Characteristics of Patients Initiating Spiriva Respimat in Asthma in the UK: a Cross-sectional Study Based on the Clinical Practice Research Datalink
Conditions: Asthma
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:
c25002535-01
BI Study Number:
0205-0537
BI Investigational
Product(s):
Spiriva Respimat
Title:
Characteristics of patients initiating Spiriva Respimat in Asthma in the 
UK: a cross-sectional study based on the Clinical Practice Research 
Datalink 
Brief Lay Title
Characteristics of patients who start to use the Spiriva Respimat® to 
treat their Asthma: a study based on the Clinical Practice Research 
Datalink in the UK
Protocol version identifier:
1.1
Date of last version of 
protocol:
Not applicable
PASS:
No
EU PAS register number:
Not  applicable
Active substance:
Tiotropium bromide (ATC code R03B B04)
Medicinal product:
Tiotropium® Respimat®
Product reference:
Not applicable
Procedure number:
Not applicable
Joint PASS:
No
Research question and 
objectives:
The main objective of the study is to describe the clinical and socio-
demographic characteristics of asthma patients prior to the initiation 
of Spiriva Respimat for the treatment of Asthma within a general 
clinical population using the Clinical Practice Research Database 
(CPRD).
A secondary objective will be to describe and compare the 
characteristics of asthma patients who initiated Spiriva Respimat to 
asthma patients who initiated a higher dose of ICS/LABA FDC, or 
leukotriene receptor antagonist (LTRA), or alternatively those who 
switched from the previous ICS/LABA FDC to a new ICS/LABA 
FDC.
Country(-ies) of study:
United Kingdom

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Author:
Tel.:
Fax:
E-mail: 
Marketing authorisation 
holder(s):
MAH contact person:
Not applicable
In case of PASS, add:
<EU-QPPV:>
Not applicable
In case of PASS, add:
<Signature of EU-
QPPV:>
Not applicable
Date:
Aug 3, 2018
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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..................................................................... 10
6.
MILESTONES..................................................................................................... 11
7.
RATIONALE AND BACKGROUND................................................................ 12
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 14
9.
RESEARCH METHODS .................................................................................... 15
9.1
STUDY DESIGN............................................................................................ 15
9.2
SETTING........................................................................................................ 15
9.3
VARIABLES .................................................................................................. 17
9.3.1
Exposures ................................................................................................ 17
9.3.2
Outcomes................................................................................................. 17
9.3.2.1
Primary outcomes..................................................................................17
9.3.2.2
Secondary outcomes..............................................................................18
9.3.3
Covariates................................................................................................ 20
9.4
DATA SOURCES........................................................................................... 22
9.5
STUDY SIZE.................................................................................................. 24
9.6
DATA MANAGEMENT................................................................................ 24
9.7
DATA ANALYSIS......................................................................................... 24
9.7.1
Main analysis........................................................................................... 24
9.7.3
Missing values......................................................................................... 25
9.8
QUALITY CONTROL................................................................................... 25
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 26
9.10
OTHER ASPECTS ......................................................................................... 27
9.11
SUBJECTS...................................................................................................... 27
9.11.1
Cases........................................................................................................ 27
9.11.2
Controls................................................................................................... 27

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9.12
BIAS................................................................................................................ 27
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 28
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 29
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 30
13.
REFERENCES .................................................................................................... 31
13.1
PUBLISHED REFERENCES......................................................................... 31
13.2
UNPUBLISHED REFERENCES................................................................... 32
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 33
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 34
ANNEX 3. CPRD MEDCODES INDICATING ASTHMA........................................ 41
ANNEX 4. CPRD MEDCODES INDICATING COPD.............................................. 47

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2.
LIST OF ABBREVIATIONS
A&E
Accident and Emergency
BI
Boehringer Ingelheim
BMI
Body mass index
BTS
British Thoracic Society
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CPRD
Clinical Practice Research Database
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
GP
General practitioner
GPP
Guideline for Good Pharmacoepidemiology Practices
HES
Hospital Episode Statistics
HES-APC
Hospital Episode Statistics Admitted Patient Care
HES A&E
Hospital Episode Statistics Accident and Emergency
ICS
Inhaled corticosteroids
IQR
Interquartile range
ISAC
Independent Scientific Advisory Committee
LABA
Long-acting beta agonists
LAMA
Long-acting muscarinic antagonists 
LTRA
Leukotriene receptor antagonist
NIS
Non-interventional study
NISed
Non-interventional study based on existing data
OCS
oral corticosteroids
PSD
Program specification document
RCP
Royal College of Physicians
RMP
Risk management plan
SIGN
Scottish Intercollegiate Guidelines Network
UTS
Up-to-standard

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3.
RESPONSIBLE PARTIES
The study investigators (Global Epidemiology) at Boehringer Ingelheim International GmbH
(BI) are responsible for the design and conduct of the study. The study protocol has been
written following the Code of Conduct by the European Network of Centres for
Pharmacoepidemiology and Pharmacovigilance (ENCePP) [R15-4870]. The investigators are
responsible for conducting the study in a manner that meets regulatory standards. The study
shall be conducted as described in the approved protocol. All revisions to the protocol will be
properly documented as protocol amendments.

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiriva® Respimat®
Name of active ingredient:
Tiotropium bromide (ATC code 
R03B B04)
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
3 Aug, 2018
0205-0537
1.0
3 Aug, 2018
Title of study:
Characteristics of patients initiating Spiriva Respimat in Asthma in the UK: a 
cross-sectional, non-interventional study based on the Clinical Practice Research 
Datalink 
Rationale and 
background:
Asthma is a respiratory condition that causes symptoms of wheezing, shortness 
of breath, chest tightness and cough. [P18-03927] According to treatment 
guidelines, asthma patients at treatment step 3 and above treated with inhaled 
corticosteroids, often in combination with long-acting beta agonists. However, 
many patients continue to have symptoms despite the use of these agents. [P10-
08936]
In late 2014, Spiriva Respimat (tiotropium bromide), a long acting 
anticholinergic, was approved for treatment of asthma in the UK. Since this 
time, it has been approved for use in asthma patients in other countries including 
Japan and the United States.  The current BTS/SIGN Guideline for the 
management of asthma recommends tiotropium by soft-mist inhaler as an 
alternate controller therapy at steps three, four and five of the asthma treatment 
paradigm, on top of inhaled corticosteroid (ICS)/LABA. [P18-03927]
As tiotropium is the first of its class approved for the use in the treatment of 
asthma, it is important to identify patient clinical and socio-demographic 
characteristics of those who initiate this treatment as opposed to other available 
treatments. This type of study will allow us to evaluate potential channeling of 
prescribing to different patient populations.
Research 
question and 
objectives:
The main objective of the study is to describe the clinical and socio-
demographic characteristics of asthma patients prior to the initiation of Spiriva 
Respimat for the treatment of Asthma within a general clinical population using 
the Clinical Practice Research Database (CPRD).
A secondary objective will be to describe and compare the characteristics of 
asthma patients who initiated Spiriva Respimat to asthma patients who initiated 
a higher dose of ICS/LABA FDC, or leukotriene receptor antagonist (LTRA), or 
alternatively those who switched from the previous ICS/LABA FDC to a new 
ICS/LABA FDC.
Study design:
A cross-sectional assessment of asthma patients who initiated Spiriva Respimat, who 
initiated leukotriene receptor antagonist (LTRA), who received a higher dose of 
ICS/LABA FDC, or who switched to a new ICS/LABA FDC in asthma in the UK 

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiriva® Respimat®
Name of active ingredient:
Tiotropium bromide (ATC code 
R03B B04)
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
3 Aug, 2018
0205-0537
1.0
3 Aug, 2018
during the study period (September, 2014-December 31, 2017). (Non-interventional 
study based on existing data, NISed)
Population:
All adult patients who had a diagnosis of asthma before the index date, who 
received ICS/LABA FDC treatment and who were new initiators of Spiriva 
Respimat or those who initiated a higher dose of ICS/LABA FDC, a LTRA, or 
alternatively, those switched to a new ICS/LABA FDC.
The index date will be defined as the date of new initiation of Spiriva Respimat 
or the date of initiation of, or switch to, the treatments specified above.
Patients with a diagnosis of COPD as well as patients on any LAMA prior to the 
index date will be excluded from the main analysis. 
A history in the database of at least 1 year of continuous up-to-standard (UTS) 
registration in the CPRD prior to index date will be required to determine 
indications of use and previous treatments.
Variables:
As stated above the patients will be grouped by type of treatment initiated or 
switched to. This will include Spiriva Respimat, a higher dose of ICS/LABA
FDC, a new ICS/LABA FDC or an LTRA. Patient characteristics will be 
identified based on data recorded on the index date (date of dispensing/initiation 
of the exposure), or when a characteristic was not recorded on the index date, 
during the pre-index period (the one closest to the index date), unless otherwise 
specified.
The outcome is whether a patient has a cardiac arrhythmias diagnosis on 
the index date or in the year prior to the index date. The secondary 
outcome is whether a patient has a cardiac failure diagnosis on the index 
date or in the year prior to the index date.
In addition, the following covariates will be assessed in this study:

Demographic characteristics

Lifestyle factors

Asthma history and lab tests

Comorbidities

Concomitant prescriptions (both asthma related and non-asthma related 
prescriptions)
Data sources:
United Kingdom’s Clinical Practice Research Datalink (CPRD) GOLD database

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiriva® Respimat®
Name of active ingredient:
Tiotropium bromide (ATC code 
R03B B04)
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
3 Aug, 2018
0205-0537
1.0
3 Aug, 2018
Study size:
The study size is dependent on the uptake of Spiriva Respimat for asthma in the 
CPRD. Table 1 provides a range of estimates for different prevalence estimates 
of disease (or characteristics). The numerator represents the number of patients 
with the comorbidity of interest and the denominator represents the number of 
new users in the population. With 500 patients we would have adequate 
confidence intervals around these estimates.
Table 1.
Precision of estimates for proportion measures
Number of 
New Users
95% Confidence Intervals for Various Prevalences of Diseases 
(%)
1%
2%
5%
7%
10%
500
0.4-2.3
1.1-3.6
3.4-7.3
5.1-9.6
7.7-12.9
800
0.5-2.0
1.2-3.2
3.7-6.7
5.4-9.0
8.1-12.3
2,000
0.6-1.5
1.5-2.7
4.1-6.0
6.0-8.2
8.8-11.3
5,000
0.8-1.3
1.6-2.4
4.4-5.6
6.3-7.7
9.2-10.9
A feasibility check was conducted to assess the number of patients in the 
tiotropium group, after application of the study inclusion and exclusion criteria. 
The result indicated that between September 2014 and December 2017, the 
number of patients in the tiotropium group was around 935, which is sufficient 
for the study aims, as per the described precision estimates.
Data analysis:
For the primary objective of the study, patient characteristics will be tabulated 
and summarized for all new users of Spiriva Respimat. 
For the secondary objectives patient characteristics will be tabulated for the 
patients that initiated or switched to the other available treatments. Patient 
characteristics will be compared among patients who initiated Spiriva Respimat 
and patients in other treatment groups. Analyses will be conducted in 
unmatched cohorts and differences between Spiriva Restinmat and each of the 
other exposure groups will be assessed using absolute standardized differences 
(ASD), where an ASD of at least 10% will be considered a meaningful 
difference [R16-1227].
Milestones:
Start of data collection: September 1, 2018
End of data collection: September 30, 2018
Final report of study results: December 31, 2018

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5.
AMENDMENTS AND UPDATES
None.

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
September 1, 2018
End of data collection
September 30, 2018
Final report of study results:
December 31, 2018

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7.
RATIONALE AND BACKGROUND
Asthma is a respiratory condition that causes symptoms of wheezing, shortness of breath, 
chest tightness and cough [P18-03927]. According to treatment guidelines, asthma patients at 
treatment step 3 and above should be treated with inhaled corticosteroids often in 
combination with long-acting beta agonists. However, many patients continue to have 
symptoms despite the use of these agents [P10-08936].
In late 2014, Spiriva Respimat (tiotropium), a long acting anticholinergic, was approved for
treatment of asthma in the UK. Since this time, it has been approved for use in asthma 
patients in other countries including Japan and the United States.  In the U.K., Spiriva® 
Respimat® is indicated as an add-on maintenance bronchodilator treatment in adult patients 
with asthma who are currently treated with the maintenance combination of inhaled 
corticosteroids (≥800µg budesonide/day or equivalent) and long-acting beta2-agonists and 
who experienced one or more severe exacerbations in the previous year.
The current BTS/SIGN Guideline for the management of asthma recommends tiotropium by
soft-mist inhaler as an alternate controller therapy at steps three, four and five of the asthma 
treatment paradigm, on top of inhaled corticosteroid (ICS)/LABA [P18-03927].
Alternatively, these patients could also be treated with a higher dose of ICS or ICS/LABA or 
MART, addition of leukotriene receptor antagonist (LTRA), addition of theophylline, beta 
agonist tablet, or switching to a different ICS/LABA, as shown in figure 1.

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Figure 1
Summary of asthma management in adults.
Tiotropium is the first of its class approved for the use in the treatment of asthma. After a 
drug is launched in the market, it is important to identify patient clinical and socio-
demographic characteristics of patients who initiate this treatment as opposed to other 
available treatments for patients at the same stage of disease. This type of study will allow us 
to evaluate potential channeling of prescribing to different patient populations. The results of 
the current study can also be used to determine the variables included in the calculation of 
propensity scores in future studies.

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8.
RESEARCH QUESTION AND OBJECTIVES
The primary objective of the study is to describe the clinical and socio-demographic 
characteristics of asthma patients at the time of the initial prescription of Spiriva Respimat for 
the treatment of Asthma within a general clinical population using the GOLD database within
Clinical Practice Research Datalink (CPRD).
A secondary objective will be to describe and compare the characteristics of asthma patients 
who initiated Spiriva Respimat to asthma patients who initiated a higher dose of ICS/LABA
FDC, or LTRA, or alternatively those who switched to a new ICS/LABA FDC.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This study is a cross-sectional, non-interventional study based on existing data (NISed). The 
UK CPRD data will be used to assess the characteristics of asthma patients who were 
prescribed ICS/LABA FDC before the index date and who initiated Spiriva Respimat, or 
received a higher dose of ICS/LABA FDC, or initiated LTRA, or switched to a new 
ICS/LABA FDC in the UK during the study period (September 2014-December 2017). This 
will allow us to assess potential channeling of prescribing to different patient populations.
Note: Study period: September 2014-December 2017. 
This is a cross-sectional study and patients will not be followed up after the index date.
Patient characteristics will be evaluated on the index date, or when a characteristic was not recorded on the index date, 
during the pre-index period (the one closest to the index date).
In the UK, nearly all residents are registered in a general medical practice that uses electronic 
medical records. Some of those records are available for research purposes in the CPRD. 
CPRD contains diagnostic and prescribing information recorded by general practitioners 
(GPs) as part of their routine clinical practice in the UK. The database currently contains data 
for over 13.2 million patients with research-quality data from 680 UK practices; 5.69 million 
of these patients are active (still registered with a contributing GP practice) [R14-5257]. 
Patients registered are representative of the whole UK population in terms of age and sex. 
More detailed description of the CPRD data is provided in section 9.4.
9.2
SETTING
The study population will be asthmatic patients who were prescribed ICS/LABA FDC before 
the index date and who initiated Spiriva Respimat, or received a higher dose of ICS/LABA
FDC, or initiated LTRA, or switched to a new ICS/LABA FDC from the previous ICS/LABA
FDC in the UK during the study period (September, 2014-December 31, 2017). Selection of 
the above therapies is based on the BTS/SIGN guideline (see figure 1 in section 7). These 
therapies are all options at adult asthma treatment steps 3 or 4. Although theophylline and 

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beta-agonist tablet are also options for add-on therapy at steps 3 and 4, we will not include 
these two in the current study because they are not widely used in the U.K.
The index prescription will be one of the follows:

The first prescription of Spiriva Respimat during the study period;

The first prescription of ICS/LABA FDC with a higher daily dose (any higher dose)
(compared to the last prescription) during the study period (if there are more than 1 dose 
increase during the study period, only the first dose increase will be used in the 
analyses);

The first prescription of LTRA during the study period;

The first prescription of a new ICS/LABA FDC during the study period.
The index date is defined as the date of the index prescription.
In this study, all patients will be required to have at least 1 year of continuous up-to-standard 
(UTS) registration in the CPRD prior to index date to determine indications of use and 
previous treatments.
The in- and exclusion criteria of this study are as follows:
Inclusion criteria:

Aged 18 years and above at the index date

At least 12 months of continuous registration prior to the index date in a practice 
contributing up to standard (UTS) data to the CPRD

Had a diagnosis of asthma before the index date (In this study, an asthma diagnosis is 
defined as at least one medcode for asthma prior to the index date. Please refer to 
annex 3 for the detailed medcodes for asthma and the related Read terms)

Being treated with ICS/LABA FDC before the index date (at least one prescription 
within 3 months before the index date)

Patients who were new users of Spiriva Respimat, or LTRA, or patients who were 
prescribed a higher dose of ICS/LABA FDC, or patients who switched to a new 
ICS/LABA FDC from the previous ICS/LABA FDC
Exclusion criteria:

Patients who were prescribed other LAMA any time before or on the index date

In the primary analysis, patients who were diagnosed with COPD before or on the index 
date will be excluded from the study.
 
(In this study, a COPD 
diagnosis is defined as at least one Readcode for COPD before or on the index date. 
Please refer to annex 4 for the detailed medcodes for COPD and the related readterms)

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9.3
VARIABLES
All the variables will be identified based on data recorded on the index date (date of 
dispensing/initiation of the exposure), or when a characteristic was not recorded on the index 
date, during the pre-index period (the one closest to the index date), unless otherwise 
specified.
9.3.1
Exposures
The study drug of interest is Spiriva Respimat. The exposure in the Spiriva group will be 
initiation of Spiriva Respimat. The exposure in the comparator group will include: 1) 
initiation of LTRA; 2) an increase in daily dose of ICS/LABA FDC; and 3) switching to a 
new ICS/LABA FDC.
To make sure that patients who initiated Spiriva Respimat or LTRA are new users of these 
drugs, patients who initiated Spiriva Respimat must have no exposure to tiotropium before 
the index date, and patients who initiated LTRA must have no exposure to LTRA before the 
index date.
An increase in daily dose of ICS/LABA FDC refers to any increase in the daily dose. If there 
was more than 1 dose increase during the study period, only the first dose increase will be 
included in the analysis.
Switching to a new ICS/LABA FDC refers to patients who switched to a new ICS/LABA 
FDC with different drug ingredient that was not prescribed during the pre-index period. If 
there was more than 1 switch during the study period, only the first switch will be used in the 
analysis.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary outcome is whether patient has Cardiac arrhythmias on the index date or in the 
year prior to the index date. Cardiac arrhythmias is defined as having the following readcode 
in the above mentioned time period:
medcode
readcode
readterm
17597
327..00
ECG: supraventricular arrhythmia
19707
328..00
ECG: ventricular arrhythmia
29371
328Z.00
ECG: ventricular arrhythmia NOS
97780
G559.00
Arrhythmogenic right ventricular cardiomyopathy
6503
G57..11
Cardiac arrhythmias
426
G577.00
Sinus arrhythmia
31690
G57yA00
Re-entry ventricular arrhythmia
53893
Gyu5a00
[X]Other specified cardiac arrhythmias
26670
2432.00
O/E - pulse irregularly irreg.
18746
662S.00
Atrial fibrillation monitoring
45773
6A9..00
Atrial fibrillation annual review

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9479
7936A00
Implant intravenous pacemaker for atrial fibrillation
92361
793M000
Perc translum ablat pulmon vein to lft atrium conduct system
105554
8CMW200
Atrial fibrillation care pathway
57832
9Os..00
Atrial fibrillation monitoring administration
90187
9Os0.00
Atrial fibrillation monitoring first letter
90188
9Os1.00
Atrial fibrillation monitoring second letter
90189
9Os2.00
Atrial fibrillation monitoring third letter
90190
9Os3.00
Atrial fibrillation monitoring verbal invite
90191
9Os4.00
Atrial fibrillation monitoring telephone invite
63350
9hF..00
Exception reporting: atrial fibrillation quality indicators
39114
9hF1.00
Excepted from atrial fibrillation qual indic: Inform dissent
2212
G573.00
Atrial fibrillation and flutter
1664
G573000
Atrial fibrillation
35127
G573300
Non-rheumatic atrial fibrillation
96277
G573400
Permanent atrial fibrillation
96076
G573500
Persistent atrial fibrillation
23437
G573z00
Atrial fibrillation and flutter NOS
9.3.2.2
Secondary outcomes
The secondary outcome is whether patient has Cardiac failure on the index date or in the year 
prior to the index date. Cardiac failure is defined as having the following readcode in the 
above mentioned time period:
medcode
readcode
readterm
15058
14A6.00
H/O: heart failure
46912
14AM.00
H/O: Heart failure in last year
21235
1J60.00
Suspected heart failure
9913
1O1..00
Heart failure confirmed
46672
388D.00
New York Heart Assoc classification heart failure symptoms
106198
661M500
Heart failure self-management plan agreed
83502
662p.00
Heart failure 6 month review
12366
662T.00
Congestive heart failure monitoring
30779
662W.00
Heart failure annual review
95835
679X.00
Heart failure education
60099
67D4.00
Heart failure information given to patient
46636
68B6.00
Heart failure screen
105542
8CeC.00
Preferred place of care for next exacerbation heart failure
32945
8CL3.00
Heart failure care plan discussed with patient
103732
8CMK.00
Has heart failure management plan
106008
8CMW800
Heart failure clinical pathway
32898
8H2S.00
Admit heart failure emergency
17851
8HBE.00
Heart failure follow-up
91288
8Hg8.00
Discharge from practice nurse heart failure clinic
102585
8HgD.00
Discharge from heart failure nurse service
26115
8HHb.00
Referral to heart failure nurse
70619
8HHz.00
Referral to heart failure exercise programme

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71235
8Hk0.00
Referred to heart failure education group
48897
8HTL.00
Referral to heart failure clinic
106894
8IE1.00
Referral to heart failure exercise programme declined
90935
9hH..00
Exception reporting: heart failure quality indicators
30749
9hH0.00
Excepted heart failure quality indicators: Patient unsuitabl
64062
9hH1.00
Excepted heart failure quality indicators: Informed dissent
106545
9m5..00
High risk of heart failure screening invitation
12627
9N0k.00
Seen in heart failure clinic
19002
9N2p.00
Seen by community heart failure nurse
95021
9N4s.00
Did not attend practice nurse heart failure clinic
83481
9N4w.00
Did not attend heart failure clinic
69062
9N6T.00
Referred by heart failure nurse specialist
32911
9Or..00
Heart failure monitoring administration
19380
9Or0.00
Heart failure review completed
90193
9Or1.00
Heart failure monitoring telephone invite
90192
9Or2.00
Heart failure monitoring verbal invite
72965
9Or3.00
Heart failure monitoring first letter
72386
9Or4.00
Heart failure monitoring second letter
89650
9Or5.00
Heart failure monitoring third letter
21837
G232.00
Hypertensive heart&renal dis wth (congestive) heart failure
28684
G233.00
Hypertensive heart and renal disease with renal failure
57987
G234.00
Hyperten heart&renal dis+both(congestv)heart and renal fail
2062
G58..00
Heart failure
1223
G58..11
Cardiac failure
398
G580.00
Congestive heart failure
2906
G580.11
Congestive cardiac failure
10079
G580.12
Right heart failure
10154
G580.13
Right ventricular failure
9524
G580.14
Biventricular failure
23707
G580000
Acute congestive heart failure
32671
G580100
Chronic congestive heart failure
27884
G580200
Decompensated cardiac failure
11424
G580300
Compensated cardiac failure
94870
G580400
Congestive heart failure due to valvular disease
884
G581.00
Left ventricular failure
23481
G581.11
Asthma - cardiac
43618
G581.12
Pulmonary oedema - acute
5942
G581.13
Impaired left ventricular function
5255
G581000
Acute left ventricular failure
27964
G582.00
Acute heart failure
101138
G583.00
Heart failure with normal ejection fraction
101137
G583.11
HFNEF - heart failure with normal ejection fraction
106897
G583.12
Heart failure with preserved ejection fraction
104275
G584.00
Right ventricular failure
4024
G58z.00
Heart failure NOS
12590
G58z.11
Weak heart

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17278
G58z.12
Cardiac failure NOS
96799
G5y4z00
Post cardiac operation heart failure NOS
8966
G5yy900
Left ventricular systolic dysfunction
12550
G5yyA00
Left ventricular diastolic dysfunction
104876
G5yyB00
Right ventricular diastolic dysfunction
104333
G5yyC00
Diastolic dysfunction
20822
Q48y100
Congenital cardiac failure
66306
SP11111
Heart failure as a complication of care
26242
ZRad.00
New York Heart Assoc classification heart failure symptoms
9.3.3
Covariates
The following patient characteristics will be assessed in this study:
Demographic characteristics:

Age on the index date (continuous variable in years)

Age on the index date (categorical variable: 18-34 years, 35-49 years, 50-64 years, 
65 years and above)

Gender (male, female)

Ethnicity (if available)

Patient level Index of Multiple Deprivation (IMD)
Lifestyle factors

Smoking status (closest to index date; if available)

Alcohol consumption (closest to index date; if available)

Body mass index (BMI) (closest to index date; if available)

Systolic and Diastolic Blood pressure measurement (closest to index date; if available)
Asthma history and lab tests

Number of asthma exacerbations in the year prior to the index date. This is defined as 
as ≤300 mg oral corticosteroids (OCS) (not prescribed during an annual asthma review), 
or an Accident and Emergency (A&E) visit, or hospital admission. Exacerbations 
recorded within 14 days after the index 1 were considered part of the same exacerbation.

Royal College of Physicians (RCP) 3 Questions for Asthma score on the index date, or 
when it was not recorded on the index date, during the pre-index period (the one closest to the 
index date) (each question scored 0 (no) or 1 (yes) for the following three questions: 
“Have you had difficulty sleeping because of your asthma symptoms (including cough)?” 
“Have you had your usual asthma symptoms during the day (cough, wheeze, chest 
tightness or breathlessness)?” and “Has your asthma interfered with your usual activities 
(e.g., housework, work, school, etc)?”[R18-1720]). 

Number of all-cause hospitalization in the year prior to the index date

Number of respiratory disease related hospitalization in the  year prior to the index date

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
Eosinophil count on the index date, or when it was not recorded on the index date, during the 
pre-index period (the one closest to the index date) (if available)
Comorbidities

Respiratory

Pneumonia

Bronchiectasis

Cardiovascular

Ischaemic heart disease

Myocardial infarction (MI)

Angina pectoris

Aneurysm

Hypertension,

Renal failure

Diabetes mellitus (any type)

Psychiatric disorders

Dementia

Delerium

Depression

Stroke

Allergic rhinitis

Sinusitis

Charlson comorbidity index [R08-1584]

Cataract

Osteoporosis

Obesity
Concomitant prescriptions

Asthma-related prescriptions in the year prior to index date

Short-acting beta agonists

Inhaled long-acting beta agonists (on top of ICS/LABA FDC)

Inhaled corticosteroid (ICS) (on top of ICS/LABA FDC)

Oral corticosteroid

Theophylline 

Leukotriene Receptor Antagonist (LTRA)

Azithromycin, 

Mucolytics

Cardiovascular medications

Cardiac Glycosides

Thiazides

Loop diuretics

Antiarrhythmics

Beta blocker

Vasodilator Antihypertensive Drug

Centrally Acting Antihypertensive Drugs

Alpha-adrenoceptor Blocking Drugs

Drugs affecting the renin-angiotensin system

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
Angiotensin Converting Enzyme Inhibitors

Angiotensin II receptor blockers

Renin Inhibitors

Other antihypertensives

Nitrates

Calcium channel blockers

Oral anticoagulants

Heparin and other low molecular weight heparins

Aspirin

Antiplatelet

Lipid-regulating Drugs

Bile Acid Sequestrants (lipid-regulating Drugs) - including Colesevelam

Ezetimibe (only in combination with Statin)

Fibrates

Statins

Nicotinic Acid Group

Omega-3 Fatty Acid Compounds

Other lipid-regulating drugs

Glucose-lowering agents

Non-steroidal anti-inflammatory drugs

Psycholeptics

Antipsychotics

Antidepressants

Agents for dementia
For concomitant medications used for diseases other than asthma the look-back time period 
will be limited to 180 days prior to the index date to increase the likelihood that the 
medications were used concomitantly. Concomitant medications will be categorized as 
current use (up to and including 60 days before index date) and past use (use any time prior to 
the 60 days before index date).
9.4
DATA SOURCES
In the UK, nearly all residents are registered in a general medical practice that uses electronic 
medical records. Some of those records are available for research purposes in the CPRD. 
CPRD contains diagnostic and prescribing information recorded by general practitioners 
(GPs) as part of their routine clinical practice in the UK. The database currently contains data 
for over 13.2 million patients with research-quality data from 680 UK practices; 5.69 million 
of these patients are active (still registered with a contributing GP practice) [R14-5257]. 
Patients registered are representative of the whole UK population in terms of age and sex. 
Data collection happens as part of normal clinical care of patients in participating practices on 
a daily basis. Patients are included in the primary care dataset from their first until their last 
contact with the participating practice. Data are collected by practices and usually uploaded 
to the CPRD secure servers on a monthly basis. 

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The CPRD contains data on demographic information, prescription details, clinical events 
(symptoms, diagnoses), preventive care provided, tests, immunisations, specialist referrals, 
hospital admissions and their major outcomes, and details relating to death. It should be noted 
that the CPRD only has prescription data but not the actual dispensing data. Data are largely 
recorded by general practice staff using version 2 Read codes, a hierarchical clinical 
classification system containing over 96, 000 codes. Numerical data on additional clinical 
measures (e.g. height, weight, blood pressure, alcohol intake) can also be recorded during 
consultations. Prescriptions issued by the GP are automatically recorded with a product name 
and British National Formulary code, alongside the dosage instructions and quantity. Results 
of laboratory tests ordered by the GP are commonly added to the patient record via electronic 
links to laboratories. Data fed back to the GP from other sources may also be entered into the 
patient record by practice staff; this might include information from secondary care such as 
key diagnoses, discharge data from hospitals, or follow-up information from specialist 
clinics. [R16-1231]
In addition, the following CPRD-linked data will be used in this study:

Hospital Episode Statistics (HES) Admitted Patient Care (HES APC) data

HES Accident and Emergency (HES A&E) data

Patient Level Index of Multiple Deprivation
HES APC data are collected on all admissions to National Health Service (NHS) hospitals in
England. HES APC also covers admissions to independent sector providers (private or 
charitable hospitals) paid for by the NHS. HES APC does not cover accident and emergency 
(A&E, emergency department) attendances or outpatient bookings. In the financial year 
2014/15 (April to March), 18,731,987 hospital episodes from 451 different NHS hospital 
trusts (known as ‘providers’) were recorded in HES APC. HES APC provides detailed 
clinical, demographic and organizational information for each Finished Consultant Episode. 
Data on drugs prescribed through hospital pharmacies to inpatients are not available in HES 
APC [R18-0523]. In this study, HES APC will be used to assess hospitalization (all-cause, 
respiratory disease related, or asthma or lower respiratory condition related) in the year prior 
to the index date among patients who were treated at English NHS health care providers.
HES A&E data consist of individual records of patient care administered in the accident and 
emergency setting in England. These data are a subset of national A&E data collected by 
NHS England to monitor the national standard that 95% of patients attending A&E should 
wait no longer than 4 hours from arrival to admission, transfer or discharge. A&E data are 
submitted by A&E providers of all types in England. Data collected includes details about 
patients’ attendance, outcomes of attendance, waiting times, referral source, A&E diagnosis, 
A&E treatment (drugs prescribed not recorded), A&E investigations and Health Resource 
Group [R18-0524]. In this study, HES A&E will be used to ascertain A&E attendance for 
asthma or low respiratory conditions, which will be used to calculate the number of asthma 
exacerbation in the year prior to the index date.
Patient Level Index of Multiple Deprivation (IMD) data are small area level measures of 
relative deprivation that are available for linkage to CPRD GOLD data through the patient 
and/or practice postcode. These measures can be used as a proxy to socio-demographic and 
socio-economic data which are generally poorly recorded in the primary care data as they do 
not directly relate to a patient's care. Data is provided as quintiles or deciles of the deprivation 

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score or rank to prevent disclosure of patient or practice area. The postcode of the practice or 
patient residence is mapped to lower layer Super Output Area (LSOA) using a postcode 
lookup file [R18-0524]. In this study, Patient Level Index of Multiple Deprivation data will 
be used to ascertain patient level IMD.
9.5
STUDY SIZE
The study size is dependent on the uptake of Spiriva Respimat for asthma in the CPRD. 
Table 1 provides a range of estimates for different prevalence estimates of disease (or 
characteristics). The numerator represents the number of patients with the comorbidity of 
interest and the denominator represents the number of new users in the population. With 500 
patients we would have adequate confidence intervals around these estimates.
Table 1
Precision of estimates for proportion measures
Number of 
New Users
95% Confidence Intervals for Various Prevalences of Diseases (%)
1%
2%
5%
7%
10%
500
0.4-2.3
1.1-3.6
3.4-7.3
5.1-9.6
7.7-12.9
800
0.5-2.0
1.2-3.2
3.7-6.7
5.4-9.0
8.1-12.3
2,000
0.6-1.5
1.5-2.7
4.1-6.0
6.0-8.2
8.8-11.3
5,000
0.8-1.3
1.6-2.4
4.4-5.6
6.3-7.7
9.2-10.9
A feasibility check was conducted to assess the number of patients in the tiotropium group, 
after application of the study inclusion and exclusion criteria. The result indicated that 
between September 2014 and December 2017, the number of patients in the tiotropium group 
was 935.
9.6
DATA MANAGEMENT
This study will use the in-house CPRD data set. Data management, tabulations, and graphics 
will be carried out with SAS 9.4 (SAS Institute, Cary NC). Source code of data management 
and data analyses will be kept for inspection at least for five years after publication of the 
results.
9.7
DATA ANALYSIS
All the analyses will be conducted with SAS 9.4 (SAS Institute, Cary NC).
9.7.1
Main analysis
The primary objective of this study is to describe the clinical and socio-demographic 
characteristics of asthma patients prior to the initiation of Spiriva Respimat for the treatment 
of Asthma. For this objective, patient baseline characteristics (as described in the “outcomes” 
and “covariates” section) will be tabulated and summarized for all new users of Spiriva 
Respimat. Means, standard deviations, medians, minimum, maximum, and interquartile range 

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(IQR) will be used to present continuous variables, counts and percentages will be used to 
present categorical variables.
The secondary objective of this study is to describe and compare the characteristics of asthma 
patients who initiated Spiriva Respimat to asthma patients who initiated a higher dose of 
ICS/LABA FDC, or LTRA, or alternatively those who switched from the previous
ICS/LABA FDC to a new ICS/LABA FDC. For this objective, patient characteristics (as 
described in the “outcomes” and “covariates” section) will be tabulated for the patients that 
initiated or switched to the other available treatments separately, using measures as described 
for the patient baseline characteristics of Spiriva.
Patient characteristics (as described in the “outcomes” and “covariates” section) will be 
compared among patients who initiated Spiriva Respimat and patients in other treatment 
groups. Analyses will be conducted in unmatched cohorts and differences between spiriva 
restinmat and each of the other exposure groups will be assessed using absolute standardized 
differences (ASD), where an ASD of at least 10% will be considered a meaningful difference
[R16-1227].
9.7.3
Missing values
No imputation will be done for missing values. For all covariates, missing values will be 
presented as a separate category.
9.8
QUALITY CONTROL
This protocol will be strictly followed in the study. All changes to this protocol will be 
documented in protocol amendments.
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-authorisation studies with regard to the best
practices and 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.

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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 statistical analytic approach will be reviewed/repeated by a second analyst to ensure 
quality control.
The study report will be reviewed, approved and archived per BI SOP and conducted upon 
ISAC approval.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The main analysis will exclude patients with other respiratory disease (e.g., COPD). This will 
exclude asthma-COPD overlap patients and some other patients and the results may not be 
representative to all asthma patients. However, Spiriva has both asthma and COPD 
indications. Therefore, for asthma-COPD overlap patients, the reason for initiating Spiriva 
Respimat can be unclear in existing data. Since the primary objective is to describe the 
characteristics of asthma patients prior to the initiation of Spiriva Respimat for the treatment 
of Asthma, it would be reasonable to exclude asthma-COPD overlap patients,
 
This study is based on existing data. It is possible that misclassification may happen for the 
measurement of comorbidities. However, we will use all the available data before the index 
date to minimize the possibility of misclassification.
Some covariates such as smoking status, alcohol use, BMI, pulmonary function, and 
eosinophil count may not be well recorded in CPRD. In the analyses we will present missing 
data as a separate category.
Some information may be recorded very infrequently or not at all in CPRD, e.g., number of 
people in a household, over-the-counter medication use, prescriptions in secondary care. 
These variables will not be assessed in this study.
The CPRD only includes patient data captured from general practitioners. Although some 
information about patient contacts with secondary care could be manually entered into the 
patient record, details about these specialty visits and hospital admissions (including dates, 
diagnoses, tests performed, length of stay) may be incomplete.
The CPRD may not be representative of all practices in the UK based on geography and size.
There are certain patient groups that are missing from primary care records, such as prisoners, 
private patients, some residential homes and the homeless. Thus, selection bias cannot be 
ruled out. However, studies suggested that CPRD patients are broadly representative of the 
UK population in terms of age and sex. Patients are also comparable to the UK census in 

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terms of ethnicity, and comparable to the Health Survey for England for body mass index 
distribution in most patient subgroups.
The HES APC data and HES A&E data only have data for patients from England. 
 
 
9.10
OTHER ASPECTS
None.
9.11
SUBJECTS
Not applicable.
9.11.1
Cases
Not applicable.
9.11.2
Controls
Not applicable.
9.12
BIAS
None.

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10.
PROTECTION OF HUMAN SUBJECTS
This study is a non-interventional study based on existing data and does not require patient 
informed consent. All the data used in this study will be anonymized. Study results will be 
presented at aggregate level. Data protection and privacy regulations will be observed in 
collecting, forwarding, processing, and storing data from study participants.
BI will submit the final study protocol for approval to the Independent Scientific Advisory
Committee (ISAC) (http://www.cprd.com/ISAC). The CPRD has obtained ethical approval
from a Multicentre Research Ethics Committee for all observational research using CPRD
data without patient involvement; however, ISAC may recommend that the Multicentre
Research Ethics Committee review the study documentation if any ethical issues arise.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
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. 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.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The study report will be prepared using the BI non-interventional study report template. Final 
study results will be posted on the ENCePP website. A scientific manuscript will be 
published in a peer-reviewed journal. Authorship and publication will follow the 
corresponding BI SOP 001-MCS-00-002 and guidelines of good scientific practice. The study 
results may also be submitted to scientific conferences for presentation.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
[P10-08936] Barnes PJ. New therapies for asthma: is there any progress? Trends Pharmacol 
Sci 31 (7), 335 - 343 (2010)
[P18-03927] British Thoracic Society, Scottish Intercollegiate Guidelines Network (SIGN). 
British guideline on the management of asthma: a national clinical guideline 
(September 2016). https://www.brit-thoracic.org.uk/document-library/clinical-
information/asthma/bt ssign-asthma-guideline-2016/ (access date: 26 April 
2018) ; Edinburgh: Scottish Intercollegiate Guidelines Network (SIGN) (2016)
[R08-1584]
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of 
classifying prognostic comorbidity in longitudinal studies: development and 
validation. J Chronic Dis 40 (5), 373 - 383 (1987)
[R11-4318] 
Guidelines for Good Pharmacoepidemiology Practices (GPP) (revision 2: 
April 2007). http://www.pharmacoepi.org/resources/guidelines_08027.cfm 
(access date: 13 September 2011) ; Bethesda: International Society for 
Pharmacoepidemiology (ISPE) (2007)
[R13-1970]
European Medicines Agency (EMA), Heads of Medicines Agencies (HMA) 
Guideline on good pharmacovigilance practices (GVP): module VI -
management and reporting of adverse reactions to medicinal products (22 June 
2012, EMA/873138/2011). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline
/2012/0 6/WC500129135.pdf (access date: 7 May 2013) ; European Medicines 
Agency (EMA), Heads of Medicines Agencies (HMA) (2012)
[R14-5257] 
Independent Scientific Advisory Committee for Medicines and Healthcare 
products Regulatory Agency (MHRA) database research (ISAC): annual 
report: Jan 2013 - Dec 2013. http://www.mhra.gov.uk/home/groups/pl-
a/documents/committeedocument/con448379.pdf (access date: 16 December 
2014) ; Medicines and Healthcare products Regulatory Agency (MHRA) 
(2013)
[R14-5279]
Gelfand JM, Margolis DJ, Dattani H. The UK General Practice Research 
Database. In: Strom BL, editor. Pharmacoepidemiology. 4th ed. Chichester: 
John Wiley & Sons, 337 - 346 (2005)
[R15-4859] 
Guidance for industry and FDA staff: best practices for conducting and 
reporting pharmacoepidemiologic safety studies using electronic healthcare 
data (May 2013, drug safety). 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformati
on/guida nces/ucm243537.pdf (access date: 28 August 2015) ; U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER) (2013)
[R15-4870] 
European Medicines Agency (EMA). The ENCePP code of conduct for 
scientific independence and transparency in the conduct of 
pharmacoepidemiological and pharmacovigilance studies (London, 21 
November 2011, EMA/929209/2011). 

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BI Study Number 0205-0537
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001-MCS-90-124_RD-01 (4.0)
http://www.encepp.eu/code_of_conduct/documents/CodeofConduct_Rev2.pdf 
(access date: 28 August 2015) ; London: European Medicines Agency (EMA), 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) (2011)
[R16-1227] 
Austin PC. Balance diagnostics for comparing the distribution of baseline 
covariates between treatment groups in propensity-score matched samples. 
Stat Med 2009; 28 (25): 3083 – 3107.
[R16-1231]
Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, Staa T van, 
Smeeth L. Data resource profile: Clinical Practice Research Datalink (CPRD). 
Int J Epidemiol 44 (3), 827 - 836 (2015)
[R18-0523] 
Herbert A, Wijlaars L, Zylbersztejn A, Cromwell D, Hardelid P. Data 
Resource Profile: Hospital Episode Statistics Admitted Patient Care (HES 
APC). Int J Epidemiol. 1;46(4):1093-1093i. (2017)
[R18-0524] 
CPRD linked data. https://www.cprd.com/dataAccess/linkeddata.asp (access 
date: 12 February 2018); Medicines and Healthcare Products Regulatory 
Agency (MHRA) (2018)
[R18-1720]
Hoskins G, Williams B, Jackson C, Norman PD, Donnan PT. Assessing 
asthma control in UK primary care: use of routinely collected prospective 
observational consultation data to determine appropriateness of a variety of 
control assessment models. BMC Fam Pract. 2011;12:105.
13.2
UNPUBLISHED REFERENCES
None.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None.

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 3)
Adopted by the ENCePP Steering Group on 01/07/2016
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 
(ENCePP) welcomes innovative designs and new methods of research. This Checklist has 
been developed by ENCePP to stimulate consideration of important principles when 
designing and writing a pharmacoepidemiological or pharmacovigilance study protocol. The 
Checklist is intended to promote the quality of such studies, not their uniformity. The user is 
also referred to the ENCePP Guide on Methodological Standards in Pharmacoepidemiology,
which reviews and gives direct electronic access to guidance for research in 
pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol 
where this issue has been discussed should be specified. It is possible that some questions do 
not apply to a particular study (for example, in the case of an innovative study design). In this 
case, the answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included 
for each section should be used to explain why. The “Comments” field can also be used to
elaborate on a “No” answer.
This Checklist should be included as an Annex by marketing authorisation holders when 
submitting the protocol of a non-interventional post-authorisation safety study (PASS) to a 
regulatory authority (see the Guidance on the format and content of the protocol of non-
interventional post-authorisation safety studies). The Checklist is a supporting document and 
does not replace the format of the protocol for PASS as recommended in the Guidance and 
Module VIII of the Good pharmacovigilance practices (GVP).
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

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Study title:
Characteristics of patients initiating Spiriva Respimat in Asthma in the UK
Study reference number:
Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1 Does the protocol specify timelines for
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Study progress report(s)
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
6
6
N/A
N/A
N/A
6
Comments:
Section 2: Research question
Yes
No
N/A
Section 
Number
2.1 Does the formulation of the research question 
and objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in the 
risk management plan, an emerging safety issue)
2.1.2 The objective(s) of the study?
7
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
2.1.4 Which hypothesis(-es) is (are) to be 
tested? 
2.1.5 If applicable, that there is no a priori
hypothesis?
9.2
N/A
N/A
Comments:
Section 3: Study design
Yes
No
N/A
Section 
Number
3.1 Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design) 
9.1
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of secondary use of data, the date from 
which data extraction starts.
2 Date from which the analytical dataset is completely available.

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Section 3: Study design
Yes
No
N/A
Section 
Number
3.2 Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.1
3.3 Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
9.7.1
3.4 Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year)
N/A
3.5 Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
11
Comments:
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1 Is the source population described?
9.2
4.2 Is the planned study population defined in terms 
of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication? 
4.2.5 Duration of follow-up?
9.2
9.2
9.2
9.2
N/A
4.3 Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.2
Comments:
Section 5: Exposure definition and 
measurement
Yes
No
N/A
Section 
Number
5.1 Does the protocol describe how the study 
exposure is defined and measured? (e.g. operational 
details for defining and categorising exposure, measurement 
of dose and duration of drug exposure)
9.3.1
5.2 Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)
N/A

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Section 5: Exposure definition and 
measurement
Yes
No
N/A
Section 
Number
5.3 Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
N/A
5.4 Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
N/A
Comments:
Section 6: Outcome definition and measurement
Yes
No
N/A
Section 
Number
6.1 Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3.2
6.2 Does the protocol describe how the outcomes are 
defined and measured? 
9.3.2
6.3 Does the protocol address the validity of outcome 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study)
N/A
6.4 Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? (e.g. 
HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease, disease management)
N/A
Comments:
Section 7: Bias
Yes
No
N/A
Section 
Number
7.1 Does the protocol describe how confounding will 
be addressed in the study?
7.1.1. Does the protocol address confounding by 
indication if applicable?
N/A
N/A
7.2 Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
9.9
9.9
7.3 Does the protocol address the validity of the 
study covariates?
N/A
Comments:

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Section 8: Effect modification
Yes
No
N/A
Section
Number
8.1 Does the protocol address effect modifiers? (e.g. 
collection of data on known effect modifiers, sub-group analyses, 
anticipated direction of effect)
N/A
Comments:
Section 9: Data sources
Yes
No
N/A
Section
Number
9.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient interview 
including scales and questionnaires, vital statistics, etc.)
9.1.3 Covariates?
9.3.1
9.3.2
9.3.3
9.2 Does the protocol describe the information 
available from the data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily dosage,  
prescriber)
8.2.2 Outcomes? (e.g. date of occurrence, multiple event, 
severity measures related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.)
9.3.1
9.3.2
9.3.3
9.3 Is a coding system described for:
9.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA)) 
9.3.3 Covariates?
9.4 Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)
NA
Comments:
Section 10: Analysis plan
Yes
No
N/A
Section 
Number
10.1 Is the choice of statistical techniques described? 
9.7
10.2 Are descriptive analyses included?
9.7

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Section 10: Analysis plan
Yes
No
N/A
Section 
Number
10.3 Are stratified analyses included?
N/A 9.7
10.4 Does the plan describe methods for adjusting 
for confounding?
N/A
10.5 Does the plan describe methods for handling 
missing data?
9.7.2
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
Section 11: Data management and quality 
control
Yes
No
N/A
Section 
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.6
11.2 Are methods of quality assurance described?
9.8
11.3 Is there a system in place for independent 
review of study results?
9.8
Comments:
Section 12: Limitations
Yes
No
N/A
Section
Number
12.1
Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
12.1.2 Information bias?
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
9.9
9.9
12.2 Does the protocol discuss study feasibility? (e.g. 
study size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment)
9.5
Comments:
Section 13: Ethical issues
Yes
No
N/A
Section
Number
13.1 Have requirements of Ethics Committee/ 
10

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Section 13: Ethical issues
Yes
No
N/A
Section
Number
Institutional Review Board been described?
13.2 Has any outcome of an ethical review procedure 
been addressed?
10
13.3 Have data protection requirements been 
described?
10
Comments:
Section 14: Amendments and deviations
Yes
No
N/A
Section 
Number
14.1 Does the protocol include a section to document 
amendments and deviations? 
5
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/A
Section 
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
12
15.2 Are plans described for disseminating study 
results externally, including publication?
12
Comments:
Name of the main author of the protocol: 
Date: Aug/31/2017
Signature: ___________________________

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001-MCS-90-124_RD-01 (4.0)
ANNEX 3. CPRD MEDCODES INDICATING ASTHMA
A) Specific asthma codes
medcode
readterm
78
asthma
81
asthma monitoring
185
acute exacerbation of asthma
232
asthma attack
233
severe asthma attack
1555
bronchial asthma
2290
allergic asthma
3018
mild asthma
3366
severe asthma
3458
occasional asthma
3665
late onset asthma
4442
asthma unspecified
4606
exercise induced asthma
4892
status asthmaticus nos
5267
intrinsic asthma
5627
hay fever with asthma
5798
chronic asthmatic bronchitis
5867
exercise induced asthma
6707
extrinsic asthma with asthma attack
7058
emergency admission, asthma
7146
extrinsic (atopic) asthma
7191
asthma limiting activities
7378
asthma management plan given
7416
asthma disturbing sleep
7731
pollen asthma
8335
asthma attack nos
8355
asthma monitored

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9018
number of asthma exacerbations in past year
9552
change in asthma management plan
9663
step up change in asthma management plan
10043
asthma annual review
10274
asthma medication review
10487
asthma - currently active
11370
asthma confirmed
12987
late-onset asthma
13064
asthma severity
13065
moderate asthma
13175
asthma disturbs sleep frequently
13176
asthma follow-up
14777
extrinsic asthma without status asthmaticus
15248
hay fever with asthma
16070
asthma nos
16667
asthma control step 2
16785
asthma control step 1
18223
step down change in asthma management plan
18224
asthma control step 3
18323
intrinsic asthma with asthma attack
19167
asthma monitoring by nurse
19519
asthma treatment compliance unsatisfactory
19520
asthma treatment compliance satisfactory
20860
asthma control step 5
20886
asthma control step 4
21232
allergic asthma nec
22752
occupational asthma
24479
emergency asthma admission since last appointment
24506
further asthma - drug prevent.
24884
asthma causes daytime symptoms 1 to 2 times per week
25181
asthma restricts exercise

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25791
asthma clinical management plan
26501
asthma never causes daytime symptoms
26503
asthma causes daytime symptoms most days
26504
asthma never restricts exercise
26506
asthma severely restricts exercise
26861
asthma sometimes restricts exercise
27926
extrinsic asthma with status asthmaticus
29325
intrinsic asthma without status asthmaticus
30458
asthma monitoring by doctor
30815
asthma causing night waking
31167
asthma night-time symptoms
31225
asthma causes daytime symptoms 1 to 2 times per month
38143
asthma never disturbs sleep
38144
asthma limits walking up hills or stairs
38145
asthma limits walking on the flat
38146
asthma disturbs sleep weekly
39478
wood asthma
39570
asthma causes night symptoms 1 to 2 times per month
40823
brittle asthma
41017
aspirin induced asthma
41020
absent from work or school due to asthma
42824
asthma daytime symptoms
45073
intrinsic asthma nos
45782
extrinsic asthma nos
46529
attends asthma monitoring
47337
asthma accident and emergency attendance since last visit
47684
detergent asthma
58196
intrinsic asthma with status asthmaticus
73522
work aggravated asthma
93353
sequoiosis (red-cedar asthma)
93736
royal college of physicians asthma assessment

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98185
asthma control test
99793
patient has a written asthma personal action plan
100107
health education - asthma self management
100397
asthma control questionnaire
100509
under care of asthma specialist nurse
100740
health education - structured asthma discussion
102170
asthma review using roy colleg of physicians three questions
102209
mini asthma quality of life questionnaire
102301
asthma trigger - seasonal
102341
asthma trigger - pollen
102395
asthma causes symptoms most nights
102400
asthma causes night time symptoms 1 to 2 times per week
102449
asthma trigger - respiratory infection
102713
asthma limits activities 1 to 2 times per month
102871
asthma trigger - exercise
102888
asthma limits activities 1 to 2 times per week
102952
asthma trigger - warm air
103318
health education - structured patient focused asthma discuss
103321
asthma trigger - animals
103612
asthma never causes night symptoms
103631
royal college physician asthma assessment 3 question score
103813
asthma trigger - cold air
103944
asthma trigger - airborne dust
103945
asthma trigger - damp
103952
asthma trigger - emotion
103955
asthma trigger - tobacco smoke
103998
asthma limits activities most days
105420
asthma self-management plan review
105674
asthma self-management plan agreed
106805
chronic asthma with fixed airflow obstruction
107167
number days absent from school due to asthma in past 6 month

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B) Non-specific asthma codes
medcode
readterm
719
h/o: asthma
1208
childhood asthma
5138
patient in asthma study
5515
seen in asthma clinic
7229
asthma prophylactic medication used
11022
asthma trigger
11387
refuses asthma monitoring
11673
excepted from asthma quality indicators: patient unsuitable
11695
excepted from asthma quality indicators: informed dissent
13066
asthma - currently dormant
13173
asthma not disturbing sleep
13174
asthma not limiting activities
16655
asthma monitoring admin.
18141
asthma monitoring due
18692
exception reporting: asthma quality indicators
18763
referral to asthma clinic
19539
asthma monitoring check done
20422
asthma clinic administration
25705
asthma monitor 3rd letter
25706
asthma monitor 2nd letter
25707
asthma monitor 1st letter
25796
mixed asthma
26496
health education - asthma
29645
asthma control step 0
30308
dna - did not attend asthma clinic
30382
asthma monitoring admin.nos
31135
asthma monitor phone invite
35927
asthma leaflet given
37943
asthma monitor verbal invite

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41554
asthma monitor offer default
43770
asthma society member
92109
asthma outreach clinic

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001-MCS-90-124_RD-01 (4.0)
ANNEX 4. CPRD MEDCODES INDICATING COPD
medcode
readterm
18476
COPD follow-up
45771
Chronic obstructive pulmonary disease does not disturb sleep
4084
Airways obstructn irreversible
794
Emphysema
998
Chronic obstructive airways disease
1001
Chronic obstructive pulmonary disease
5710
Chronic obstructive airways disease NOS
9520
Chronic obstructive pulmonary disease monitoring
9876
Severe chronic obstructive pulmonary disease
10802
Moderate chronic obstructive pulmonary disease
10863
Mild chronic obstructive pulmonary disease
10980
Centrilobular emphysema
11287
Chronic obstructive pulmonary disease annual review
14798
Emphysematous bronchitis
18621
Chronic obstructive pulmonary disease follow-up
18792
Chronic obstructive pulmonary disease monitoring admin
23492
Chronic bullous emphysema NOS
26018
Chronic obstructive pulmonary disease monitoring by nurse
26306
Chronic bullous emphysema
28755
Chronic obstructive pulmonary disease monitoring 1st letter
33450
Emphysema NOS
34202
Chronic obstructive pulmonary disease monitoring 2nd letter
34215
Chronic obstructive pulmonary disease monitoring 3rd letter
37247
Chronic obstructive pulmonary disease NOS
37371
Chronic obstructive pulmonary disease monitoring due
44525
Obstructive chronic bronchitis NOS
45998
Chronic obstructive pulmonary disease monitoring by doctor
93568
Very severe chronic obstructive pulmonary disease
12166
Other specified chronic obstructive airways disease
38074
Chronic obstructive pulmonary disease monitor phone invite
42258
Chronic obstructive pulmonary disease monitoring verb invite
42313
Health education - chronic obstructive pulmonary disease
45770
Chronic obstructive pulmonary disease disturbs sleep
45777
Chronic obstructive pulmonary disease clini management plan

 
 
 
 
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c25002535
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tina-channeling-protocol-july-2018-clean
Characteristics of patients initiating Spiriva Respimat in Asthma in the UK: a
cross-sectional study based on the Clinical Practice Research Datalink
Approval-
 of Global
Epidemiology
09 Aug 2018 20:09 CEST
Approval-Team Member Medicine
10 Aug 2018 16:28 CEST
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 Safety Evaluation
Therapeutic Area
13 Aug 2018 08:56 CEST
Approval-Other
14 Aug 2018 09:25 CEST

Boehringer Ingelheim 
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c25002535
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