Early Intervention Effectiveness of Tiotropium / Olodaterol Compared to Tiotropium in COPD
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
TITLE PAGE
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
c30708153-01
BI Study Number:
1237.100
BI Investigational
Product(s):
Spiolto® Respimat®, Spiriva® Respimat®
Title:
Early intervention effectiveness of tiotropium / olodaterol 
compared to tiotropium in COPD
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
27 Feb 2020
PASS:
No
EU PAS register 
number:
EUPAS33426
Active substance:
Tiotropium and Olodaterol
Tiotropium      
Medicinal product:
Spiolto® Respimat®; Spiriva® Respimat®
Product reference:
N/A
Procedure number:
N/A
Joint PASS:
No
Research question and 
objectives:
To compare the early intervention effectiveness of Tio/Olo vs. 
Tio among COPD patients.
Country(-ies) of study:
Japan
Author:
Email:

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
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001-MCS-90-124_RD-01 (4.0)
Email:
T: 
Email:
 
Email: 
Email: 
 
 contact person: 
  
Email:
  
Email:

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Email:
Marketing authorisation 
holder(s):
N/A
MAH contact person:
N/A
In case of PASS, add:
<EU-QPPV:>
N/A
In case of PASS, add:
<Signature of EU-
QPPV:>
N/A
Date:
27 Feb 2020
Page 1 of 41
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 4
2.
LIST OF ABBREVIATIONS................................................................................ 6
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 18
6.
MILESTONES..................................................................................................... 19
7.
RATIONALE AND BACKGROUND................................................................ 20
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 22
9.
RESEARCH METHODS .................................................................................... 23
9.1
STUDY DESIGN............................................................................................ 23
9.2
SETTING........................................................................................................ 23
9.2.1
Definitions............................................................................................... 23
9.2.2
Study population ..................................................................................... 24
9.3
VARIABLES .................................................................................................. 27
9.3.1
Exposures ................................................................................................ 27
9.3.2
Outcomes................................................................................................. 27
9.3.2.1
Primary outcomes..................................................................................27
9.3.2.2
Secondary outcomes and further endpoints...........................................28
9.3.3
Covariates................................................................................................ 29
9.4
DATA SOURCES........................................................................................... 31
9.5
STUDY SIZE.................................................................................................. 32
9.6
DATA MANAGEMENT................................................................................ 32
9.7
DATA ANALYSIS......................................................................................... 33
9.7.1
Main analysis........................................................................................... 33
9.7.1.1
Descriptive Analysis..............................................................................33
9.7.1.2
Rates and Risks .....................................................................................33
9.7.1.3
Comparative Effectiveness....................................................................33
9.7.2
Subgroup analysis ................................................................................... 34
9.7.3
Sensitivity Analyses ................................................................................ 34
9.8
QUALITY CONTROL................................................................................... 34
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 35
9.10
OTHER ASPECTS ......................................................................................... 36

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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
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001-MCS-90-124_RD-01 (4.0)
9.11
SUBJECTS...................................................................................................... 36
9.11.1
Cases........................................................................................................ 36
9.11.2
Controls................................................................................................... 36
9.12
BIAS................................................................................................................ 36
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 38
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 38
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 38
13.
REFERENCES .................................................................................................... 39
13.1
PUBLISHED REFERENCES......................................................................... 39
13.2
UNPUBLISHED REFERENCES................................................................... 41

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
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Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
2.
LIST OF ABBREVIATIONS
AMI
Acute Myocardial Infarction
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
DPC
Diagnosis Procedure Combination
ENCEP
P
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
FDC
Fixed Dose Combination
GERD
Gastroesophageal Reflux Disease
GOLD
Global Initiative for Chronic Obstructive Lung Disease
hdPS
High Dimensional Propensity Scores
HF
Heart Failure
HR
Hazard Ratio
IBD
Inflammatory Bowel Disease
ICD
International Classification of Diseases
ICS
Inhaled Corticosteroid
IQR
Interquartile Range
IRB
Institutional Review Board
LABA
Long-Acting Beta-Agonists
LAMA
Long-Acting Muscarinic Antagonists
MDV
Medical Data Vision
MS
Multiple Sclerosis
Olo
Olodaterol
PUD
Peptic Ulcer Disease
PVD
Peripheral Vascular Disease
PS
Propensity Score
SABA
Short-acting Beta Agonist
SAMA
Short-acting Muscarinic Antagonist
SD
Standard Deviation
Tio
Tiotropium      

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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
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Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
3.
RESPONSIBLE PARTIES
Email: 
Email:
Email:
  
 
Email:
Email:
T: 
Email: 
 
Email: 

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
Title of study:
Early intervention effectiveness of tiotropium / olodaterol compared to 
tiotropium in COPD
Rationale and 
background:
Chronic obstructive pulmonary disease (COPD) is a common disease 
with a significant morbidity and cost burden. Long-acting muscarinic 
antagonists (LAMA) and long-acting beta agonist (LABA) have been 
the first line of treatment for COPD. Recent clinical trials have 
suggested that a combination of LAMA and LABA is more effective in 
improving lung function than their mono-components alone. The 
combination therapy may delay the progression to uncontrolled COPD 
managed with triple therapy. There is, however, limited research from 
real world setting showing LAMA+LABA combination therapy 
provides more benefit than LAMA monotherapy in Japanese patients 
with COPD.
Spiolto® Respimat®, a combination of Olodaterol (a LABA) and 
Tiotropium (a LAMA) (herein referred to as Tio/Olo) was approved in 
September 2015 in Japan. Spiriva® Respimat®, a Tiotropium (a 
LAMA) monotherapy (herein referred to as Tio), was approved in 
October 2004 in Japan. 
This study aims to evaluate the time to escalation to triple therapy 
among the Japanese COPD patients newly initiating therapy with Tio 
or Tio/Olo using real world data.

Boehringer Ingelheim
Page 9 of 41
Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
Research question 
and objectives:
To compare the early intervention effectiveness of Tio/Olo vs. Tio 
among COPD patients.
To compare the early intervention effectiveness of Tio/Olo vs. Tio 
among COPD patients. 
The primary objective of the study is to 
-
Compare time to LAMA/LABA/ICS triple therapy initiation 
among initiators of Tio/Olo vs. initiators of Tio.      
The secondary objective of the study is to compare the following 
among initiators of Tio/Olo vs. initiators of Tio:
-
Time to First Moderate or Severe COPD Exacerbation
-
Number of Moderate or Severe COPD Exacerbations
Further endpoints:
-
All-Cause Mortality,
-
Number of Unique Pulmonary Medication Prescriptions 
-
Number of Hospitalizations for a Respiratory Condition
-
Major Cardiovascular Adverse Event (MACE)
-          Home oxygen therapy (HOT)
Study design:
This will be a new-user, active comparator retrospective comparative 
cohort study using MDV Japan, a Japanese electronic healthcare 
research database. It will employ high dimensional propensity scores 
(hdPS) to match 1 Tiotropium initiator for each Tiotropium/ Olodaterol 
initiator.

Boehringer Ingelheim
Page 10 of 41
Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
Population:
The study cohort will include all patients who initiate Tiotropium/ 
Olodaterol (Tio/Olo) or Tiotropium (Tio) during the patient selection 
period (28 September 2015 to 31 December 2018). Initiation (new use) 
will be determined based on no prescription claims for Tio/Olo or Tio 
during the 180-day baseline period or during all available data prior 
to cohort entry date. All patients will additionally be required to have 
a second claim for the index medication within 60 days after cohort 
entry to ensure primary adherence of index therapy and regular visit to 
one of the MDV facilities for treatment of COPD on or any time prior 
to cohort entry.  
The following exclusion criteria will then be applied to generate the 
unmatched cohort:
●
Aged <40 years on cohort entry.
●
Any LAMA, LABA, or ICS maintenance therapy (alone or in 
combination) during the 180-day baseline period prior to cohort entry 
for maintenance treatment and duration >30 days, or any prescription 
within the 30 days prior to cohort entry.
●
Patients without continuous enrolment (days since first 
inpatient/ outpatient encounter in the data) during the baseline period. 
●
No prior diagnosis of COPD [ICD-10: J41*, J43*, J44* and 
doubt (UTAGAIFLG) = 0 (no)] 
●
Patients without a second prescription claim of their index 
medication within 60 days after the cohort entry date.
●
Diagnosis of asthma [ICD-10: J45* and doubt (UTAGAIFLG) 
= 0 (no)] during the baseline period.
●
Diagnosis of lung cancer [ICD-10: C34*, D02.2, Z80.1, Z85.1 
and doubt (UTALAIFLG) = 0 (no)] or lung transplant (Health claim 
code: 150317670, 150322510, 150322610, 150336510, 150336610, 
150336710, 150399270) prior to the cohort entry date using all 
available data.
●
Patients who initiate both Tio/Olo and Tio simultaneously on 
the cohort entry date.

Boehringer Ingelheim
Page 11 of 41
Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
●
Any use of triple therapy (LAMA + LABA + ICS) during the 
baseline period or between the cohort entry date and 1 day prior to the 
start of follow-up.      
All patients will be selected into the first treatment arm (Tio/Olo or 
Tio) that they qualify for and will not be allowed to re-enter the cohort 
by design. 
The cohort will then be used to construct two matched cohorts (not 
mutually exclusive) according to the: 1) basic propensity scores and 2) 
high dimensional propensity scores.

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
Variables:
Exposures
●
Exposure: Tiotropium/Olodaterol (Spiolto®).
●
Reference: Tiotropium (Spiriva®).
Primary Outcome
The primary outcome of interest is time to triple therapy initiation (first 
event per patient) defined as any LAMA/LABA/ICS fixed dose 
combination or any concurrent use for 30 consecutive days of the 
following:
●
any LAMA/LABA fixed dose combination + any ICS single 
formulation
●
any LAMA single formulation + any LABA/ICS fixed dose 
combination
●
any LAMA single formulation + any LABA single formulation 
+ any ICS single formulation
Secondary outcomes
●
Time to First Moderate or Severe COPD Exacerbation
●
Number of Moderate or Severe COPD Exacerbations
Further endpoints
●
All-Cause Inpatient Mortality
●
Number of Unique Pulmonary Medication Prescriptions 
●
Number of Hospitalizations for a Respiratory Condition
●
Major Cardiovascular Adverse Events (MACE)
●
Home oxygen therapy (HOT)
Covariates
●
Demographics (last recorded):  Age, Sex, Year of Cohort Entry, 
Hospital Size (as a proxy for urban/rural). 
●
Concomitant Medications (see detail below)
Comorbidities/Symptoms (see detail below)

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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
Data sources:
MDV is an electronic, record-based healthcare database that spans 
from 01 April 2008 to 31 March 2019, and contains 25.1 million 
observable patients from 374 medical facilities across Japan.
Study size:
There are 1,829 new users of Tiotropium/Olodaterol and 13,132 new 
users of Tiotropium between 28 September 2015 and 31 October 2018 
who satisfied the initial inclusion criteria of new use with at least 2 
prescriptions for the index medication within 60 days, and excluding 
patients without a COPD diagnosis during the baseline period, age 
<40, diagnosis of asthma during the baseline period, no history of lung 
cancer or lung transplant, any LAMA, LABA, or ICS maintenance 
therapy within the 30 days prior to cohort entry, and without 
continuous enrolment (days since first inpatient/outpatient encounter in 
the data) during the baseline period. 
Based on the result of study by Hahn B et al, it is assumed that the 
triple therapy initiation rate during 1 year is 6% in Tio+Olo group and 
10% in Tio group. In total, 1856 patients are needed to observe 141 
events and to detect the difference (HR of 1.7) with 2-sided alpha of 
0.05 and 90% power. 
After propensity score matching, it will be assessed whether sufficient 
number of sample size is available to detect the expected difference. If 
not available, the treatment difference will be explored in highly 
explorative manner (i.e., p-value is considered descriptively and point 
estimate with confidence interval is focused).

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
Data analysis:
●
Descriptive analyses
For demographic and lifestyle variables, the value recorded on the 
cohort entry date will be reported, otherwise the most recent known 
value will be reported. Presence of comorbidities and use of 
concomitant medication use will be determined based on whether they 
ever occurred within the 180-day baseline period preceding the index 
date.  Differences in the confounder distributions will be inspected for 
successful confounder balance of measured characteristics.
●
Rate of Triple Therapy Initiation 
Among the unmatched and matched cohorts, rates of triple therapy use 
for each treatment group will be reported as the number of events (first 
per patient) divided by the total number of person-years at risk during 
follow-up. Comparative rates and corresponding 95% Cis will be 
reported as both the rate ratio and rate difference per 1,000 person-
years at risk. 
●
Risk of Triple Therapy Initiation
Among the unmatched and matched cohorts, risk of triple therapy use 
for each treatment group will be reported as the number of events (first 
per patient) divided by the total number of patients at risk. 
Comparative risks and corresponding 95% CIs will be reported as both 
the risk ratio and risk difference per 1,000 person at risk. 
Comparative Effectiveness
●
Hazard Ratio for Triple Therapy Use Initiation
Among both the basic propensity score matched and high dimensional 

Boehringer Ingelheim
Page 15 of 41
Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
propensity score matched cohort, Cox regression will be used to 
estimate the hazard ratios and 95% CI for Tiotropium/Olodaterol 
compared to patients treated with Tiotropium during follow-up for 
time-to-first triple therapy initiation using an intention-to-treat 
censoring approach. 
Sensitivity Analyses
1.
Less Stringent Qualifying Event Criterion
Instead of defining the qualifying event as two prescriptions within 60 
days, patients may enter on only one prescription. While some 
confidence is lost in whether the patients truly took their index 
medications, the less stringent qualifying event criterion will allow 
more patients to be included, increasing statistical power. Furthermore, 
the possibility of immortal time bias is also mitigated, since the time 
between prescriptions is no longer present.
2.
As-treated Censoring
     
The analysis will use an as-treated approach for primary, secondary 
and further endpoint outcomes. In addition to the censoring criteria 
mentioned for the intention-to-treat approach  (outcome, death, or end 
of data), patients will also be censored after medication discontinuation 
or switching over to the other arm. 
3.
Alternative algorithm for COPD as exclusion criterion
The analysis will use a different set of diagnosis codes for COPD 
(J43*, J44*) to identify patients with COPD. Compared to the primary 
analysis, this identification approach omits the diagnostic code for 
chronic bronchitis (J41*), as this code is commonly used by 
pulmonologists when prescribing Mucolytics to patients without 

Boehringer Ingelheim
Page 16 of 41
Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
chronic bronchitis. While some true chronic bronchitis patients may be 
excluded, this approach may increase specificity in identifying patients 
with COPD.
4.
Asthma patients with doubt
Asthma patients with doubt are defined as patients with a diagnosis 
code for asthma and without evidence of any asthma specific treatment 
(ie., ICS, ICS/LABA) This sensitivity analysis will include patients 
identified with asthma with doubt.
5.
Asthma-COPD Overlap Syndrome (ACOS) sensitivity analysis 
Patients that have evidence of asthma during the follow-up period will 
have their data censored on the date of asthma diagnosis during the 
follow-up period. This will ensure that they contribute information 
during their COPD disease trajectory up until the time they develop 
asthma. This approach will mitigate introducing immortal time bias for 
those patients with ACOS during the follow-up period.

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
c30708153-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®; Spiriva® 
Respimat®
Name of active ingredient:
Tiotropium / Olodaterol      fixed dose 
combination (ATC R03AL06); 
Tiotropium (ATC R03BB04)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 Feb 2020
1237.100
1.0
N/A
Milestones:
10-Sept-2019: Kickoff
16-Sept-2019: Initial Protocol Draft 
18-Oct-2019: BI Review of Draft Protocol
08-Nov-2019: Revise Protocol per BI Feedback
15-Nov-2019: Protocol approval from BI
28-Feb-2020: Implement Study
14-Mar-2020: Review of preliminary results and discussion of report 
priorities
31-Mar-2020: Sensitivity Analysis
TBD 2020: Manuscript kickoff / initial discussion with medical writing 
team
TBD: 
 to provide manuscript outline with key results for 
medical writer
30-May-2020: Draft Study Report
TBD-2020: BI Review of Study Report
TBD-2020: Revise Report per BI Feedback

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001-MCS-90-124_RD-01 (4.0)
5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
<1>
DD Month 
YYYY
<Text>
<Text>
<Text>
<2>
DD Month 
YYYY
<Text>
<Text>
<Text>
<n>
DD Month 
YYYY
<Text>
<Text>
<Text>

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Protocol for non-interventional studies based on existing data
BI Study Number 1237.100
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001-MCS-90-124_RD-01 (4.0)
6.
MILESTONES
Activities
Date
Responsible Party
Deliverable if applicable
Project Kickoff
10-Sept-2019
/BI
Draft Initial Protocol 
16-Sept-2019
Protocol Draft
BI Review of Draft Protocol
18-Oct-2019
BI
Revise Protocol per BI Feedback
08-Nov-2019*
Submit Protocol
Protocol approval from BI
15-Nov-2019
BI
Protocol approval
Implement Study
Feb-2020*
Primary Results Table, 
Review of preliminary results and 
discussion of report priorities
Mar-2020     
/BI
Sensitivity Analysis
Mar-2020
Sensitivity Result Tables
Manuscript kickoff / initial 
discussion with medical writing 
team
TBD 2020
/Medical 
Writing Team
Manuscript outline 
summarizing background and 
methods
Manuscript outline with summary 
of key results
TBD
 
Manuscript outline for 
medical writer with added 
result summary
Draft Study Report
TBD-2020
Study Report Draft
BI Review of Study Report
TBD-2020
BI
Revise Report per BI Feedback
TBD-2020*
Final Report
Manuscript Review
TBD
BI-led, 
supported
*Pending time for approval and suggested changes proposed by BI. All subsequent dates are subject to 
shift forward if review is delayed.

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7.
RATIONALE AND BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a common disease characterized by airway 
obstruction confirmed by spirometry, often including small airway obstruction, chronic 
bronchitis, and emphysema (Barnes 2015). It is a leading cause of death in the USA, 
affecting 16 million Americans (National Heart Lung and Blood Institute, USA). The 
prevalence of COPD in Japan is about 8.6% (Fukuchi 2004), costing approximately ¥805.5 
billion (US$6.8 billion) per year (Nishimura 2004). 
No known medications can reverse COPD, but regular maintenance treatments can help 
manage symptoms, reduce the frequency of exacerbations, and improve health-related quality 
of life (Braido 2016).  Bronchodilators have been the cornerstone of COPD disease 
management and are prescribed as first-line therapy for patients with COPD. According to 
the 2017 GOLD guidelines, a long-acting muscarinic antagonists (LAMA) or long-acting 
beta agonist (LABA) is recommended as the first line treatment in GOLD B , followed by 
combination therapy LAMA + LABA if the COPD patients are still symptomatic in GOLD 
D. Several studies have found LAMA+LABA combinations to be more effective than their 
mono-components and without minimal increase in adverse events. In a review study, Mosely 
et al. reported that the combination of tiotropium and olodaterol hydrochloride is more 
effective at improving FEV1 than either of the two agents used alone (Mosely 2016). Singh 
et al., in a phase III trial, found patients receiving tiotropium and olodaterol responded better 
than those receiving tiotropium monotherapy, and conclude that tiotropium + olodaterol 
should be considered as a treatment option in patients with moderate COPD who are 
initiating maintenance therapy (Singh 2016).  Other clinical trials, such as Tonado 1 and 
Tonado 2, have also shown that tiotropium/olodaterol fixed-dose combination (FDC) therapy 
provides significantly improved lung function and quality of life, compared with either 
therapy used individually in COPD (Buhl 2015, Ichinose 2016). In addition, recent clinical 
trials have found tiotropium/olodaterol FDC therapy significantly improved exercise 
capacity, and physical activity compared with tiotropium monotherapy. (Minakata 2019,  
Ichinose 2018)
Patients with uncontrolled COPD experiencing exacerbations may escalate to triple LAMA/ 
LABA/ Inhaled Corticosteroids (ICS) therapy (Vogelmeier 2017). According to prior COPD 
guidelines, ICS can be used for frequent exacerbations, but the most recent GOLD guidelines 
recommend that ICS only be used for Asthma-COPD-overlap patients (Vogelmeier 2017). 
However, in the DYNAGITO study, the prevalence of LAMA/LABA/ICS (triple therapy) at 
baseline was 40.8% in moderate to very severe COPD patients in Japan (Calverley 2018, 
Ichinose 2018). ICSs may lead to several minor and major complications. The side effects of 
ICS treatment can range from weight gain and local side effects, such as pneumonia, oral 
candidiasis and dysphonia, to adrenal suppression, cataracts, and osteoporosis (Tariq 2016, 
Wilkie 2015). In addition, patients with low blood eosinophil counts may not respond to ICS 
(Hizawa 2015). 
Several clinical trials have shown that new LAMA/LABA inhalers could better manage 
patients, potentially reducing the use of ICS as part and parcel of maintenance therapy in 
COPD (Magnussen 2014). However, the evidence obtained from previous clinical trials is 
not always reflected in clinical practice, and there is limited research from real world settings 

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that show LAMA+LABA combination therapy provides more benefit than LAMA 
monotherapy in Japanese patients with COPD. Therefore, real world evidence from Japanese 
COPD patients is crucial in addressing this gap in knowledge.  It is also essential to 
understand real world treatment patterns and outcomes, in particular, escalation to triple 
therapy as a proxy for worsening COPD condition.  
Spiolto® Respimat®, a combination of Olodaterol (a LABA) and Tiotropium (a LAMA) 
(herein referred to as Tio/Olo) was approved in September 2015 in Japan. Spiriva® 
Respimat®, a Tiotropium  (a LAMA) monotherapy (herein referred to as Tio), was approved 
in October 2004 and widely used in Japan. Both maintenance therapies are available, but real 
world evidence is lacking if one therapy is superior to the other, and whether it can prolong 
the duration to triple therapy that includes ICS.
This study aims to evaluate the time to escalation to triple therapy among the Japanese COPD 
patients newly initiating therapy with Tio or Tio/Olo using real world data.

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8.
RESEARCH QUESTION AND OBJECTIVES
To compare the early intervention effectiveness of Tio/Olo vs. Tio among COPD patients.
The primary objective of this study is to:
-
Compare time to LAMA/LABA/ICS triple therapy initiation among initiators of 
Tio/Olo vs. initiators of Tio.
The secondary objectives of the study are to compare the following among initiators of 
Tio/Olo vs. initiators of Tio:
Secondary outcomes
●
Time to First Moderate or Severe COPD Exacerbation
○
Time to First Moderate COPD Exacerbation
○
Time to First Severe COPD Exacerbation
●
Number of Moderate or Severe COPD Exacerbations
○
Number of Moderate COPD Exacerbations
○
Number of Severe COPD Exacerbations
Further endpoints:
●
All-Cause Mortality,
●
Number of Unique Pulmonary Medication Prescriptions 
●
Number of Hospitalizations for a Respiratory Condition
●
Major Cardiovascular Adverse Events (MACE)
●
Home oxygen therapy (HOT)

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This will be a new-user, active comparator retrospective comparative cohort study using 
MDV Japan, a Japanese electronic healthcare research database. It will employ high 
dimensional propensity scores (hdPS) to match 1 Tiotropium initiator for each 
Tiotropium/Olodaterol initiator.
9.2
SETTING
9.2.1
Definitions
Study Period: the entire period of time that includes the baseline period, the cohort entry date (index 
date), and follow-up period for the study population. The study period will be from 01 April 2015
(180 days prior to Spiolto approval date of 28 September 2015 in Japan) to 31 March 2019 (end of 
available data).
Patient Selection Period: the period of time for which patients are eligible to enter the cohort. The 
earliest date of the patient selection period is 28 September 2015, (the Spiolto approval date in Japan). 
The latest date of the patient selection period is 31 December 2018, corresponding to 90     days 
before the end of available data (31 March 2019), ensuring that all patients have at least 60 days after 
the cohort entry date to identify a second prescription for index therapy and at least 30 days to be 
capable of the 30-day overlap to determine the triple therapy initiation outcome.
Cohort Entry Date: Date of entry to the initial cohort of Tio/Olo vs. Tio users (first prescription).
Baseline Period: the 180-day period that ends 1 day prior to the cohort entry date used to assess 
covariate information. The earliest start of the baseline period would be 01 April 2015, corresponding 
to 180 days prior to the approval date of Spiolto.
Follow-Up Period: the period starting at the second prescription for Tio/Olo or Tio within 60 days of 
the cohort entry date (first prescription) and ending at the earliest occurrence of the outcome (use of 
triple therapy), or the first occurrence of inpatient death, disenrollment, or end of the study period (31-
Mar-2019). A sensitivity analysis will employ an as-treated censoring approach to further censor upon 
discontinuation of index therapy or initiation of the other index treatment arm. Patients may have 
different lengths of follow-up (i.e. variable follow-up). 
Since health care is nationalized in Japan, the notion of enrollment is not applicable. Therefore, a 
proxy enrolment criterion defined as start of enrolment = date of first inpatient/outpatient encounter;
end of enrolment = date of last inpatient/outpatient encounter will be used. “Enrolment” herein will 
refer to this proxy enrolment measure. For entry into the study population, patients will be required to 
have had at least 180 days of enrollment prior to the cohort entry date. 
Data during the baseline period will be used to confirm study eligibility and classification of 
exposure. The follow-up period will be used for identifying the outcome. This is illustrated in Figure 
1.

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Figure 1
Study timeline
*Patients are allowed to enter the cohort between 28-September-2015 and 31-December-2018. The last allowable date for 
start of follow-up is 1-March-2019. The follow-up ends at the earliest occurrence of the outcome, or the first occurrence of 
inpatient death, disenrollment, or end of the study period (31-Mar-2019). A sensitivity analysis will employ an as-treated 
censoring approach to further censor upon discontinuation of index therapy or initiation of the other index treatment arm.
9.2.2
Study population
The study cohort will include all patients who initiate Tiotropium/Olodaterol (Tio/Olo) or 
Tiotropium (Tio) during the patient selection period. Initiation (new use) will be determined 
based on no prescription claims for Tio/Olo or Tio during the baseline period or during all 
available data prior to cohort entry date. All patients will additionally be required to have a 
second claim for the index medication within 60 days after cohort entry to ensure primary 
adherence of index therapy.  
The following exclusion criteria will then be applied to generate the unmatched cohort:
●
Aged <40 years on cohort entry.

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●
Any LAMA, LABA, ICS maintenance therapy (alone or in combination) during the 
180-day baseline period prior to cohort entry for maintenance treatment and not cough, i.e. 
duration >30 days, or any prescription within the 30 days prior to cohort entry.
●
Patients without continuous enrolment (days since first inpatient/outpatient encounter 
in the data) during the baseline period. 
●
No prior diagnosis of COPD [ICD-10: J41*, J43*, J44* and doubt (UTAGAIFLG) = 
0 (no)] 
●
Patients without a second prescription claim of their index medication within 60 days 
after the cohort entry date.
●
Diagnosis of asthma [ICD-10: J45* and doubt (UTAGAIFLG) = 0 (no)] during the 
baseline period.
●
Diagnosis of lung cancer [ICD-10: C34*, D02.2, Z80.1, Z85.1 and doubt 
(UTALAIFLG) = 0 (no)] or lung transplant (Health claim code: 150317670, 150322510, 
150322610, 150336510, 150336610, 150336710, 150399270) prior to the cohort entry date 
using all available data.
●
Patients who initiate both Tio/Olo and Tio simultaneously on the cohort entry date.
●
Any use of triple therapy (LAMA + LABA + ICS) during the baseline period or 
between the cohort entry date and 1 day prior to the start of follow-up.
All patients will be selected into the first treatment arm (Tio/Olo or Tio) that they qualify for 
and will not be allowed to re-enter the cohort by design. 
The cohort will then be used to construct two matched cohorts (not mutually exclusive) 
according to the: 1) basic propensity scores and 2) high dimensional propensity scores
Figure 2
Depicts the flow diagram of patients.

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Basic Propensity Score Matching
Basic propensity score will be used to assess comparative effectiveness between the two exposure 
groups. The basic propensity score will be estimated using logistic regression with Tio/Olo treatment 
as the outcome and the following variables determined a priori as predictors:
a) predefined demographic variables (measured at time of cohort entry):
●
Age
●
Sex
●
Calendar Year of Index
●
Hospital Size (as a proxy for urban/rural)
b) all concomitant medications and comorbidities/conditions/other variables enumerated in Section 
9.3.3.
The final basic propensity score will then be used to identify one initiator of Tiotropium for each 
initiator of Tiotropium/Olodaterol with the same propensity score (± a caliper of 5%) (Austin 2011). 
High Dimensional Propensity Score Matching
In addition to the basic propensity scores, high dimensional propensity score (hdPS) analysis will also 
be used to assess comparative effectiveness between the two exposure comparison groups. hdPS is a 
modification of traditional propensity scores that incorporate additional steps for empirical variable 
selection. Briefly, hdPS includes additional covariates by ranking a complete list of available 
variables of a given attribute (e.g. all ICD-10 codes) based on prevalence, recurrence, association 
between covariate and exposure, and association between covariate and outcome, and then including 
the top covariates in that list in the propensity score prediction. This technique has been shown to 
produce improved effect estimates compared to using all predefined covariates in the propensity score 
prediction (Schneeweiss 2009).
The set of covariates to estimate the propensity scores will include the same predefined covariates as 
in the basic propensity scores (categories a and b), but also an empirically chosen set of covariates 
(category c):
a) predefined demographic variables (measured at time of cohort entry):
●
Age
●
Sex
●
Calendar Year of the Cohort Entry Date
●
Hospital Size (as a proxy for urban/rural)
b) all concomitant medications and comorbidities/conditions/other variables enumerated in Section 
9.3.3.
c) The top variables (number of variables determined by the 
) chosen by the 
hdPS algorithm described above. The following attributes will be used to select variables eligible for 
hdPS analysis:
●
Disease Data – ICD-10 Codes
●
Inpatient ACT – Health Claim Code
●
Outpatient ACT – Health Claim Code
●
Lab Data – Laboratory Code 
In selecting diseases eligible for hdPS, the ICD-10 code will be truncated after the dot. Importance of 
variables will be ordered using the bias ranking method. Health service intensity variables will also be 

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used. Health service intensity variables are calculated for each attribute by counting the total number 
of codes for each patient, counting the number of distinct codes for each patient, and creating eight 
binary variables representing the quartiles for both the total number of codes and number of distinct 
codes. Along with the binary variables created for each code, the eight binary intensity variables are 
used in the hdPS algorithm resulting in 2000-8000 binary variables total depending on the attributes 
selected.
Logistic regression conditional on the final set of covariates will be used to compute the propensity to 
initiate Tiotropium/Olodaterol versus Tiotropium given all the variables in a, b, and c above.
The final hdPS will then be used to identify one initiator of Tiotropium for each initiator of 
Tiotropium/Olodaterol with the same propensity score (± a caliper of 5%) (Austin 2011).
9.3
VARIABLES
9.3.1
Exposures
●
Exposure: Tiotropium/Olodaterol (Spiolto®).
●
Reference: Tiotropium (Spiriva®).
Both groups will be identified according to brand name as the first of two prescriptions of the 
respective drug within 60 days. Given the limited information on treatment duration in the MDV data, 
a days supply of 14 days will be assumed for “Spiolto Respimat 28puffs.” Otherwise, 30 days will be 
assumed for “Spiriva Inhalation Capsules 18microg”, “Spiriva 2.5microg Respimat 60puffs 
150microg”, “Spiolto Respimat 28puffs” and “Spiolto Respimat 60puffs”. A grace period of 14 days 
between assumed end of days supply and subsequent prescription will be used as an allowable gap.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Triple Therapy Use
The primary outcome of interest is incident rate of triple therapy initiation (first event per patient) 
defined as any LAMA/LABA/ICS fixed dose combination or any concurrent use for 30 consecutive 
days of the following:
- any LAMA/LABA fixed dose combination + any ICS single formulation
- any LAMA single formulation + any LABA/ICS fixed dose combination
- any LAMA single formulation + any LABA single formulation + any ICS single formulation
MDV data has limited information on treatment duration with the days of prescription recorded as 1 
day for most patients. Therefore, a days supply of 30 days will be assumed. Although we will require 
at least 30 days of overlap, the first date of triple therapy overlap will serve as the outcome event date, 
as corresponds to the initiation of triple therapy. Looking into the future to satisfy the requirement of 
overlap for at least 30 days has the potential to inflict immortal person-time, but is necessary to 
differentiate concurrent use when subsequent medication is added (see Figure 3 - example Patient A) 
from an early sequential prescription fill when subsequent medication is switched to (see Figure 3 -
example Patient B).

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Figure 3
Illustration of outcome
Censoring
Patients will be censored if they had an occurrence of any of the following: outcome (initiation of 
triple therapy), death, or end of data. The analysis will use an intention-to-treat censoring approach, 
which does not account for treatment change. A sensitivity analysis will employ an as-treated 
censoring approach to further censor upon discontinuation of index therapy or initiation of the other 
index treatment arm. Thus, events will be assigned to exposure groups according to that patient’s 
original index medication, even if that patient discontinued or crossed over.
9.3.2.2
Secondary outcomes and further endpoints
Secondary outcomes
●
Time to First Moderate or Severe COPD Exacerbation  
○
Time to First Moderate COPD Exacerbation  
○
Time to First Severe COPD Exacerbation  
●
Number of Moderate or Severe COPD Exacerbations
○
Number of Moderate COPD Exacerbations
○
Number of Severe COPD Exacerbations
Further endpoints:
●
All-Cause Inpatient Mortality
●
Number of Unique Pulmonary Medications 
●
Number of Hospitalizations for a Respiratory Condition
●
Major Cardiovascular Adverse Events (MACE)        
●
Home oxygen therapy (HOT)            
Moderate exacerbations will be defined as an outpatient visit with a diagnosis code for COPD in any 
field + a prescription for an oral corticosteroid or an antibiotic for respiratory infections,. Severe 

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exacerbations will be defined as a hospitalization with a primary diagnosis for COPD. (Chatterjee 
2012)
Unique pulmonary medications will be defined as the following treatments: LAMA, LABA, 
SAMA, SABA, inhaled/oral glucocorticoids, systemic glucococorticoids, antileukotriene 
agents, biologics (anti-IgE, anti-IL-5, anti-Il-4), allergy medications, xanthines 
(theophylline), and mycolytics. 
Major Cardiovascular Adverse Event (MACE) will be defined as ischemic stroke, myocardial 
infarction (MI), or inpatient death. Stroke will be defined as absence of a doubt flag and a disease 
claim for ICD-10 I60.x - Subarachnoid haemorrhage, I61.x - Intracerebral haemorrhage, I63.x -
Cerebral infarction, or I67.8 - Other specified cerebrovascular diseases, a measure previously 
validated based on ICD-9 code equivalents to have a PPV between 85 and 98% [Andrade 2012; 
Tirschwell 2002; Roumie 2008]. MI will be defined as absence of a doubt flag and a disease claim 
for ICD-10 I21.x - Acute myocardial infarction or I22 - Subsequent myocardial, a measure previously 
validated based on ICD-9 code equivalents to have a PPV of 94% using US Medicare claims [Kiyota 
2004] and 88.4% PPV using US commercial claims [Wahl 2010]. Inpatient death will be defined as 
either absence of a doubt flag and a disease claim or Discharge Summary Data with a death-related 
diagnosis (ICD-10 O96.x - Death from any obstetric cause; O97.x - Death from sequelae of obstetric 
causes; I46.1 - Sudden cardiac death, so described; R96 - Other sudden death, cause unknown; R98 -
Unattended death; R99 - Other ill-defined and unspecified causes of mortality) or the occurrence of 
Discharge Summary Data with either Destination After Discharge as 8 - Completed (Death and so 
on.) or Discharge Summary Data with Outcome at the Time of Discharge is Death.
Home oxygen therapy (HOT) will be defined according to presence of the following:
●
Health claim codes that include home/domiciliary oxygen therapy:
○
114041610 - Add-on fee of materials for domiciliary oxygen therapy (others)
○
114042770 - Oxygen therapy add-on fee (home-care patient home visit fee (1) 1)
○
114043670 - Oxygen therapy add-on fee (home-care patient home visit fee (2) a)
○
114045470 - Remote monitoring add-on fee (home oxygen therapy guidance 
management fee [others])
○
114004910 - Installation type liquid oxygen reservoir add-on fee
○
114005010 - Portable type liquid oxygen reservoir add-on fee
○
114006110 - Oxygen tank add-on fee (others)
○
114006210 - Oxygen enricher add-on fee
○
114006310 - Oxygen tank add-on fee (portable oxygen tank)
○
739210000 - Liquid oxygen/portable liquid oxygen container (LGC)
○
739220000 - Oxygen cylinder/large size
○
739230000 - Oxygen cylinder/small size
○
739250000 - Liquid oxygen/portable liquid oxygen container (LGC) (remote islands 
and other)
○
739260000 - Oxygen cylinder/large size (remote islands and other)
○
739270000 - Oxygen cylinder/small size (remote islands and other)
9.3.3
Covariates
The covariates listed below consist of demographics, medications, comorbidities, and other variables 
that are hypothesized to confound the relationship between exposure and outcome. Covariates will be 
identified based on data recorded within 180 days prior to or on the index date (date of 

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dispensing/initiation of the exposure), unless otherwise specified. If multiple measurements are made 
in the baseline period, then the most recent measurement will be used. 
There is an additional variable for “doubt diagnosis” related to each disease diagnosis. Only 
confirmed diagnoses will be used for all disease variables (this represents ~95% of all diagnoses).
Absolute and relative frequencies of each covariate will also be reported. Detailed descriptions of the 
listed covariates can be found in Annexes      2 and      3. The measure definitions for diagnoses are 
subject to modification to further incorporate disease codes/names as deemed appropriate upon further 
exploration of the data during study implementation.
Demographics (last recorded)
●
Age 
●
Sex 
●
Year of Cohort Entry
●
Hospital Size (as a proxy for urban/rural).
Concomitant Medications 
●
Oral/Injected Corticosteroids
●
Short acting beta agonist (SABA) (number of claims)
●
Short acting muscarinic antagonist (SAMA) (number of claims)
●
Systemic Xanthines
●
Systemic Antileukotrienes
●
Interleukin Inhibitors for Asthma
●
Non-steroidal Respiratory Anti-inflammatories
●
Opioids/Narcotics
●
Systemic Antihistamines
●
Oral Antibiotics for a Respiratory Condition (number of claims)
●
Cough and Cold Preparations
●
Diabetes Mellitus Medications, excluding Insulin
●
Insulin
●
Cytostatics
●
Antirheumatics, Biologic
●
Antirheumatics, Non-Steroidal
●
Antithrombotic Agents
●
Lipid-lowering Agents
●
Antihypertensives/Diuretics
●
Antiepileptics/Psycholeptics/Psychoanaleptics
●
Antipsoriatics
●
Antivirals
●
Thyroid Therapies
●
Vaccinations
[Antibiotics + Respiratory diagnosis, 
 can try to find antibiotics specific to respiratory 
conditions]
Comorbidities/Symptoms
●
COPD Exacerbations (number of exacerbations)
●
All-Cause Hospitalization
●
Hospitalization due to Respiratory Condition
●
Acute Myocardial Infarction, AMI
●
Angina Pectoris
●
Peripheral Vascular Disease, PVD
●
Heart Failure, HF

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●
Hypertension
●
Cardiac Arrhythmias
●
Cerebrovascular Disease
●
Any Cancer (except nonmelanoma skin cancer)
●
Allergic Rhinitis
●
Chronic Sinusitis
●
Bronchiectasis
●
Pneumonia
●
Chronic Bronchitis
●
Tuberculosis
●
Influenza
●
Anxiety
●
Dementia
●
Depression
●
Osteoporosis
●
Acute Liver Injury or Failure
●
Chronic Kidney Disease, CKD
●
Peptic Ulcer Disease, PUD
●
Gastroesophageal Reflux Disease, GERD
●
Type 1 Diabetes Mellitus
●
Type 2 Diabetes Mellitus
●
Hypothyroidism
●
Hyperthyroidism
●
Anemia
●
Rheumatoid Arthritis
●
Lupus
●
Inflammatory Bowel Disease, IBD
●
Multiple Sclerosis, MS
●
Psoriasis and Psoriatic Arthritis
●
Eczema
●
Blood eosinophil concentration (will be reported in the descriptive summary, but not included 
in the propensity score model given that this lab value is available for <10% of COPD 
patients in this data source).
9.4
DATA SOURCES
The proposed study will utilize data from Medical Data Vision (MDV).
MDV is an electronic, record-based healthcare database that spans from April 1, 2008 to 31 
March 2019, and contains 25.1 million observable patients. It contains patient-level 
information on demographics, diagnoses and prescription information from 374 medical 
facilities across Japan. The distribution of patients in the database is similar to that of the 
national demographics for patients seeking healthcare, although the MDV database has more 
elderly and sicker patients.
The Japanese health care structure enables anyone to seek medical treatment at any facility of 
their choosing, including hospitals. Thus, acute hospitals in Japan consist of both primary 
(outpatient) and secondary (inpatient) care facilities. In fact, the MDV database is built out of 
more than 80% outpatient data, which allows for identification of patients who visit hospitals 
without severe conditions. These hospitals follow a diagnosis procedure combination (DPC) 
billing structure unique to Japan that enables capture of inpatient discharge summary 

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information (disease name, operations, adjuvant treatment, etc.), health claims for procedures 
(surgery information, departments, wards, etc.), and health claims for treatments 
(medications, medical devices, devices, etc.). A smaller subset of consenting hospitals also 
provide data on blood test results.
Thus, it is expected that 1) patients with COPD in these hospitals provide a good 
representation of the general Japanese COPD population; and 2) data from patients treated in 
the different hospitals cannot be linked. Due to the nature of the database, inclusion criteria to 
ensure that the patients are treated for COPD in the same hospitals continuously are defined 
as described in Section 9.2.2.
9.5
STUDY SIZE
There are 1,829 new users of Tiotropium/Olodaterol and 13,132 new users of Tiotropium between 28 
Sep 2015 and 31 October 2018 who satisfied the initial inclusion criteria of new use with at least 2 
prescriptions for the index medication within 60 days, and excluding patients without a COPD 
diagnosis during the baseline period, age <40, diagnosis of asthma during the baseline period, no 
history of lung cancer or lung transplant, any LAMA, LABA, or ICS maintenance therapy within the 
30 days prior to cohort entry, and without continuous enrolment (days since first inpatient/outpatient 
encounter in the data) during the baseline period. 
Based on the result of study by Hahn B et al, it is assumed that the triple therapy initiation rate during 
1 year is 6% in Tio+Olo group and 10% in Tio group. In total, 1856 patients are needed to observe 
141 events and to detect the difference (HR of 1.73) with 2-sided alpha of 0.05 and 90% power.
After propensity score matching, it will be assessed whether sufficient number of sample size is 
available to detect the expected difference. If not available, the treatment difference will be explored 
in highly explorative manner (i.e., p-value is considered descriptively and point estimate with 
confidence interval is focused).
9.6
DATA MANAGEMENT
Dataset
The Medical Data Vision dataset is comprised of administrative records of longitudinal 
inpatient, outpatient and drug data from multiple hospitals that have been standardized and 
de-identified prior to use for the analysis. The statistical analysis will be conducted using the 
COPD Maintenance Therapy Drug Duration
Given limited information on treatment duration in the MDV data, a days supply of 14 days 
will be assumed for “Spiolto Respimat 28puffs.” Otherwise, 30 days will be assumed for all 
LAMA, LABA, and ICS maintenance therapies, including “Spiriva Inhalation Capsules 
18microg”, “Spiriva 2.5microg Respimat 60puffs 150microg”, “Spiriva 1.25microg Respimat 
60puffs 75microg”, and “Spiolto Respimat 60puffs”. A grace period of 14 days between 
assumed end of days supply and subsequent prescription will be used as an allowable gap.
Handling of Missing Data
Missing data that occurs in covariates or descriptive variables will be classified as its own 
level (i.e. missing data indicator). In addition, a feasibility assessment before beginning the 

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analyses will be done, and variables with >75 % missing values will be excluded from all 
analyses, other than baseline characteristics. If a variable is left with only one level other than 
missing, the variable will be excluded completely from all analyses.
9.7
DATA ANALYSIS
9.7.1
Main analysis
For all analyses, variables will be reported as follows:
●
Continuous variables (e.g., age) will be presented as means (with standard deviation, SD) 
and/or medians (with interquartile range, IQR), minimum, maximum.
●
Categorical variables (e.g., sex) will be presented as absolute and relative frequencies.
9.7.1.1
Descriptive Analysis
All variables specified in section 9.3.3 will be reported. For demographic and lifestyle 
variables, the value recorded on the cohort entry date will be reported, otherwise the most 
recent known value will be reported. Presence of comorbidities and use of concomitant 
medication use will be determined based on whether they ever occurred during the baseline 
period prior to the cohort entry date. Differences in the confounder distributions will be 
inspected for successful confounder balance of measured characteristics and standardized 
differences will be reported.
9.7.1.2
Rates and Risks
●
Rate of Triple Therapy Initiation 
Among the unmatched and matched cohorts, rates of triple therapy use for each treatment 
group will be reported as the number of events (first per patient) divided by the total number 
of person-years at risk during follow-up. Comparative rates and corresponding 95% CIs will 
be reported as both the rate ratio and rate difference per 1,000 person-years at risk. 
●
Risk of Triple Therapy Initiation
Among the unmatched and matched cohorts, risk of triple therapy use for each treatment 
group  will be reported as the number of events (first per patient) divided by the total number 
of patients at risk. Comparative risks and corresponding 95% CIs will be reported as both the 
risk ratio and risk difference per 1,000 person at risk.
9.7.1.3
Comparative Effectiveness
●
Hazard Ratio for Triple Therapy Use Initiation
Among both the basic propensity score matched and high dimensional propensity score 
matched cohort, Cox regression will be used to estimate the hazard ratios and 95% CI for 
Tiotropium/Olodaterol compared to patients treated with Tiotropium during follow-up for 
time-to-first triple therapy initiation using an intention-to-treat censoring approach.

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9.7.2
Subgroup analysis
Not applicable.
9.7.3
Sensitivity Analyses
1.
Less Stringent Qualifying Event Criterion
Instead of defining the event to qualify patients for inclusion based on two prescriptions 
within 60 days, patients may enter upon only one prescription. While some confidence is lost 
in whether the patients truly took their index medications, the less stringent qualifying event 
criterion will allow more patients to be included, increasing statistical power. Furthermore, 
the possibility of immortal time bias is also mitigated, since the time between prescriptions is 
no longer present.
                         
2.
As-treated Censoring
The analysis will use an as-treated approach for primary, secondary and further endpoint 
outcomes. In addition to the censoring criteria mentioned for the intention-to-treat approach  
(outcome, death, or end of data), patients will also be censored after medication 
discontinuation or switching over to the other arm.      
3.
Alternative algorithm for COPD
The analysis will use a different set of diagnosis codes for COPD (J43*, J44*) when selecting 
COPD patients. Compared to the primary analysis, this algorithm omits the diagnostic code 
for chronic bronchitis (J41*), as this code is commonly used by pulmonologists when 
prescribing Mucodyne to patients who do not actually have chronic bronchitis. While some 
true chronic bronchitis patients may be excluded, the selection of patient will increase 
specificity.
4.
Asthma patients with doubt
Asthma patients with doubt are defined as patients with a diagnosis code for asthma and 
without evidence of any asthma specific treatment (ie., ICS, ICS/LABA) This sensitivity 
analysis will include patients identified with asthma with doubt.
5.
ACOS sensitivity analysis 
Patients that have evidence of asthma during the follow-up period will have their data 
censored on the date of asthma diagnosis during the follow-up period. This will ensure that 
they contribute information during their COPD disease trajectory up until the time they 
develop asthma. This approach will mitigate introducing immortal time bias for those patients 
with ACOS during the follow-up period.
9.8
QUALITY CONTROL
The study protocol has been written following the Code of Conduct by the European Network of 
Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) [R15-4870] that provides a set 
of rules and principles for post-authorization studies with regard to the best practices and 

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transparency, thereby promoting scientific independence of such studies. The study will be registered 
to the ENCePP’s E-register and the results will also be published on the same site.
The study protocol also follows the key elements of the Guideline for Good Pharmacoepidemiology 
Practices (GPP) by International Society for Pharmacoepidemiology [R11-4318], and the recent draft 
Guidance for Industry and FDA Staff “Best Practices for Conducting and Reporting 
Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets” [R15-4859]. The 
guidelines for good pharmacoepidemiology practices (GEP) in non-interventional studies will be 
respected along with any applicable local laws and regulations. This trial is not in the scope of Good 
Clinical Practice (GCP) studies.
 will build measures for cohort inclusion, outcomes and covariates. Some of the measure 
algorithms will be based on those collaboratively developed for another respiratory-related protocol 
with clinical input from external pulmonology experts (i.e. ICD-10 code lists for comorbidities). 
Regarding medications, because the health claim coding system in MDV is unique to Japan and not 
well documented in academic articles, queries based on generic name/brand name will be used to 
determine the code list for each medication measure.
All measures created, cohorts developed, statistical analyses implemented, and tables completed will 
undergo quality control review by at least 1 additional analyst or scientist under the supervision of the 
Principal Scientist. Quality controls include checks for the validity and logical content of codes and 
checks for missing values and variables. In order to control for potential inconsistencies and errors, all 
variables will be tabulated. In addition, the distribution of each variable will be examined. Extreme 
observations with values larger than ± 3 standard deviations (SD) will be examined as potential 
outliers and consequently excluded from the dataset.
This protocol will be strictly followed in the study. However, measure definitions may undergo 
modification if determined to be scientifically sensible. All changes to this protocol will be 
documented in protocol amendments.
9.9
LIMITATIONS OF THE RESEARCH METHODS
This study will be conducted using hospital-based health insurance claims following the DPC 
payment system and is subject to certain limitations. One limitation is that these are based on 
a large, non-random convenience sample based in Japan, which may contain biases or lack 
generalizability to other populations. Data also come from a subset of hospitals in Japan, 
which would lead to failure to record events if patients visit medical centers not included in 
MDV’s data sources (Tanaka 2015). Moreover, because healthcare is nationalized in Japan, 
the notion of enrolment is not applicable, and all patients are assumed to be observable 
throughout the global date range of the data. However, if a patient’s emigration or mortality 
is not captured, then they would remain in the study despite not truly being eligible for any 
events, thereby leading underestimations of the risks and rates and possible bias in the hazard 
ratio is these patients are differentially distributed between the exposed and unexposed 
groups.
Another limitation of the study is that patients on monotherapy may escalate to double 
therapy before receiving the triple therapy. The patients starting on double therapy do not 
have this option. Therefore, patients on monotherapy may take longer to get to triple therapy 
than the patients on double therapy. 

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Additionally, the MDV database also poses some limitations inherent to prescription claims 
data. Electronic outpatient pharmacy dispensing records are considered accurate because 
pharmacists fill prescriptions with little room for interpretation and are reimbursed by the 
government on the basis of detailed, complete, and accurate claims submitted electronically 
(Stergachi 1988, Levy 2003). Pharmacy dispensing information is usually seen as the gold 
standard of drug exposure information compared to self-reported information (West 1995) or 
prescribing records in outpatient medical records (West 1994). However, claims data are 
subject to certain limitations. The presence of a claim for a filled prescription does not 
indicate that the medication was consumed or that it was taken as prescribed, and any 
medications filled over-the-counter or provided as samples by the physician will not be 
observed in the claims data. This concern is somewhat mitigated by requiring 2 claims within 
60 days for cohort entry. Finally, patients are required not to have a claim for 
Tiotropium/Olodaterol or Tiotropium during the baseline period, but patients may have taken 
maintenance therapies prior to the start of the baseline period.
MDV database only captures in-patient deaths, and mortality, one of the secondary outcomes, 
maybe under-reported in the data.  However, the magnitude of the underestimation is unlikely 
to differ by exposure and comparison cohorts.  
In the analytical portion of this protocol, propensity score matching will be used to ultimately 
derive the causal parameters of interest. Many covariates are included in the prediction model 
of the propensity scores, but as with all non-interventional studies, the potential for 
unmeasured and residual confounding cannot be ruled out.
9.10
OTHER ASPECTS
Not applicable.
9.11
SUBJECTS
9.11.1
Cases
See Section 9.2.2.
9.11.2
Controls
Not applicable.
9.12
BIAS
In principle, electronic pharmacy dispensing records are considered accurate because 
pharmacists fill prescriptions with little room for interpretation, and are reimbursed by 
insurers based on detailed, complete, and accurate claims submitted electronically (Levy 
2003; Stergachis 1988). Pharmacy dispensing information is usually seen as the gold 
standard of drug exposure information compared to self-reported information or prescribing 
records in medical records. 
The population-based nature of the database will avoid selection bias and ensure external 
validity. Confounding bias through observable covariates will be controlled for by the design, 
which includes propensity score matching. Specifically, compared to traditional propensity 

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score matching, high dimensional propensity scores will be used to reduce overfitting while 
retaining baseline covariate balance in matched groups (Schneeweiss 2009).
To minimize misclassification of the recorded patient characteristics, previously validated 
algorithms or code lists will be used whenever available. Code lists will be reviewed by the 
qualified medical reviewers prior to implementation. Basic plausibility checks will be 
implemented for continuous variables (e.g. age, etc.).
The covariates chosen in section 9.3.3. are hypothesized to be confounders in the relationship 
between exposure and outcome. The range and quantity of variables selected are aimed to 
make the two exposure groups more comparable so that the effect estimates may more readily 
have a causal interpretation.
COPD patients who start on Spiriva® Respimat® may be different than Spiolto® Respimat® 
initiators in the clinical course and severity of COPD. Use of propensity score matching aim 
to reduce bias due to confounding. The addition of covariates chosen by hdPS will further aid 
in reducing bias by empirically selecting for strong confounders. However, it is possible that 
inclusion of some variables may introduce rather than remove bias (i.e. as collider bias or M-
bias). Nevertheless, such biases are demonstrated to be minor, and inclusion of variables 
preceding exposure are generally thought to improve rather than degrade validity (Rassen 
2011).
The requirement of second fill for inclusion in the study could lead to immortal time bias. 
However, as the follow-up will begin after the second fill rather than at the cohort entry date, 
this requirement is unlikely to bias the findings.      
To assess the primary outcome of triple therapy among those who are not on triple therapy 
fixed dose combination or filling all the three medications at the same time, an algorithm will 
be employed to assess the concurrent use  (previously described). This algorithm will require 
us to look into the future to determine the start of the triple therapy and may introduce bias. 
However, it requires an overlap of only 30 days, and it is unlikely to significantly affect the 
results. 
The primary analysis is being conducted as an Intention to Treat (ITT) approach in which 
patients are analyzed according to first exposure.  However, it is likely that some patients 
may discontinue their COPD medication or switch over to another cohort. The 
misclassification of exposure may bias the results.  A sensitivity analysis using On Treatment 
approach will be conducted, which will take into account discontinuation and switching of 
cohort from one medication to the other.

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10.
PROTECTION OF HUMAN SUBJECTS
As the present study is a non-interventional retrospective cohort study, the most significant 
potential impact on the participants would be the potential for individual identification and 
loss of privacy. Patients in the MDV dataset are de-identified, such that names are not linked 
to patient IDs. Thus, the risks to participants are expected to be minimal.
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Data is anonymized and extracted, analyzed, validated and reported in aggregate. 
There is no potential that any employee of BI or agent working on behalf of BI will access 
individual patient data in which the patient may be identified during data compilation, data 
reporting or data analysis.
Based on current guidelines from the International Society for Pharmacoepidemiology [R11 
4318] and the EMA [R13-1970], non-interventional studies such as the one described in this 
protocol, conducted using health care records, do not require expedited reporting of suspected 
adverse events/reactions. Specifically, as stated in section VI.C.1.2.1 of Guideline on Good 
Pharmacovigilance Practices (GVP), Module VI – Management and Reporting of Adverse 
Reactions to Medicinal Products, for non-interventional study designs, which are based on 
use of secondary data, reporting of adverse reactions is not required.
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
These baseline results will be published as an abstract and/or manuscript. Conference and 
Journal to be decided.

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13.
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