using these data we estimate (with a two-sample test of proportions) that 290 subjects per arm would provide 
90% power with the following assumptions:  (1) a type I error rate of .05; (2) 10% loss to follow-up and (3) 
approximately 20% lower effect size given the Flight studies were based on a more severe patient population. 
Our primary analysis will define “response” as both a ≥4 unit decrease in SGRQ and an absence of treatment 
failure during the 12 week treatment period. This additional requirement is designed to protect against bias 
towards the null that would occur if subjects randomized to placebo have a greater number of treatment 
failures and thus a greater number of subjects who are switched to active drug during the study.  We do not 
have data available on the effect size of bronchodilators in the GOLD 0 population or the specific effect that our 
composite outcome (including the treatment failure definition) will have.  However we believe that a sample 
size estimate using this approach should provide a realistic estimate of power given that we are assuming a 
lower effect size and protecting against bias towards the null result.  
10. Identification and Access to Source Data 
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Source documents and source data are considered to be the original documentation where subject 
information, visits consultations, examinations and other information are recorded.   Documentation of source 
data is necessary for the reconstruction, evaluation and validation of clinical findings, observations and other 
activities during a clinical trial.  
10.2 
Access to Source Data 
The site investigators and site staff will make all source data available to the DCC as well as to relevant health 
authorities.  Authorized representatives as noted above are bound to maintain the strict confidentiality of 
medical and research information that may be linked to identified individuals. 
11. Protocol Deviations 
11.1 
Protocol Deviation Definitions 
 
Protocol Deviation – The investigators and site staff will conduct the study in accordance to the protocol; no 
deviations from the protocol are permitted.  Any change, divergence, or departure from the study design or 
procedures constitutes a protocol deviation.  As a result of any deviation, corrective actions will be developed 
by the site and implemented promptly. 
 
Major Protocol Deviation (Protocol Violation) - A Protocol Violation is a deviation from the IRB approved 
protocol that may affect the subject's rights, safety, or well-being and/or the completeness, accuracy and 
reliability of the study data.  In addition, protocol violations include willful or knowing breaches of human 
subject protection regulations, or policies, any action that is inconsistent with the NIH Human Research 
Protection Program’s research, medical, and ethical principles, and a serious or continuing noncompliance with 
federal, state, local or institutional human subject protection regulations, policies, or procedures.  
 
Non-Major Protocol Deviation - A non-major protocol deviation is any change, divergence, or departure from 
the study design or procedures of a research protocol that does not have a major impact on the subject's 
rights, safety or well-being, or the completeness, accuracy and reliability of the study data. 
11.2 
Reporting and Managing Protocol Deviations 
The study site principal investigator has the responsibility to identify, document and report protocol deviations 
as directed by the study Sponsor.  However, protocol deviations may also be identified during site monitoring 
visits or during other forms of study conduct review. Upon determination that a protocol deviation has occurred, 
the study staff will a) notify the site Principal investigator, b) notify the DCC and the Protocol Chairs, c) will 
complete a Protocol Deviation eCRF, d) and report the deviation to the local regulatory authorities.  The 
Protocol Chairs and the DCC will make the decision as to whether the deviation is major or not and what the 
impact of the deviation on the study participant or the entire study may be.  Protocol Deviations will also be 
reported by the Protocol Chairs and the DCC and DSMB. 
11.3 Ethical Considerations and Compliance with Good Clinical Practice 
11.4 Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for Industry: 
E6 Good Clinical Practice Consolidated Guidance, and according to the criteria specified in this study protocol.  
Before study initiation, the protocol and the informed consent documents will be reviewed and approved by the 
IRB.  Any amendments to the protocol or to the consent materials will also be approved by the IRB before they 
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11.5 Informed Consent Process 
The consent process will provide information about the study to a prospective participant and will allow 
adequate time for review and discussion prior to his/her decision.  The principal investigator or designee listed 
on the Investigator of Record form, will review the consent and answer questions.  The participant will have the 
option to speak to the principal investigator for any questions regarding the study and consent. The prospective 
participant will be told that being in the trial is voluntary and that he or she may withdraw from the study at any 
time, for any reason.  All participants (or their legally acceptable representative) will read, sign, and date a 
consent form before undergoing any study procedures.  Consent materials will be presented in English and a 
copy of the signed consent form will be given to the participant.  The consent form will be revised when 
important new safety information is available, the protocol is amended, and/or new information becomes 
available that may affect participation in the study. 
11.6 Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant will be 
assigned a unique identification number and these numbers rather than names will be used to collect, store, 
and report participant information.  Site personnel will not transmit documents containing personal health 
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References 
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Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, 
Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR, 
Network CCR. Azithromycin for prevention of exacerbations of COPD. The New England journal of 
medicine 2011; 365: 689-698. 
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