Clinical trial NCT03964207
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim
Start date: 2019-11-25; Completion date: 2021-11-16
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The objective of this study is to investigate the patient acceptability/preference of Respimat® compared with Handihaler® in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) to demonstrate the superiority of Respimat®.

Detailed description:

Arms: arm 1: From Day 1 of Period 1 participants received Test treatment (T1): tiotropium Respimat® (Spiriva® Respimat®) 5 microgram (μg) once daily for a duration of 4 weeks, given as 2.5μg per puff, two puffs (2.5μg per puff) inhalation solution of tiotropium, orally via Respimat®.

From Day 1 of Period 2 participants received comparator treatment(T2): tiotropium Handihaler® (Spiriva®) 18μg once daily for a duration of 4 weeks, inhalation powder tiotropium with 1 Handihaler® device. arm 2: From Day 1 of Period 1 participants received comparator treatment (T2): tiotropium Handihaler® (Spiriva®) 18 microgram (μg) once daily for a duration of 4 weeks, inhalation powder tiotropium with 1 Handihaler® device.

From Day 1 of Period 2 participants received Test treatment (T1): tiotropium Respimat® (Spiriva® Respimat®) 5 microgram (μg) once daily for a duration of 4 weeks, given as 2.5μg per puff, two puffs (2.5μg per puff) inhalation solution of tiotropium, orally via Respimat®.
Interventions: intervention 1: Tiotropium Respimat® (T1) intervention 2: Tiotropium Handihaler® (T2)
Intervention descriptions: intervention 1: inhalation solution intervention 2: Inhalation Powder

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (15.0) / Saved on: 30 Nov 2017
CLINICAL TRIAL PROTOCAL
TITLE PAGE
Document Number:
c25762461-03
EudraCT No.
EU Trial No.
Not Applicable
BI Trial No.
0205-0541
BI Investigational
Medicinal Product(s)
Tiotropium Respimat® (Spiriva® Respimat®)
Title
A randomized, open-label, two-way crossover study to compare 
patient acceptability/preference of Tiotropium Respimat® with 
Tiotropium Handihaler® in patients with moderate to severe 
chronic obstructive pulmonary disease (COPD).
Lay Title
A study on whether patients prefer the Spiriva® Respimat® or the 
Spiriva® Handihaler® for treating their chronic obstructive 
pulmonary disease (COPD)
Clinical Phase
Phase IV
Trial Clinical 
Monitor
Coordinating 
Investigator
Status
Final Protocol (Revised Protocol based on global amendment 2)
Version and Date
Version: 3.0
Date: 23 Mar 2020
Page 1 of 64
Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
08 Oct 2018
Revision date
23 Mar 2020
BI trial number
0205-0541
Title of trial
A randomized, open-label, two-way crossover study to compare 
patient acceptability/preference of Tiotropium Respimat® with 
Tiotropium Handihaler® in patients with moderate to severe chronic 
obstructive pulmonary disease (COPD).
Coordinating 
Investigator
Trial site(s)
Multi-center trial
Clinical phase
Phase IV
Trial rationale
The purpose of this study is to evaluate the patient 
acceptability/preference of Tiotropium Respimat® comparing with 
Tiotropium Handihaler® in patients with chronic obstructive 
pulmonary disease (COPD). The validated Patient satisfaction and 
preference questionnaire (PASAPQ) will be applied to evaluate the 
outcomes. Based on the previous studies, Tiotropium Respimat®
showed better patient acceptability/preference compared with two 
DPIs, Diskus or Turbuhaler using PASAPQ as measurement. 
However, no studies have been done to compare the patient 
acceptability/preference between Tiotropium Respimat® and 
Tiotropium Handihaler®. The Tiotropium Safety and Performance in 
Respimat® (TIOSPIR) [P13-11053] study showed the efficacy of 
tiotropium via Respimat® or Handihaler® was similar in terms of lung 
function improvement and COPD exacerbation prevention. In real-
life practice, the effectiveness might be influenced by different
factors. The patient’s acceptability/preference on the inhalers can 
impact the adherence to therapy, and then possibly control of disease. 
Therefore, we consider it is of clinical importance to investigate the 
patient acceptability/preference between Tiotropium Respimat® and 
Tiotropium Handihaler®, so that Health care professionals (HCPs)
can refer to this trial to make appropriate decision on the choice 
between these two devices.
Trial objective(s)
The objective of this study is to investigate the patient 
acceptability/preference of Tiotropium Respimat® compared with 
Tiotropium Handihaler® in patients with moderate to severe chronic 
obstructive pulmonary disease (COPD) to demonstrate the superiority 
of Tiotropium Respimat®.
Trial endpoints
Primary endpoints: 
Performance domain of PASAPQ;
Secondary endpoints:
•
PASAPQ total score;


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•
Proportion of patients indicating preference; 
•
Overall Satisfaction Question Score from PASAPQ;
•
Score on willingness to continue after treatment.
Trial design
Multicentre, randomised, open-label, two-way cross-over study
Total number of patients
randomised
71 entered
Number of patients on 
each treatment
71
Diagnosis
COPD
Main in- and exclusion 
criteria
Main inclusion criteria:
•
Clinical diagnosis COPD (post-bronchodilator FEV1/FVC<70%)
•
GOLD Stage II/III COPD (30%<post-bronchodilator FEV1<80% of 
predicted)
•
Male or female, age: 40-80 years
•
Written informed consent provided by the patient
Main exclusion criteria:
•
Had visual, cognitive, or motor impairment that, as judged by the 
investigator, did not allow the patient to independently read and 
complete the PASAPQ questionnaire
•
Patients have any previous experience of using Tiotropium Respimat®
or Tiotropium Handihaler® within one year prior to screening
•
Exacerbations during 6 weeks prior to screening.
Test product(s)
Tiotropium Respimat® (Spiriva® Respimat®)
dose
5 μg once daily, given as 2.5μg, two puffs.
method and route of 
administration
inhalation
Comparator product(s)
Tiotropium Handihaler® (Spiriva®)
dose
18μg once daily
method and route of
administration
inhalation
Duration of treatment
•
Screening period: 1 week
•
Treatment period: 8 weeks (2*4 weeks treatment periods)
Statistical methods
Primary endpoint will be analysed using Restricted Maximum 
Likelihood Estimation based Mixed-effects Model for Repeated 
Measures analysis to obtain adjusted means for the treatment groups. 
This model will include treatment and period as fixed effects and 
patient as a random effect. Compound symmetry will be used as a 
covariance structure for within-patient variation. 
Secondary endpoints will be analysed using the same model as the 
primary endpoint.
Chi-squared test will be performed to analyse proportion of patients 
indicating preference.
Descriptive statistics will be used for safety analysis.


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FLOW CHART
Trial Periods
Screening 
Period
Randomization
Randomised Treatment 
Period
Follow-up 
Period
Visit
1
2
35
4
52
Weeks
-1
0
4
8
12
Days
-7
1
28
56
84
Visit window (days)
-7 days
N/A
±1 day
±1 day
±2 days
Informed consent
X
Demographics
X
  
Medical history
X
Rescue Medication Training
X
Tiotropium Respimat® Training
X
X
Tiotropium Handihaler® Training
X
X
Physical examination (with Vital 
signs)
X
X1
Laboratory tests-Blood and urine
X
X1
12 lead-ECG
X
X1
pregnancy testing (urine)
X
X
Screening/Qualifying Pulmonary 
Function Test (FEV1 and FVC), 
seated6
X
Smoking Status
X
Review of in-/exclusion criteria
X
X
Randomization
X
Dispense trial medication
X
X
Dispense rescue medication
X3
X3
X3
Dispense patient diary
X
X
X
Dispense trial identification card 
(TIC)
X
Collect Respimat® or Handihaler®
X
X1
Collect Rescue Medication
X4
X4
X4
Collect and review patient diary
X
X
X1
Adverse events
X
X
X1
X
Compliance check
X
X
Concomitant therapy
X
X
X
X1
X1
PASAPQ: question 1-14
X
X
PASAPQ: question 15-16
X
Conclusion of Patient participation
X1
1.
To be completed by all patients including those who discontinue early because visit 4 is the end of study treatment.
2.
Visit 5 is the end of study visit.
3.
To be dispensed from Visit 1 to Visit 3.
4.
Rescue medication should be collected at next visit whether the patient use or not.
5.
At Visit 3, the investigator will instruct the patient how to use first study drug intake on site. To avoid overdosing, the 
investigator needs to confirm whether the patient has already taken the medication at home on the day of V3 visit. If so, 
the patient will not take the first dose of the newly assigned treatment at Visit 3.
6.
Historical data from spirometry measurements within the past 6 months either at the site or at the other hospital may be 
used. If the measurements are not performed at the trial site a signed copies of the measurement printouts must be 
provided to the trial site for source data verification. In case several qualifying spirometry measurements are available, 
the most recent one should be referred to as long as it was not performed during an exacerbation. Patients may not be 
randomised to the study without the availability of spirometry data at the actual study site.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................5
ABBREVIATIONS..................................................................................................................9
1.
INTRODUCTION...............................................................................................11
1.1
MEDICAL BACKGROUND.............................................................................11
1.2
DRUG PROFILE................................................................................................11
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................12
1.4
BENEFIT - RISK ASSESSMENT.....................................................................13
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................14
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........14
2.1.1
Main objectives....................................................................................................14
2.1.2
Primary endpoint(s)............................................................................................14
2.1.3
Secondary endpoint(s) ........................................................................................14
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................15
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................15
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................15
3.3
SELECTION OF TRIAL POPULATION .......................................................15
3.3.1
Main diagnosis for trial entry ............................................................................16
3.3.2
Inclusion criteria .................................................................................................16
3.3.3
Exclusion criteria ................................................................................................17
3.3.4
Withdrawal of patients from treatment or assessments..................................18
3.3.4.1
Discontinuation of trial treatment.....................................................................18
3.3.4.2
Withdrawal of consent to trial participation....................................................19
3.3.4.3
Discontinuation of the trial by the sponsor.......................................................19
4.
TREATMENTS...................................................................................................20
4.1
INVESTIGATIONAL TREATMENTS ...........................................................20
4.1.1
Identity of the Investigational Medicinal Products (IMPs).............................20
4.1.2
Selection of doses in the trial and dose modifications......................................21
4.1.3
Method of assigning patients to treatment groups...........................................21
4.1.4
Drug assignment and administration of doses for each patient......................21
4.1.4.1
Instructing the patient............................................................................................22
4.1.4.2
Trial medication administration at home ..............................................................23
4.1.4.3
Trial medication return..........................................................................................23
4.1.5
Blinding and procedures for unblinding...........................................................23
4.1.6
Packaging, labelling, and re-supply...................................................................23
4.1.7
Storage conditions...............................................................................................23
4.1.8
Drug accountability.............................................................................................24


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................24
4.2.1
Other treatments and emergency procedures..................................................24
4.2.2
Restrictions ..........................................................................................................25
4.2.2.1
Restrictions regarding concomitant treatment ................................................25
4.2.2.2
Restrictions on diet and life style.......................................................................26
4.2.2.3
Contraception requirements..............................................................................26
4.3
TREATMENT COMPLIANCE........................................................................27
5.
ASSESSMENTS..................................................................................................28
5.1
ASSESSMENT OF EFFICACY........................................................................28
5.1.1
Primary endpoint................................................................................................28
5.1.2
Secondary endpoints...........................................................................................28
5.2
ASSESSMENT OF SAFETY.............................................................................29
5.2.1
Physical examination ..........................................................................................29
5.2.2
Vital signs.............................................................................................................29
5.2.3
Safety laboratory parameters ............................................................................29
5.2.4
Electrocardiogram ..............................................................................................30
5.2.5
Other ....................................................................................................................30
5.2.6
Assessment of adverse events.............................................................................31
5.2.6.1
Definitions of AEs................................................................................................31
5.2.6.1.1
Adverse event........................................................................................................31
5.2.6.1.2
Serious adverse event............................................................................................31
5.2.6.1.3
AEs considered “Always Serious”........................................................................31
5.2.6.1.4
Adverse events of special interest.........................................................................32
5.2.6.1.5
Intensity (severity) of AEs....................................................................................32
5.2.6.1.6
Causal relationship of AEs....................................................................................32
5.2.6.2
Adverse event collection and reporting.............................................................33
5.2.6.2.1
AE Collection........................................................................................................33
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................34
5.2.6.2.3
Information required .............................................................................................34
5.2.6.2.4
Pregnancy..............................................................................................................34
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................35
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................35
5.5
BIOBANKING ....................................................................................................35
5.6
OTHER ASSESSMENTS...................................................................................35
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................35
6.
INVESTIGATIONAL PLAN.............................................................................36
6.1
VISIT SCHEDULE.............................................................................................36
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................36
6.2.1
Screening period(s) .............................................................................................36
6.2.2
Treatment period(s)............................................................................................37
6.2.3
Follow-up Period ( 84 days±2 days )..................................................................38
6.2.3.1
Vital status for patients who discontinue early ................................................38
6.2.4
Removal of patients from therapy assessment .................................................39


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................40
7.1
STATISTICAL DESIGN - MODEL.................................................................40
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................40
7.3
PLANNED ANALYSES.....................................................................................40
7.3.1
Primary endpoint analyses.................................................................................41
7.3.2
Secondary endpoint analyses .............................................................................41
7.3.4
Safety analyses.....................................................................................................41
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................42
7.4
INTERIM ANALYSES ......................................................................................42
7.5
HANDLING OF MISSING DATA ...................................................................42
7.6
RANDOMISATION ...........................................................................................42
7.7
DETERMINATION OF SAMPLE SIZE .........................................................43
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........44
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................44
8.2
DATA QUALITY ASSURANCE ......................................................................45
8.3
RECORDS...........................................................................................................45
8.3.1
Source documents ...............................................................................................45
8.3.2
Direct access to source data and documents.....................................................46
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................47
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........47
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................47
8.6
TRIAL MILESTONES.......................................................................................47
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................48
9.
REFERENCES....................................................................................................49
9.1
PUBLISHED REFERENCES............................................................................49
9.2
UNPUBLISHED REFERENCES......................................................................50
10.
APPENDICES.....................................................................................................51
10.1
INSTRUCTIONS FOR THE USE OF THE RESPIMAT® ............................51
10.2
INSTRUCTIONS FOR THE USE OF THE HANDIHALER®......................53
10.3
INSTRUCTIONS FOR THE USE OF SALBUTAMOL SULPHATE 
AEROSOL...........................................................................................................56
10.4
PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE.....57
10.4.1
PASAPQ at Visit 3 ..............................................................................................57
10.4.2
PASAPQ at Visit 4 ..............................................................................................58
10.5
PHARMACOKINETIC METHODS AND ANALYSES................................60
10.6
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................60
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................61


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11.1
GLOBAL AMENDMENT 1 ..............................................................................61
11.2
GLOBAL AMENDMENT 2 ..............................................................................63


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase 
BAC
Benzalkonium Chloride
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
DBL
Database Lock
DPIs
Drypowder Inhalers
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic Acid
FC
Flow Chart
FEV
Forced Expiratory Volume
FUP
Follow Up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCG
Human Chorionic Gonadotropin
HCPs
Health care professionals
IB
Investigator’s Brochure
ICH
International Council on Harmonization


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IEC
Independent Ethics Committee
IMPs
Investigational Medicinal Products
IPVs
Important Protocol Violations
IRB
Institutional Review Board
ISF
Investigator Site File
IUD
Intrauterine Device
LRTI
Lower respiratory tract infection
MCID
Minimal Clinically Important Difference
MDIs
Metered-dose Inhalers 
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed effect repeated measures model 
PASAPQ
Patient satisfaction and preference questionnaire
PFT(s)
Pulmonary function test(s)
pMDIs
Pressurized Metered Dose Inhalers
PRN
As needed
REP
Residual Effect Period
SAE
Serious Adverse Event
SABA
Short-acting β Agonist
SAMA
Short-acting Muscarinic Antagonist
SGOT
Serum Glutamic-oxaloacetic Transaminase
SGPT
Serum Glutamic-pyruvic Transaminase
SMI
Soft Mist Inhalers
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TMF
Trial Master File
TIC
Trial Identification Card 
TIOSPIR
Tiotropium Safety and Performance in Respimat®
ULN
Upper Level of Normal
URI
Upper Respiratory Infection
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a complex disease with increasing 
morbidity and mortality [P13-09537]. It is estimated that by year 2020, COPD will be the 
third leading cause of mortality worldwide [R18-2760]. COPD represents a significant 
societal and economic burden throughout the world [P13-09537], [P18-08335]. Current 
strategy for the management of COPD recommends the use of inhaled medication for 
relieving symptoms and preventing complications and exacerbations [P13-09537].
Despite advancement in medical treatment, poor adherence remains a major challenge in the 
management of COPD [R15-5710], and adversely impacts health outcomes, quality of life, 
and healthcare expenditures [R18-2759]. Between 40% and 60% of patients with COPD do 
not adhere to the prescribed regimen [P13-04349]. Factors impacting adherence in COPD 
may be associated with patients (health beliefs, cognitive ability, co-morbidities, and
psychological condition), drug treatment (method of drug administration, dosing regimen, 
polypharmacy, and side effects), and societal factors (access to medication, social support,
device training, and follow-up) [P13-04349].
Efficient delivery of inhaled medication is essential for the success of COPD therapy [P13-
09537], [P05-02701]. The inhaler device may contribute to optimal drug delivery [P06-
04747] and also impact patient adherence [P10-05294]. A wide range of inhaler devices are 
available, including pressurized metered dose inhalers (pMDIs), drypowder inhalers (DPIs),
nebulizers, and soft mist inhalers (SMI) [P10-05294]. Each type of device has its own 
advantages and disadvantages [P06-04748].
When considered independently of drug class, choice of inhaler device depends on 
availability and cost of inhalation treatment, clinical setting, age of the patient, dosing 
regimen, physician and patient acceptability/preference, and ability of the patient to use the 
inhaler[P05-02701], [P10-05294], [P06-04749]. Patient satisfaction, and consequently
adherence, largely depend on the patients’ attitude towards the inhaler and their ability to use 
the device [P05-02701], [R18-2765].
Patient satisfaction with their inhaler is an acknowledged predictor of treatment adherence
[R07-1426], [R18-2768], [R18-2761], [R18-2764]. In a large, multinational, cross-sectional, 
real-world survey reported by Chrystyn et al [R18-2764], patient satisfaction with their 
inhaler was closely linked to treatment compliance and loosely associated with fewer 
exacerbations and lower utilization of health-care resources [R18-2761]. Reporting of patient 
satisfaction with inhalers is therefore gaining increasing attention and is now recognized as 
an important patient-reported outcome in clinical trials involving patients with COPD or 
asthma [R18-2763].
1.2
DRUG PROFILE
Tiotropium:


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Tiotropium is a non-chiral, quaternary, ammonium compound developed as a long-acting 
anticholinergic bronchodilator for treatment of bronchospasm and dyspnoea in patients with 
COPD. It is two to four-times more potent than ipratropium bromide and has a slower onset 
of action. The duration of action for tiotropium exceeds 24 hours compared to 6 hours for 
ipratropium bromide. As with other inhaled quaternary anticholinergic agents, tiotropium 
does not cross the blood-brain barrier to any significant extent. It has low oral bioavailability.
Inhalation Device: Handihaler®
Handihaler® belongs to the single dose dry powder inhalers (DPIs). The drug powder is 
stored in the capsules which is placed in the centre chamber of the device and is by pressing 
the pierced button. 
Inhalation Device: Tiotropium Respimat® inhaler
The Tiotropium Respimat® is a multi-dose inhaler that differs from currently marketed dry 
powder and pressurized metered-dose inhalers (MDIs) in several ways. It relies on a spring, 
rather than propellants, to generate a slow-moving cloud from a solution of medication 
contained in the cartridge. The energy from turning the transparent base to the right (half a 
turn) compresses a spring, which draws a pre-defined, metered volume of solution through 
the capillary tube and into a micro-pump. When the dose-release button is pressed, the energy 
released forces the solution through the unblock; this produces a slow-moving cloud over 
approximately 1.5 seconds. The total delivered volume is 22.1 μL per dose (i.e. 2 actuations), 
and the fine particle fraction around 60%. The Tiotropium Respimat® also offers 
technological advances that enhance the proper use by the patient (e.g. a dose indicator and a 
locking mechanism that prevent tail-off of dosing after the declared number of doses)
1.3
RATIONALE FOR PERFORMING THE TRIAL
The purpose of this study is to evaluate the patient acceptability/preference of Tiotropium 
Respimat® comparing with Tiotropium Handihaler® in patients with chronic obstructive 
pulmonary disease (COPD). The validated PASAPQ will be applied to evaluate the 
outcomes. Based on the previous studies, Tiotropium Respimat® showed better patient 
acceptability/preference compared with two DPIs, Diskus or Turbuhaler using PASAPQ as 
measurement. However, no studies have been done to compare the patient 
acceptability/preference between Tiotropium Respimat® and Tiotropium Handihaler®. The 
TIOSPIR study showed the efficacy of tiotropium via Respimat® or Handihaler® was similar 
in terms of lung function improvement and COPD exacerbation prevention. In real-life 
practice, the effectiveness might be influenced by different factors; including the use of 
inhalers. The patient’s acceptability/preference on the inhalers can impact the adherence to 
therapy, and then possibly the control of disease. Therefore, we consider it is of clinical 
importance to investigate the patient acceptability/preference between Tiotropium Respimat®
and Tiotropium Handihaler®, so that HCPs can refer to this trial to make appropriate decision 
on the choice between these two devices.


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1.4
BENEFIT - RISK ASSESSMENT
Tiotropium HandiHaler® (18 μg inhalation capsules) and tiotropium inhalation solution 5 μg
(2 × 2.5 μg) delivered via the Respimat® Inhaler are both widely approved for the 
maintenance treatment of patients with COPD (including chronic bronchitis and emphysema). 
Both products are effective drugs for the maintenance treatment of COPD and have 
demonstrated benefits to patients on multiple clinical endpoints including lung function, 
health-related quality of life, and exacerbations.
All classes of maintenance respiratory medications are permitted throughout this trial.  Only 
non-study drug inhaled anticholinergics will need to be discontinued. Patients will have 
access to all available treatments. Exacerbations may be treated with oral steroids and 
antibiotics according to medical need and the trial medication may be continued throughout 
the treatment period or after the episode at the discretion of the patient and the investigator. 
Safety will be monitored at site visits.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The objective of this study is to investigate the patient acceptability/preference of Respimat®
compared with Handihaler® in patients with moderate to severe chronic obstructive 
pulmonary disease (COPD) to demonstrate the superiority of Respimat®.
2.1.2
Primary endpoint(s)
The primary endpoint of the study is the performance domain of the Patient satisfaction and 
preference questionnaire (PASAPQ) after 4 weeks of treatment.
The PASAPQ is a two-part questionnaire. Part I consists of 14 questions. The first 13 
questions generate the Performance domain (7 questions) and the Convenience domain (6 
questions), which form a Total Score (all 13 questions). Question 14 asks for overall 
satisfaction with the device used in the study. Part II consists of stand-alone questions 
concerning a subject’s device preference (question 15) and willingness to continue use 
(question 16). The first 14 questions in PASAPQ have Likert-type response options of 1 
(very dissatisfied) to 7 (very satisfied). Question 15 ask for a response to indicate the 
preference for the trial device. Question 16 asks for a response between 0 and 100 with 0 
indicating not willing to continue using the trial device and 100 indicating definitely willing 
to continue.
The performance domain score is the sum of 7 questions within the domain (Q1, Q2, Q3, Q4, 
Q5, Q10 and Q11) and then transformed to a 0 (least) to 100 (most) point scale.
2.1.3
Secondary endpoint(s)
1. PASAPQ total score after 4 weeks of treatment. Total score is the sum of 13 questions 
(Q1-Q13) and then transformed to a 0 (least) to 100 (most) point scale.
2. Proportion of patients indicating preference which will be administered at Week 8.
3. Overall Satisfaction Question Score from PASAPQ will be administered at week 4 and 8.
4. Score on willingness to continue will be administered at week 8.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multicentre, randomised, open-label, two-way cross-over study to compare the 
patient acceptability/preference between Tiotropium Respimat® and Tiotropium Handihaler®. 
Following an initial screening assessment, eligible patients will be randomized to the open-
label phase of the trial during which one group of patients will received 5µg tiotropium (2 
puffs of 2.5μg) administered once daily by Respimat® (T1), the other group will receive 18µg
tiotropium once daily by Handihaler® (T2) for 4 weeks. After the first 4-week treatment, these 
two groups of patients will be switched to the second period treatment.
Figure 3.1:1 A 8-week, two way cross-over, open-label study
Patients who withdraw prematurely from the randomised treatment period will be followed 
up regarding COPD exacerbations, SAEs and vital status until their predicted normal exit 
date from the trial.
Refer to the Flow Chart (FC) for an overview of procedures to be done at each visit.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A cross-over design is appropriate for the evaluation of patients’ assessment on their 
acceptability/preference with the inhalers. Four-week treatment with inhalers would suffice 
for patients to evaluate the inhalers. As efficacy endpoints are not evaluated in this trial, no 
wash-out period is required.
3.3
SELECTION OF TRIAL POPULATION
A sufficient number of patients (approximately 71) will be randomized to ensure that a
minimum of 60 patients of either sex, 40 years of age or older, with a diagnosis of COPD will 


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complete the 8-week treatment study. Approximately 7 sites will be initiated in mainland 
China. Each site is expected to enter approximately 10 patients within 6 months after study 
initiation.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Patients of either sex, 40 years of age or older, with a diagnosis of COPD will be selected as 
subjects for the trial.
Please refer to Section 8.3.1. (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. All patients must have a diagnosis of COPD and must meet the following spirometric
criteria at Visit 1 (Screening).
•
Relatively stable, moderate to severe airway obstruction with a post-bronchodilator 30% 
≤FEV1 ≤80% of predicted normal and FEV1/FVC <70%. Spirometry should be done at 
baseline and approximately 1/2 hour following 4 inhalations of albuterol.
Male = exp [−10.61669 + 2.27078 × ln (− in cm) + 0.06622 × ln (age in year) + Mspline]
Female = exp [−9.69716 + 2.09385 × ln (− in cm) + 0.02006 × ln (age in year) + 
Mspline]
Historical data from spirometry measurements within the past 6 either at the site or at the 
other hospital may be used. If the measurements are not performed at the trial site a 
referral letter and signed copies of the measurement printouts must be provided to the 
trial site for source data verification. In case several qualifying spirometry measurements 
are available, the most recent one should be referred to as long as it was not performed 
during an exacerbation. Patients may not be randomised to the study without the 
availability of spirometry data at the actual study site.
2. Male or female, age: 40-80 years
3. Patients must be current or ex-smokers with a smoking history of ≥10 pack years. 
(Patients who have never smoked cigarettes must be excluded).


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Pack Years =
	 
 	/
20 	/
year of smoking
4. Signed and dated written informed consent in accordance with International Council on 
Harmonization (ICH) ICH-GCP and local legislation prior to admission to the trial 
5. Patients must be able to inhale medication from the Tiotropium Respimat® and
Tiotropium HandiHaler®
6. Patients must be able to perform all study related procedures, and must be able to 
maintain records (patient diary) during the study period as required by the protocol
3.3.3
Exclusion criteria
1.
Had visual, cognitive, or motor impairment that, as judged by the investigator, did not 
allow the patient to independently read and complete the PASAPQ questionnaire
2.
Patients have any previous experience of using Respimat® or Handihaler® or generic 
Handihaler within one year prior to screening. 
3.
Patients with significant diseases other than COPD will be excluded. A significant 
disease is defined as a disease or condition which, in the opinion of the investigator, may 
put the patients at risk because of participation in the study or may influence either the 
results of the study or the patient’s ability to participate in the study.
4.
All patients with an Aspartate Transaminase (AST) (serum glutamic-oxaloacetic 
transaminase, SGOT) >80 IU/L, Alanine Aminotransferase (ALT) (Serum Glutamic-
pyruvic Transaminase, SGPT) >80 IU/L, Bilirubin >2.0 mg/dL or Creatinine >2.0 mg/dL 
will be excluded regardless of the clinical condition. Repeat laboratory evaluation will 
not be conducted in these subjects.
5.
Patients with a recent history (i.e., one year or less) of myocardial infarction.
6.
Patients who have been hospitalized or being treated for heart failure within the past 
year.
7.
Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention 
or change in drug therapy during the last year.
8.
Patients with a history of cancer, other than treated basal cell carcinoma, within the last
five years.
9.
Known active tuberculosis.
10. Patients with a history of asthma, cystic fibrosis, bronchiectasis, interstitial lung disease, 
or pulmonary thromboembolic disease
11. History of thoracotomy with pulmonary resection. Patients with a history of thoracotomy 
for other reasons should be evaluated as per exclusion criterion 3. 
12. Patients with any respiratory tract infection or COPD exacerbation in the 6 weeks prior 
to the initial screening visit (Visit 1).


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13. Patients with known symptomatic prostatic hypertrophy or bladder neck obstruction.
Patients whose symptoms are controlled on treatment may be included.
14. Patients with known narrow-angle glaucoma.
15. Use of systemic corticosteroid medication at unstable doses (i.e., less than six weeks on 
stable dose) or at doses in excess of the equivalent of 10 milligrams (mg) prednisolone 
per day.
16. Patients who regularly use daytime oxygen therapy for more than 1 hour per day and in
the investigator’s opinion will be unable to abstain from the use of oxygen therapy.
17. Pregnant or nursing women or women of childbearing potential not using a medically
approved means of contraception (i.e., oral or injectable contraceptives, intrauterine
devices (IUD) or diaphragm with spermicide, or Norplant®).
18. Significant alcohol or drug abuse within the past 12 months
19. Known hypersensitivity to anticholinergic drugs, lactose, benzalkonium chloride (BAC), 
ethylenediaminetetraacetic acid (EDTA) or any other components of the HandiHaler® or 
Respimat® inhalation solution delivery system.
20. Patients currently in any pulmonary rehabilitation program or scheduled to participate in
any such program during the study period.
21. Previous participation in this study. (The patient cannot re-enroll into this study.)
22. Patients who are currently participating in another interventional study.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole 
(“withdrawal of consent”) with very different implications, please see sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the randomised patients in the trial.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomization, as well as the
explanation of the consequences of withdrawal. 
Patients who fail to complete all treatment and PASAPQ as required in the protocol, will not 
be considered complete. The decision to withdraw from trial treatment or from the whole trial 
as well as the reason must be documented in the patient files and Case Report Form (CRF).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.


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
The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment.

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).
In case of a temporary reason, trial treatment should be restarted if medically justified, please 
see Section 4.1.4.
Even if the trial treatment is discontinued, the patient remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow chart and section.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Violation of Good Clinical Practice (GCP), the trial protocol, or the contract impairing 
the appropriate conduct of the trial.
The investigator/the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products (IMPs)
The test product Tiotropium Respimat(SpirivaRespimat), and the comparator product 
Tiotropium Handihaler(Spiriva) will be supplied by Boehringer Ingelheim Pharma GmbH 
& Co. KG, Germany. The composition of the drugs is described as follow:
Table 4.1.1:1 Test product: Tiotropium Respimat(SpirivaRespimat)
Substance:
Tiotropium
Pharmaceutical formulation:
inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
2.5μg per puff, 60 puffs with 1 RespimatInhaler
Posology:
5 μg once daily, given as 2.5μg per puff, two puffs
Method and route of 
administration:
Oral Inhalation via Respimat
Table 4.1.1:2 Comparator products: Tiotropium Handihaler(Spiriva)
Substance:
Tiotropium 
Pharmaceutical formulation:
Inhalation Powder
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
30 capsules with 1 Handihalerdevice
Posology:
18μg once daily
Method and route of 
administration:
Oral Inhalation via Handihaler


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Tiotropium Respimatand Tiotropium Handihalerboth have the same active ingredient in 
the medicine: tiotropium bromide.
Tiotropium Respimatdelivers a very slow-moving mist that is designed to help the patient 
inhale the medicine easier. The amount of medicine the patient takes in does not depend on 
how fast they are able to inhale. Patients receive one dose per day, which lasts for 24 hours.
The medicine in Tiotropium Handihalercomes in a dry powder contained in a capsule that 
is put into a special inhaler. The patient takes the medicine by breathing in two inhalations 
through the Handihaler. The medicine lasts for 24 hours, so patients take one dose (two 
inhalations) of Tiotropium Handihalerper day in the morning. Patients use a new capsule 
for each dose.
4.1.2
Selection of doses in the trial and dose modifications
Tiotropium Respimat® and Tiotropium Handihaler® have been available on the market, so 
dose selection please follow the local package inserts, that is, randomized patients will 
receive tiotropium 5 µg inhalation solution from the Respimat® inhaler or tiotropium 
inhalation capsules 18 µg delivered by the HandiHaler®.
4.1.3
Method of assigning patients to treatment groups
Technical and statistical features of the process of treatment sequence allocation are provided
in Section 7.
Each patient will get a patient number when informed consent is signed at Visit 1and a 
randomization number at Visit 2, which will be recorded in the electronic case report form 
(eCRF). 
Since the medication dispensed to the patient is one device of Respimat® or Handihaler® each 
time, only the device type will be recorded in the eCRF and there will be no medication 
number.
After assessment of all in- and exclusion criteria, each eligible patient will be randomised to 
the open-label phase of the trial (Visit 2) during which one group of patients will received 
5μg tiotropium (2 puffs of 2.5μg) administered once daily by Respimat® (T1), the other group 
will receive 18μg tiotropium once daily by Handihaler® (T2) for 4 weeks.
Randomisation of patients to treatment sequence is based on randomization envelope at visit 
2. After the first 4-week treatment, these two treatment groups of patients will switch to the 
Tiotropium Respimat® and Tiotropium Handihaler® vice versa. The appropriate 
randomization number and correspondent device type will be assigned by randomization 
envelope at Visit 2. Note that there is no medication number exists during the study and 
medication device type should be recorded in eCRF.
4.1.4
Drug assignment and administration of doses for each patient
At Visit 1, all patients should be trained on the use of rescue medication Salbutamol Sulphate 
Aerosol (pMDI).


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At Visit 2 and Visit 3, patients will be assigned to one of the two treatment groups. At each of 
these visits, patients will be trained on how to use the Tiotropium Respimat® or Handihaler®
properly. 
4.1.4.1
Instructing the patient
Detailed written instructions and training for the use of the Respimat®, Handihaler® and 
Salbutamol Sulphate Aerosol will be given to the patient at Visit 2 and 3 (see Section 10.1, 
10.2 and 10.3). 
The Respimat® inhalers and cartridges will be dispensed to patients unassembled and 
packaged in one box (each box containing one Tiotropium Respimat® inhaler and one 
Tiotropium Respimat® cartridge), and patients will be instructed on how to prepare the 
inhaler for use, including inserting the cartridge into the inhaler and priming the unit, and on 
using the Tiotropium Respimat® inhaler. 
Note: Patients who are randomized to Tiotropium Respimat® must follow the instructions for 
this inhaler in Section 10.1. These patients must be instructed to take two puffs of Tiotropium 
Respimat® one time a day.
Patients who are randomized to Tiotropium Handihaler® must follow the instructions for this
product according to Section 10.2. These patients must take one capsule of tiotropium 
bromide once daily with the HandiHaler® device at the same time of day. 
Table 4.1.4.1: 1
Dosage and treatment schedule
Treatment
Visit Number
Tiotropium Respimat®
Tiotropium Handihaler®
μg/daily
1
Visit 2 - Visit 3 (Week 0-4)
5μg (2 puffs of 2.5μg)
-
Visit 3 - Visit 4 (Week 4-8)
-
18μg (one capsule)
2
Visit 2 - Visit 3 (Week 0-4)
-
18μg (one capsule)
Visit 3 - Visit 4 (Week 4-8)
5μg (2 puffs of 2.5μg)
-
The Tiotropium Respimat® contains 60 puffs per cartridge and 2.5μg tiotropium per puff, 
with drug concentration of 0.2262 mg/ml (calculated as tiotropium) after preparing the 
inhaler for first use. There is enough medicine for 30 days when it is used as two puffs of 
Tiotropium Respimat® one time a day.
Each Tiotropium Handihaler® contains 30 capsules with the HandiHaler® device. Each 
capsule contains 18µg (as tiotropium, equivalent to 22.5µg tiotropium bromide 
monohydrate), enough for 30 days if used as one capsule once daily with the HandiHaler®
device.
Two treatment groups of patients will be assigned to therapy with either Tiotropium 


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Respimat® or Tiotropium HandiHaler® for 4 weeks respectively before completing the 
PASAPQ at a single visit to the study site.
4.1.4.2
Trial medication administration at home
Patients will be instructed to refer to the detailed written inhaler directions provided at either 
Visit 2 or Visit 3, or to phone the site if they have questions.
The patient will record whether he/she took the daily doses (number of puffs orcapsule) of 
the medication in a patient diary. If a patient misses a dose, he/she should take the next dose 
at the next scheduled time and make a note of the missed dose in his/ her patient diary.
4.1.4.3
Trial medication return
All used and unused trial medication, used device will be returned to the clinic at the next 
treatment visit.
Any inhaler that is reported to have malfunctioned by the patient or study staff should be
returned to BI for further investigation. Please see the ISF for specific instructions regarding
the procedure to return such devices.
Note: Tiotropium HandiHaler® capsules are to be used only with the HandiHaler® device.
Tiotropium Respimat® cartridges are to be used only with the Respimat® inhaler.
4.1.5
Blinding and procedures for unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI. They will be labelled in accordance with 
the principles of Good Manufacturing Practice (GMP). Re-supply to the sites will be 
managed via site staff and CRA, which will also monitor expiry dates of supplies available at 
the sites.
For details of the description of the label, refer to the ISF.
4.1.7
Storage conditions
Trial medication must be stored under the recommended storage conditions indicated on the
drug information leaflets. 

Tiotropium Respimat®: Do not freeze. Store in a safe place out of the reach of children!

Tiotropium Handihaler®: Do not store above 25C. Do not freeze. Store in a safe place 
out of the reach of children!

Salbutamol Sulphate Aerosol: Store under 30C.  Keep away from light and avoid 
freezing and direct sunlight.
A temperature log must be maintained by the site to make certain that the drug supplies are 
stored at the correct temperature. If the storage conditions are found to be outside the


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specified range, the Clinical Trial Manager (CTM) for the study should be contacted
immediately.
Trial medication must be stored securely at the study sites, out of reach of children and be
protected from freezing, e.g. in a locked cupboard or at a pharmacy. It may only be dispensed 
to trial patients fulfilling the inclusion and exclusion criteria by authorized study personnel as 
documented in the ISF. Receipt, usage, and return of the study medication must also be 
documented on the respective forms in the ISF.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee ,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator
IMPs are not allowed to be used outside the context of this protocol. They must not be 
forwarded to other investigators or clinics. Patients should be instructed to return unused 
IMPs.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
medication device type and trial patients. The investigator or designee will maintain records 
that document adequately that the patients were provided the doses specified by the Clinical 
Trial Protocol (CTP) and reconcile all IMPs received from the sponsor. At the time of return 
to the sponsor, the investigator or designee must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in
the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures

Rescue medication(s)
Salbutamol Sulphate Aerosol (pMDI) will be provided as rescue medication. Administration 
of rescue medication can occur at any time during the study. The number of puffs used for 
rescue will be recorded by the patient in the Patient Diary. In the case of potentially life-


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threatening COPD exacerbations, any and all therapies and interventions deemed medically 
necessary by the treating physician could be prescribed.
The following medications are allowed to control acute exacerbations as medically necessary
during the treatment period.
1.
As needed (PRN) Salbutamol Sulphate Aerosol (pMDI) (provided by 
 
 and to be recorded on the Patient Diary).
2.
Temporary of nebulised short-acting βagonist (SABA) and/or short-acting muscarinic 
antagonist (SAMA) can be allowed during exacerbation.
3.
Temporary increases in the dose of theophylline preparations of up to 7 days each are
allowed during the study. Temporary increases in the dose or addition of, oral steroids of 
up to 7 days each are allowed during the study. 
4.
The use of antibiotics is not restricted and may be used as medically necessary for
exacerbations and other infections.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Table 4.2.2.1:1 Restrictions for concomitant treatment
Drug class
Screening period
Treatment period
Oral corticosteroids1
(≤10 mg prednisone per day)
Permitted
Permitted
Inhaled corticosteroids1
Permitted
Permitted
Theophylline1
Permitted
Permitted
Mucolytics1
Permitted
Permitted
Antihistamines,
Antilerkotrienes, Cromolyn1
Permitted
Permitted
Inhaled long-acting-beta-
adrenergics1
Permitted
Permitted
Oral beta-adrenergics1
Permitted
Permitted
Inhaled short-acting-beta-
adrenergics
PRN as supplied for study 
only - recorded in patient
Diary
PRN as supplied for study 
only - recorded in patient
Diary


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Inhaled short-acting-
anticholinergics
Only for exacerbation 
treatment.
Only for exacerbation 
treatment.
Inhaled long-acting-
anticholinergics
Not permitted
Trial medication
1.
If stabilized for 6 weeks before screening (visit 1)
The following inhalation devices or medications are not allowed during the screening period or the treatment
period.

Inhalation devices other than the investigational devices which have not been stably used for 6 weeks prior 
to the screening period.

Use of systemic corticosteroid medication at unstable doses (i.e., less than six weeks on stable dose) or at 
doses in excess of the equivalent of 10 milligrams (mg) prednisolone per day.

Long-acting anticholinergic drugs other than the investigational drugs during the randomization treatment 
period.
4.2.2.2
Restrictions on diet and life style
No restrictions on diet or life style.
4.2.2.3
Contraception requirements
For tiotropium, no clinical data on exposed pregnancies are available. Preclinical studies do
not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / foetal
development, parturition or postnatal development. 
Clinical data from nursing women exposed to tiotropium are not available. Based on lactating 
rodent studies, a small amount of tiotropium is excreted into breast milk. Therefore, 
tiotropium should not be used in pregnant or nursing women unless the expected benefit 
outweighs any possible risk to the unborn child or the infant. Pregnant and nursing women 
are generally excluded from tiotropium clinical trials.
Clinical data on fertility are not available for tiotropium. A non-clinical study performed with 
tiotropium showed no indication of any adverse effect on fertility.
Woman of childbearing potential (WOCBP) (for the definition please refer to Section 3.3.3.) 
and men able to father a child must use two medically approved methods of birth control 
throughout the trial, and for a period of at least 30 days after last trial drug intake. They must 
use one barrier method, i.e. condom or occlusive cap with spermicide, or vasectomized 
partner, and one highly effective non-barrier method including oral, injected or implanted 
hormonal contraceptives, intrauterine device or system.
Male patients: 
Men whose partner is a WOCBP must use a condom during the study, and for a period of at 
least 30 days after the last dose of study drug.
Female patients: 
WOCBP must use a highly effective method of birth control per ICH M3 (R2) that results in 
a low failure rate of less than 1% per year when used consistently and correctly during the 
study, and for a period of at least 30 days after the last dose of study drug.


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Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion

Vasectomised sexual partner with documented absence of sperm.
Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
4.3
TREATMENT COMPLIANCE
The patient will enter, in the Patient Diary, the number of puffs or capsules of study 
medication taken. The investigator/study staff will review these records with the patient at 
each study visit to assess treatment compliance. The investigator / study staff should also 
examine the inhalers used since last visit. The Tiotropium Respimat® dose indicator should 
concur with the patient diary. And the residual of Tiotropium Handihaler® should be in 
accord with the patient diary. If compliance rate is not between 80-120%, site staff will 
explain to the patient the importance of treatment compliance, and the reason of non-
compliance should be recorded in the source document. CTM should be notified if patients 
continue to be non-compliant. Patients will be asked to return all used and unused study 
medication to the clinic at each scheduled visit and at the end of study.
The study site must transfer data regarding study medication use and rescue medication from
Patient Diary to the eCRF within 1 week after each visit.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Primary endpoint
The primary endpoint for patient preference is the performance domain of the Patient 
Satisfaction and Preference Questionnaire (PASAPQ).
The PASAPQ is a two-part questionnaire. Part I consists of 14 questions. The first 13 
questions generate the Performance domain (7 questions) and the Convenience domain (6 
questions), which form a Total Score (all 13 questions). Question 14 asks for overall 
satisfaction with the device used in the study. Part II consists of stand-alone questions 
concerning a subject’s device preference (question 15) and willingness to continue use 
(question 16). The first 14 questions in PASAPQ have Likert-type response options of 1 
(very dissatisfied) to 7 (very satisfied). Question 15 ask for a response to indicate the 
preference for the trial device. Question 16 asks for a response between 0 and 100 with 0 
indicating not willing to continue using the trial device and 100 indicating definitely willing 
to continue.
The performance domain score is the sum of 7 questions within the domain (Q1, Q2, Q3, Q4, 
Q5 Q10 and Q11) and then transformed to a 0 (least) to 100 (most) point scale.
5.1.2
Secondary endpoints
Total score of PASAPQ:
Total score domain containing 13 questions will be evaluated at Visit 3 (week 4) and Visit 4
(week 8). 
The proportion of patients indicating preference:
Preference for either inhalation device will be evaluated at Visit 4 (week 8).
Overall Satisfaction Question Score from PASAPQ:
The answer to the PASAPQ question “Overall, how satisfied are you with your inhaler”
measured using a 7-point Likert scale (1 meaning very dissatisfied and 7 means very satisfied)
at Visit 3 (week 4) and Visit 4 (week 8). 
Willingness to continue:
Question 16 asks for a response between 0 and 100 with 0 indicating not willing to continue 
using the trial device and 100 indicating definitely willing to continue, which will be 
evaluated at Visit 4 (week 8). 


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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A full physical examination will be completed on all patients at screening (Visit 1) and Visit 
4.All clinically relevant abnormal findings at the screening visit will be recorded on the 
Medical History/Baseline Conditions eCRF page. Clinically relevant new abnormal findings 
or worsening of baseline conditions detected at follow-up physical examinations will be
recorded as AEs on the appropriate eCRF page. All (S)AEs, including those persisting after 
individual patient’s end of trial must be followed up until they have resolved, have been 
assessed as ‘chronic’ or ‘stable’, or no further information can be obtained.
5.2.2
Vital signs
Pulse rate and blood pressure will be measured and recorded at screening Visit 1 and Visit 4.
Vital Status for patients who discontinue early:
The objective of obtaining vital status is to ascertain information on health status in patients
who withdraw prematurely from randomized treatment up to the previously projected exit
date from the trial. Depending on the time of discontinuation, there will be 1 or 2 calls made 
to the patients to assess their vital status. The site must make at least 2 attempts to contact the 
patient at each projected time point. The following information should be obtained during 
these phone calls: 1) date of follow up; 2) status (alive, deceased or lost to follow up); if lost 
to follow up, last date known alive, if patient is deceased the date and cause of death must be 
recorded. In this case the site must complete and forward an SAE form to 
 
.and the reason for lost to follow up should be 
recorded.
5.2.3
Safety laboratory parameters
Clinical laboratory testing will be conducted on all patients at the Screening Visit (Visit 1)
and (Visit 4).
Laboratory specimens (blood and urine) will be collected in the morning with the patient
having fasted for at least 8 hours. The patient may have a light snack after blood collection on 
these pulmonary function test-days. 
Hematology testing will include hemoglobin, hematocrit, erythrocytes, platelets, total 
leukocyte count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), and absolute eosinophil count. Serum chemistry testing will include albumin, 
alkaline phosphatase, calcium, chloride, creatinine, glucose, inorganic phosphorus, LDH, 
potassium, AST (SGOT), ALT (SGPT), sodium, total bilirubin, total protein, uric acid, urea
nitrogen (or urea). 
The urinalysis will include specific gravity, pH, glucose, protein, leukocytes and erythrocyte.
A urine pregnancy test will be conducted at the screening visit and visit 4 in all women of 
child-bearing potential. 


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All clinical laboratory tests will be performed at local laboratory. Comments should be given 
for each value considered clinically relevant (for instance, outside the reference range or if 
any value that differs importantly from previous ones). If the baseline laboratory evaluation is 
repeated, only the most recent results are used for evaluation of patient participation. The 
significant abnormality as judged by the investigator will be recorded as adverse events.
5.2.4
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be recorded as scheduled in the flowchart. 
The investigator or a designee will evaluate whether the ECG is normal or abnormal and 
whether it is clinically relevant, if abnormal.
All electrocardiograms should be performed prior to pulmonary function. The interpretation
of the ECG will be performed by the investigator or a qualified designee.
The purpose of the baseline ECG (Visit 1) is to obtain information about the patient's baseline
condition that may have not been elicited in obtaining the medical history; therefore, any
significant findings from this examination are recorded on the Medical History/Concomitant
Diagnoses page.
The purpose of the ECG at Visit 4 is to find any new condition or worsening on baseline 
condition. Clinically relevant abnormal findings should be reported as an adverse event.
If necessary, additional ECGs may be recorded for safety reasons. Dated and signed printouts 
of ECG with findings should be documented in patient’s medical record.
5.2.5
Other 
Medical History
A complete medical history by body system will be performed on all patients at the screening
visit. All active and resolved historical disorders for the last 5 years will be recorded on the
eCRF.
Record of Investigational Drug
A paper Patient Diary will be kept documenting the administration of the investigational drug 
during the study.
Concomitant Therapies
All concomitant therapies taken in the 2 months preceding the screening visit and throughout 
the study (including baseline period) will be recorded on the Concomitant Therapy eCRF 
page.
Smoking Status
The smoking status (current smoker or ex-smoker) of each patient will be recorded at the
screening visit (Visit 1).


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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions 
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation,
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.6.1.3
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.


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In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
5.2.6.1.4
Adverse events of special interest 
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

An elevation of AST (aspartate transaminase) and/or ALT (alanine aminotransferase) ≥3 
fold Upper Level of Normal (ULN) combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 


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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
report any occurrence of cancer and related SAEs and related AESIs of which the 
investigator may become aware of by any means of communication, e.g. phone call.
Those AEs should however not be reported in the CRF.
All adverse events, regardless of causality, will be recorded on the adverse event eCRF page
after review of the Patient Daily Record, the paper Patient Diary and discussions with the 
patient. Information concerning the onset, duration, intensity, severity, medication taken,


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action taken with study medication and causality of the adverse event will be collected on the
eCRF page. Where relevant (e.g., paradoxical bronchospasm) the temporal relationship
(minutes) between the onset of an adverse event and the time of drug administration should
be recorded in the comment section of the adverse event eCRF page. 
All AE should be recorded in CRF as soon as possibleafter the investigator becomes aware. 
Vital Status Data Collection
Patients who discontinue trial medication prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in Section 3.3.4.1
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must report all deaths/fatal AEs regardless of relationship, related SAEs and 
related AESIs the investigator becomes aware of.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Additionally, serious adverse events leading to death, which is related to IMP, should 
additionally fax to local PV immediately (contact details will be provided in the ISF).
5.2.6.2.3
Information required
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been assessed as “chronic” or “stable” , or no further 
information can be obtained.
5.2.6.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).


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The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B) as 
well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable.
5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
Not applicable.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The study will consist of three sequential periods, a Screening period of up to 7 days, a
treatment period of 8 weeks and a follow-up period of 4 weeks. The maximum duration is 
expected to be 93 days.
Following an initial screening, eligible patients will be randomized to enter the first 4-week 
treatment periods in which they will be given Tiotropium Respimat® or Tiotropium 
HandiHaler® respectively. Before the treatment phase, patients will be trained to use these 
two inhalers correctly. After the first treatment period, patients will enter the next 4-week 
treatment phase and have to switch to the other inhaler. After each of the treatment period, 
patients will fill-in the performance domain, convenience domain and overall satisfaction. 
After conclusion of both treatment phases (at visit 4), all patients will indicate their
preference and willingness to continue of these two inhalers in the PASAPQ. 
Adverse events will be tracked from screening to the follow-up period. All SAEs or any AE 
associated with trial medication persisting after trial completion must be followed up until 
they have been resolved or have been fully characterized (have been assessed as “chronic” or 
“stable”, or no further information can be obtained).
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period(s)
Written informed consent will be obtained prior to initiating any study-related evaluation. 
Upon obtaining consent, the patient will be instructed on the medication and other restrictions 
for the screening test.
All tests for the visits during the study period are detailed in the Flow Chart and completed at 
local sites.
Screening Period (Visit 1, up to 7 days)

A complete medical history, including demographic information.

A complete physical examination including vital sign measurements and 12-lead ECG.

Smoking status (smoker vs. ex-smoker) will be recorded.

Concomitant therapy for the two months will be recorded in the CRF.

Blood and urine samples will be collected for laboratory analysis and determination of
eligibility as well as a urine pregnancy for females of child-bearing potential. The patient 
will perform a baseline pulmonary function test (PFT) that will consist of three 
manoeuvres and the highest FEV1 and FVC of those manoeuvres will be recorded on the 
eCRF. The patient will be required to have a post-bronchodilator 30% ≤FEV1 ≤80% of 
predicted normal and FEV1/FVC ≤70%. Spirometry must be done at baseline and
approximately 1/2 hour following 4 inhalations of albuterol. Predicted normal values will 
be calculated according to the Jinping Zheng’s study [R18-2762]. Historical data from 


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spirometry measurements within the past 6 months either at the site or at the other 
hospital may be used. Please refer to flow chart for details.

Patients will be assessed for the eligibility as per the inclusion and exclusion criteria.

Patients will be dispensed a Salbutamol Sulphate Aerosol (pMDI) as rescue medication.
The usage guidance will be given.

The Patient Diary will be dispensed to the patient. Directions will be provided on proper 
completion. 

Trial Identification Card (TIC) with trial information and study Doctor’s contact 
information will be provided for the patient.

Patients will be instructed on medication restrictions.

Details of any patient who is screened for the trial but are found to be ineligible must be 
entered in an enrolment log and documented in the case report form.
6.2.2
Treatment period(s)
Visit 2 (1 day):
This visit will be scheduled for after the completion of the screening period.
The inclusion and exclusion criteria will be reviewed prior to randomization, and if the 
patient qualifies for the screen period of the trial, patients will be randomized into 2 groups 
by envelope randomization. When one group (T1) is randomized into Respimat® arm, and 
another group (T2) will enter into Handihaler® arm for 4-week treatment. 
After randomization the following will be performed:
●
Rescue medication and patient diary dispensed at Visit 1 need to be collected.
●
Adverse events and concomitant therapy since last visit will be reviewed and recorded on 
the eCRF.
●
Patients will be trained by the investigator to use the randomized inhalers, i.e. Respimat®
or Handihaler®. The placebo of each inhaler will be provided for the training to patients, 
which will follow the instructions in the local product information and demonstration 
video.
●
The tiotropium Respimat® or Tiotropium Handihaler® will be provided to the patients.
The patient will assemble (Tiotropium Respimat®, only) and prime his/her assigned 
inhaler(s) in the presence of the trial staff.
●
The first dose of trial medication will be administered at the clinic.
●
Patients will be provided with rescue medication and a new patient diary. He/she will be 
instructed to return to the clinic in 29 days for the next scheduled visit = visit 3.
Visit 3 ( 28 days±1 days ): T1 will enter into Handihaler® arm for 4 weeks after the 
completion of all procedures as listed below; on the contrary, T2 will enter into Respimat®
arm for 4 weeks.

Patients will have to complete the PASAPQ including total score (Q1-13), overall 
satisfaction (Q14), except for the preference question prior to any other procedures or 
evaluations.

Patients' diary will be collected and reviewed for patient compliance.


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
Concomitant therapy and any adverse events since last visit will be checked and recorded
on the eCRF.

All trial medication (used and un-used) will be collected.

Patients will be trained by the investigator in the use of the next randomised inhalers, i.e. 
Respimat® or Handihaler®. The placebo of each inhaler will be provided for the training 
to patients, following the instructions in the local product information and demonstration 
video.

The first dose of trial medication should be administered at the clinic. To avoid 
overdosing, the investigator needs to confirm whether the patient has already taken the 
medication at home on the day of V3 visit. If so, the patient will not take the first dose of 
the newly assigned treatment at Visit 3.

The tiotropium Respimat® or Tiotropium Handihaler® will be provided to the patients. 
The patient will assemble (Tiotropium Respimat®, only) and prime his/her assigned 
inhaler(s) in the presence of the trial staff.

The first dose of trial medication will be administered at the clinic.

Patients will be provided with rescue medication and a new patient diary. He/she will be 
instructed to return to the clinic in 29 days for the next scheduled visit = visit 4.
Visit 4 ( 56 days±1 days ).
The following trial procedures must be performed by all completed patients at Visit 4 as well 
as by all patients who discontinue the study prematurely (prior to 8 weeks of treatment).

Patients should complete PASAPQ, including total score (Q1-13), overall satisfaction
(Q14), preference and willingness to continue (Q15 and Q16) prior to any other 
procedures or evaluations. 

Patients' diary will be collected and reviewed for patient compliance. 

All trial medication (used and un-used) will be collected.

Patients will receive a complete final physical examination with vitals. 

12 lead-ECG should be done.

Blood and urine samples will be collected for laboratory analysis.

Pregnancy test (urine) will be performed on applicable female patients.

Adverse events and concomitant therapy since last visit will be reviewed and recorded on 
the eCRF.

Conclusion of Patient participation
6.2.3
Follow-up Period ( 84 days±2 days )
During the follow-up period, the investigator should collect AE&SAE information and 
concomitant therapy by telephone.
Patients who discontinue study treatment early should complete all assessments as soon as 
possible, which is the same as visit 4, especially, AE check and safety test, such as 12 lead-
ECG, Laboratory tests, and so on.
6.2.3.1
Vital status for patients who discontinue early
Patients who withdraw permanently from the randomized treatment period will be followed 
up by phone regarding their health status until their projected normal exit date from the trial. 


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The phone calls should be made at approximately 4 and 8 weeks after the patient is 
randomized. The site must make at least two attempts to contact the patient.
6.2.4
Removal of patients from therapy assessment
Criteria and rules for stopping subject treatment
To be considered complete, a patient must complete the use of both devices as specified in 
the protocol without violations of the protocol significant enough to obscure the patient 
acceptability/preference. Patients who fail to complete all treatment will not be replaced.
Dropouts and Withdrawals
Randomized patients who fail to complete all treatment and all of the testing as specified in
the protocol will not be considered complete, may not be enrolled at a later date and will not
be replaced. If the investigator feels a subject should be discontinued, the Local Clinical
Monitor should be contacted.
A record will be kept of all patients who fail to complete all test-days and their reasons for
discontinuation. A final physical examination should be conducted on all discontinued
patients. All safety information collected from discontinued patients will be included in the
safety analysis of the study.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
Details of all analyses will be provided in the Trial Statistical Analysis Plan (TSAP).
7.1
STATISTICAL DESIGN - MODEL
This is a multi-center, randomized, open-label, two-way cross-over study to investigate the 
patient acceptability/preference of Tiotropium Respimat® compared with Tiotropium
Handihaler® in patients with moderate to severe chronic obstructive pulmonary disease 
(COPD).
Based upon these design considerations, the primary endpoint (performance domain of 
PASAPQ) will be analysed using Mixed-effects Model for Repeated Measures (MMRM), 
with treatment and period as fixed effects, and patient as a random effect. Compound
symmetry will be used as a covariance structure for within-patient variation.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The following hypothesis (two-sided α = 0.05) will be tested for the primary endpoint –
performance domain of PASAPQ after 4 weeks of treatment:
: mean performance score for Tiotropium Respimat= mean performance score for 
Tiotropium Handihaler
: mean performance score for Tiotropium Respimat≠mean performance score for 
Tiotropium Handihaler
7.3
PLANNED ANALYSES
The analysis will be based on the following populations:
•
Treated set (TS) is defined as all patients who were dispensed study medication and were
documented to have at least one dose of investigational treatment.
•
Full analysis set (FAS) is defined as all patients who were randomized to treatment 
sequence and received at least one dose of one study drug and providing at least one
PASAPQ score measurement.
The primary endpoint will be analyzed on the FAS (as the primary analysis). The secondary
endpoints will be analyzed on the FAS.
Safety analyses will be performed on the TS.
Demographic and baseline characteristics will be analyzed on the TS using descriptive
statistics.


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7.3.1
Primary endpoint analyses
In the primary analysis, comparisons between treatment groups for the performance domain 
of PASAPQ will be based on a mixed effect repeated measures model (MMRM). This model 
will include treatment and period as fixed effects and patient as a random effect. Compound 
symmetry will be used as a covariance structure for within-patient variation. The SAS 
procedure MIXED will be used involving the restricted maximum likelihood estimation and 
the Kenward-Roger approximation for denominator degrees of freedom (Kenward, 2010). 
Adjusted mean values as well as treatment contrasts will be presented together with the 95% 
confidence intervals (CI) and p-values.
7.3.2
Secondary endpoint analyses
Continuous secondary endpoints will be analysed using a similar MMRM model as for the 
primary endpoint. Chi-squared test will be performed to analyse proportion of patients 
indicating preference.
7.3.4
Safety analyses
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of and end of the REP, a period of 4 weeks after the last dose of 
trial medication, will be assigned to the on-treatment period for evaluation.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Vital signs (blood pressure and pulse rate), physical examinations, or other safety-relevant 
data observed at screening, during the course of the trial and at the end-of-trial evaluation will 
be assessed with regard to possible changes compared to findings before start of treatment.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.


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Vital signs (blood pressure and pulse rate), physical examinations, or other safety-relevant 
data observed at screening, during the course of the trial and at the end-of-trial evaluation will 
be assessed with regard to possible changes compared to findings before start of treatment.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
No pharmacokinetic analysis is planned for this study.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
Every effort should be made to collect the complete data at the planned time points for this 
trial. 
For PASAPQ, imputation of responses to individual questions will follow the “half-scale
rule”. If a patient missed less than four of the seven questions in the Performance domain or
less than four of the six questions in the Convenience domain in the PASAPQ, then the
missing item in this domain is imputed using the observed mean from the same domain, and
then the Total score is calculated as the sum of the 13 items after substitution for missing
items at the domain level has taken place. If a patient missed more than three items in either
domain, then the domain and the Total score are set to missing and will not be imputed. 
The number of patients who cannot be included in the FAS will be summarised by treatment 
group and period.  Sensitivity analyses, in which missing data will be imputed according to 
the reason they are missing, will be described in the TSAP.
7.6
RANDOMISATION
This is a cross-over study with two treatment groups. After screening, eligible patients will be 
randomized in equal ratio to one of the two treatment sequences.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.


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7.7
DETERMINATION OF SAMPLE SIZE
Calculations were performed using nQuery Advisor® 6.1 statistical package by 
The Minimal Clinically Important Difference (MCID) is 8-10 points for PASAPQ assessment 
which is meaningful to patients (Richard Hodder, 2009). Based on previous studies, the 
standard deviation of difference between Respimat® versus DPI devices or MDI devices 
ranges from 18-22 (Schürmann W, 2005) (Gary T Ferguson, 2013) (Price, 2009). The study 
sample size was based on the calculation that 60 completed patients would be required to 
have a 85% power to detect a minimum 8-point difference in the mean performance domain 
score between patients using Respimat® and Handihaler®, and using a two-sided 5% 
significant level, assuming that the standard deviation for treatment difference is 20.0 using t-
test (ANOVA) for difference of means in 2 x 2 crossover design (nQuery Advisor 7.0). To 
account for 15% potential patients with no evaluable data, a total number of 71 patients were 
planned.
Table 7.7: 1 Sample size calculation based on t-test (ANOVA) for difference of means in 
2X2 crossover design
Treatment Difference
SD for difference
Power
90%
85%
80%
6
18
98
84
74
20
120
102
90
22
144
124
108
8
18
54
48
42
20
68
60
52
22
82
70
62
10
18
38
32
28
20
46
38
34
22
54
46
42


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs) and other 
relevant regulations. Investigators and site staff must adhere to these principles.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national regulations. The same applies for 
the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements. Each signature must be personally dated by each signatory 
and the informed consent and any additional patient-information form retained by the 
investigator as part of the trial records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.”
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 


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The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign and date the informed consent form. Re-consenting 
may become necessary when new relevant information becomes available and should be 
conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
The trial will be conducted in accordance with the International Conference on
Harmonization (ICH) Good Clinical Practice (GCP) guidelines, local regulations, and the
company standard operating procedures (SOPs). The following necessary steps will be taken
to ensure accurate, consistent, complete and reliable data.

An investigator meeting will be held prior to the initiation of the study. The protocol,
eCRFs, safety reporting, and GCP / ICH requirements will be reviewed with the
investigators and study coordinators.

Adverse events, concomitant therapies, and diagnoses will be coded using the MedDRA 
coding system. Coding will be reviewed by the Clinical Monitor for appropriateness and 
consistency.

On-site monitoring will be conducted every 6 weeks during the trial.

Data will be collected using a Remote Data Capture (RDC) system, and will be source
verified by the field monitors before the Principal Investigators approve the data in RDC. 
Training will be provided to all investigators, coordinators and field monitors to ensure 
consistency and accuracy of the data.

The data management procedures to ensure the quality of the data are described in detail 
in the trial data management and analysis plan (TDMAP) available in the CTMF.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
section 4.1.7.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).


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Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make three documented attempts to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Before sending or uploading those copies of source documents, the investigator must ensure 
that all patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification (gender, date of birth)

Patient participation in the trial (substance, trial number, patient number)

Dates of Patient’s visits

Dates of ECG tracings

Medical history (including trial indication and concomitant diseases, if applicable)

Adverse events (onset date)

Serious adverse events (onset date)

Concomitant therapy (onset date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Patient responses on the Patient Daily and PASAPQ

Conclusion of Patient’s Participation in the trial
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, laboratory and medical test results, which must be 
available at all times for review by the CRA, auditor and regulatory inspector (e.g. FDA). 
They may review all CRFs and informed consents. The accuracy of the data will be verified 
by direct comparison with the source documents described in Section 8.3.1. The sponsor will 
also monitor compliance with the protocol and GCP.
Storage period of records Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
There is no protocol specified exempted events.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.6. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Not applicable.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signed
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as the 
date on which the last patient in the whole trial is administered the last dose of trial treatment 
(as scheduled per protocol or prematurely). 
Individual investigators will be notified of Suspected Unexpected Serious Adverse Reaction 
(SUSARs) occurring with the trial medication until 30 days after LPLT at their site. Early 
termination of the trial is defined as the premature termination of the trial due to any reasons 
before the end of the trial as specified in this protocol. Temporary halt of the trial is defined 
as any unplanned interruption of the trial by the sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
One coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required activities, 
in order to
-
Manage the trial in accordance with applicable regulations and internal sop.
-
Direct the clinical trial team in the preparation, conduct and reporting of the trial.
-
Ensure appropriate training and information of Clinical Trial Manager (CTM), 
Clinical Research Associate (CRA), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organization 9Operationg Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation CRO) with which the 
responsibilities and tasks will have been agrees and a written contract filed before initiation 
of the clinical trial. Data Management will be done by a CRO with which the responsibilities 
and tasks will have been agreed and a written contract filed before initiation of the clinical 
trial. Statistical Evaluation will be done by BI according to BI SOPs. IRT will not be used for 
this study. The local laboratory service at each site will be used for this study.
Tasks and functions assigned in order to organise, manage and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
[P05-02701]
Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL: 
Device selection and outcomes of aerosol therapy: Evidence-based 
guidelines: American College of Chest Physicians/American College of 
Asthma, Allergy, and Immunology. Chest. 2005; 127: 335–371
[P06-04747]
Bateman ED: Improving inhaler use in COPD and the role of patient 
preference. Eur Respir Rev. 2005; 14: 85–88
[P06-04748]
Newman SP: Inhaler treatment options in COPD. Eur Respir Rev. 2005;
14:102–108
[P06-04749]
Anderson P: Patient preference for and satisfaction with inhaler devices. 
Eur Respir Rev. 2005; 14:109–116
[R07-1426]
Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of 
treatment satisfaction, the Treatment Satisfaction Questionnaire for 
Medication (TSQM), using a national panel study of chronic disease. 
Health Qual Life Outcomes. 2004; 2:12
[P10-05294]
Vincken W, Dekhuijzen PR, Barnes P: The ADMIT series— Issues in 
inhalation therapy. 4) How to choose inhaler devices for the treatment of 
COPD. Prim Care Respir J. 2010; 19:10–20
[P13-04349]
Restrepo RD, Alvarez MT, Wittnebel LD, Sorenson H, Wettstein R, Vines 
DL, Sikkema-Ortiz J, Gardner DD, and Wilkins RL: Medication adherence 
issues in patients treated for COPD. Int J Chron Obstruct Pulmon Dis. 
2008; 3: 371–384
[P13-09537]
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
Strategy for the Diagnosis, Management and Prevention of Chronic 
Obstructive Pulmonary Disease. Available from: 
http://www.goldcopd.org. 2013. Accessed August 26, 2013
[P13-11053]
Wise RA, et al. N Engl J Med. 2013; 369
[R15-5710]
George J, Kong DC, and Stewart K: Adherence to disease management 
programs in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2007;
2:253–262
[P18-08335]
Mannino DM, and Kiriz VA: Changing the burden of COPD mortality. Int 
J Chron Obstruct Pulmon Dis. 2006; 1: 219–233
[R18-2759]
DiMatteo MR: Variations in patients’ adherence to medical 
recommendations: A quantitative review of 50 years of research. Med 
Care. 2004; 42:200–209
[R18-2760]
World Health Organization. Chronic obstructive pulmonary disease 
(COPD). Available from http://www.who.int/respiratory/copd/en/. 2013. 
Accessed July 10, 2013


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[R18-2761]
Small M, Anderson P, Vickers A, Kay S, Fermer S. Importance of inhaler-
device satisfaction in asthma treatment: real-world observations of 
physician-observed compliance and clinical/patient-reported outcomes. 
Adv Ther. 2011; 28(3):202–212
[R18-2762]
Jinping Zheng. J Thorac Dis 2017;9(11):4538-4549
[R18-2763]
Moroni-Zentgraf P. Impact of patient needs on design and usage of an 
inhalation device in respiratory medicine. Respir Drug Deliv Eur. 2013;
1:141–152
[R18-2764]
Chrystyn H, Small M, Milligan G, Higgins V, Gil EG, Estruch J. Impact of 
patients’ satisfaction with their inhalers on treatment compliance and 
health status in COPD. Respir Med. 2014; 108(2):358–365
[R18-2765]
Makela MJ, Backer V, Hedegaard M, and Larsson K: Adherence to 
inhaled therapies, health outcomes and costs in patients with asthma and 
COPD. Respir Med. 2013; 107: 1481–1490
[R18-2768]
Shikiar R, Rentz AM. Satisfaction with medication: an overview of 
conceptual, methodologic, and regulatory issues. Value Health. 2004
9.2
UNPUBLISHED REFERENCES
Not applicable.


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10.
APPENDICES
10.1
INSTRUCTIONS FOR THE USE OF THE RESPIMAT®
Instructions for Use:
Remember to carefully follow your doctor’s instructions for using 
SPIRIVA®. The HandiHaler® is especially designed for SPIRIVA®. You 
must not use it to take any other medication. You can use your 
HandiHaler® for up to one year to take your medication.
The HandiHaler®
1
Dust cap
2
Mouthpiece
3
Base
4
Piercing button
5
Centre chamber
1.  To release the dust cap press the piercing button completely in 
and let go.
   
2.  Open the dust cap completely by pulling it upwards.
Then open the mouthpiece by pulling it upwards.
3.  Remove a SPIRIVA® capsule from the blister (only immediately 
before use) and place it in the centre chamber (5), as illustrated. It does 
not matter which way the capsule is placed in the chamber.


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Cleaning your HandiHaler®
4.  Close the mouthpiece firmly until you hear a click, leaving the dust
cap open.
5.  Hold the HandiHaler® device with the mouthpiece upwards and 
press the piercing button completely in only once, and release.
This makes holes in the capsule and allows the medication to be released 
when you breathe in.
6.  Breathe out completely. 
Important: Please avoid breathing into the mouthpiece at any time.
7.  Raise the HandiHaler® to your mouth and close your lips tightly 
around the mouthpiece. Keep your head in an upright position and 
breathe in slowly and deeply but at a rate sufficient to hear or feel the 
capsule vibrate.
Breathe in until your lungs are full; then hold your breath as long as 
comfortable and at the same time take the HandiHaler® out of your mouth. 
Resume normal breathing.
Repeat steps 6 and 7 once, in order to empty the capsule completely.
8.  Open the mouthpiece again. Tip out the used capsule and dispose.
Close the mouthpiece and dust cap for storage of your HandiHaler®
device.
Clean the HandiHaler® once a month. Open the dust cap and mouthpiece. 
Then open the base by lifting the piercing button. Rinse the complete 
inhaler with warm water to remove any powder. Dry the HandiHaler®
thoroughly by tipping excess of water out on a paper towel and air-dry 
afterwards, leaving the dust cap, mouthpiece and base open. It takes 24 
hours to air dry, so clean it right after you used it and it will be ready for 
your next dose. If needed, the outside of the mouthpiece may be cleaned 
with a moist but not wet tissue.


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Blister handling
A. Separate the blister strips by tearing along the perforation.
B. Peel back foil (only immediately before use) using the tab until one 
capsule is fully visible.
In case a second capsule is exposed to air inadvertently this capsule has to 
be discarded.
C. Remove capsule.
SPIRIVA® capsules contain only a small amount of powder so that the capsule is only 
partially filled.
10.2
INSTRUCTIONS FOR THE USE OF THE HANDIHALER®
Instructions for Use
Introduction
It is the product of tiotropium bromide Spray. Read these Instructions for Use before you start using
it.
You will need to use this inhaler only ONCE A DAY. Each time you use it take TWO PUFFS.


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•
If Spiriva® Respimat® has not been used for more than 7 days release one puff towards the 
ground. 
•
If Spiriva® Respimat® has not been used for more than 21 days repeat steps 4 to 6 under 
‘Prepare for first use’ until a cloud is visible. Then repeat steps 4 to 6 three more times. 
•
Do not touch the piercing element inside the clear base. 
How to care for your Spiriva® Respimat®
Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, 
at least once a week. 
Any minor discoloration in the mouthpiece does not affect your Spiriva® Respimat® inhaler 
performance. 
If necessary, wipe the outside of your Spiriva® Respimat® inhaler with a damp cloth.
When to get a new Spiriva® Respimat®
•
Your Spiriva Respimat® inhaler contains 60 puffs (30 doses) if used as indicated (two 
puffs/once daily). 
•
The dose indicator shows approximately how much medication is left. 
•
When the dose indicator enters the red area of the scale you need to get a new prescription; 
there is approximately medication for 7 days left (14 puffs). 
•
Once the dose indicator reaches the end of the red scale, your Spiriva® Respimat® locks 
automatically – no more doses can be released. At this point, the clear base cannot be turned 
any further. 
•
Spiriva® Respimat® should be discarded three months after you have prepared it for first use, 
even if it has not been fully used or used at all.
Prepare for first use
1. Remove clear base

Keep the cap closed.

Press the safety catch while firmly 
pulling off the clear base with your 
other hand.
2. Insert cartridge

Insert the narrow end of the cartridge 
into the inhaler.

Place the inhaler on a firm surface and 
push down firmly until it clicks into 
place.

Do not remove the cartridge once it 
has been inserted into the inhaler.


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3. Replace clear base

Put the clear base back into place until 
it clicks. 

Do not remove the clear base again.
4. Turn

Keep the cap closed.

Turn the clear base in the direction of 
the arrows on the label until it clicks 
(half a turn).
5. Open

Open the cap until it snaps fully open.
6. Press

Point the inhaler toward the ground

Press the dose-release button.

Close the cap.

Repeat steps 4-6 until a cloud is 
visible.

After a cloud is visible, repeat steps 
4-6 three more times.
Your inhaler is now ready to use. These 
steps will not affect the number of doses 
available. After preparation your inhaler 
will be able to deliver 60 puffs (30 
doses). 
Daily use 
TURN

Keep the cap closed.

TURN the clear base in the direction 
of the arrows on the label until it 
clicks (half a turn).


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OPEN

OPEN the cap until it snaps fully 
open.
PRESS

Breathe out slowly and fully.

Close your lips around the 
mouthpiece without covering the air 
vents.

While taking a slow, deep breath 
through your mouth, PRESS the dose-
release button and continue to breathe 
in.

Hold your breath for 10 seconds or 
for as long as comfortable.

Repeat Turn, Open, Press for a total 
of 2 puffs.

Close the cap until you use your 
inhaler again. 
10.3
INSTRUCTIONS FOR THE USE OF SALBUTAMOL SULPHATE 
AEROSOL
Instructions for Use and Handling
The drug in the aerosol is inhaled into the lungs. Shake the inhaler well, place the mouthpiece of the 
inhaler in the mouth, close the lips, press the actuation button, and do inhale the sprayed drug into 
lungs while breathing in (see [Guidance for Use]). 
[Guidance for Use]
1.
Remove the mouthpiece cover by gently squeezing the sides of the cover. Hold the aerosol as 
shown in Figure 1, check inside and outside of the inhaler including the mouthpiece for the 
presence of loose objects. Shake the inhaler well to ensure that any loose objects are removed and 
that the contents of the inhaler are evenly mixed.
Figure 1


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2.
Breathe out gently until no air can be breathed out of the lungs (Figure 2), and then 
immediately…
Figure 2
3.
Place the mouthpiece in your mouth between your teeth and close your lips around it. Just after 
starting to breathe in through your mouth press down on the top of the inhaler to release Ventolin®
(Figure 3) while still breathing in steadily and deeply.
Figure 3
4.
Hold your breath for ten seconds or continue holding your breath for as long as is comfortable, 
and then slowly breathe out. 
Figure 4
5.
If you are to take further actuations, wait at least one minute before repeating steps two to four. 
6. After use, push and snap the cover back to the mouthpiece. 
10.4
PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE
10.4.1
PASAPQ at Visit 3
PART 1: RATING OF SATISFACTION WITH INHALER ATTRIBUTES
Instructions: For the following questions, please check the response that best describes how 
satisfied you are with each of the following items.  Please take as much time 
as you need to answer each question.


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Very Dissatisfied
Dissatisfied
Somewhat Dissatisfied
Neither Satisfied
nor Dissatisfied
Somewhat Satisfied
Satisfied
Very Satisfied
How satisfied are you…
1.
With the overall feeling of inhaling your 
medicine?
2.
With the feeling that the inhaled dose goes to 
your lungs?
3.
That you can tell the amount of medication 
left in your inhaler?
4.
That the inhaler works reliably?
5.
With the ease of inhaling a dose from the 
inhaler?
6.
With the instructions for use?
7.
With the size of your inhaler?
8.
That the inhaler is durable (hard wearing)?
9.
With the ease of cleaning your inhaler?
10.
With using the inhaler?
11.
With the speed at which medicine comes out 
of the inhaler?
12.
With the ease of holding the inhaler during 
use?
13.
With the overall convenience of carrying the 
inhaler with you?
14.
Overall, how satisfied are you with your 
inhaler?
10.4.2
PASAPQ at Visit 4
PART 1: RATING OF SATISFACTION WITH INHALER ATTRIBUTES
Instructions: For the following questions, please check the response that best describes how 
satisfied you are with each of the following items.  Please take as much time 
as you need to answer each question.


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Very Dissatisfied
Dissatisfied
Somewhat Dissatisfied
Neither Satisfied
nor Dissatisfied
Somewhat Satisfied
Satisfied
Very Satisfied
How satisfied are you…
1.
With the overall feeling of inhaling your 
medicine?
2.
With the feeling that the inhaled dose goes to 
your lungs?
3.
That you can tell the amount of medication 
left in your inhaler?
4.
That the inhaler works reliably?
5.
With the ease of inhaling a dose from the 
inhaler?
6.
With the instructions for use?
7.
With the size of your inhaler?
8.
That the inhaler is durable (hard wearing)?
9.
With the ease of cleaning your inhaler?
10.
With using the inhaler?
11.
With the speed at which medicine comes out 
of the inhaler?
12.
With the ease of holding the inhaler during 
use?
13.
With the overall convenience of carrying the 
inhaler with you?
14.
Overall, how satisfied are you with your 
inhaler?
PART 2: RATING OF PREFERENCE AND WILLINGNESS TO CONTINUE WITH 
INHALER
15.
Comparing the two inhalers that you have used during the study, overall, would you prefer to 
use Respimat® or Handihaler®?
Please check one box
I prefer Respimat®
I prefer Handihaler®


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No preference
16.
Comparing the two inhalers that you have used during the study, overall, how would you feel 
about continuing to use Respimat® or Handihaler®?
Please indicate your willingness to continue using each of the inhalers that you used during 
the study by providing a value between 0 and 100.
0 indicates that you would not be willing to continue using this inhaler and 100 indicates that 
you would definitely be willing to continue.
Please write in a number in each box that is between 0 and 100.
Respimat®
Handihaler®
Both boxes should contain a number between 0 and 100.
10.5
PHARMACOKINETIC METHODS AND ANALYSES
Not applicable.
10.6
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
17 Apr 2019
EudraCT number
EU number
Not applicable
BI Trial number
0205-0541
BI Investigational Medicinal 
Product(s)
Tiotropium Respimat® (Spiriva®  Respimat®)
Title of protocol
A randomized, open-label, two-way crossover 
study to compare patient
acceptability/preference of Tiotropium 
Respimat® with Tiotropium Handihaler® in 
patients with moderate to severe chronic 
obstructive pulmonary disease (COPD).
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Clinical Trial Protocol Synopsis：Trial 
endpoints
Description of change
Deleted “4 weeks ”
Rationale for change
Revised error in previous version.
Section to be changed
Flow Chart
Description of change
•
Changed from “PASAPQ question 1-14, 
question 16” to “PASAPQ question: 1-14”, and 
added the item into the column of “Visit 4”
•
Changed from “PASAPQ question 1-16” to 
“PASAPQ question: 15-16”
Rationale for change
Revised error in previous version.
Section to be changed
2.1.3
Secondary endpoint(s)
Description of change
Changed from “Score on willingness to continue 
after 4 weeks treatment which will be administered 
at week 4 and 8. “ to “Score on willingness to 
continue will be administered at week 8.“
Rationale for change
Revised error in previous version.
Section to be changed
5.1.2
Secondary endpoints：
Description of change
•
Underlined “The proportion of patients 
indicating preference”
•
Willingness to continue: changed 
from“Question 15”to “Question 16”, and 
deleted “Visit 3 (week 4) and”
Rationale for change
Revised error in previous version.
Section to be changed
5.2.3
Safety laboratory parameters


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Description of change
Deleted the test for“CO2”
Rationale for change
Not required
Section to be changed
6.1
Visit schedule
Description of change
Revised from“After each of the treatment period, 
patients will fill-in the performance domain, 
convenience domain, overall satisfaction and 
willingness to continue. After conclusion of both 
treatment phases (at visit 4), all patients will 
indicate their preference of these two inhalers in the 
PASAPQ.” to “After each of the treatment period, 
patients will fill-in the performance domain, 
convenience domain and overall satisfaction. After
conclusion of both treatment phases (at visit 4), all 
patients will indicate their preference and 
willingness to continue of these two inhalers in the 
PASAPQ.”
Rationale for change
Revised error in previous version.
Section to be changed
6.2.2
Treatment period(s): Visit 3 ( 28 days±1 
days )
Description of change
Changed from “Patients will have to complete the 
PASAPQ including total score (Q1-13), overall 
satisfaction (Q14) and willingness to continue 
(Q16), except for the preference question prior to 
any other procedures or evaluations. ” to “Patients 
will have to complete the PASAPQ including total 
score (Q1-13), overall satisfaction (Q14), except for 
the preference question prior to any other 
procedures or evaluations.”
Rationale for change
Revised error in previous version.
Section to be changed
10.4
Patient  satisfaction and preference
questionnaire
Description of change
PASAPQ was divided into two questionnaires.
Rationale for change
Patients only will have to complete PASAPQ 
question 1-14 at Visit 3 and PASAPQ question 1-
16 at Visit4.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
23 Mar 2020
EudraCT number
EU number
Not applicable
BI Trial number
0205-0541
BI Investigational Medicinal 
Product(s)
Tiotropium Respimat® (Spiriva®  Respimat®)
Title of protocol
A randomized, open-label, two-way crossover 
study to compare patient
acceptability/preference of Tiotropium 
Respimat® with Tiotropium Handihaler® in 
patients with moderate to severe chronic 
obstructive pulmonary disease (COPD).
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
5.2.3
Safety laboratory parameters     
Description of change
Added “urea” and changed to “Serum chemistry 
testing will include albumin, alkaline phosphatase, 
calcium, chloride, creatinine, glucose, inorganic 
phosphorus, LDH, potassium, AST (SGOT), ALT 
(SGPT), sodium, total bilirubin, total protein, uric 
acid, urea nitrogen (or urea). ”
Rationale for change
Most sites couldn’t test urea nitrogen. Because 
either urea nitrogen or urea can reflect the patient’s 
renal function, urea nitrogen testing or urea testing
can be accepted. 
Section to be changed
5.2.3
Safety laboratory parameters     
Description of change
Deleted “hemoglobin” and added “leukocytes and 
erythrocyte”, changed to “The urinalysis will 
include specific gravity, pH, glucose, protein, 
leukocytes and erythrocyte.”
Rationale for change
Most sites couldn’t test hemoglobin. Delete 
“hemoglobin” and add “leukocytes and 
erythrocyte” which can also reflect “haemoglobin” 
to evaluate the patient’s body index.
Section to be changed
5.2.4
Electrocardiogram
Description of change
Deleted “and one minute rhythm strip will be 
performed as scheduled in the flowchart.” And 
changed to “A standard 12-lead electrocardiogram 
(ECG) will be recorded as scheduled in the 
flowchart. The investigator or a designee will 
evaluate whether the ECG is normal or abnormal 


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and whether it is clinically relevant, if abnormal.”
Rationale for change
Most sites couldn’t test ECG for one minute rhythm 
strip. The site can assess the patient’s related factor
via local ECG result.
Clinical Trial Protocol Synopsis
Description of change
Deleted “84 enrolled, (assuming a 15%-screening 
failure rate)” and changed to “Total number of 
patients randomised: 71 entered”
Rationale for change
Actual screening failure rate is higher than planned 
screening failure rate. The enrolled number and 
screening failure rate are not yet determined, so 
were deleted to avoid subsequent protocol revision.
Section to be changed
Flow Chart and 3.3.2  Inclusion criteria
Description of change
Historical data from spirometry measurements 
within the past 6 months either at the site or at the
other hospital may be used. If the measurements are 
not performed at the trial site a signed copies of the 
measurement printouts must be provided to the trial 
site for source data verification. In case several 
qualifying spirometry measurements are available, 
the most recent one should be referred to as long as 
it was not performed during an exacerbation. 
Patients may not be randomised to the study 
without the availability of spirometry data at the 
actual study site.
Rationale for change
The timeline of spirometry measurements need to 
be fleshed out in order to instruct the investigator to 
screen the patient effectively.
Section to be changed
6.2.1 Screening Period (Visit 1, up to 7 days)
Description of change
Historical data from spirometry measurements 
within the past 6 months either at the site or at the 
other hospital may be used. Please refer to flow 
chart for details.
Rationale for change
After reviewed the reference, the data within the
past 6 months can be accepted.

SAP_001.pdf: 
 
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TITLE PAGE 
TRIAL STATISTICAL ANALYSIS PLAN 
 
 
BI Trial No.: 
0205-0541 
Title: 
A randomized, open-label, two-way crossover study to compare 
patient acceptability/preference of Tiotropium Respimat® with 
Tiotropium Handihaler® in patients with moderate to very severe 
chronic obstructive pulmonary disease (COPD). 
Investigational 
Product(s): 
Tiotropium Respimat® (Spiriva® Respimat®) 
Responsible trial 
statistician(s): 
Phone: +
 
Date of statistical 
analysis plan: 
14JUL2021  
Version: 
Final 
Page 1 of 18 
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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...................................................................................... 2 
LIST OF TABLES ................................................................................................................... 3 
2. 
LIST OF ABBREVIATIONS .............................................................................. 4 
3. 
INTRODUCTION ................................................................................................. 6 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...................... 7 
5. 
ENDPOINTS(S) .................................................................................................... 8 
5.1 
PRIMARY ENDPOINT(S) .................................................................................. 8 
5.2 
SECONDARY ENDPOINT(S) ............................................................................ 8 
5.2.1 
Key secondary endpoint(s) ................................................................................... 8 
5.2.2 
Secondary endpoint(s) .......................................................................................... 8 
6. 
GENERAL ANALYSIS DEFINITIONS .......................................................... 10 
6.1 
TREATMENT(S) ................................................................................................ 10 
6.2 
IMPORTANT PROTOCOL DEVIATIONS.................................................... 10 
6.3 
SUBJECT SETS ANALYSED ........................................................................... 11 
6.5 
POOLING OF CENTRES ................................................................................. 12 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS .................................... 12 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS ................... 12 
7. 
PLANNED ANALYSIS ...................................................................................... 13 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......... 13 
7.2 
CONCOMITANT DISEASES AND MEDICATION ..................................... 13 
7.3 
TREATMENT COMPLIANCE ........................................................................ 13 
7.4 
PRIMARY ENDPOINT(S) ................................................................................ 13 
7.5 
SECONDARY ENDPOINT(S) .......................................................................... 14 
7.5.1 
Key secondary endpoint(s) ................................................................................. 14 
7.5.2 
(Other) Secondary endpoint(s) .......................................................................... 14 
7.7 
EXTENT OF EXPOSURE ................................................................................. 14 
7.8 
SAFETY ANALYSIS .......................................................................................... 14 
7.8.1 
Adverse events ..................................................................................................... 14 
7.8.2 
Laboratory data .................................................................................................. 15 
7.8.3 
Vital signs and ECG data ................................................................................... 15 
8. 
REFERENCES .................................................................................................... 16 


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10. 
HISTORY TABLE .............................................................................................. 18 
  
LIST OF TABLES 
Table 6.1: 1 
Definition of analyzing treatments ................................................................... 10 
Table 6.2: 1 
Important protocol deviations  ......................................................................... 11 
Table 6.3: 1 
Subject sets analyzed ........................................................................................ 11 
Table 10: 1     History table...................................................................................................... 18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. 
LIST OF ABBREVIATIONS 
Term 
Definition / description 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BI 
Boehringer Ingelheim 
CI 
Confidence Interval 
COPD 
Chronic Obstructive Pulmonary Disease 
CRA 
Clinical Research Associate 
CRF 
Case Report Form, paper or electronic (sometimes referred to as 
“eCRF”) 
CTM 
Clinical Trial Manager 
CTP 
Clinical Trial Protocol 
DBL 
Database Lock 
DPIs 
Drypowder Inhalers 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic Acid 
FC 
Flow Chart 
FEV 
Forced Expiratory Volume 
FUP 
Follow Up 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee 
IMPs 
Investigational Medicinal Products 
IPDs 
Important Protocol Deviations 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
IUD 
Intrauterine Device 


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MC 
Mean Completer 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MMRM 
Mixed effect repeated measures model  
PASAPQ 
Patient satisfaction and preference questionnaire 
PFT(s) 
Pulmonary function test(s) 
pMDIs 
Pressurized Metered Dose Inhalers 
PRN 
As needed 
REP 
Residual Effect Period 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-emergent adverse events 
TMF 
Trial Master File 
TIC 
Trial Identification Card  
TIOSPIR 
Tiotropium Safety and Performance in Respimat® 
URI 
Upper Respiratory Infection 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 


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3. 
INTRODUCTION 
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data. 
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization. 
SAS® Version 9.4 (or later) will be used for all analyses. 
 


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4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
No change concerning statistical analysis has occurred since the CTP was finalized.  


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5. 
ENDPOINTS(S) 
5.1 
PRIMARY ENDPOINT(S) 
The primary endpoint of the study is the performance domain of the Patient satisfaction and 
preference questionnaire (PASAPQ) after 4 weeks of treatment. 
 
The PASAPQ is a two-part questionnaire. Part I consists of 14 questions. The first 13 
questions generate the Performance domain (7 questions) and the Convenience domain (6 
questions), which form a Total Score (all 13 questions). Question 14 asks for overall 
satisfaction with the device used in the study. Part II consists of stand-alone questions 
concerning a subject’s device preference (question 15) and willingness to continue use 
(question 16). The first 14 questions in PASAPQ have Likert-type response options of 1 (very 
dissatisfied) to 7 (very satisfied). Question 15 asks for a response to indicate the preference 
for the trial device. Question 16 asks for a response between 0 and 100 with 0 indicating not 
willing to continue using the trial device and 100 indicating definitely willing to continue. 
 
The performance domain score is the sum of 7 questions within the domain (Q1, Q2, Q3, Q4, 
Q5, Q10 and Q11) and then transformed to a 0 (least) to 100 (most) point scale. 
 
Assessment of primary endpoints are described in section 5.1.1 of the CTP. 
5.2 
SECONDARY ENDPOINT(S) 
5.2.1 
Key secondary endpoint(s) 
Not applicable, since there are no key secondary endpoints specified in the protocol. 
5.2.2 
Secondary endpoint(s) 
1. PASAPQ total score after 4 weeks of treatment. Total score is the sum of 13 questions 
(Q1-Q13) and then transformed to a 0 (least) to 100 (most) point scale. 
2. Proportion of patients indicating preference which will be administered at Week 8. 
3. Overall Satisfaction Question Score from PASAPQ will be administered at week 4 and 8. 
4. Score on willingness to continue will be administered at week 8.  
Assessment of secondary endpoints are described in section 5.1.2 of the CTP. 


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6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENT(S) 
This is a crossover trial consisting of a one-week screening period followed by two four-week 
treatment periods and a four-week follow-up period. In this study, there will be no theorical 
washout between treatment periods.  
 
The definition below is the analyzing treatment. The same labels and sort order as for the 
randomized treatment groups will be used. 
Table 6.1: 1 
Definition of analyzing treatments 
Label 
Sort order 
Start date  
Stop date  
Screening 
  
Date of informed consent 
Date of first administration 
Treatment 
1 
Date of first received Respimat® 
Date of last received Respimat®  
Treatment 
2 
Date of first received Handihaler® 
Date of last received Handihaler® 
Follow-up 
  
Date of last administration + 1 days 
Date of last contact 
 
For the main safety analysis, data occurring before the first drug intake date is assigned to 
"screening". Data occurring during the treatment periods and within 4 weeks of stop of study 
drug will be assigned to the respective treatment for that period. 
 
6.2 
IMPORTANT PROTOCOL DEVIATIONS 
All subjects with important deviations from the protocol will be listed (Appendix 16.2 of 
the CTR). The IN/EX numbers refer to the definition given in the CTP and CRF. 
Subjects with potentially important protocol deviations (iPDs) will be identified based on 
Table 6.2: 1 and documented. The table defines the different categories of important PDs. The 
final column describes which PDs will be used to exclude subjects from the different subject 
analysis sets.  
The list of PDs in Table 6.2: 1 is considered a ‘working’ list, which is expected to be 
updated throughout the trial and finalized prior to the Database Lock (DBL). In any case, all 
important PDs will be tracked during the study at Medical Quality Review Meetings 
(MQRMs) or Blinded Reported Plan Meeting (BRPM) to verify the quality of the inclusion 
and the conduct of the study. 


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Table 6.2: 1 
Important protocol deviations  
Category / 
Code 
Description 
Requirements 
Excluded 
from 
A 
 
Entrance criteria not met 
 
 
 
A1 
Inclusion criteria not met 
Inclusion criteria 5 not met as specified 
in the protocol. 
None 
 
A2 
Exclusion criteria not met 
Exclusion criteria 1, 2, 3 not met as 
specified in the protocol 
None 
B 
 
Informed consent 
 
 
 
B1 
Informed consent not 
available/not done 
Informed consent date missing 
All 
 
B2 
Informed consent too late 
Informed consent date was after Visit 2 
date 
None 
C 
 
Trial medication  
 
 
 
C1 
Incorrect trial medication taken 
during study 
Incorrect trial medication taken during 
study 
Incorrect rescue medication taken during 
study 
None 
 
C2 
Randomization not followed 
Not following randomized treatment 
sequence or randomized treatment 
devices 
None 
D 
 
Concomitant medication 
 
 
 
 
Prohibited medication use during 
study 
According to CTP section 4.2.2.1 
Restrictions regarding concomitant 
treatment 
None 
E 
 
Missing critical data 
 
 
 
E1 
Primary endpoint related data 
missing 
Patients missed PASAPQ both in Visit 3 
and Visit 4 
FAS 
 
6.3 
SUBJECT SETS ANALYSED 
The analysis will be based on the following populations (Table 6.3:1): 
Treated set (TS) is defined as all patients who were dispensed study medication and were 
documented to have at least one dose of investigational treatment. 
Full analysis set (FAS) is defined as all patients who were randomized to treatment sequence 
and received at least one dose of one study drug and providing at least one PASAPQ score 
measurement. 
Table 6.3: 1 
Subject sets analyzed 
Class of endpoint  
Treated set 
Full analysis set 
(TS) 
(FAS) 
Primary endpoint 
 
primary analysis 
Secondary endpoints  
 
X 
Safety endpoints  
X 
 


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Demographic/baseline endpoints 
X 
  
The number of subjects with available data for an endpoint may differ. For details, see Section 6.6. 
6.5 
POOLING OF CENTRES 
Not applicable. 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
Every effort should be made to collect the complete data at the planned time points for this 
trial.  
For PASAPQ, imputation of responses to individual questions will follow the “half-scale 
rule”. If a patient missed less than four of the seven questions in the Performance domain or 
less than four of the six questions in the Convenience domain in the PASAPQ, then the 
missing item in this domain is imputed using the observed mean from the same domain(Mean 
Completer), and then the Total score is calculated as the sum of the 13 items after substitution 
for missing items at the domain level has taken place. If a patient missed more than three 
items in either domain, then the domain and the Total score are set to missing and will not be 
imputed. The number of patients who cannot be included in the FAS will be summarised by 
treatment group and period. If a patient missed a visit due to reasons unrelated to the patient's 
response to the treatment, the missing data will not be imputed. The MMRM will handle data 
missing at random based on the likelihood method. Sensitivity analyses will be conducted to 
compare imputed data and un-imputed data in primary endpoint only if imputation happens. 
Missing or incomplete AE dates are imputed according to BI standards. 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS 
‘Baseline’ is defined as the non-missing last available pre-treatment assessment. 
 
Planned and actual study day will be included in the analysis data sets. These will both be 
calculated relative to the beginning of the study and to the beginning of respective study 
periods in the crossover design as indicated in the following table. 
 
Table 6.7: 1  Planned and actual study days, and time windows 
 
Relative to period start 
Relative to study start 
Visit 
Planned day 
Actual day (visit window) 
Planned day 
Actual day (Visit window) 
2 
1 
1 (NA) 
1 
1 (NA) 
3 
28 
Visit 3 date – Visit 2 date + 1 
(±1 day) 
28 
Visit 3 date – Visit 2 date + 1 
(±1 day) 
4 
28 
Visit 4 date – Visit 3 date + 1 
(±1 day) 
56 
Visit 4 date – Visit 3 date + 1 
(±1 day) 
5 
28 
Visit 5 date – Visit 4 date + 1 
(±2 day) 
84 
Visit 5 date – Visit 4 date + 1 
(±2 day) 
 


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7. 
PLANNED ANALYSIS   
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / Standard deviation 
(SD) / Min / Median / Max. 
 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, SD, minimum and maximum. 
 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not).  
 
The precision for percentages should be one decimal point, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers. 
The category missing will be displayed only if there are actually missing values. 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Only descriptive statistics are planned for this section of the report. Demographic and baseline 
characteristics will be displayed for TS by treatment group and for the total. 
7.2 
CONCOMITANT DISEASES AND MEDICATION 
Concomitant diseases and medication on-treatment period will be displayed for TS 
population. Only descriptive statistics are planned for this section of the report. 
Concomitant therapy medication will be displayed by Anatomical Therapeutic Chemical level 
3 (ATC3) and Preferred Term (PT) respectively by treatment group and for the total.  
7.3 
TREATMENT COMPLIANCE 
Only descriptive statistics are planned for this section of the report. Summary statistics will be 
given for percent compliance along with the number (%) of patients with compliance in the 
categories 80% - 120%, <80% or >120%. Treatment compliance will be displayed for the TS 
population. 
7.4 
PRIMARY ENDPOINT(S) 
In the primary analysis, comparisons between treatment groups for the performance domain 
of PASAPQ will be based on a mixed effect repeated measures model (MMRM). This model 
will include treatment and period as fixed effects and patient as a random effect. Compound 
symmetry will be used as a covariance structure for within-patient variation. The SAS 
procedure MIXED will be used involving the restricted maximum likelihood estimation and 
the Kenward-Roger approximation for denominator degrees of freedom. Adjusted mean 
values as well as treatment contrasts will be presented together with the 95% confidence 
intervals (CI) and p-values. 
 


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7.5 
SECONDARY ENDPOINT(S) 
Continuous secondary endpoints will be analyzed using a similar MMRM model as for the 
primary endpoint. Chi-squared test will be performed to analysis proportion of patients 
indicating preference. 
 
7.5.1 
Key secondary endpoint(s) 
Not applicable. 
7.5.2 
(Other) Secondary endpoint(s) 
Not applicable. 
7.7 
EXTENT OF EXPOSURE 
Extent of exposure will be summarized using descriptive statistics for the total treatment 
exposure in days. 
7.8 
SAFETY ANALYSIS 
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned. 
7.8.1 
Adverse events 
The analyses of AEs will be descriptive in nature and will be based on BI guideline 'Handling 
and summarization of AE data for CTRs and integrated summaries'. All analyses of AE will 
be based on the number of patients with AEs and NOT on the number of AEs. For this 
purpose, AE data will be combined in a 2-step procedure into AE records. 
In the first step, AE occurrences, i.e. AE entries collected in the eCRF, will be collapsed into 
AE episodes provided that all the following applies: 
• 
The same MedDRA lowest level term was reported for the occurrences 
• 
The occurrences are time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence) 
• 
Treatment did not change between the onset of the occurrences or treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence. 
In the second step, AE episodes will be condensed into AE records provided that the episodes 
were reported with the same term on the respective MedDRA level and that the episodes are 
assigned to the same treatment. For further details on summarization of AE data, please refer 
to BI guideline 'Handling and summarization of AE data for CTRs and integrated summaries'. 
 


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Analyses of AEs are based on the concept of treatment emergent adverse events. This means 
that all AEs occurring between first drug intake and 28 days after last drug intake are assigned  
to the respective analyzing treatment. All AEs occurring before first drug intake are assigned 
to ‘screening’, AEs starting after trial completion date are assigned to ‘post-study’. 
Screening and post-study AEs are presented in subject data listings only. For details on the 
treatment definition, see Section 6.1. 
 
An overall summary of AEs will be presented. 
 
The frequency of patients with AEs will be summarized by treatment, primary SOC and PT. 
Separate tables will be provided for patients with other significant adverse events according to 
ICH E3, for patients with AEs leading to treatment discontinuation, for patients with AEs 
leading to death, for patients with investigator determined drug-related adverse events, for 
patients with SAEs and for patients with AESI. 
 
According to ICH E3, AEs classified as ‘other significant’ include those non-serious and  
non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or 
(ii) marked haematological and other lab abnormalities or that lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator and confirmed at a BRPM. 
 
The system organ classes will be sorted according to the standard sort order specified by the 
European Medicines Agency, PTs will be sorted by frequency (within SOC). 
 
7.8.2 
Laboratory data 
Laboratory data will be calculated both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarized. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values. 
7.8.3 
Vital signs and ECG data 
Vital signs and ECG data observed at screening, during the course of the trial and at the end-
of-trial evaluation will be assessed with regard to possible changes compared to findings 
before start of treatment. 


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8. 
REFERENCES 
 
1. CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version. 
2. 001-MCS 36-472: "Standards and processes for analyses performed within Clinical  
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON. 
3. 001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON. 
4. 001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON. 
5. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version 
 


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10. 
HISTORY TABLE 
Table 10: 1 
History table 
Version 
Date 
(DD-MMM-YY) 
Author 
Sections 
changed 
Brief description of change 
Initial 
 
 
 
 
Final