Exacerbation Risk in Asthma
Conditions: Asthma
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Non-Interventional Study (NIS) Protocol
TITLE PAGE
Document Number:
c35930967-01
BI Study Number:
0205-0547
BI Investigational
Product(s):
Spiriva Respimat
Title:
Exacerbation Risk and Health Care Resource use among patients with 
asthma using ICS+Tiotropium versus ICS/LABA
Brief lay title:
Exacerbation Risk in Asthma
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
5/12/2021
PASS:
No
EU PAS register 
number:
Study not registered
Active substance:
Tiotropium 1.25 mcq.
Medicinal product:
N/A
Product reference:
N/A
Procedure number:
N/A
Marketing authorisation 
holder(s):
N/A
Joint PASS:
N/A
Research question and 
objectives:
To conduct a comparative effective analysis of patients using 
Tiotropium in combination with Inhaled Corticosteroids (ICS) versus 
those that use LABA medication in combination with ICS.
Country(-ies) of study:
US

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Author:
Marketing authorisation 
holder(s):
N/A
In case of PASS, add:
MAH contact person:
N/A
In case of PASS, add: 
N/A
In case of PASS, add: 
N/A
Date:
5/12/2021
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© 2021 Boehringer Ingelheim Group of 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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1. TABLE OF CONTENTS
                                                                                                                            
          
TITLE PAGE
1
1.
TABLE OF CONTENTS
3
2. LIST OF ABBREVIATIONS
5
3.
RESPONSIBLE PARTIES
6
4.
ABSTRACT
7
5 . AMENDMENTS AND UPDATES
11
6.
MILESTONES
11
7.
RATIONALE AND BACKGROUND
11
8.
RESEARCH QUESTION AND OBJECTIVES
13
9.
RESEARCH METHODS
13
9.1 STUDY DESIGN
13
9.2 SETTING
16
9.2.1 Study sites
16
9.2.2 Study population
16
9.2.3 Study visits
16
9.2.4 Study discontinuation
16
9.3  VARIABLES
16
9.3.1 Exposures
16
9.3.2 Endpoints
17
9.3.2.1 Primary endpoints
17
9.3.2.2 Secondary endpoints
17
9.3.3  Covariates
17
9.4 DATA SOURCES
18
9.5 STUDY SIZE
19
9.6 DATA MANAGEMENT
19
9.7 DATA ANALYSIS
19
9.7.1 Main analysis
19
9.7.3 Safety Analysis
20
9.8 QUALITY CONTROL
20
9.9 LIMITATIONS OF THE RESEARCH METHODS
20

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9.10 OTHER ASPECTS
20
9.10.1   Data quality assurance
20
9.10.2 Study records
20
9.10.2.1 Source documents
21
9.10.2.2 Direct access to source data and documents
21
9.10.3 Completion of study
21
9.10.4 Protocol deviations
21
9.10.5 Compensation available to the patient in the event of study related injury
21
10.PROTECTION OF HUMAN SUBJECTS
21
10.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED    CONSENT
21
10.2 STATEMENT OF CONFIDENTIALITY
21
11.MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS
21
12.PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
21
13.REFERENCES
22
13.1 PUBLISHED REFERENCES
22
13.2 UNPUBLISHED REFERENCES
23
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
23
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
23
ANNEX 3. ADDITIONAL INFORMATION
23
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES
23

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2. LIST OF ABBREVIATIONS
ADR , Adverse Drug Reaction 
AE , Adverse Event 
AESI , Adverse Event of Special interest 
CA , Competent Authority 
CCDS , Company Core Data Sheet 
CI , Confidence Interval 
CML , Local Clinical Monitor  
CRA , Clinical Research Associate 
CRF , Case Report Form 
CTCAE , Common Terminology Criteria for Adverse Events 
CTP , Clinical Trial Protocol 
eCRF , Electronic Case Report Form 
ENCePP  , European Network of Centres for Pharmacoepidemiology and Pharmacovigilance  
FDA , Food and Drug Administration 
GCP , Good Clinical Practice 
GEP , Good Epidemiological Practice 
GPP , Good Pharmacoepidemiology Practice 
GVP , Good Pharmacovigilance Practices 
IB , Investigator’s Brochure 
IEC , Independent Ethics Committee 
IRB , Institutional Review Board 
MAH , Marketing Authorization Holder 
MedDRA , Medical Dictionary for Regulatory Activities 
NIS , Non-Interventional Study 
PASS , Post-Authorization Safety Study 
SAE , Serious Adverse Event Adapt and complete as appropriate

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3. RESPONSIBLE PARTIES
Institution
Investigators
BI

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4. ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiriva Respimat
Name of active ingredient:
Tiotropium
Protocol date: Study number:
Version/Revision:
Version/Revision date:
12 May 2021
0205-0547
1.0
12 May 2021
Title of study: Exacerbation Risk and Health Care Resource use among patients with 
asthma using ICS+Tiotropium versus ICS/LABA
Date: 05/12 2021
Version Number:1
Rationale and 
background:
Regardless of severity level, patients with uncontrolled asthma are prone to 
exacerbations, increased use of systemic corticosteroids, and rescue 
medications. Guidelines recommend increasing the dose of ICS product or 
use of ICS in combination with long-acting β2-agonists (LABA), and/or 
other add-on therapy such as with a long-acting muscarinic antagonist 
(LAMA), leukotriene receptor antagonists (LTRA), biologics or oral 
corticosteroids. RCTs have found similar responses in terms of lung function 
and exacerbations between patients on ICS/Tiotropium and ICS/LABA. 
ICS/LABA is very commonly used in the real world since 2003, and 
Tiotropium was only available in the US since 2016, so it’s important we 
generate real world evidence data complimenting the ICS/Tiotropium RCT 
data as an alternative to ICS/LABA. It is important to evaluate the role of a 
LAMA in combination with ICS using real world data to support further 
treatment recommendations.
Research 
question and 
objectives:
To conduct a comparative analysis of patients using Tiotropium in 
combination with Inhaled Corticosteroids (ICS) versus those that use LABA 
medication in combination with ICS.
Study design:
This is a non-interventional study based on existing data. Patients will be 
classified into two groups: 1. ICS+Tio and 2. ICS/LABA. We will record 
various baseline measures, including demographics such as gender, age, and 
region, comorbidity level defined using Charlson Comorbidity Index (CCI), 
other specific comorbidities not included in the CCI, inhaled medication use, 
ICS dose level, control level, and other listed measures. Using propensity 
score matching (PSM) technique, we will develop matched cohorts of 
patients between the ICS+Tio and ICS/LABA groups.   
Population:
1. ICS+Tio; and 2: ICS/LABA.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiriva Respimat
Name of active ingredient:
Tiotropium
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
12 May 2021
0205-0547
1.0
12 May 2021
Variables:
The exposure variables are ICS+Tio use vs. ICS/LABA use in 
combination with ICS.
PSM 
●
Gender
●
Age group
●
Region
●
ICS dose level
●
Control level
●
Rescue medication use
●
Comorbidities included in the Charlson Comorbidity Index 
●
ICS history (yes/no)
●
ICS history duration
●
Season of index date
●
Index year
●
Baseline all-cause resource use (presence vs. absences of 
hospitalizations, or ER visits, or outpatient visits)
●
Baseline other asthma medications (use vs. no use)
●
Baseline overall medication history (polypharmacy defined as 
number of unique medications)
●
Insurance type
●
Hypertension
●
Gastroesophageal reflux disease
●
Allergic Rhinitis
●
Obesity
●
Sinusitis
●
Obstructive sleep apnea
●
Cardiovascular disease
●
Diabetes
●
Renal failure
●
Arthritis
●
Osteoporosis
●
Depression
●
Cancer (excluding basal cell carcinoma)  
●
Baseline pneumonia diagnosis 
●
Diagnosis of dyspnea during baseline identified using ICD 9 786.0x 
and ICD 10 R06.0x

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiriva Respimat
Name of active ingredient:
Tiotropium
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
12 May 2021
0205-0547
1.0
12 May 2021
Variables:
●
Diagnosis of alcohol dependence during baseline identified using 
ICD 9 303.xx, 305.0x and ICD 10 F10.xx 
●
Smoking dependence during baseline identified using ICD 9 305.1 
and ICD 10 F17.xx
Regression
In addition to the key independent variable of interest (ICS+TIO vs 
ICS/LABA group), we will include time varying medication exposure as a 
covariate in the regression.
Data sources:
We will utilize medical and pharmacy claim records from
medical 
and pharmacy claims data. This database is comprised of adjudicated 
claims for more than 150 million commercially insured and Medicare lives 
in the US.
Study size:
There are 25,291 patients with a prescription claim for tiotropium 
(1.25mcg, October 2015-May 2020) identified for analysis and 1,125,657 
patients with ICS/LABA prescription claims (July 2014-May 2020). After 
excluding patients with COPD there are 17,882 patients in the Tio group 
and 921,804 patients in the ICS/LABA group. Further inclusion-exclusion 
criteria as well as restricting the Tio group to those with concurrent ICS 
monotherapy, will be applied to arrive at the final sample.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiriva Respimat
Name of active ingredient:
Tiotropium
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
12 May 2021
0205-0547
1.0
12 May 2021
Data analysis
Sample attrition at each step of the inclusion-exclusion criteria will be 
provided. We will develop the breakdown of the distribution of 
demographic, comorbidity, and baseline measures prior to and after the 
PSM (unmatched and matched cohorts). Significance of differences will 
be tested at P<0.05 for the matched cohort. Additionally, we will consider 
the use of standardized mean differences as noted above, in which SMD 
<0.1 indicates balance. The primary endpoint measure is time to first 
severe exacerbation and severe exacerbation will be defined as a 
hospitalization or an ER visit with a primary diagnosis of asthma. We will 
calculate the time in days to first exacerbation. We will conduct Cox 
proportional hazards modeling to estimate the risk of exacerbation and 
provide corresponding KM curves for the primary endpoint. Exposure to 
each of the study comparators (ICS+Tio and ICS/LABA) will be recorded 
using time-varying covariates for all primary and secondary endpoints. 
ICS+Tio vs. ICS/LABA will be the key independent variable and 
medication exposure will be a covariate included in the regression. 
Secondary endpoints will include time (in days) to first moderate-or-
severe exacerbation defined as use of systemic corticosteroid or a 
hospitalization or ER visit with a primary diagnosis of asthma. Cox PH 
and KM curves will be conducted for this secondary end point as well. We 
will also calculate and compare the rate of exacerbation, proportion of 
patients with exacerbations after 6 months and one year among the sub-
population of patients having at least 6 months and a one year of follow-
up, respectively. We will report rates in patient-years to account for 
variable follow-up time. We will also compare the mean monthly (to 
account for variable follow-up time) per patient HCRU (all-cause and 
asthma related hospitalizations, ER visits, and outpatient visits) during the 
follow-up period, between the two groups. Proportions of patients with 
and without rescue medication use will be compared between the two 
groups as well.

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5 . AMENDMENTS AND UPDATES
None
6. MILESTONES
Study design and core group alignment
Week 1-2
Data receipt, extraction, cleaning and evaluation for protocol 
development
Week 2
Study protocol draft
Week 4
Study protocol final
Week 6
IET/NPCC approval
Week 8/9
Descriptive statistics draft
Week 11-12
Multivariate analysis draft
Week 12-14
Final results (Excel)
Week 16-17
Study narrative report 
Week 17-18
7. RATIONALE AND BACKGROUND
Asthma is associated with a significant burden on the healthcare system. More than half the 
population of asthma patients remains uncontrolled despite therapy, and uncontrolled asthma 
is associated with greater economic and health care burden (Braido et al. 2013; Peters et al. 
2007). Stepwise treatment approach depending on control and severity levels has been the 
corner stone of asthma therapy. Regardless of severity level, patients with uncontrolled 
asthma are prone to exacerbations, increased use of systemic corticosteroids, rescue 
medications, deteriorating lung function (Chung et al. 2014), reduced quality of life, and 
increased health care resource use. In such cases, guidelines recommend increasing the dose 
of ICS product or use of ICS in combination with long-acting β2-agonists (LABA), and/or 
other add-on therapy such as with a long-acting muscarinic antagonist (LAMA), leukotriene 
receptor antagonists (LTRA), biologics or oral corticosteroids. Treatment strategies that rely 
on step treatment may not always be sufficient in controlling asthma. 
Given the unmet needs, other therapeutic options should be considered in this population. In 
investigating Tiotropium (Handihaler and Respimat) for the treatment of asthma, 6 clinical 
trials (found similar responses in lung function and exacerbations when comparing 
ICS/Tiotropium to ICS/LABA. In a randomized controlled trial of moderate asthma patients, 
Kerstjens et al 2015 reported a lower rate of exacerbations among patients with 
ICS/Tiotropium when compared to ICS/Salmeterol (ICS/LABA)  however formal 
comparisons could not be made since the ICS/salmeterol group was included to provide a 
standard add-on active comparator and was not part of the inferential analysis. Kerstjens et al 
study concluded that “Once-daily tiotropium as add-on treatment to medium-dose inhaled 
corticosteroids provided significant improvements in lung function and asthma control that 
were similar to those recorded for twice-daily salmeterol. In summary, RCTs have found 

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similar responses in terms of lung function and exacerbations between patients on 
ICS/Tiotropium and ICS/LABA.
In 2020 NHLBI updated the Asthma guidelines recommending low dose ICS+LAMA as an 
alternative in Steps 3 and 4 noting that” the majority of LAMA studies use a comparative 
efficacy design and thus, their clinical impact is not well understood in real-world settings.” 
The NHLBI response highlighted the need for RWE to close this data gap. This proposed real 
world evidence (RWE) study will fill a data gap of assessing exacerbation differences with 
ICS/Tiotropium.  ICS/LABA is very commonly used in the real world since 2003, and 
Tiotropium was only available in the US since 2016, so it’s important we generate real world 
evidence data complimenting the ICS/Tiotropium RCT data as an alternative to ICS/LABA 
using real world data to support further treatment recommendations.

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8. RESEARCH QUESTION AND OBJECTIVES
To conduct a comparative analysis of patients using Tiotropium in combination with Inhaled 
Corticosteroids (ICS) versus those that use LABA medication in combination with ICS.
9. RESEARCH METHODS
      9.1 STUDY DESIGN
1. Patients with least two asthma diagnosis (ICD 9 CM: 493.xx or ICD 10: J45-
J45.999) will be included. 
2. Patients will be required to be concurrently on ICS+Tiotropium (specifically 
Tiotropium Respimat® 1.25 mcg) or ICS/LABA. 
3. Patients with least two diagnosis of COPD at any time during the study period 
will be excluded.  
4. Patients less than 12 years of age will be excluded.
5. Patients will be required to have enrollment for at least 6 months prior to 
ICS+Tio or ICS/LABA use. 
6. Patients on biologics within 6 months prior to ICS+Tio or ICS/LABA use will 
be excluded. 
7. Patients with prior Tio or ICS/LABA use during the 6-month baseline period
will be excluded.
8. Patients with urinary bladder obstruction, urinary retention, and glaucoma 
will be excluded.
9. After the PSM process, unmatched patients will be excluded.
Patients will be classified into two groups based on the exposure on the index date: 1. 
ICS+Tio; and 2: ICS/LABA. The date of concurrent medication initiation will be defined as 
the index date based on the date of the first prescription claim defining their add-on 
medication. We will record various baseline measures, including demographics such as 
gender, age, and region, comorbidity level defined using Charlson Comorbidity Index (CCI), 
other specific comorbidities not included in the CCI (Table 1), inhaled medication use, and 
control level as defined in Table 1. Additionally, we will classify patients based on their 
daily ICS dose levels as ‘low dose ICS’, ‘medium dose ICS’, and ‘high dose ICS’. The dose 
levels will be assigned per GINA 2020 criteria (Global Initiative for Asthma. Global Strategy 
for Asthma Management and Prevention 2020). Medications that are available with only two 
dose level indications will be tagged as ‘low’ for the lower of the two dose levels, and ‘high’ 
for the highest dose level. 

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           Table 1: Baseline Parameters and Variable Definitions
Variable Name and Type
Description and Definition
Covariate Adjustment Method 
Demographics 
Age (5-year increments), Gender,
PSM
Region
Region (Northeast, Midwest, South, West)
PSM
CCI 
Charlson Comorbidity Index score
PSM
Inhaled medication use 
Identified using unique claims during the baseline 
period  
PSM
Control Status:
Not Well Controlled or 
Well Control 
“Not Well Controlled” if patient has any one of 
the following events

Prescription for OCS

Asthma-related ER

Asthma-related hospitalizations
“Well controlled” if patient has none of the above 
events 
(Ref: Stempel JACI 2005)
PSM
ICS history 
Defined by use of ICS monotherapy prior to 
index date
PSM
ICS history duration
Days on ICS monotherapy prior to index date
PSM
ICS dose level 
Daily dose of ICS classified as low dose ICS, 
medium dose ICS, and high dose ICS
PSM
Season
Season of cohort entry (Summer, Spring, Fall, 
Winter)
PSM
Index year
Year of the index date
PSM
All-cause resource use
All-cause hospitalizations, ER visits, outpatient 
visits
PSM
Other asthma medications
Leukotriene modifiers 
PSM
Medication history
Polypharmacy calculated based on number of 
unique medications
PSM
Insurance type
Identified using payer type data field
PSM
Hypertension
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Allergic rhinitis
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Sinusitis
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Obstructive sleep apnea
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Gastro-esophageal reflux 
disease
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Obesity
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Cardiovascular disease
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Diabetes
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM

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Table 1: Baseline Parameters and Variable Definitions (cont)
Variable Name and Type
Description and Definition
Covariate Adjustment Method 
Renal failure
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Arthritis
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Depression
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Osteoporosis
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Cancer (excluding basal 
cell carcinoma)  
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Pneumonia
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Acute bronchitis
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Dyspnea
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Alcohol dependence
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Smoking dependence
Identified using appropriate ICD codes. Coded as 
binary (yes/no) variables
PSM
Using propensity score matching (PSM) technique, we will develop matched cohorts of 
patients between the ICS+Tio and ICS/LABA groups. We will conduct 1:2 matching using 
nearest neighbor matching approach. Upon completion of matching, we will assess whether
the cohorts are balanced by examining the statistically significant differences at p<0.05. We 
will also assess balance by calculating standardized mean differences (SMD). An SMD <0.1 
will be considered balanced. Follow-up time will be calculated between index date and 
‘Censor date’ which will be defined as the date of either one of the following events: 1. Date 
of first exacerbation, 2. Date of medication switch, 3. Discontinuation of medication (defined 
as date of prescription claim plus days’ supply, plus 50% additional days), 4. Enrollment end 
date, or 5. Last date available in the dataset/End of study period. In this “new user”, study 
design, primary analysis will be an “as-treated” analysis. In order to attribute events and 
outcomes to patients during the time that they are exposed to treatment (based on days-
supply of prescription claims + a buffer window) as well as account for differences in inter-
group adherence levels, we will use a time-varying covariate approach to classify drug 
exposure time for each comparator drug during follow up. This approach has been chosen to 
minimize bias based on potentially large differences in medication adherence rates, by only 
attributing outcomes to the time in which patients have medication in their possession based 
on days’ supply as described below. For each individual study drug, we will identify and 
define medication exposure and non-exposure windows during the follow-up time for each 
medication using the date of prescription filled plus the days’ supply listed on the 
prescription claim plus 50% additional days (to account for residual doses in canister, poor 
real-world adherence and latency of drug effects). For example, exposure start and stop dates 

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for a patient with a prescription claim with 30 days supply on January 1st will be January 1st
and February 15th respectively (30 days’ supply +15 days). We will run sensitivity analyses 
on the exposure window using 0% and 100% additional days. These time varying exposure 
covariates will be included in the Cox PH regression.
If statistical differences are found after PSM, then the study team will make a determination 
to either include them as covariates in the regression analysis (Cox PH), or develop 
interaction terms to match on, or discontinue the study. In the event of study discontinuation, 
partial results (all analysis leading up to and including PSM) will be provided in a final 
report. 
      9.2 SETTING
       Please see section 9.1.
       9.2.1 Study sites     
           Please see section 9.1 and 9.4
       9.2.2 Study population
              Please see section 9.1.
       9.2.3 Study visits
            Not applicable
       9.2.4 Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Violation of Good Pharmacoepidemiology Practice (GPP), the study protocol, or the 
contract by a study site, investigator, or research collaborator, disturbing the appropriate 
conduct of the study
The investigator/the study site/research collaborator will be reimbursed for reasonable 
expenses incurred in case of study/site termination (except in case of the third reason).
      9.3 VARIABLES
      9.3.1 Exposures
The exposure variables are Tio use vs. LABA use in combination with ICS. The operational 
definitions are provided in the sections above. After PSM, the cohort group will be the key 
predictor for the Cox PH regression to assess the primary outcome.

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       9.3.2 Endpoints
            9.3.2.1 Primary endpoints
The primary endpoint measure is time to first severe exacerbation. Severe exacerbations will 
be defined as: 
●
A hospitalization with a primary diagnosis of asthma or
●
An ER visit with a primary diagnosis of asthma
           9.3.2.2 Secondary endpoints
Secondary endpoints will include:
●
Time to first moderate-or-severe exacerbation 
o
Any systemic corticosteroid use or
o
A hospitalization with a primary diagnosis of asthma or
An ER visit with a primary diagnosis of asthma
●
Proportion of patients with exacerbation
●
Rate of exacerbation at 6 months and one year
●
Proportions of patients with Health care resource utilization (HCRU). HCRU is 
defined as hospitalizations, emergency room (ER) visits, and outpatient visits during 
follow-up, all-cause and asthma related. 
●
Mean monthly HCRU (including frequency of hospitalizations, ER visits, OP visits)
●
Proportion of patients with use of rescue medications (defined as patients with one or 
more SABA claims during the follow-up period)
    
    
      9.3.3  Covariates
      The covariates included in the PSM will be 
●
Gender
●
Age group
●
Region
●
ICS dose level
●
Control level
●
Rescue medication use
●
Comorbidities included in the Charlson Comorbidity Index 
●
ICS history (yes/no)
●
ICS history duration
●
Season of index date
●
Index year
●
Baseline all-cause resource use (presence vs. absences of hospitalizations, or ER 
visits, or outpatient visits)
●
Baseline other asthma medications (use vs. no use)

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●
Baseline overall medication history (polypharmacy defined as number of unique 
medications)
●
Insurance type
●
Hypertension
●
Gastroesophageal reflux disease
●
Allergic Rhinitis
●
Obesity
●
Sinusitis
●
Obstructive sleep apnea
●
Cardiovascular disease
●
Diabetes
●
Renal failure
●
Arthritis
●
Osteoporosis
●
Depression
●
Cancer (excluding basal cell carcinoma)  
●
Baseline pneumonia diagnosis 
●
Baseline acute bronchitis diagnosis 
●
Diagnosis of dyspnea during baseline identified using ICD 9 786.0x and ICD 10 
R06.0x
●
Diagnosis of alcohol dependence during baseline identified using ICD 9 303.xx, 
305.0x and ICD 10 F10.xx 
●
Smoking dependence during baseline identified using ICD 9 305.1 and ICD 10 
F17.xx
In addition to the key independent variable of interest (ICS+TIO vs ICS/LABA group), we
will include time varying medication exposure as a covariate in the regression.
        9.4 DATA SOURCES
We will utilize medical and pharmacy claim records from 
medical and pharmacy claims data. This database is comprised of adjudicated claims for 
more than 150 million commercially insured and Medicare lives in the US. Data between 
2014 and 2020 will be extracted, with the first patient follow-up period for tiotropium 1.25 
mcg dose patients starting in October of 2015.  This longitudinal database allows 
documentation and analysis of the patient journey from diagnosis to intervention and follow-
up. The database includes patients in the majority of three-digit zip codes and in every 
metropolitan statistical area of the US.  It also covers data from 90% of US hospitals, 80% of 
all US doctors, and represents 85% of the Fortune 100 companies, with current HIPAA 
(Health Insurance Portability and Accountability Act) regulations. The database is 
constructed from a variety of geographic regions and employer groups and maintains a level 
of diversity while representing the overall trend in commercial health plan coverage. The 
underrepresentation of the population aged 65 years and older may affect external validity in 
the case of Medicare, Medicare Advantage or Medicaid patients.

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        9.5 STUDY SIZE
There are 25,291 patients with a prescription claim for tiotropium (1.25mcg, October 2015-
May 2020) identified for analysis and 1,125,657 patients with ICS/LABA prescription claims 
(July 2014-May 2020). After excluding patients with COPD there are 17,882 patients in the 
Tio group and 921,804 patients in the ICS/LABA group. Further inclusion-exclusion criteria 
as well as restricting the Tio group to those with concurrent ICS monotherapy, will be applied 
to arrive at the final sample. 
       9.6 DATA MANAGEMENT
The data management plan is summarized below. Full details of the data management plan 
are documented in a separate NIS-Data Management and Review Plan (NIS-DMRP).
All established security and confidentiality procedures will be observed by BI and/or 
 personnel who are assigned appropriate access to the data. Enrolment data, medical 
claims, and prescription claims will be accessed from the administrative claims dataset. The 
analyses will be performed on limited data sets that are void of member protected health 
information and all results were shared in aggregate form only.
        9.7 DATA ANALYSIS
        9.7.1 Main analysis
Sample attrition at each step of the inclusion-exclusion criteria will be provided. We will 
develop the breakdown of the distribution of demographic, comorbidity, and baseline 
measures prior to and after the PSM (unmatched and matched cohorts). Significance of 
differences will be tested at P<0.05 for the matched cohort. Additionally, we will consider the 
use of standardized mean differences as noted above, in which SMD <0.1 indicates balance
of baseline covariates. The primary endpoint measure is time to first severe exacerbation and 
severe exacerbation will be defined as a hospitalization or an ER visit with a primary 
diagnosis of asthma. We will calculate the time in days to first exacerbation. Also, as part of 
the primary end point analysis, we will develop KM curves based on initial exposure and 
conduct time varying Cox proportional hazards modeling accounting for changes in exposure 
status over the follow up time to estimate the risk of exacerbation between ICS+Tio vs. 
ICS/LABA. Secondary endpoints will include a number of measures. We will calculate the 
time in days to first moderate-or-severe exacerbation defined as use of systemic 
corticosteroid or a hospitalization or ER visit with a primary diagnosis of asthma. KM curves
based on initial exposure and time varying Cox PH models will be conducted for this 
secondary end point as well. We will also calculate and compare the rate of exacerbation, 
proportion of patients with exacerbations after 6 months and one year among the sub-
population of patients having at least 6 months and a year of follow-up, respectively. We will 
report rates in patient-years to account for variable follow-up time. We will also compare the 
mean monthly (to account for variable follow-up time) per patient HCRU (all-cause and 
asthma related hospitalizations, ER visits, and outpatient visits) during the follow-up period, 
between the two groups. Proportions of patients with and without rescue medication use will 
be compared between the two groups as well.

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        9.7.3 Safety Analysis
              
         No Adverse Events are anticipated to be identified in this study.
        9.8 QUALITY CONTROL
The quality control, review, and monitoring plan are summarized below. Greater details are 
documented in the NIS-DMRP.
All programming will be quality controlled by two-step code checking by 
. All 
results generated will be reviewed internally by two co-investigators separately prior to 
finalization.
        9.9 LIMITATIONS OF THE RESEARCH METHODS
As with all studies utilizing claims data, there are certain limitations. The presence of a claim 
for a filled prescription or prescription absent claim does not indicate that the medication was 
consumed or that it was taken as prescribed. Medications filled over-the-counter or provided 
as samples by the physician will not be observed in the claims data. Patients with commercial 
health insurance may be different from those with non-commercial or without (commercial) 
health insurance, and hence study results may not be generalizable to the overall population. 
Population aged 65 years and older might be underrepresented, which may affect external 
validity in the case of Medicare, Medicare Advantage or Medicaid patients. Socioeconomic 
data is not available and can affect asthma outcomes. Since unmatched patients will be 
excluded, the results may not be generalizable to all patients. Some study measures and 
outcomes will include missing data and hence reduce the sample size. Patient 
misclassification, missing data, objective and reliable measurement of patient outcomes, and 
lack of detailed information regarding subjects’ clinical history or clinical status during the 
study timeframe may undermine the accuracy of our study results.
       9.10 OTHER ASPECTS
               None
        9.10.1   Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
        9.10.2 Study records
               NA

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             9.10.2.1 Source documents
                NA
               9.10.2.2 Direct access to source data and documents
               NA
         9.10.3 Completion of study
                
              NA
         9.10.4 Protocol deviations
               
               NA
         9.10.5 Compensation available to the patient in the event of study related injury
                   
                 NA
10.PROTECTION OF HUMAN SUBJECTS
Ethical approval is not required for this study.
       10.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED    
CONSENT
NA
       10.2 STATEMENT OF CONFIDENTIALITY
NA
11.MANAGEMENT AND REPORTING OF ADVERSE
EVENTS/ADVERSE REACTIONS
Not applicable based on secondary use of data without any potential that any employee of BI 
or agent working on behalf of BI will access individually identifiable patient data.  
12.PLANS FOR DISSEMINATING AND COMMUNICATING STUDY
RESULTS
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.

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13.REFERENCES
13.1 PUBLISHED REFERENCES
P10-10772 Peters SP, Kunselman SJ, Icitovic N et al. Tiotropium bromide step-up therapy for 
adults with uncontrolled asthma.N. Engl. J. Med., 363 (2010), pp. 1715-1726
P11-09529  Bateman ED, Kornmann O, Schmidt P et al. Tiotropium is noninferior to 
salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma J. 
Allergy Clin. Immunol., 128 (2011), pp. 315-322
P14-03600 Chung KF et al. International ERS/ATS Guidelines on definition evaluation and 
treatment of severe asthma. Eur Respir J 43, 343-373 (2014)
P15-01655 Kerstjens HA et al. Tiotropium or salmeterol as add-on therapy to inhaled 
corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, 
placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respiratory 
Medicine. 2015 May;3(5):367-76.
P15-10269 Feehan M et al. Adherence to controller asthma medications: 6-month prevalence 
across a US community pharmacy chain. Journal of Clinical Pharmacy and Therapeutics, 
2015
P15-11415 Wechsler M, Yawn B, Fuhlbrigge A et al. Anticholinergic vs Long-Acting β-
Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma: The 
BELT Randomized Clinical Trial. JAMA. 2015 Oct 27;314(16):1720-30.
P18-01651 Zhang L, Huang G, Jin L et al. Therapeutic effects of a long-acting cholinergic 
receptor blocker, tiotropium bromide, on asthma.Med. Sci. Mon. Int. Med. J. Exp. Clin. Res., 
24 (2018), pp. 944-950
P18-08471 Buhl R, FitzGerald JM, Busse W. Tiotropium add-on to inhaled corticosteroids 
versus addition of long-acting β2-agonists for adults with asthma. Respiratory Medicine. 
2018. 143. Pages 82-90.
P19-00715 Braido F. Failure in Asthma control: Reasons and Conseuqences. Scientifica 
2013.  549252 (2013)
P20-04444 Chipps B, Mosnaim G, Mathur SK, et al. Add-on tiotropium versus step-up 
inhaled corticosteroid plus long-acting beta-2-agonist in real-world patients with asthma. 
Allergy Asthma Proc. 2020;41(4):248-255. doi:10.2500/aap.2020.41.200036
P20-10184 Global Initiative for Asthma. Global Strategy for Asthma Management and 
Prevention (online appendix, updated 2020) 
https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-Appendix_final-wms.pd f (access 
date: 6 November 2020); 2020

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R16-0701 Peters SP, Jones CA, Haselkorn T, Mink DR, Valacer DJ, Weiss ST. Real- world 
Evaluation of Asthma Control and Treatment (REACT): findings from a national web-based 
survey.  J Allergy Clin Immunol 119 (6) 1454-1461 (2007)
R21-2127 Wu A et al. Primary Adherence to Controller Medications for Asthma Is Poor. Ann 
Am Thorac Soc. 2015 Feb;12(2):161-6
R21-2128 Stempel, David A. et al.Patterns of asthma control: A 3-year analysis of patient 
claims
Journal of Allergy and Clinical Immunology, Volume 115, Issue 5, 935-939
13.2 UNPUBLISHED REFERENCES
         NA
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Not applicable
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable
ANNEX 3. ADDITIONAL INFORMATION
None
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES
Signatures will be provided electronically via approval workflow in the DMS for submission 
documents.