Clinical trial NCT02969317
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim
Start date: 2017-02-24; Completion date: 2017-06-15
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to assess the pharmacokinetics of tiotropium + olodaterol fixed-dose combination (FDC) (5 μg/ 5 μg) delivered by the RESPIMAT inhaler after single dose and at steady state in Chinese patients with COPD.

The secondary objective is to assess the safety of tiotropium + olodaterol FDC (5 μg/ 5 μg) delivered by the RESPIMAT inhaler after 3 weeks once daily treatment in Chinese patients with COPD.

Detailed description:

Arms: arm 1: Fixed dose combination
Interventions: intervention 1: Tiotropium intervention 2: Olodaterol
Intervention descriptions: intervention 1: Fixed dose combination intervention 2: Fixed dose combination

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c07779972-03
EudraCT No.:
Not applicable
BI Trial No.:
1237.30
BI Investigational 
Products:
Tiotropium+olodaterol RESPIMAT solution for inhalation. 
Title:
An open-label trial to assess pharmacokinetics and safety of tiotropium 
+ olodaterol fixed-dose combination (5 µg / 5 µg) delivered by the 
RESPIMAT inhaler after single and multiple dose treatment in Chinese 
patients with Chronic Obstructive Pulmonary Disease (COPD)
Brief Title:
Bioavailability of tiotropium + olodaterol fixed-dose combination (5 
µg / 5 µg) in Chinese COPD patients 
Clinical Phase:
Ib
Trial Clinical 
Monitor:
Principal 
Investigator：
Status:
Final Protocol (Revised Protocol (based on Global Amendment(s)2))
Version and Date:
Version:
Date:
3.0
20 Feb 2017
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Proprietary confidential information.
2017 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
Name of company:
Boehringer Ingelheim
Name of finished product:
Tiotropium+olodaterol RESPIMAT
Name of active ingredient:
Tiotropium+olodaterol RESPIMAT 
solution for inhalation. 
Protocol date:
19 Nov 2015
Trial number:
1237.30
Revision date:
20 Feb 2017
Title of trial:
An open-label trial to assess pharmacokinetics and safety of tiotropium + 
olodaterol fixed-dose combination (5 µg/ 5 µg) delivered by the 
RESPIMAT inhaler after single and multiple dose treatment in Chinese
patients with Chronic Obstructive Pulmonary Disease (COPD)
Principal Investigator
Trial site:
Clinical phase:
Ib
Objective:
The primary objective of this study is to assess the pharmacokinetics of 
tiotropium + olodaterol fixed-dose combination (5 µg / 5 µg) delivered by 
the RESPIMAT inhaler after single dose and at steady state in Chinese 
patients with COPD.
Methodology:
Open-label design
No. of patients: 
total entered:
16 (at least 12 completed)
each treatment:
16 (at least 12 completed)
Diagnosis :
Chronic Obstructive Pulmonary Disease (COPD)
Main criteria
for inclusion:
Male and Female Chinese outpatients, aged 40 years with a diagnosis of 
COPD; smoking history >10 pack years, post-bronchodilator FEV1 30% 
and <80% predicted, post-bronchodilator FEV1/FVC <70%.
Test product:
Tiotropium + olodaterol FDC solution for inhalation - RESPIMAT
dose:
5 μg tiotropium + 5 μg olodaterol
mode of administration:
Oral inhalation
Comparator products:
Not applicable
dose:
Not applicable


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Name of company:
Boehringer Ingelheim
Name of finished product:
Tiotropium+olodaterol RESPIMAT
Name of active ingredient:
Tiotropium+olodaterol RESPIMAT 
solution for inhalation. 
Protocol date:
19 Nov 2015
Trial number:
1237.30
Revision date:
20 Feb 2017
mode of administration:
Not applicable
Duration of treatment:
3 weeks 
Endpoints
Pharmacokinetics:
PK parameters of tiotropium and olodaterol:
Primary endpoints :
After a single dosing: Cmax, tmax, AUC0-6
After multiple dosing: Cmax,ss, tmax,ss, AUC0-6,ss, AUCτ,ss, Cpre,ss, 
Accumulation ratio based on Cmax and AUC0-6
Secondary endpoints: 
The number (%) of subjects with drug related Adverse Events
 
 
 
Safety criteria:
Adverse events (including physical examination), vital signs, laboratory 
evaluations, 12-lead ECG
Statistical methods:
Safety and pharmacokinetic parameters will be summarised by using 
descriptive statistics. Attainment of steady state will be explored by using 
repeated-measurement ANOVA.


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FLOW CHART
Trial periods
Screening
Treatment period
Follow-up
Visit
0
1 6
28
3 15
4
EOT
5
Week
-
-2
0
0-2
3
+3
Day
-
-14
1
2-20
21
+21
Time window (days)
-14
+7
+7
Informed consent1
X
Demographic
X
Medical history
X
COPD/patient characteristics
X
Smoking status
X
In-/Exclusion criteria
X
Physical examination 
X
X
X11
X12
Patient allocation
X14
Administration of trial medication in clinic
X13
X9,11
X10, 11
Training in use of RESPIMAT (placebo) 
inhalation in clinic
X
X
PFT (FEV1 and FVC) 
X7
Vital sign (BP, PR) 2
X
X13
X10, 11
X12
12-lead ECG
X
X
X
X12
Laboratory tests
X
X13
X10, 11
X12
Pregnancy test4
X
X13
X10, 11
X
PK sampling (blood/ urine)
X13
X9,11
X10, 11
Adverse events/Concomitant therapy
X
X
X11
X11
X
Dispense trial medication
X3
Collect trial medication
X11
Dispense rescue medication5
X
X
X
X11
X11
Collect rescue medication
X
Dispense patient medication worksheet
X
Collect patient medication worksheet
X11
Review patient medication worksheet
X
X11
Med washout compliance check
X
Termination of trial medication
X 11
Trial completion
X
Meal in clinic
X
X9
X10
EOT: End of treatment
1. All patients must sign an informed consent consistent with GCP guidelines prior to 
participation in the trial, which includes medication washout and restrictions. 
2. After 5 minutes rest in supine position.
3. The drug will be marked by subject number when collected, while the same drug will be 
dispensed to subjects correspondingly for multiple dose period.


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4. To be completed on all women of childbearing potential. A serum HCG will be performed at 
Visit 1. A urine pregnancy test will be performed prior to trial medication administration at 
Visits 2,   4 and 5
5. Additional salbutamol MDI will be only issued if needed from Visit 1 to Visit 3.
6. Visit 1 will be scheduled within 28 days after signing informed consent. Note: patient who 
takes Spiriva (RESPIMAT or HANDIHALER) need at least 3 weeks wash-out before Visit 2
and 1 week wash out before visit 1.
7. PFTs before and after inhalation of salbutamol MDI (See Section 10.4).
8. The screening period (i.e. period between Visits 1 and Visit 2) may be extended by 2 weeks
(total up to 4 weeks) for administrative reasons.
9. For details, see flow chart “timing of procedure at Visit 3”.
10. For details, see flow chart “timing of procedure at Visit 4”.
11. Assessments to be completed by all patients including patients who discontinue early. For 
patients who discontinue early, whether PK sampling will be obtained or not will be 
determined by discussion between investigator and sponsor. 
12. To be performed only if relevant findings at Visit 4.
13. For details, see flow chart “timing of procedure at Visit 2”.
14. Assignment of patients to medication numbers will be according to the order of their 
attendance to the study site. 
15. Patients should at least arrive at site for PK sampling at days 7, 14 and stay at site from day 
18 to visit 4. If the investigator agrees, the patients could discharge at day 2-6, 8-13, 15-17 in 
visit 3.


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TIMING OF PROCEDURE at Visit 2
Timing (relate to first drug administration) (HH:MM)
Before -
1:00
-0:45
-0:30
-0:05
0:00
0:02
0:05
0:07
0:10
0:20
0:30
0:40
1:00
2:00
3:00
4:00
6:00
± 5
Test drug inhalation 
instruction and training 
(inhalation of placebo)
X
Vital signs (supine)
X
X
Laboratory tests for safety 
assessment
X
ECG
X
Meal in clinic1
X
X
Urine pregnancy test2
X
Administration of trial 
medication3
X
Blood sampling for PK (from 
iv line)
X5
X
X
X
X
X
X
X
X
X
X
X
X
Urine sampling for PK4
X5
1.
Meal could be taken after completing laboratory test, and should not impact other procedure.
2.
After urine pregnancy test, site personnel dispense one urine sample for laboratory test. Site personnel add citric acid solution before dispensing 3 urine samples for PK blank. Patient should be instructed to empty 
the bladder prior to the trial medication administration.
3.
Trial medications to be administered after all assessments are completed.
4.
Intervals (related to drug administration) for urine PK after drug administration: 0 to 2, 2 to 4, 4 to 6 h. 
5.
PK samples should be taken before drug administration.


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TIMING OF PROCEDURE at Visit 3
Day2-Day20
(counting from
day1 in visit 2)
Timing (relate to first drug administration) (HH:MM)
143:45
144:00
144:20
311:45
312:00
312:20
407:45
408:00
408:20
431:45
432:00
432:20
455:45
456:00
456:20
Administration of 
trial medication1
X
X
X
X
X
Blood sampling for 
PK (from iv line)
X2
X
X2
X
X2
X
X2
X
X2
X
1. Administration of trial medication should be within ± 5 minutes of the administration time at Visit 2. 
2. PK blood samples should be taken before drug administration.
TIMING OF PROCEDURE at Visit 4
Visit 4 Timing (relative to trial medication inhalation time)(HH:MM)
Before
-0:30
-0:30
-0:15
0:00
0:02
0:05
0:07
0:10
0:20
0:30
0:40
1:00
2:00
3:00
4:00
6:00
12:00
24:00
± 5 
± 5 
Administration of trial 
medication1
X
Vital signs (supine)
X
X
Laboratory tests for 
safety assessment
X
ECG
X5
Standardised meal in 
clinic2
X
Urine pregnancy test
X
Blood sampling for PK 
(from iv line)
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sampling for PK3
1.
Administration of trial medication should be within ± 5 minutes of the administration time at Visit 2 . 
2.
Meal could be taken after completing laboratory test, and should not impact other procedure.
3.
Patient should be instructed to empty the bladder prior to inhalation of trial medication administration. For PK urine sampling, all urine voided during the periods from 0 to 2, 2 to 4, 4 to 6, 6 to 12, 12 to 24 h will 
be collected.
4.
PK blood samples should be taken before drug administration. The ECG should be performed after completing the PK sampling


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................14
MEDICAL BACKGROUND.............................................................................14
1.1
DRUG PROFILE................................................................................................14
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....16
RATIONALE FOR PERFORMING THE TRIAL.........................................16
2.1
TRIAL OBJECTIVES........................................................................................16
2.2
BENEFIT - RISK ASSESSMENT.....................................................................16
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................18
OVERALL TRIAL DESIGN AND PLAN .......................................................18
3.1
3.1.1
Administrative structure of the trial.................................................................18
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................19
SELECTION OF TRIAL POPULATION .......................................................20
3.3
3.3.1
Main diagnosis for trial entry ............................................................................20
3.3.2
Inclusion criteria .................................................................................................20
3.3.3
Exclusion criteria ................................................................................................21
3.3.4
Removal of patients from therapy or assessments...........................................22
Removal of individual patients .............................................................................22
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................23
3.3.4.2
4.
TREATMENTS...................................................................................................24
TREATMENTS TO BE ADMINISTERED.....................................................24
4.1
4.1.1
Identity of BI investigational products and comparator product ..................24
4.1.2
Method of assigning patients to treatment groups...........................................24
4.1.3
Selection of doses in the trial..............................................................................24
4.1.4
Drug assignment and administration of doses for each patient......................25
4.1.5
Blinding and procedures for unblinding...........................................................26
Blinding.................................................................................................................26
4.1.5.1
Unblinding and breaking the code ........................................................................26
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................26
4.1.7
Storage conditions...............................................................................................27
4.1.8
Drug accountability.............................................................................................28
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE    
4.2
TREATMENT.....................................................................................................28
4.2.1
Rescue medication, emergency procedures, and additional treatments........28
Rescue medication ................................................................................................28
4.2.1.1
Emergency procedures..........................................................................................28
4.2.1.2
Additional treatments............................................................................................28
4.2.1.3
4.2.2
Restrictions ..........................................................................................................29
Restrictions regarding concomitant treatment ......................................................29
4.2.2.1
Restrictions on diet and life style..........................................................................33
4.2.2.2
TREATMENT COMPLIANCE........................................................................34
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................35


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TRIAL ENDPOINTS..........................................................................................35
5.1
5.1.1
Primary Endpoints..............................................................................................35
5.1.2
Secondary Endpoints..........................................................................................35
............................................................................................35
ASSESSMENT OF EFFICACY........................................................................36
5.2
ASSESSMENT OF SAFETY.............................................................................36
5.3
5.3.1
Physical examination ..........................................................................................36
5.3.2
Vital Signs............................................................................................................36
5.3.3
Safety laboratory parameters ............................................................................37
5.3.4
Electrocardiogram ..............................................................................................37
5.3.5
Other safety parameters.....................................................................................38
5.3.6
Assessment of adverse events.............................................................................38
Definitions of AEs ................................................................................................38
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................40
DRUG CONCENTRATION MEASUREMENTS AND    
5.4
PHARMACOKINETICS...................................................................................42
5.4.1
Assessment of Pharmacokinetics.......................................................................42
5.4.2
Methods of sample collection .............................................................................44
5.4.3
Analytical determinations ..................................................................................46
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................46
ASSESSMENT OF EXPLORATORY BIOMARKERS.................................46
5.5
5.5.1
Biobanking...........................................................................................................46
OTHER ASSESSMENTS...................................................................................46
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................46
5.7
6.
INVESTIGATIONAL PLAN.............................................................................47
VISIT SCHEDULE.............................................................................................47
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................47
6.2
6.2.1
Screening and run-in period ..............................................................................47
6.2.2
Treatment periods...............................................................................................49
Visit 2....................................................................................................................49
6.2.2.1
Visit 3....................................................................................................................49
6.2.2.2
Visit 4....................................................................................................................50
6.2.2.3
6.2.3
Follow Up Period and Trial Completion...........................................................50
6.2.4
Premature withdrawal........................................................................................51
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE52
STATISTICAL DESIGN - MODEL.................................................................52
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................52
7.2
PLANNED ANALYSES.....................................................................................52
7.3
7.3.1
Primary endpoint analyses.................................................................................52
7.3.2
Secondary endpoint analyses .............................................................................52
.................................................................................53
7.3.4
Safety analyses.....................................................................................................53
7.3.5
Pharmacokinetic analyses ..................................................................................53
INTERIM ANALYSES ......................................................................................54
7.4
HANDLING OF MISSING DATA ...................................................................54
7.5
7.5.1
Plasma concentration - time profiles.................................................................54
7.5.2
Pharmacokinetic parameters.............................................................................55
7.5.3
Safety....................................................................................................................55
RANDOMISATION ...........................................................................................55
7.6
DETERMINATION OF SAMPLE SIZE .........................................................55
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........56


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TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED
8.1
CONSENT ...........................................................................................................56
DATA QUALITY ASSURANCE ......................................................................57
8.2
RECORDS...........................................................................................................57
8.3
8.3.1
Source documents ...............................................................................................57
8.3.2
Direct access to source data and documents.....................................................58
8.3.3
Storage period of records ...................................................................................58
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS58
8.4
8.4.1
Listedness.............................................................................................................58
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................59
STATEMENT OF CONFIDENTIALITY........................................................59
8.5
END OF TRIAL..................................................................................................59
8.6
PROTOCOL VIOLATIONS .............................................................................59
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................59
9.
REFERENCES....................................................................................................60
PUBLISHED REFERENCES............................................................................60
9.1
UNPUBLISHED REFERENCES......................................................................61
9.2
10.
APPENDICES.....................................................................................................62
PHARMACOKINETIC METHODS................................................................62
10.1
THE RESPIMAT INHALER ............................................................................64
10.2
RETURN OF INHALERS/CARTRIDGES......................................................70
10.3
ADDITIONAL INFORMATION REGARDING IN/ EX CRITERIA..........70
10.4
11.
DESCRIPTION OF GLOBAL AMENDMENT..............................................72


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AP
Alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATS
American Thoracic Society
AUC
area under the plasma concentration-time curve
AUC,ss
area under the plasma concentration-time curve at steady state over a uniform 
dosing interval 
 
AUCt1-t2,ss
area under the concentration time curve in plasma over the time interval t1 to t2 at 
steady state
BAC
benzalkonium chloride
BI
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
BLQ
below limit of quantification
BP
blood pressure
CCDS
Company Core Data Sheet
CI
Confidence Interval
CK
creatine kinase
CK-MB
creatine kinase-MB
Cmax
maximum measured concentration in plasma
Cmax,ss
maximum measured concentration in plasma at steady state
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
COPD
chronic obstructive pulmonary disease
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DMC
Data Monitoring Committee
DILI
drug induced lever injury
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ePRO
Electronic Patient Reported Outcome
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FEV1
forced expiratory volume in one second
FVC
forced vital capacity
FC
Flow Chart
gCV
geometric coefficient of variation
gMean
geometric mean


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GOLD
Global Initiative for Chronic Obstructive Lung Disease
GCP
Good Clinical Practice
h
hours
HB
hepatitis B
HbsAg
hepatitis B surface antigen
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HEV
hepatitis E virus
HPLC
high performance liquid chromatography
HPC
Human Pharmacology Center
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICS
inhaled corticosteroid
IEC
Independent Ethics Committee
Ig G
immunoglobulin G
Ig M
immunoglobulin M
INR
internal normalised ratio
IR
incidence rate
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IU
international units
L
litres
LABA
long-acting beta-adrenoceptor agonist
LAMA
long acting muscarinic antagonist
LDH
lactate dehydrogenase
log
logarithmic
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
LoEE
List of Essential Element 
MedDRA
Medical Dictionary for Drug Regulatory Activities
MST
Medical Sub team
max
maximal
MDI
metered dose inhaler
mg
milligram
min
minute
mL
millilitres
MS/MS
tandem mass spectrometry
NA
not applicable
NBI
Nippon Boehringer Ingelheim, Co., Ltd.
NC
not calculated
NDA
new drug application
No.
number
NOA
not analysed
NOAEL
no observed adverse effects level
NOR
no valid result
NOS
no sample
OPU
Operative Unit
PD
Pharmacodynamics
PFT
pulmonary function test
PK
Pharmacokinetics
p.o.
per os (oral)
PCC
Protocol Challenge Committee


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PMDA
Pharmaceuticals and medical devices agency
PR
pulse rate
PT
prothrombin time
PRN
as occasion requires
q.d.
quaque die (once a day)
QT interval
time in seconds from onset of QRS complex to end of T wave
QTc
heart rate corrected QT interval
QTcF
heart rate corrected QT interval (using the Fridericia adjustment)
RA
rheumatoid arthritis
RDC
remote data capture
RNA
ribo nucleic acid
REP
Residual effect period, after the last dose of medication with measureable drug 
levels or pharmacodynamic effects still likely to be present
SABA
short-acting beta-adrenergic
SAE
Serious Adverse Event
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
ss
(at) steady state
SUSAR
suspected unexpected serious adverse reaction
s.c.
subcutaneous
SPC
Summary of Product Characteristics
TBL
total bilirubin
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TMW
Trial Medical Writer
TLC
tal lung capacity
TSAP
Trial Statistical Analysis Plan
T, t 
time
TdP
Torsades de Pointes
tmax
time from dosing to the maximum concentration in plasma
tmax,ss
time from dosing to the maximum concentration in plasma at steady state
ULN
upper limit of normal


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Treatment guidelines (ERS, ATS and GOLD) all place bronchodilators as the foundation of 
pharmacologic management of COPD. In patients with moderate to very severe pulmonary 
impairment (i.e. GOLD Stage II to IV) whose symptoms are not adequately controlled with as-
needed short-acting bronchodilators, adding regular treatment with one or more long-acting inhaled 
bronchodilators is recommended (long acting β2-agonists (LABAs), long-acting muscarinic 
antagonist (LAMAs)), [P04-07409].
The rationale for combining bronchodilators with different mechanisms is based on the notion of 
additive relaxation of airway smooth muscle by direct inhibition of cholinergic activity and 
functional antagonism of bronchoconstriction through β2-adrenergic pathways, with the expectation 
of an increase in the degree of bronchodilation for equivalent or lesser side effects.  Several recent 
studies have provided evidence in support of this increased bronchodilatory effect when LABAs are 
added to LAMAs.
When beta-agonists and muscarinic antagonists with similar or equivalent posologies are combined, 
the opportunity exists for offering a simpler or more convenient administration regimen with the 
development of fixed dose combinations within the same inhaler device.  Fixed dose combinations of 
a short-acting β2-agonist and a short-acting anticholinergic have been developed and have been 
shown to be safe, efficacious and convenient for the patient (e.g: Combivent®: salbutamol + 
ipratropium bromide; [P94-01346].  The recent interest in the development of LABAs and LAMAs 
with a once daily posology has presented the opportunity for the development of LABA/LAMA 
fixed dose combinations with a once daily posology.
DRUG PROFILE
1.2
Tiotropium
Tiotropium is a non-chiral, long-acting, inhaled anticholinergic bronchodilator, with a superior
muscarinic receptor subtype selectivity profile and duration of action compared with ipratropium. 
Complete details of the currently available information regarding the pharmacological, 
pharmacokinetic, toxicological and clinical profile of tiotropium as mono-product are available in the 
respective Investigator's Brochure (U06-3029).
Olodaterol
Olodaterol has an optimised inhaled LABA profile of topical lung selectivity, high β2-selectivity, 
almost full intrinsic activity at β2-adrenoceptors and low intrinsic activity at β2-adrenoceptors.  
Complete details of the currently available information regarding the pharmacological, 
pharmacokinetic, toxicological and clinical profile of olodaterol as monoproduct are available in the 
respective Investigator’s Brochure (U06-3029).
Tiotropium + olodaterol combination


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Tiotropium + olodaterol FDC is an aqueous solution of tiotropium and olodaterol contained in a 
cartridge. It is administered by using the Respimat® inhaler. The same device is used for tiotropium 
(Spiriva® Respimat®) and olodaterol (Striverdi®). One cartridge is used per inhaler, which is inserted 
into the device prior to first use. 
In the pivotal studies (1237.5/.6) tiotropium + olodaterol FDC showed statistically significant 
improvements in Forced Expiratory Volume in one second (FEV1) Area Under the Curve (AUC0-3h) 
response and trough FEV1 response after 24 weeks compared to the mono-components and these 
improvements were maintained up to 52 weeks. Tiotropium + olodaterol FDC showed statistically 
significant improvements in health-related quality of life St. George's Respiratory Questionnaire 
(SGRQ) and dyspnea experienced during everyday activities Transitional Dyspnea Index (TDI) after 
24 weeks compared to the mono-components. More patients treated with the combination had an 
improvement in SGRQ total score and TDI greater than the Minimal Clinically Important Difference 
(MCID). Treatment with tiotropium + olodaterol FDC also resulted in reductions in both daytime 
and night time rescue bronchodilator use compared to the mono-components.
Tiotropium + olodaterol FDC was shown to be safe and well tolerated over 1 year in a moderate to 
very severe COPD population. The overall incidences of adverse events (AEs), serious adverse event 
(SAEs), fatal AEs, frequencies for cardiac events and Major Adverse Cardiovascular Event (MACE) 
in the tiotropium + olodaterol FDC treatment group were similar to the mono-components. The 
nature and frequency of AEs in general was consistent with the disease under study. There were no 
results in the clinical development program suggesting the need for absolute contraindications for the 
combination product.
For a more detailed description of the drug profile, please refer to the current Investigator’s Brochure 
(IB) which is included in the Investigator Site File (ISF).
RESPIMAT Inhaler
Boehringer Ingelheim’s Respimat® Inhaler will be used for administration of tiotropium + olodaterol 
FDC and olodaterol. The Respimat® Inhaler is a novel device which creates a soft mist aerosol 
without the use of propellants. The medication is provided as an aqueous solution in a cartridge, 
which is inserted into the device prior to first use. The Respimat® Inhaler generates a soft mist which 
is released over a period of approximately 1.5 seconds. The fraction of fine particles accessible to 
lungs and airways is very high compared with many metered dose aerosols or dry powder devices. 
The solution is adjusted to pH 2.9 because the drug in solution is stable at acidic pH values. Due to 
the multi-dose characteristics of the Respimat® Inhaler, the drug formulation contains the chelating 
agent disodium edentate (EDTA) and the antimicrobial preservative benzalkonium chloride (BAC). 
However, the concentrations of EDTA and BAC in tiotropium plus olodaterol FDC solution and 
tiotropium solution for inhalation with the Respimat® Inhaler are well below the levels, which have 
been reported to induce bronchospasms in some patients inhaling aerosols of solutions from a 
nebulizer. The use of the Respimat® Inhaler in phase III trials has been shown to be safe with regards 
to paradoxical bronchoconstriction during chronic use in patients with COPD (P05-08465).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
In a dedicated PK interaction study in caucasian COPD patients (1237.3) the 90% confidence 
intervals for the ratios of Cmax,ss, AUC0-1,ss, AUC0-2,ss, and Ae0-24,ss for olodaterol when administered 
in combination with tiotropium compared with administration as monotherapy were generally
completely located within the accepted bioequivalence limits of 80 to 125%, suggesting no relevant 
effect of tiotropium on the systemic exposure to olodaterol; the time point of the maximum 
olodaterol plasma concentration (tmax,ss) was identical after both treatments. Similarly, the 90% 
confidence intervals for the ratio of Ae0- 24,ss and Cmax,ss for tiotropium when administered in 
combination with olodaterol compared with administration as monotherapy were all completely 
located within the generally accepted bioequivalence limits of 80 to 125%, suggesting no relevant 
effect of olodaterol on the systemic exposure to tiotropium; the time point of the maximum 
tiotropium plasma concentration (tmax,ss) was identical after both treatments.
The trial 1237.30 is designed to characterize the PK of tiotropium and olodaterol following the 
administration of the fixed dose combination of tiotropium+olodaterol (5 µg/5 µg) in Chinese
patients with COPD. China Food and Drug Administration (CFDA) requested to obtain the PK data 
with the fixed dose combination of tiotropium+olodaterol (5 µg/5 µg) in Chinese patients with 
COPD.
TRIAL OBJECTIVES
2.2
The primary objective of this study is to assess the pharmacokinetics of tiotropium + olodaterol FDC 
(5 µg/ 5 µg) delivered by the RESPIMAT inhaler after single dose and at steady state in Chinese
patients with COPD.
The secondary objective is to assess the safety of tiotropium + olodaterol FDC (5 µg/ 5 µg) delivered 
by the RESPIMAT inhaler after 3 weeks once daily treatment in Chinese patients with COPD.
BENEFIT - RISK ASSESSMENT
2.3
The clinical trials conducted to date have shown tiotropium + olodaterol 5/5 μg to be a safe, well 
tolerated and efficacious combination therapy according to treatment guidelines in a moderate to 
very severe COPD patient population that included patients with concomitant cardiovascular
diseases.
The observed incremental bronchodilator response for tiotropium + olodaterol 5/5 μg compared to 
the individual components translated into benefits that were meaningful to the patient, with
improvements in several patient centred outcomes. As such, tiotropium + olodaterol 5/5 μg will be a 
valuable additional therapeutic option for patients with COPD, offering increased treatment benefit 
compared to the monotherapies with a comparable safety profile.


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Based on the overall assessment of benefit to risk, the application for marketing authorization for 
tiotropium + olodaterol FDC was submitted in the EU and the US in May 2014, and then 
subsequently in several other countries, including Canada.
The trial design requires that all eligible patients complete a 3 to 4 week screening period in which 
LABAs and LAMAs are withdrawn prior to treatment. Site will provide open-label salbutamol 
(albuterol) as needed (PRN) rescue medication for all patients who have signed Informed Consent.
All patients will receive active treatment with tiotropium + olodaterol FDC (5 µg / 5 µg) during the 
treatment periods. There is no placebo comparator in this trial.
Patients receiving inhaled corticosteroids before enrolment will continue their treatment (or the 
inhaled corticosteroids component alone if taken as a fixed combination with bronchodilator) at the 
same equivalent dose and regimen during the study. The only medications that are excluded during 
the treatment period are anticholinergic and long-acting β-adrenergic other than the study drugs.
Safety will be monitored (as described in section 5.2) at site visits and withdrawal criteria is provided 
for investigators’ consideration (as listed in section 3.3.4.1).Women of childbearing potential may be 
included in clinical trials for tiotropium + olodaterol provided appropriate precautions are taken to 
minimize the risk of pregnancy. These precautions include pregnancy testing and use of a highly 
effective method of birth control. Continued testing and monitoring during the trial should be 
sufficient to ensure compliance with the measures not to become pregnant during the period of drug 
exposure (including the 3 weeks follow-up period) [R10-5669].
Safety will be monitored including adverse events, physical examination, vital signs, laboratory tests, 
pregnancy tests, , 12-lead ECG (as described in Section 5.2) at site visits. 
Potential benefits for participating patients in this trial are associated with the bronchodilating effects 
of the active treatments during the treatment period. Careful monitoring of safety is planned at site to 
decrease risks. This trial is designed to provide data for evaluating the pharmacokinetic 
characteristics of tiotropium + olodaterol FDC at the planned registration dose in Chinese patients 
with COPD. The potential benefits for patients outweigh potential risks.
Although rare, a potential for drug-induced liver injury is under constant surveillance by sponsors 
and regulators. Therefore, this trial requires timely detection, evaluation, and follow-up of laboratory
alterations in selected liver laboratory parameters to ensure patients´ safety, see also section 5.3.6.1.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is an open-label trial to assess PK and safety of tiotropium + olodaterol FDC (5 µg/ 5 µg)
delivered by the RESPIMAT inhaler after single dose and at steady state in Chinese patients with 
COPD.
Following an initial screening visit, patients enter a 2-week screening period to ensure clinical 
stability (i.e. no exacerbations). Patients who successfully complete this phase will be allocated into 
the 3-week open-label treatment period. PK profiles will be determined at Visit 2 (1st dose 
administration), during the 3 week treatment period at Visit 3 and at Visit 4 (the end of the 3-week 
treatment period). At Visit 2 and Visit 4, blood and urine samples for PK measurement will be 
collected prior to administration and for a 6 hour period and a 24-hour period post dose of allocated
treatment, respectively. At visit 3, a pre-dose sample and a sample at 20 minutes after the drug 
administration will be collected at days 7,14,18,19 and 20. Safety measurements will be conducted 
such as adverse events, vital signs, laboratory tests, 12-lead ECG recording and physical examination.
All patients (including patients who discontinue early) will be evaluated for an additional 3-week
following the final dose of study medication. 
Adverse events will be tracked throughout the 8 weeks study period. Analysis of clinical laboratory 
samples will be performed at the trial site.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim. 
BI will appoint a Trial Clinical Monitor (TCM), responsible for coordinating the activities required 
in order to manage the trial in accordance with applicable regulations and internal standard operating 
procedures (SOPs), directing the clinical trial team in the preparation, conduct, and reporting of the 
trial, order the materials as needed for the trial, ensures appropriate training and information of 
clinical monitors local (CML), clinical research associates (CRAs), and investigators.


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Data Management and Statistical evaluation will be done by BI according to BI SOPs. For these 
activities, a Trial Data Manager and a Trial Statistician will be appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be defined 
according to BI SOPs. A list of responsible persons and relevant local information (as protocol 
reference if applicable) are in the investigator site file (ISF) and the Trial Master File (TMF) 
document.
The analyses of tiotropium and olodaterol will be performed at 
The organisation of the trial will be done by the BI with which the responsibilities and tasks have 
been agreed and a written contract has been filed before initiation of the clinical trial. All contracts 
and relevant meeting minutes will be stored by BI in the TMF.
A CML will be appointed and will be responsible for coordinating the activities required to manage 
the trial in accordance with applicable regulations and internal SOPs inChina.
Documents on participating investigators, especially their curricula vitae, will be filed in the TMF 
document. 
Details on handling of the trial supplies including responsible institutions are given in Section 4 of 
this protocol.
The ISF document will be kept in print-out version at the sites as far as required by regulation and BI 
SOPs. A copy of the ISF documents will be kept as an electronic TMF document according to BI 
SOPs.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL 
3.2
GROUP
A 3-week treatment period is justified because the pharmacokinetic results obtained in healthy 
volunteers suggested that pharmacokinetic steady state is reached within 3 weeks.
Patients with moderate to severe COPD will be included in this trial. Pharmacotherapy with long-
acting bronchodilators (as single-agent therapy or as combination therapy) is the recommended 
maintenance treatment for these patients according to various international clinical guidelines for the 
management of this disease [P01-02794, P04-07409]. Therefore, the systemic exposure in Chinese
patients with COPD under maintenance treatment, i.e. at pharmacokinetic steady state, is the relevant 
endpoint for determining the PK of tiotropium and olodaterol in the dose combination to be used in 
the FDC.
Following once daily inhalation of the tiotropium + olodaterol FDC, the terminal half-life of both 
tiotropium and olodaterol was about 60 h and pharmacokinetic steady state was reached latest at day 
8 to 10 for both compounds [U08-2169]


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SELECTION OF TRIAL POPULATION
3.3
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated with 
investigational drug or not.
3.3.1
Main diagnosis for trial entry
16 patients will be included in the trial to ensure that a minimum of 12 evaluable patients of both sex, 
40 years of age or older, and with a diagnosis of COPD complete the study, trial could be ended in 
case 12 evaluable patients are available. The evaluable patients are defined as the patients who have 
available blood samples for PK measurement at Visit 2, 3 and 4 as described in Flowchart. Every 
effort should be made to keep patients in the study until they complete all study procedures and all 
test days.
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 sign an informed consent consistent with ICH-GCP guidelines and local 
legislations prior to any study-related procedures, which includes medication washout and 
restrictions.
2.
All patients must have a diagnosis of COPD [P11-05865] and must meet the following 
spirometric criteria:
Patients must have relatively stable airway obstruction with a post-bronchodilator FEV1
30% of predicted normal and <80% of predicted normal (ECSC, [R94-1408]; and a post-
bronchodilator FEV1/ FVC<70% at Visit 1 (See Appendix 10.4 for ECSC predicted normal 
equations).
3.
Male or female patients, 40 years of age or older.
4.
Patients must be current or ex-smokers with a smoking history of more than 10 pack years. 
(See Appendix 10.4 for calculation).
Patients who have never smoked cigarettes must be excluded.
5.
Patients must be able to
•
perform technically acceptable pulmonary function tests,
•
maintain medication worksheet records during the study period,
•
perform all other assessments as required in the protocol.
6.
Patients must be able to inhale medication in a competent manner from the RESPIMAT
inhaler (See Appendix 10.2) and from a metered dose inhaler (MDI).
7.
Male or female patients. Women of childbearing potential* must be ready and able to use 
highly effective methods of birth control per ICH M3(R2) that result in a low failure rate of 
less than 1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the patient information.
*Women of childbearing potential are defined as:
Any female who has experienced menarche and does not meet the criteria for "women not of 
childbearing potential" as described below.


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Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an alternative medical cause) 
or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or 
bilateral salpingectomy).
3.3.3
Exclusion criteria
1.
Patients with a significant disease other than COPD; a significant disease is defined as a
disease which, in the opinion of the investigator, may (i) put the patient at risk because of 
participation in the study, (ii) influence the results of the study, or (iii) cause concern 
regarding the patient’s ability to participate in the study.
2.
Patients with a, in the opinion of the investigator, clinically relevant abnormal baseline
haematology, blood chemistry, or urinalysis; all patients with an SGOT > 2 x ULN, SGPT >
2 x ULN, bilirubin > 2 x ULN or creatinine > 2 x ULN will be excluded regardless of clinical 
condition (a repeat laboratory evaluation will not be conducted in these patients).
3.
Patients with a history of asthma. For patients with allergic rhinitis or atopy, source 
documentation is required to verify that the patient does not have asthma. If a patient has a 
total blood eosinophil count ≥600/mm3, source documentation is required to verify that the 
increased eosinophil count is related to a non-asthmatic condition.
Patients with any of the following conditions:
4.
A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists).
5.
A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known class side 
effect profile of ß2-agonists)
6.
A history of myocardial infarction within 1 year of screening visit (Visit 1).
7.
Unstable or life-threatening cardiac arrhythmia.
8.
Hospitalization for heart failure within the past year.
9.
Known active tuberculosis.
10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy 
within last five years (patients with treated basal cell carcinoma are allowed).
11. A history of life-threatening pulmonary obstruction.
12. A history of cystic fibrosis.
13. Clinically evident bronchiectasis.
14. A history of significant alcohol or drug abuse.
15. Patients who have undergone thoracotomy with pulmonary resection (patients with a history 
of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1).
16. Patients being treated with oral or patch β-adrenergics.
17. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six 
weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day 
or 20 mg every other day.
18. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the 
investigator’s opinion will be unable to abstain from the use of oxygen therapy during clinic 
visits.
19. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the 
screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program.


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20. Patients who have taken an investigational drug within one month or six half lives or (in case 
the investigational drug (sub) class is listed in Table 4.2.2.1:1) within the wash out period 
specified in Table 4.2.2.1:1 (whichever is greater) prior to screening visit (Visit 1).
21. Patients with known hypersensitivity to β-adrenergics and/or anticholinergic drugs, BAC, 
EDTA or any other component of the RESPIMAT inhalation solution.
22. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
23. Women of childbearing potential not using two highly effective methods of birth control*.
Female patients will be considered to be of childbearing potential unless surgically sterilised 
by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years.
*
as per ICH M3 (R2) [R10-5669]: a highly effective method of birth control is defined as 
those which result in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly.
24. Patients who have previously been allocated in this study or are currently participating in 
another study.
25. Patients who are unable to comply with pulmonary medication restrictions prior to allocation.
Note: 
1.
Extreme caution should be used when including patients:
-
with cardiovascular disorders, especially coronary insufficiency and hypertension* 
-
being treated with monoamine oxidase inhibitors or tricyclic antidepressants*
2.
Caution should be used when including patients on treatment with non potassium-sparing 
diuretics*
3.
Patients with moderate to severe renal impairment (creatinine clearance ≤50 mL/min) should 
be monitored closely by the investigator, as tiotropium is a predominantly renally excreted 
drug.
4. Beta-blockers do not only block the pulmonary effect of beta-agonists, but may also produce 
severe bronchospasm in patients with COPD. Therefore, patients should not normally be treated with 
beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, 
there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with 
COPD. In this setting, cardio selective beta-blockers could be considered, although they should be 
administered with caution.*  
5. As an anticholinergic drug, tiotropium may potentially worsen symptoms and signs associated 
with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction and should be used 
with caution in patients with any of these conditions. 
*
cf prescribing information for registered LABAs (salmeterol/formoterol) and olodaterol
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from the trial if any of the following criteria apply:
1. The patient withdraws consent, without the need to justify the decision. 
2. The patient is no longer able to participate for medical reasons (e.g. pregnancy, surgery, adverse 
events, or other diseases), or contraindications for exercise testing have occurred. 


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3. Administrative reasons (protocol violations, persistent non-compliance). 
4. Decision by Boehringer Ingelheim to discontinue one or all patients (e.g., new toxicological 
findings or SAEs invalidate the earlier positive benefit–risk assessment).
No patient should be discontinued from the trial for a protocol violation before discussion with the 
clinical monitor. In the event of a COPD exacerbation, please contact the CML / TCM to discuss the 
possibilities to re-schedule the clinic visits.
Data of patients who discontinue or withdraw prior to allocation will be entered in the trial database 
and will be listed. Data of patients who discontinue or withdraw after allocation must be documented 
with the reason for withdrawal in source document and must be recorded in the electronic case report 
form (eCRF). The data must be included in the trial database and must be reported.
See Section 6.2.4 for procedures to be followed for patients prematurely terminating the trial.
Pregnancy
If a patient becomes pregnant during the trial the investigational product needs to be stopped and the 
patient should be followed up until birth or until termination of the pregnancy. The data of the patient 
will be collected and reported in the CTR until patient's last visit and any events thereafter will be 
reported in the BI drug safety database. See Section 5.3.7 for detailed information on event reporting 
in case of pregnancy.
Discontinuation of the trial by the sponsor
3.3.4.2
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 GCP, the CTP, or the contract disturbing 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
TREATMENTS TO BE ADMINISTERED
4.1
Patients will be allocated to the following treatments according to the order they enter the study site, 
while be assigned to Tiotropium+Olodaterol FDC treatment group:
Tiotropium + olodaterol FDC (5 µg/ 5 µg) solution for inhalation
During the entire 3-week treatment period, the patients inhale 2 puffs from the RESPIMAT inhaler, 
once a day, in the morning.
The investigational products will be provided by Boehringer Ingelheim.
4.1.1
Identity of BI investigational products and comparator product
Table 4.1.1: 1
Test product:
Substance:
Tiotropium + olodaterol fixed-dose combination
Pharmaceutical formulation:
Solution for inhalation
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
2.5µg/ 2.5µg per actuation
(tiotropium/olodaterol)
Posology
2 inhalations once daily (AM dosing)
Route of administration:
Oral inhalation via RESPIMAT inhaler (A5)
4.1.2
Method of assigning patients to treatment groups
Upon signing informed consent, patients will be assigned a unique patient number using the remote 
data capture (RDC) system.
Patients are allocated to treatment groups at Visit 2. After assessment of all in- and exclusion criteria, 
each eligible patient will be assigned the lowest available medication number at the time of treatment. 
The 16 medications, medication number starting from the lowest, contain Tiotropium + olodaterol 
fixed-dose combination. Note that the medication number is different from the patient number (the 
latter is assigned at trial entry). Site personnel will enter the medication number on the eCRF.
See Section 4.1.6 for details on packaging and labelling.
4.1.3
Selection of doses in the trial
Tiotropium + olodaterol FDC (5 µg/ 5 µg) will be the submitted doses in China. These doses are 
included in the trial in order to assess PK in Chinese patients with COPD as required by CFDA.


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4.1.4
Drug assignment and administration of doses for each patient
Dispensing of trial medication
Trial medication will be dispensed to the patient by the investigator/pharmacist. The amount of trial 
medication dispensed will be recorded on the drug accountability forms.
Priming of the RESPIMAT inhaler
Each newly assembled RESPIMAT inhaler has to be primed. Priming should NOT take place in the 
same room where the patient is inhaling trial medication nor where samples for PK analyses are 
drawn or processed (to avoid contamination of the environment). At Visit 2, priming should be 
performed by site personnel, and not by the patient himself. The inhaler should be primed by 
actuating it until an aerosol is visible plus three additional actuations. All priming actuations should 
be directed to the ground. For detailed priming instructions，please see the RESPIMAT inhaler 
handling instructions in Appendix 10.2.
Once the cartridge is inserted into the Respimat inhaler, the shelf-life of the RESPIMAT with trial
medication is 3 months. Once assembled, the shelf-life of the RESPIMAT with training medication 
is also 3 months. Therefore it is important to ALWAYS enter the date of the cartridge insertion on 
the medication label of the RESPIMAT immediately after the cartridge is inserted.
Testing of the MDI (rescue medication)
Before using for the first time, one actuation should be released into the air to make sure the device is 
working. 
Trial medication administration at clinic visits
Detailed written instructions and training for the use of the RESPIMAT inhaler will be given to the 
patient at Visit 1 and the patient will inhale from the training device. (See Appendix 10.2). The 
investigator or qualified study personnel will observe the inhalation procedure and will reinforce a 
correct inhalation technique. At Visit 2, detailed instructions on the use of the device will be repeated, 
but the patient will not inhale from the training device. Patients inhale the first dose of trial 
medication at Visit 2.
The utmost care should be taken to ensure that the study medication is not taken prior to coming to 
the site at Visit 3 and Visit 4. At Visit 2 (after all assessment completion) ,Visit 3 and Visit 4 puffs of 
the study medication from the assigned RESPIMAT inhaler will be self-administered by the patient 
under the direct supervision of the investigating physician or deputy. Gloves must be worn and 
discarded immediately after the priming to avoid contamination of the PK samples to be taken and 
processed subsequently. The patient should not be present while priming takes place. Inhalation
should NOT take place in the same room where samples for PK analyses are drawn or processed (to 
avoid contamination of the environment). Patient should inhale his/her medication in an isolated area 
from other patients (to avoid contamination of the environment).
Trial medication administration at home
Patients will receive two medication boxes; only one RESPIMAT inhaler should be ready for use (= 
cartridge inserted and primed). Once a cartridge is inserted in a RESPIMAT inhaler, the shelf-life is 
limited.


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Each morning except on the days of a clinic visit, two puffs of the trial medication from the assigned 
RESPIMAT inhaler will be self-administered by the patient. 
Patients have to be instructed that for the three days proceeding the days with PK sampling, the 
appropriate dose of study medication must be self-administered within ±5 min of time of drug
administration at Visit 2 AND between 7:00 AM and 10:00 AM in order to avoid influence on the data 
collected on the Visits 3 and 4.
If the patient forgot to inhale the study medication within the specified time window, the patient is 
allowed to administer the dose until 12:00 PM (noon). After 12:00 PM the patient should skip the 
dose and take the next dose at the next scheduled time the following day and make a note of the 
missed dose in his/her medication worksheet.
RESPIMAT inhaler return
The RESPIMAT inhalers dispensed for the treatment period can be used for approximately 30 days 
each. All used and unused trial medication must be returned at Visit 4 by the patient.
Any RESPIMAT inhaler that has been reported as malfunctioning by a patient or investigator will be 
returned to the BI for investigation. See the ISF for specific instructions and for details regarding 
drug accountability requirements. Details of the procedure for the return of malfunctioning inhalers 
are provided in Appendix 10.3.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Not applicable since this is an open-label trial.
Unblinding and breaking the code
4.1.5.2
Not applicable since this is an open-label trial.
4.1.6
Packaging, labelling, and re-supply
All trial medication will be contained in individual RESPIMAT treatment boxes identified with the 
trial number and a medication number. The boxes will have a two-part tear-off label. One part of 
each tear-off label will remain on the box, and the other part will be attached to a special drug 
dispensing log which will be part of the ISF. Examples of the labels are provided in the ISF.
The investigator or designee should fill out the following information on the medication label prior 
to dispensing the medication to the patient:

date of cartridge insertion (RESPIMAT inhaler only; should be entered at time of  
cartridge insertion)
For details of packaging and the description of the label, see the ISF.
RESPIMAT treatment box
The RESPIMAT treatment box will contain one RESPIMAT inhaler plus one drug-filled cartridge 
and contains sufficient medication for 30 days of treatment.
The RESPIMAT inhaler will lock after 60 actuations have been administered and will no longer 


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actuate any medication. 
Medication dispensing
Two boxes are packed in one outer box with medication number. The one box should be used for the 
treatment period and the other box is for reserve.
The one RESPIMAT inhaler will be primed by the site staff (See Section 4.1.4) used to dose the 
patient at inhalation at the end of Visit 2, as well as continued to be used at home until Visit 4. The 
other RESPIMAT for reserve medication is to allow the patient the flexibility of not having to return 
to the site immediately to replace a lost or malfunctioning RESPIMAT inhaler. 
NOTE:   The RESPIMAT and drug-filled cartridge that is not yet in use by the patient should NOT 
be assembled prior to leaving the site. The patient must assemble and prime the reserve device at 
home if needed (See Appendix 10.2).
The date of cartridge insertion should be entered (label of RESPIMAT inhaler only) at time of 
cartridge insertion only, i.e. for the first RESPIMAT inhaler this is entered by site staff (at Visit 2), 
for the second RESPIMAT inhaler the patient is advised to do so when assembling this device at 
home during the treatment period.
Supplies other than treatment medication
BI will provide the following open-label supplies:

RESPIMAT inhalers, placebo cartridges for training purposes. One training device will be 
used for several patients. The training RESPIMAT can be used until 3 months after first 
insertion of the cartridge or until the device is empty. The date of the cartridge insertion 
should be entered on the medication label of the RESPIMAT immediately after the cartridge 
is inserted.

Salbutamol MDI inhalation aerosol (100 µg per actuation) for use as rescue medication 
during screening, treatment and follow-up periods (Visit 0 to Visit 4). It will also be used for 
reversibility testing at Visit 1. Salbutamol will be purchased at site and dispensed to the 
patient at site visits as needed.

Ipratropium bromide will be purchased at site and provided to be dispensed at the discretion 
of the investigator for use by patients on long acting anticholinergics (LAMA) during the 3-
week washout period of LAMA preceding Visit 2.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
All clinical trial supplies, which will be provided by the sponsor, must be stored in a secure, limited 
access storage area under the storage conditions defined on the label and may only be dispensed to 
patients according to protocol. A temperature log must be maintained at 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 specified range, immediately contact the CML. 
Regarding to the drug which will be used by patient at home, a patient dairy will be provided to 
patient which including the drug storage temperature record. 
Further details are provided in the labels, a sample of which will be part of the ISF.


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4.1.8
Drug accountability
The Investigator or Pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head of the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

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
The Investigator or Pharmacist or investigational drug storage manager 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 alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, and the 
unique code numbers assigned to the investigational product and trial patients. The Investigator / 
Pharmacist / investigational drug storage manager will maintain records that document adequately 
that the patients were provided the doses specified by the CTP and reconcile all investigational 
products received from the Sponsor. At the time of return to the Sponsor or appointed CRO, the 
Investigator / Pharmacist / investigational drug storage manager 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.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT
4.2
The investigator must record all medication used by the patient for the three months preceding the 
Screening Visit (Visit 1) and throughout the trial, on the eCRF. This record will include the name of 
the medication, the total daily dose, route of administration, dates when medication was started and 
stopped, and the indication for medication usage.
4.2.1
Rescue medication, emergency procedures, and additional treatments
Rescue medication
4.2.1.1
Administration of rescue medication can occur at any point during the trial as deemed necessary by 
the patient or the investigator. Open label salbutamol MDI (100 µg per puff) will be provided as 
rescue medication by Site; the salbutamol MDIpurchased at site is allowed for rescue medication use. 
Emergency procedures
4.2.1.2
There are no special emergency procedures to be followed.
Additional treatments
4.2.1.3
Medications Allowed to Control Acute Exacerbations as Medically Necessary during the Treatment 
Period: 

Salbutamol inhalation aerosol from MDI for p.r.n. use provided by Site.


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
Temporary increases in the dose or addition of oral steroids are allowed during the treatment 
portion of the study. Pulmonary function testing should not occur within seven days of the last 
administered dose of an increase or addition of oral steroids. Pulmonary function testing may be 
postponed up to 14 days to meet this restriction. Subsequent visits will be scheduled according to 
the patient's regular schedule. 

Temporary additions of theophylline preparations are allowed during the treatment portion of the 
study. Pulmonary function testing should not occur within seven days of the last dose. Pulmonary 
function testing may be postponed up to 14 days to accommodate this restriction. Subsequent 
visits will be scheduled according to the patient's regular schedule. 

The use of antibiotics is not restricted and may be prescribed as medically necessary for 
exacerbations and / or infections. If antibiotics are prescribed for a respiratory infection prior to 
pulmonary function testing days, the testing will be postponed for at least two days but not more 
than seven days after the last dose is given. Subsequent visits will be scheduled according to the 
patient's regular schedule. There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
The following Table provides an overview of permitted and restricted medication.


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Table 4.2.2.1: 1 Permitted Medications and Medication Restrictions 
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment Period
Follow up Period
Corticosteroids4
Inhaled corticosteroids
(stabilized 6 wks prior to V1)
Permitted 
Permitted
Permitted
Permitted
Oral corticosteroids 
[≤10 mg prednisone per day or ≤20 mg prednisone 
every other day (or equivalent); stabilized 6 wks 
prior to V1]
Permitted
Permitted
Permitted
Permitted
Injected corticosteroids – local administration 
(for treatment of e.g. bursitis)
Permitted
Permitted
Permitted
Permitted
β-adrenergics
Inhaled short-acting β-adrenergics
Permitted1
Rescue1
Rescue1
Permitted
Inhaled long-acting β-adrenergics (bid)
(e.g. formoterol / salmeterol)
Permitted
(w.o. 48 hrs prior to V1)
NOT permitted
NOT permitted
Permitted
Inhaled long-acting β-adrenergics (qd)
(e.g. indacaterol, olodaterol)
Permitted
(w.o. 1 week prior to V1)
NOT permitted
(w.o. 3 wks prior to 
[visit 2])
Study medication
Permitted
Oral and patch beta-adrenergics
Permitted
(w.o. 4 wks prior to V1)
NOT permitted
NOT permitted
Permitted
Beta blockers  
(cautionary statement, Section 3.3.3;
stabilized 6 wks prior to V1)
Permitted
Permitted 
Permitted 
Permitted 


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Table 4.2.2.1: 1 Permitted Medications and Medication Restrictions (cont.)
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment Period
Follow up Period
Anticholinergics
Short-acting anticholinergics
(e.g. inhalation aerosol, nasal spray)
Permitted1
Permitted until [visit 2]   (w.o. 
8 hrs prior to [visit 2])
NOT permitted
Permitted
Long-acting anticholinergics (bid / qd)
(e.g. tiotropium, aclidinium, glycopyrronium, umeclidinium)
Permitted
(w.o. 1 week prior to V1)
NOT permitted
(w.o. 3 wks prior to [visit 2])
Study medication
Permitted
Combinations
ICS / long-acting β-adrenergics (bid)
(switch to ICS mono-product, no change to steroid dose, at 
least 48 hrs prior to V1)
Permitted1
NOT permitted
NOT permitted
Permitted
ICS / long-acting β-adrenergics (qd)
(switch to ICS mono-product, no change to steroid dose + 
LABA bid, at least 3 weeks prior to V1)
(e.g. fluticasone+vilanterol)
Permitted1
NOT permitted
NOT permitted
Permitted
ICS / short-acting β-adrenergics
(switch to ICS mono-product, no change of steroid dose, at 
least 8 hrs prior to V1)
Permitted1
NOT permitted
NOT permitted
Permitted
Short-acting anticholinergic / short-acting β-adrenergics
Permitted
(w.o. 8 hrs prior to V1)
NOT permitted 
NOT permitted
Permitted
Long-acting anticholinergics / long-acting β-adrenergics3
(e.g. glycopyrronium+indacaterol, umeclidinium+vilanterol)
Permitted
(w.o. 1 week prior to V1)
NOT permitted
(w.o. 3 wks prior to [visit 2])
Study medication
Permitted


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Table 4.2.2.1: 1 Permitted Medications and Medication Restrictions (cont.)
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment Period
Follow up Period
Miscellaneous
Other investigational drugs
(*see exclusion criterion #xx)
NOT permitted* 
NOT permitted
NOT permitted
NOT permitted
Cromolyn sodium / nedocromil sodium
(* if prescribed for non-asthma condition)
Permitted* 
Permitted*
Permitted*
Permitted*
Antihistamines, antileukotrienes
(* if prescribed for non-asthma condition)
Permitted* 
Permitted* 
Permitted*
Permitted* 
Methylxanthines/Theophyllines
(* if prescribed for non-asthma condition)
Permitted*1
Permitted*1
Permitted*1
Permitted
Mucolytics   
(*not containing bronchodilators; stabilized 6 wks prior to V1)
Permitted*
Permitted
Permitted
Permitted
PDE-4 inhibitors 
(e.g. roflumilast)
NOT permitted2
NOT permitted
NOT permitted
NOT permitted
w.o.: wash out, V: Visit
1.
Refer to Section 4.2.2.1 for washout period prior to PFTs.
Refer to Section 4.2.1 for washout period prior to PFTs in case of treatment of a COPD exacerbation. 
2.
Patients currently using PDE4-inhibitors (e.g. roflumilast) should not be enrolled and roflumilast should not be withdrawn for the purpose of enrolling in this study.
Patients who were using roflumilast in the past may be included if their last use was a minimum of 3 months prior to Visit 1. In the event a patient with prior use of roflumilast is enrolled, past medical records are 
required to support and document why and when roflumilast was stopped.
3.
Patients may be switched to bid LABA and / or short acting anticholinergic. Refer to Section 4.2.2.1 for washout period prior to PFTs 
4.
Patients are not allowed to initiate nor change the dose of  Inhaled corticosteroids and oral corticosteroids during the trial.


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Medication restrictions for pulmonary function testing for reviewing eligibility of patient at 
Visit 1:

At least an 8-hour washout of short-acting beta-adrenergic bronchodilators prior to 
Visit 1.

At least an 8-hour washout of short-acting anticholinergic bronchodilators prior to 
Visit 1.

At least a 1-week washout of long-acting anticholinergic bronchodilators prior to 
Visit 1.

At least a 1-week washout of long-acting beta-adrenergic bronchodilators (q.d.) prior 
to Visit 1.

At least a 48-hour washout of long-acting beta-adrenergic bronchodilators (b.i.d.) 
prior to Visit 1.

The morning dose of inhaled steroids should not be taken in the 1-hour period prior to 
PFTs.

At least a 24-hour washout of short-acting (b.i.d. or more frequent administration) 
theophylline preparations.

At least a 48-hour washout of long-acting (q.d. administration) theophylline 
preparation.
Restrictions on diet and life style
4.2.2.2
Restrictions prior to PFT at Visit 1

Medication washout restrictions should be adhered to as described in Section 4.2.2.1.

Patients must refrain from strenuous activity for at least 12 hours prior to pulmonary 
function testing at Visit 1. Patients should also avoid cold temperatures, 
environmental smoke, dust or areas with strong odours (e.g. perfumes).

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and 
ice-cold beverages are not allowed at least 2 hours prior to and during the pulmonary 
function testing. Decaffeinated beverages are acceptable.

Smoking should be discouraged for the 12 hours prior to pulmonary function testing 
and throughout the test day and will not be permitted in the 30-minute period prior to 
spirometry.


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TREATMENT COMPLIANCE
4.3
The patient will complete a patient’s medication worksheet confirming that trial medication 
has been taken each day during treatment periods. The investigator will review these records 
with the patient at Visits 3, 4 to assess treatment compliance of trial medication. Treatment 
compliance should be emphasized with a goal of at least 80% compliance rate.
Each patient will be trained on the screening visit, Visit 1 as to the correct inhalation using a 
training RESPIMAT inhaler containing placebo. On Visit 2, the trial staff should ensure that 
the patient knows how to inhale from the RESPIMAT inhaler correctly. 


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
Pharmacokinetics and safety will be assessed at the time points indicated in the flow chart. In 
the case of premature withdrawal from the trial, all end of study assessments are to be 
performed.
5.1.1
Primary Endpoints
The following pharmacokinetic parameters will be determined as primary endpoints:
After a single dose:

Cmax (maximum measured concentration in plasma).

tmax (time from dosing to the maximum concentration in plasma).

AUC0-6 (area under the concentration time curve in plasma over the time interval from 0 
to 6 hours after drug administration).
After multiple dosing:

Cmax,ss (maximum measured concentration in plasma at steady state).

tmax,ss (time from dosing to the maximum concentration in plasma at steady state).

AUC0-6,ss (area under the concentration time curve in plasma over the time interval from 0 
to 6 hours at steady state).

AUCτ,ss (area under the concentration-time curve in plasma at steady state over a uniform 
dosing interval τ at steady state).

Cpre,ss (pre-dose concentration in plasma at steady state).

Accumulation ratios in plasma (RA,Cmax =Cmax,ss/Cmax and RA,AUC =AUC0-6,ss/AUC0-6)
5.1.2
Secondary Endpoints
The number (%) of subjects with drug related Adverse Events will be determined as 
secondary endpoint to assess safety and tolerability of tiotropium + olodaterol fixed-dose 
combination (5 µg/ 5 µg).


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ASSESSMENT OF EFFICACY
5.2
No efficacy endpoint is defined in this trial.
ASSESSMENT OF SAFETY
5.3

All adverse events (including physical examination) until the end of study 

Vital signs: pulse rate and blood pressure (supine position) 

Routine blood chemistry, haematology and urinalysis

12-lead ECG
5.3.1
Physical examination
Physical examination will be performed according to Flow Chart. 
5.3.2
Vital Signs
Pulse rate and blood pressure will be measured and recorded. Measurements will always be 
obtained with the patient with supine position and rested for a minimum of 5 min. Preferably, 


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the same person using the same sphygmomanometer on the same (dominant) arm should 
perform all recordings. 
5.3.3
Safety laboratory parameters
Laboratory tests
Clinical laboratory testing will be conducted on all patients at the screening visit (Visit 1), at 
Visit 2 and at Visit 3& 4(or at the withdrawal visit if the patient does not complete all study 
visits). Follow-up clinical laboratory testing may be performed at Visit 5 if there are any 
clinically significant findings at Visit 4. The laboratory tests at Visit 2 will be considered as 
the baseline measurements. Patients should be instructed not to do any unaccustomed 
physical exercise 36 hours prior to laboratory testing. Haematology, blood chemistry and 
urinalysis will be conducted at trial site. Laboratory values will be recorded on the eCRF. In 
case the investigator indicates a laboratory value to be clinically significant this needs to be 
entered in eCRF as an AE.
Haematology
Haemoglobin, haematocrit, red blood cell count, white blood cell count including differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), total eosinophil count and 
platelet count.
Blood chemistry
Alkaline phosphatase, LDH, Gamma-GT, SGOT, SGPT, glucose, calcium, inorganic 
phosphorus, uric acid, urea nitrogen, creatinine, total protein, potassium, sodium, chloride, 
total bilirubin, creatin phosphokinase.
Urinalysis
Specific gravity, pH, glucose, protein, occult blood. 
Pregnancy Testing
A serum human chorionic gonadotropin (HCG) test will be performed on all females of child-
bearing potential at Visit 1. A urine dip stick pregnancy test will be performed at Visit 2, 
Visit 4 and Visit 5.
5.3.4
Electrocardiogram
The ECGs will be recorded for 10 seconds duration after the subjects have rested for at least 
5 minutes in a supine position.
Printed paper traces from 12 lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be collected 


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at screening visit, visit 2 and at the end of the trial for all subjects. In the event of any cardiac 
symptoms (i.e. suspicion of heart rhythm disorders or cardiac ischemia), an additional ECG 
will be recorded. All ECGs will be evaluated, (signed, dated and commented upon) by the 
treating physician/investigator and stored locally. Any clinically relevant changes in the ECG 
will be reported as AEs and followed up and/or treated locally until normal or stable 
condition.
For those subjects experiencing clinically relevant changes in the ECG classified as an AE, 
the ECG abnormalities will be carefully monitored and if necessary the subject will be 
removed from the trial and medically treated. All ECGs recorded during trial conduct 
including the baseline ECG will be stored at a site with other source documents.
5.3.5
Other safety parameters
Not applicable
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,


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
is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context 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.
Every new occurrence of cancer must be reported as a serious event regardless of the duration 
between discontinuation of the drug and the occurrence of the cancer.
The following events will be handled as “deemed serious for any other reason”. An AE which 
possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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 given 
above.
The latest list of “Always Serious AEs” can be found in the RDCs. These events should 
always be reported as SAEs as described in section 5.3.7.
Adverse events of special interest (AESIs)
The term 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. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 


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
an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

marked peak 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.
via the RDC-system.
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.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of signs or symptoms that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment 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.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
5.3.7
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:


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•
From signing the informed consent onwards through the Residual Effect Period 
(REP),until 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 AEs but should only
report relevant SAEs and relevant AESIs of which the investigator may become aware 
of.
•
The REP is defined as 21 days after last trial medication application. All AEs which 
occurred through the treatment phase throughout the REP will be considered as on 
treatment please see section 7.3.4.Events which occurred after the REP will be 
considered as posttreatment events.
AE reporting to 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.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drugs. The Investigator 
should determine the causal relationship to the trial medication, and any possible interactions 
between the investigational drugs and a Non-Investigational Medicinal Product (NIMP).


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The following should also be recorded as an (S)AE in the (e)CRF and 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 pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a study.  Once a subject, has been enrolled into the 
clinical trial after having taken trial medication the investigator must report any drug 
exposure during pregnancy which occurred in a female subject or in a partner to a male 
subject to the Sponsor immediately (within 24 hours) by means of Part A of the Pregnancy 
Monitoring Form to the Sponsor's unique entry point.
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). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
As far as feasible, the following pharmacokinetic parameters will be determined for 
tiotropium and olodaterol, after a single dose at Visit 2 (day 1) and after multiple dosing at


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Visit 4 (3 weeks after 1st drug administration). Single dose:

Cmax (maximum measured concentration in plasma.

tmax (time from dosing to the maximum concentration in plasma).

AUCt1-t2 (area under the concentration time curve in plasma over the time interval t1 to t2).
 
Multiple dosing
(If steady state can be reasonably assumed, the parameters will be denoted with ‘ss’ as 
shown; otherwise, they will be denoted with the dose number of the last dose):

Cmax,ss (maximum measured concentration in plasma at steady state).

tmax,ss (time from dosing to the maximum concentration in plasma at steady state).

AUCt1-t2,ss (area under the concentration time curve in plasma over the time interval t1 to 
t2 at steady state).
 

AUCτ,ss (area under the concentration-time curve in plasma at steady state over a uniform 
dosing interval τ at steady state).

MRTih,ss (mean residence time in the body after inhalation at steady state)

Cpre,ss (pre-dose concentration in plasma at steady state).
 
 
In addition, accumulation ratios in plasma (RA,Cmax and RA,AUC) will be calculated based on 
Cmax,ss/Cmax and AUCt1-t2,ss/AUCt1-t2, respectively.
Further pharmacokinetic parameters may be calculated as appropriate. Terminal half-lives
and terminal rate constants in plasma at steady state (t1/2,ss, λz,ss) will be calculated if sufficient
data points from the terminal phase are available, i.e. plasma concentrations are quantifiable
up to the 24-hour post dose sampling time point.


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For investigation of the attainment of steady state, the plasma concentrations prior to dosing 
and 20 min after dosing will be determined on days 7, 14, 18, 19, and 20 on visit 3.
See Appendix 10.1 for details derivation of pharmacokinetic parameters.
5.4.2
Methods of sample collection
Blood sampling
Date and exact clock time of administration as well as of pharmacokinetic blood sampling 
have to be recorded. A blank blood sample will be collected prior to drug administration (i.e. 
at Visit 2, 5min (± 5 min) before the trial drug administration). Blood samples shall be drawn 
as close to the planned time as possible. 
The time point zero for pharmacokinetic sampling is defined as end of (last) inhalation. Exact 
time points of plasma sampling will be documented in the eCRFs by the medical personnel. 
These actual sampling times will be used for the determination of pharmacokinetic 
parameters.
For quantification of drug plasma concentrations, about 6 mL of blood will be taken from a 
forearm vein using a blood collection tube containing potassium EDTA as anticoagulant
blood drawing tube at the times indicated in the Flow chart.
After completion of each blood drawing procedure, the indwelling catheter can be filled with 
up to 0.5 mL of sterile heparinised saline (50 IU heparin/mL 0.9% saline) in order to prevent 
clotting (per local clinical practice). Prior to every new blood drawing a small blood volume 
(approximately 0.5 mL) must be aspirated and discarded in order to avoid contamination of 
blood samples with heparin.
The EDTA-anticoagulated blood samples will be centrifuged as soon as possible after 
collection (within 40 min). Centrifugation will last for about 10 min (at about 2000 x g to 
4000 x g) at room temperature or below. Two aliquots of at least 1 mL EDTA plasma 
samples will be obtained. One aliquot is intended for analysis of olodaterol, the second 
aliquot for analysis of tiotropium. Plasma samples will be frozen within 90 min after 
sampling and stored at the study site at about -20°C or below.
Detailed instructions for shipment of plasma samples are provided in the ISF or lab manual. 
In order to avoid contamination of plasma samples, study personnel are required to wash their 
hands with soap prior to collecting the plasma or handling of plasma samples. The 
RESPIMAT inhalers should be handled with gloves on and these gloves should be changed 
and discarded as soon as any container for PK samples is touched. As soon as the plasma is 


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obtained from the blood, gloves should again be changed. Plasma vials should be stored 
closed and only opened if necessary for the procedure.
The PK procedures should NOT take place in the same room where priming of the 
RESPIMAT inhaler or drug inhalation takes place. 
Urine sampling
In order to enable a sufficient urine flow patients might be asked to drink at least 150 to 
200 mL of a non-caffeinated beverage 20 min prior to the end of each urine fraction in order 
to support a miction in time. 
At Visit 2, a blank urine sample will be collected prior to drug administration. 1 mL of a 1 
molar citric acid stock solution (21 g citric acid monohydrate in 100 mL water) is added. Two 
aliquots for PK blank samples retained to check for analytical interference (5 mL per aliquot). 
All urine voided during the sampling intervals listed in the “Timing of procedure at Visit 2”
will be collected in containers. At Visit 4, all urine voided during the sampling intervals listed 
in the “Timing of procedure at Visit 4” will be collected in containers. Urine containers will 
be stored at room temperature or below between collection time points. For urine collection, 
the weight of the empty containers has to be determined (e.g. documented on a worksheet 
and/or the container, eCRF). Then, 10 mL of a 1 molar citric acid stock solution (21 g citric 
acid monohydrate in 100 mL water) is added to each 2 L container and urine is collected over 
the collection interval. At the end of the collection interval, patients have to empty their 
bladder and the weight of the filled urine container will be determined. Urine container 
weights (i.e. tare and gross) and times of collection will be documented in the eCRFs (weight 
will be set equal to volume without correction for specific gravity of urine when calculating 
the urine volume for analysis). Two aliquots of 5 mL urine samples will be obtained.
One aliquot is intended for analysis of olodaterol, the second aliquot for analysis of 
tiotropium. Storage of urine samples at the study site will be at about -20°C or below.
Detailed instructions for shipment of urine samples are provided in the ISF.
Detailed instructions for shipment of urine samples are provided in the ISF. 
In order to avoid contamination of urine samples, study personnel are required to wash their 
hands with soap prior to collecting the urine or handling of urine samples. The RESPIMAT 
inhalers should be handled with gloves on and these gloves should be changed and discarded 
as soon as any container for urine samples is touched. Urine containers should only be stored 
closed and only opened if necessary for collection.
The handling and processing of urine samples should NOT take place in the same room 
where priming of the RESPIMAT inhaler or drug inhalation takes place.


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5.4.3
Analytical determinations
Plasma and urine concentrations of olodaterol and tiotropium will be determined by validated 
high performance liquid chromatography tandem mass spectrometric (HPLC-MS/MS) 
assays. The analyses will be performed at
and will be described in appendices to the Clinical Trial Report.
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not Applicable
ASSESSMENT OF EXPLORATORY BIOMARKERS
5.5
Not Applicable
5.5.1
Biobanking
Not Applicable
OTHER ASSESSMENTS
5.6
Not applicable
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety and tolerability aspects and to measure pharmacokinetic 
parameters in an appropriate way.
The pharmacokinetic parameters and measurements outlined in Section 5.4 are generally used 
as measurements to assess drug exposure.
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values and ECG. These endpoints are standard and accepted for 
evaluation of safety and tolerability of the drug, and they are widely used in these kinds of 
studies.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
Following the screening visit (Visit 1) and the required minimum of 2-week screening period, 
eligible patients will be entered (at Visit 2) into the 3-week open-label, treatment period
(Visits 2–4). PK measurement for single dose will be taken at visit 2 (1st day), then followed 
by a sparse PK sampling at visit 3 (days 7,14,18,19 and 20). At visit 4 (day 21), PK 
assessment will be performed for steady state.  After completion of treatment period (Visit 4), 
there will be one post-treatment follow-up visit (Visit 5).
The screening period may be extended by up to 2 weeks (i.e. total up to 4 weeks or 28 days) 
for administrative reasons. Washout of LAMA must be at least 3 weeks before treatment for 
patients who used LAMA before participation to the trial. The subsequent treatment period 
cannot be shorter than 3 weeks. Any deviant rescheduling of visits should be discussed with 
the CML and will have to be documented. See the flow chart for time windows for the visits.
Patients should make every attempt to complete the protocol as specified. Investigators 
should encourage patient treatment compliance and adherence to other protocol specific 
activities. 
Rescheduling prior to rtreatment

The 2-week screening period (between Visit 1 and Visit 2) may be extended by 2
weeks (i.e. total up to 4 weeks or 28 days) for administrative reasons. 

If the screening period is to be extended more than an additional 2 weeks, i.e. it 
exceeds 4 weeks in total, the sponsor (i.e.CML) should be contacted.
Rescheduling of Visit 4

If the patient did not take their trial medication for the 3 days preceding Visit 4, this 
visit must be rescheduled after at least 10 days continual administration. 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening and run-in period
Informed consent visit (Visit 0)

Informed consent will be obtained prior to patient participation in the trial, which 
includes any medication washout procedures or restrictions. Upon obtaining informed 
consent, the patient will be instructed on the medication washout and other restrictions 


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for the screening pulmonary function test at Visit 1.

Patients taking LAMA should discontinue the treatment more than 3 weeks prior to Visit 
2. Alternative bronchodilator medications may be introduced at the investigator’s 
discretion (See Section 4.2.2).

The patient will receive directions on the as needed use of the salbutamol MDI (as rescue 
medication) that will be dispensed at this visit.

A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid 
unnecessary washout procedures in non-eligible patients.

Upon obtaining Informed Consent, the patient will receive a trial identification card and 
a patient appointment card (visit schedule), templates will be provided by the sponsor.
Observations and procedures at Visit 1

Visit 1 will be scheduled within 28 days after signing informed consent (the period of 
time between signing informed consent and Visit 1 will depend on medication washout 
requirements).

Blood samples will be collected for haematology, serum chemistry and pregnancy 
testing (if applicable). Blood samples need to be taken prior to the salbutamol dosing.

Pulmonary function testing with the CHEST spirometer will be conducted between 
7:00 AM and 10:00 AM, 10 min prior to the inhalation and between 10 to15 min after 
the inhalation of 4 puffs of salbutamol, (reversibility testing). 

Patients qualified to enter the 2-week (up to 4-week) screening period of the trial will 
be issued additional rescue medication, if needed.

Patients will receive training and instructions on
-
the use of the RESPIMAT inhaler in using the training RESPIMAT inhaler 
containing placebo
-
the use of rescue medication (salbutamol MDI)
-
medication restrictions (i.e. washout of LAMA) for the screening period and 
subsequent visits
-
returning all issued medication and the patient medication work sheet to the 
site on all subsequent visits.
Screening Period
If there is any indication during the screening period that the patient is not stable enough to 
complete the trial or that the patient will be non-compliant with the trial medication or 
restrictions, the patient should not be treated. This evaluation should take place by the 


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investigator.
Details of any patient who is screened for the trial but is found to be ineligible must be 
entered in the Enrolment Log and documented in the eCRF.
6.2.2
Treatment periods
Visit 2
6.2.2.1

12-lead ECG will be measured before test drug administration.. 

Trial medications must be administered in an area isolated from PK sampling and 
from other patients’ administration in order to prevent any environmental 
contamination.

Urine pregnancy test and laboratory test sampling should be done before dispensing
urine for blank PK samples.

The patient should be instructed to empty the bladder prior to dosing. .

Urine sampling for PK measurement: Post-dosing urine sampling will be performed 
as indicated in the “Timing of procedure at Visit 2”.

Blood sampling for PK measurement: Blood sampling will be performed 5min (± 5
min) before the trial drug administration and post-dose at indicated in the “Timing of 
procedure at Visit 2”.

Before dosing with trial medication, site personnel should ensure that the patient 
knows how to use and inhale properly from the RESPIMAT inhaler. A training 
inhalation with placebo will be performed as indicated in the “Timing of procedure at 
Visit 2”

The patient will be issued a patient medication worksheet to record their trial 
medication use, the time of administration of trial medication as of 3 days before Visit 
3 and other concomitant therapy used between Visit 2 and 4 date. Patients will be 
instructed to return to the site with the medication worksheet at the Visit 4, so that the
medication worksheet can be collected and reviewed.
Visit 3
6.2.2.2

Trial medications must be administered in an area isolated from PK sampling and from 
other patients’ administration in order to prevent any environmental contamination.


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
Blood sampling for PK measurement: Blood sampling will be performed 15 min prior to 
trial medication administration and post-dose at indicated in the “Timing of procedure at 
Visit 3”

Three days prior to the clinic visits on days 7, 14  and 18, a telephone contact will be 
made to each patient in order to remind him/ her of the medication restrictions, the use of 
the medication worksheet and to bring their trial medication to the site at Visit 3. From 
day 18 up to the end of Visit 4, the patient will stay in the clinic.
Visit 4
6.2.2.3

Drug administration time should be within ± 5 min of the time of drug inhalation at 
Visit 2.

Trial medications must be administered in an area isolated from PK sampling and 
from other patients’ administration in order to prevent any environmental 
contamination.

Urine pregnancy test and laboratory test sampling should be done before inhalation of 
trial medication. 

Urine sampling for PK measurement: The patient should be asked to empty the 
bladder prior to dosing. Post-dosing urine sampling will be performed as indicated in 
the “Timing of procedure at Visit 4”.

Blood sampling for PK measurement: Blood sampling will be performed 15 min prior 
to trial medication administration and post-dose as indicated in the “Timing of 
procedure at Visit 4”.

12-lead ECG will be measured after last PK sampling.
Note: 
If the patient did not take one of the trial medication for the 3 days preceding day 18, this 
visit must be re-scheduled after at least 10 days continual administration. 
6.2.3
Follow Up Period and Trial Completion
Following the treatment phase of the trial, i.e. following the end of 3-week treatment period, 
patients will be followed up for an additional 3 weeks period. Patients may return to their 
regular medication after completion of Visit 4. They will be seen at the end of this period 
(Visit 5) and their AEs, concomitant therapies will be reviewed and recorded. A urine 


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pregnancy test will be performed where applicable. Dispensed rescue medication (as needed) 
must be returned. If the physical examination, vital signs or laboratory tests performed at 
Visit 4 yield abnormal values representing clinically significant changes from baseline, they
(for12-lead ECG) will be repeated at the follow-up visit (Visit 5). Any persistently abnormal 
test must be fully explained by the investigator and follow-up evaluation performed, if 
necessary. Additionally, all (S)AEs that occur within 21 days after a patient terminates trial 
medication must be reported.
The sponsor must be consulted on all persistently abnormal tests and (S)AEs until it is agreed 
that follow-up is no longer necessary.
6.2.4
Premature withdrawal 
The physical examination (including vital signs), clinical laboratory test, PK sampling and 
one 12-lead ECG will be performed following any premature withdrawal in a withdrawal 
visit at the earliest convenience. For patients who discontinue early, whether PK sampling
will be obtained or not will be determined by discussion between investigator and TCM. Any 
AEs and changes in concomitant therapies will be recorded. The current patient medication 
worksheet is to be collected. Patients should be converted to their regular medication upon 
premature withdrawal. The investigator should make every effort to perform a follow-up 
visit; 3 weeks after the withdrawal visit (please see flow chart). During follow-up period, 
rescue medication is dispensed as needed. If the physical examination, vital signs, 12-lead 
ECG, or laboratory tests performed at the withdrawal visit yield abnormal values representing 
clinically significant changes from baseline, they will be repeated at the follow-up visit (Visit 
5). 
The sponsor must be consulted on all persistently abnormal tests and (S)AEs until it is agreed 
that follow-up is no longer necessary. 


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
Design
This is an open-label trial in which 3 weeks of treatment are preceded by a 2-week screening 
period and followed by a 3-week follow-up period.
Objectives
The objectives of this trial is to assess the pharmacokinetics and safety of tiotropium + 
olodaterol FDC (5 µg/5 µg) delivered by the RESPIMAT inhaler after single dose and at 
steady state in Chinese patients with COPD.
Endpoints
No efficacy endpoint is defined in this trial. For safety and pharmacokinetic endpoints, see 
Sections 5.3 and 5.4.1, respectively.
Baseline
In general, baseline value will be defined as the last measurement before the first trial drug 
intake at Visit 2. 
NULL AND ALTERNATIVE HYPOTHESES
7.2
No efficacy endpoint is defined in the trial. It is not planned to test any statistical hypothesis 
with regard to pharmacokinetic and safety endpoints.
PLANNED ANALYSES
7.3
7.3.1
Primary endpoint analyses
See Sections 7.3.5 for pharmacokinetic analyses which are the primary objectives of this trial.
7.3.2
Secondary endpoint analyses
See Sections 7.3.4 for safety analyses which are the secondary objectives of this trial.


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 21 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.
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.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’.  Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
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).
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 highlighted in the 
listings.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, 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.
7.3.5
Pharmacokinetic analyses
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. Only concentrations within the validated concentration range will be 
used for the calculation of PK parameters.
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the 


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drug plasma concentration-time tables. For the presentation of the mean profiles the 
arithmetic mean and the planned blood sampling times will be used.
The following descriptive statistics will be calculated for plasma concentrations as well as for 
all PK parameters: N, arithmetic mean, standard deviation, minimum, median, maximum, 
arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. 
The descriptive statistics of PK parameters will be calculated using the individual values with 
the number of decimal places as provided by the evaluation program. Then the individual 
values as well as the descriptive statistics will be reported with three significant digits in the 
CTR.
Time to attainment of steady-state will be explored by repeated-measurement ANOVA model 
through pairwise comparing trough concentrations and concentrations at 20 min after drug 
administration on days 1, 7, 14, 18-21. The model will be on logarithm scale including 
“subject” as a fixed effect and “time” as a repeated effect.
INTERIM ANALYSES
7.4
No interim analyse is planned.
HANDLING OF MISSING DATA
7.5
7.5.1
Plasma concentration - time profiles
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not 
analysed), BLQ (below the limit of quantification) will be ignored and not replaced by zero at 
any time point (applies also to the lag phase including the pre-dose value). Descriptive 
statistics of concentrations at specific time points will be calculated only when at least 2/3 of 
the individuals have concentrations within the validated concentration range. The overall 
sample size to decide whether the “2/3 rule” is fulfilled will be based on the total number of 
samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, NOA are included).
Every effort will be made to include all concentration data in an analysis. If not possible a 
case by case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis.

If a concentration is only excluded from half life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.


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
If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However, the excluded concentration itself will be listed in the tables in 
the CTR associated with an appropriate flag.
7.5.2
Pharmacokinetic parameters
In the non-compartmental analysis concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ values in the lag-phase will be set to zero. The lag phase is 
defined as the period between time zero and the first time point with a concentration above 
the quantification limit. All other BLQ values of the profile will be ignored.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).
7.5.3
Safety
It is not planned to impute missing values for safety data, except for missing or incomplete 
AE dates. Missing or incomplete AE dates will be imputed according to BI standards.
RANDOMISATION
7.6
Not applicable
DETERMINATION OF SAMPLE SIZE
7.7
The sample size is not determined based on formal calculation since this is a study for 
assessing PK and safety. The size of 12 patients is commonly used in multiple dose Phase I 
trial of this type. Assuming a dropout rate of 25%, 4 more patients will be needed. Thus, at 
least 16 patients are planned to be entered into the trial. Should the drop-out rate raise over 
25%, additional patients will be entered to reach the target of 12 evaluable patients.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
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 Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and 
relevant regulations*.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
The rights of the investigator/ trial site and of the sponsor with regard to publication of the 
results of this trial are described in the investigator contract/trial site’s contract. As a general 
rule, no trial results should be published prior to finalisation of the CTR.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
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 and international 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 of the participating country. 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 must give a full explanation to trial patients including the items listed below 
in association with the use of the patient information form, which is prepared avoiding the 
use of technical terms and expressions. The patient is given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 


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The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
DATA QUALITY ASSURANCE
8.2
This trial will be conducted in accordance with the ICH-GCP guidelines, local regulations 
and BI SOPs. 
In order to achieve a high level of standardised processes, data collection of PK will be 
coordinated centrally.
A laboratory at site will be used to collect, analyse and report the results of all blood samples 
and cultures. The site laboratory need to be certified.
Training will be provided to all investigators, coordinators and CRAs to ensure consistency 
and accuracy of the data. The data will be source verified by the CRAs. 
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 TMF.
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (e)CRF for individual patients will be provided by the Sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.


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For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all eCRF, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source documents and essential documents for a period defined 
by the GCP regulation and trial site’s contract with the sponsor.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For the 5 μg tiotropium inhalation solution this is the current version of the Investigator’s 
Brochure [U06-3029]. For the 5 μg olodaterol inhalation solution this is the current version of 
the Investigator’s Brochure [U06-3029]. For the FDC of tiotropium and olodaterol this is the 
current version of the Investigator’s Brochure [U06-3029]. For the non-investigational 
medicinal product salbutamol the reference document is the US-PI (Proair HFA) and for the 
non-investigational medicinal product ipratropium bromide, the reference document is the 
UK-SPC (Atrovent Inhaler CFC-Free).  The current versions of these reference documents 


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are to be provided in the ISF. No AEs are classified as listed for matching placebo (for 
training purposes only), study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
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 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.
END OF TRIAL
8.6
The end of the trial is defined as all subjects finished visit 5 or follow the agreement between 
sponsor and investigator.
PROTOCOL VIOLATIONS
8.7
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the Sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P94-01346
Bone R, et al. In chronic obstructive pulmonary disease, a combination of 
ipratropium and albuterol is more effective than either agent alone:  an 85-day 
multicenter trial. Chest 105 (5), 1411-1419 (1994).
P01-02794
Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS. Global strategy 
for the diagnosis, management, and prevention of chronic obstructive 
pulmonary diseaese: NHLBI/WHO Global Initiative for Chronic Obstructive  
Lung Disease (GOLD) workshop summary. Am J. Respir Crit Care Med 
2001:163 (5):1256-1276
P04-07409
Celli BR, MacNee W. Standards for the diagnosis and treatment of patients 
with COPD:  a summary of the ATS/ERS position paper. Eur Respir J 23(6), 
932-946 (2004).
P05-08465
Hodder R, Pavia D, Dewberry H, Alexander K, Iacono P, Ponitz H, Beck E. 
Low incidence of paradoxical bronchoconstriction in asthma and COPD 
patientsduring chronic use of Respimat Soft Mist inhaler. Respir Med 2005;
99:1087-1095.
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et 
al.Standardisation of spirometry. Eur Respir J 2005;26(2):319-338.
P11-05865
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease: updated 2010. Website: goldcopd.com.
R94-1408
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. 
Lung volumes and forced ventilatory flows. Report Working Party 
Standardization of Lung Function Tests, European Community for Steel and 
Coal. Official Statement of the European Respiratory Society. Eur Respir J 
1993; 6(Suppl 16):5-40.


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R04-4303
Foradil Aerolizer (Schering) (formoterol fumarate inhalation powder), Rx only 
(rev. June 2003). Website: pdrel.thomsonhc.com; In: PDR Electronic Library. 
Thomson; 2004. 
R04-4304
Rote Liste Win 2003/II, Version 3.2, Editio Cantor, Freigabedatum: 
01.07.2003; 2003.
R04-4305
Rote Liste Win 2003/II, Version 3.2, Editio Cantor, Freigabedatum: 
01.07.2003; 2003
R10-5669
ICH harmonised tripartite guideline: maintenance of the ICH guideline on 
non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals M3
(R2) (Current step 4 version, 11 June 2009)
UNPUBLISHED REFERENCES
9.2
U06-3029
Investigator's Brochure 1237.P1 07-Aug-2012
U08-2169
Clinical trial report: Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising inhalative doses (2 mcg/5 mcg, 10 
mcg/5 mcg, and 40 mcg/10 mcg) of BI 1744 CL in fixed dose combination 
with Tiotropium Bromide for 14 days in healthy male volunteers (double-
blind, randomised, placebo controlled [at each dose level] study 1237.2 18 
November 2008
U08-1543
 A double-blind, randomised, placebo 
controlled, six-way crossover study including an open-label positive control 
(moxifloxacin) to assess the influence of via Respimat inhaled BI 1744 CL 
(single doses of 10 µg, 20 µg, 30 µg and 50 µg) on the QT/QTc interval of the 
ECG in healthy male and female volunteers. (1222.8) 03 June 2008. Revised 
08 December 2010.


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10.
APPENDICES
PHARMACOKINETIC METHODS 
10.1
Concentrations will be used for calculations in the format that is reported in the bioanalytical 
report. The data format for descriptive statistics of concentrations will be identical with the 
data format of the respective concentrations. For the calculation of PK parameters, only 
concentrations within the validated concentration range will be used. The descriptive 
statistics of PK parameters will be calculated using the individual values with the number of 
decimal places as provided by the evaluation program. Then the individual values as well as 
the descriptive statistics will be reported with three significant digits in the CTR. The actual 
sampling times will be used. For pre-dose samples, the actual sampling time will be set to 
zero. Noncompartmental PK parameters will be determined using WinNonlin or another 
validated program.
Analyte plasma concentrations will be plotted graphically versus time for all subjects as listed 
in the analyte plasma concentration-time tables. For the presentation of the mean profiles, the 
arithmetic mean and the planned blood sampling times will be used.
Individual Cmax(,ss) and tmax(,ss) values will be directly determined from the plasma 
concentration time profiles of each subject. If the same Cmax(ss) concentration occurs at 
different time points, tmax(,ss) is assigned to the first occurrence of Cmax(,ss).
AUC: The area under the curve will be calculated using the linear up/log down algorithm. If 
an analyte concentration is equal to or higher than the preceding concentration, the linear 
trapezoidal method will be used. If the analyte concentration is smaller than the preceding 
concentration, the logarithmic method will be used.
Linear trapezoidal rule (t2 > t1 and Ct2 Ct1):
The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed 
by:



t2
t1
1
2
t2
-
t1
C
C
t
t
0.5
AUC





Logarithmic trapezoid rule (t2 > t1 and Ct2 < Ct1):
The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed 
by:





t1
t2
t1
t2
1
2
t2
t1
/C
C
ln
C
C
t
t
AUC





MRTih,ss: MRTih,ss calculation in the steady state will be performed according to the


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following equation:
,ss
ss
ih,ss
AUC
AUMC
MRT


AUMCss is the area under the first moment curve at steady state.

 
 
 
 
 

RA,Cmax and RA,AUC: Accumulation ratios are derived as follows for the respective doses:
max
max,ss
Cmax
A,
C
C
R

t2
-
t1
ss
t2,
-
t1
AUC
A,
AUC
AUC
R

gMean, gCV: The geometric mean (gMean) and coefficient of variation, gCV (given in %), 
will be calculated by the formulae:

)
ln(x
exp
)
ln(x
exp
gMean
i
n
1
i
i
n
1









1
))
Var(ln(x
exp
100
gCV(%)
i



where


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

2
n
1
i
i
i
i
)
ln(x
)
ln(x
1
n
1
))
Var(ln(x





THE RESPIMAT INHALER
10.2
Instructions for Use
RESPIMAT inhaler
How to use your RESPIMAT® inhaler
This leaflet explains how to use and care for your RESPIMAT® inhaler. Please read and 
carefully follow these instructions.
The RESPIMAT® inhaler releases medication slowly and gently, making it easy to inhale it 
into your lungs.
The RESPIMAT® inhaler enables you to inhale the medicine contained in a cartridge. You 
will need to use this inhaler only ONCE A DAY. Each time you use it take 2 PUFFS. In the 
box you will find the RESPIMAT® inhaler and the RESPIMAT® cartridge. Before the 
RESPIMAT ® inhaler is used for the first time, the cartridge provided must be inserted.


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RESPIMAT® inhaler and the RESPIMAT® cartridge
Inserting the cartridge and preparation for use 
The following steps 1-6 are necessary before first use:
1
1
With the grey cap closed, press the safety catch (E) and 
pull off the clear base (G).
2a
2
Take the cartridge (H) out of the box. Push the narrow end of 
the cartridge into the inhaler until it clicks into place (2a). The 
cartridge should be pushed gently against a firm surface to 
ensure that it has gone all the way in (2b).
Do not remove the cartridge once it has been inserted into the 
inhaler.
Safety catch


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2b
3
3
Replace the clear base (G). 
Do not remove the clear base again.


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To prepare the RESPIMAT® inhaler for first-time use
4
4
Hold RESPIMAT® inhaler upright, with the grey cap (A) 
closed. Turn the clear base (G) in the direction of the red 
arrows on the label until it clicks (half a turn).
5
5
Open the grey cap (A) until it snaps fully open.
6
6
Point the RESPIMAT® inhaler towards the ground. 
Press the dose release button (D). Close the grey cap (A).
Repeat steps 4, 5 and 6 until a cloud is visible. 
Then repeat steps 4, 5 and 6 three more times to ensure the 
inhaler is prepared for use. 
Your RESPIMAT® inhaler is now ready to use.  
These steps will not affect the number of doses available. After 
preparation your RESPIMAT® inhaler will be able to deliver 
60 puffs.
Using the RESPIMAT® inhaler
You will need to use this inhaler only ONCE A DAY. 
Each time you use it take 2 PUFFS.


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I
I
Hold RESPIMAT® inhaler upright, with the grey cap (A) 
closed, to avoid accidental release of dose. Turn the clear base 
(G) in the direction of the red arrows on the label until it clicks 
(half a turn).
II
II
Open the grey cap (A) until it snaps fully open. Breathe out 
slowly and fully, and then close your lips around the end of the 
mouthpiece without covering the air vents (C). Point your 
RESPIMAT® inhaler to the back of your throat.  
While taking in a slow, deep breath through your mouth, press 
the dose release button (D) and continue to breathe in slowly 
for as long as you can. Hold your breath for 10 seconds or for 
as long as comfortable.
III
Repeat steps I and II so that you get the full dose.
You will need to use this inhaler only ONCE A DAY.
Close the grey cap until you use your RESPIMAT® inhaler 
again.
If the RESPIMAT® inhaler has not been used for more than 3 days 
release one puff towards the ground. If the RESPIMAT® inhaler has not 
been used for more than 21 days repeat steps 4 to 6 until a cloud is 
visible. Then repeat steps 4 to 6 three more times.
When to get a new RESPIMAT® inhaler
The RESPIMAT® inhaler contains 60 puffs (30 doses). The dose 
indicator shows approximately how many doses are left. When the 
pointer enters the red area of the scale, there is, approximately, 
medication for 14 puffs (7 days) left.  
Once the dose indicator has reached the end of the red scale (i.e., all 30
doses have been used), the RESPIMAT® inhaler is empty and locks 
automatically. At this point, the base cannot be turned any further. 
What if...


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What if...
Reason
What to do
I can’t turn the base easily.
a) 
The RESPIMAT®
inhaler is already prepared 
and ready to use. 
b) 
The RESPIMAT®
inhaler is locked after 60 
puffs (30 doses).
a) 
The RESPIMAT®
inhaler can be used as it is.
b) 
Prepare and use your 
new RESPIMAT® inhaler.
I can’t press the dose release 
button.
The clear base has not been 
turned.
Turn the clear base until it 
clicks. (half a turn)
The clear base springs back 
after I have turned it.
The clear base was not 
turned far enough.
Prepare the RESPIMAT®
inhaler for use by turning the 
clear base until it clicks. 
(half a turn)
I can turn the clear base past 
the point where it clicks.
Either the dose release button 
has been pressed, or the clear 
base has been turned too far.
With the grey cap closed, 
turn the base until it clicks. 
(half a turn) 
How to care for your inhaler
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 the performance of your 
RESPIMAT® inhaler.
If necessary, wipe the outside of your RESPIMAT inhaler with a damp cloth.
Further information
The RESPIMAT® inhaler must not be disassembled after inserting the cartridge and replacing 
the clear base.
Do not touch the piercing element inside the base.
Keep out of the reach and sight of children.
Do not freeze.
Boehringer Ingelheim Pharma GmbH & Co. KG


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D - 55216 Ingelheim, Germany
  0123 HI-Master-Version-04-BI 1744 + tiotropium combination-Respimat-20090831
RETURN OF INHALERS/CARTRIDGES
10.3
Return of Malfunctioning RESPIMAT inhalers
RESPIMAT inhalers, with the used cartridge in situ, that appeared to malfunction, will be returned 
to Boehringer Ingelheim Int’l Trading (Shanghai) Co., Ltd by responsible CRA as soon as possible.  
The following information should be included in malfunction report form when the inhaler is 
returned:
a)
Medication number
b)
Visit number
c)
Date of malfunction
d)
Description of malfunction and cause of malfunction (if known)
e)
Person identifying malfunction
f)
Trial number 
Investigator’s name/center number
The original version of the Returned Inhaler Form should be included with the returned 
inhaler. A copy should be filed in Section 4 of ISF.
All inhalers and cartridges should be wrapped in bubble wrap or a similar packing material, 
placed in a secure shipping box (not a packing envelope) and shipped. Any questions 
regarding shipping and handling should be directed to the CML.
ADDITIONAL INFORMATION REGARDING IN/ EX CRITERIA
10.4
FEV1 and FVC - Pulmonary Function Testing
The qualifying pulmonary function tests (FEV1 and FVC) will be conducted at the screening 
visit (Visit 1) for reviewing eligibility of the patient.
Spirometers and their use, including daily calibration, must meet ATS/ERS criteria [P05-
12782]. Spirometry will be conducted with the patient in a seated position and it is preferable 
that the same trained individual performs the PFTs for a given patient. At each time point, 
spirometric maneuvers will be conducted in triplicate. The highest FEV1 and FVC from an 
acceptable maneuver will be recorded regardless of whether they come from different 
spirometric maneuvers or from the same maneuver. The 24-hour clock time of the first 
maneuver for each PFT time point will be recorded.


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Reversibility testing [P05-12782]
At the screening visit (Visit 1), following the completion of 3 acceptable pre-bronchodilator 
forced expiratory manoeuvres, salbutamol will be administered to each patient in order to 
document the degree of reversibility. Immediately after (within 10 min) pre-bronchodilator 
forced expiratory manoeuvres and after a gentle and incomplete expiration, a dose of 100 μg 
of salbutamol is inhaled in 1 breath to total lung capacity (TLC). The breath is then held for 
5-10 s before the subject exhales. Four separate doses (total dose 400 μg) are delivered at 
approximately 30-s intervals (this dose ensures that the response is high on the salbutamol 
dose-response curve). Three additional, acceptable post-bronchodilator forced expiratory 
manoeuvre tests are recorded ≥10 min and up to 15 min later after the last dose of salbutamol 
is inhaled.
Calculation of predicted normal values according to ECSC [R94-1408]
For height measured in inches
Males: FEV1 predicted (L) = 4.30 x [height (inches)/39.37] - 0.029 x [age (yrs)] - 2.49
Females:
FEV1 predicted (L) = 3.95 x [height (inches)/39.37] - 0.025 x [age (yrs)] - 2.60
For height measured in meters
Males: FEV1 predicted (L) = 4.30 x [height (m)] - 0.029 x [age (yrs)] - 2.49
Females:
FEV1 predicted (L) = 3.95 x [height (m)] - 0.025 x [age (yrs)] - 2.60
Ethnic adjustments may be made as appropriate as per ATS/ERS recommendations (R94-
1408).
Calculation of number of pack years
Pack years =
Number of cigarettes/day
x years of smoking
20


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Trial Protocol
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11.
DESCRIPTION OF GLOBAL AMENDMENT
Number of global amendment
1
Date of CTP revision
13 Jul 2016
EudraCT number
NA
BI Trial number
1237.30
BI Investigational Products
Tiotropium+olodaterol RESPIMAT solution for 
inhalation. Olodaterol RESPIMAT solution for 
inhalation
Title of protocol
An open-label trial to assess pharmacokinetics and 
safety of tiotropium + olodaterol fixed-dose 
combination (5 µg/ 5 µg) and olodaterol 5µg
delivered by the RESPIMAT inhaler after single 
and multiple dose treatment in Chinese patients 
with Chronic Obstructive Pulmonary Disease 
(COPD)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis  
Description of change
Was changed to :
Rationale for change
Site was changed


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Section to be changed
Synopsis  and section 3.3.1 Main diagnosis for trial 
entry
Description of change
‘approximately  sex ratio: 1:1’
was changed to 
‘at least 1/3 of each gender’
Rationale for change
To meet the lowest criteria of CFDA 
Section to be changed
4.1.2 Method of assigning patients to treatment 
groups
Description of change
‘Note that the medication number is same with the 
patient number (the latter is assigned at trial entry)’
was changed to 
‘Note that the medication number is different from
the patient number (the latter is assigned at trial 
entry)’
Rationale for change
As in patients trial eCRF will collect screening 
failure patients data, this process can’t guarantee 
the patient number and medication number are 
same
Section to be changed
5.4.2 Methods of sample collection
The 4th paragraph
Description of change
‘After completion of each blood drawing 
procedure, the indwelling catheter can be filled 
with up to 0.5 mL of sterile heparinised saline 
(50 IU heparin/mL 0.9% saline) in order to prevent 
clotting.
’ was changed to
‘After completion of each blood drawing 
procedure, the indwelling catheter maybe filled 
with up to 0.5 mL of sterile heparinised saline 
(50 IU heparin/mL 0.9% saline) if necessary to
prevent clotting.’
Rationale for change
To maintain flexible for action of prevent clotting. 


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Number of global amendment
2
Date of CTP revision
20 Feb 2017
EudraCT number
NA
BI Trial number
1237.30
BI Investigational Products
Tiotropium+olodaterol RESPIMAT solution for 
inhalation. Olodaterol RESPIMAT solution for 
inhalation
Title of protocol
An open-label trial to assess pharmacokinetics and 
safety of tiotropium + olodaterol fixed-dose 
combination (5 µg/ 5 µg) and olodaterol 5µg
delivered by the RESPIMAT inhaler after single 
and multiple dose treatment in Chinese patients 
with Chronic Obstructive Pulmonary Disease 
(COPD)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis  and section 3.3.1 Main diagnosis for trial 
entry
Description of change
‘at least 1/3 of each gender’
was deleted 
Rationale for change
According to experience of Japanese Phase II trial 
and PI , It is almost impossible to recruit 1/3 
female patient  
Section to be changed
Synopsis,section 1-7
Description of change
‘and olodaterol 5µg ’ was deleted
Rationale for change
Olodaterol 5µg treatment group is unnecessary for 
NDA application.


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Section to be changed
Section 6.2.2.1
Description of change
‘15 min prior to the training administration of 
placebo’
was changed to 
‘5min (± 5 min) before the trial drug 
administration’
Rationale for change
To Keep consistent with Flow Chart and section 
5.4.2
Section to be changed
Synopsis,section 3.3.1 and 7.7
Description of change
‘32 (at least 24 completed)’ was changed to ‘16 (at 
least 12 completed)’
‘trial could be ended in case 12 evaluable patients
are available’
Rationale for change
Olodaterol 5µg treatment group is unnecessary for 
NDA application.
Section to be changed
Flow Chart, Section 3.1 and  4
Description of change
‘The first 16 recruited patients will be assigned to 
the olodaterol treatment and the other patients will 
be assigned to tiotropium + olodaterol FDC
treatment’ was deleted
Rationale for change
Olodaterol 5µg treatment group is unnecessary for 
NDA application.
Section to be changed
Section 7.4
Description of change
’To support new drug submission for olodaterol in 
China and to fulfil the timeline requirement by 
CFDA, the database will be locked after the last 
patient in olodaterol treatment group 
completes/withdraws from the trial. Interim 
analyses will be performed including all the 
planned analyses on pharmacokinetic and safety 
endpoints for patients treated by olodaterol. This 
will be the basis of the primary clinical trial report 


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and submission to regulatory agencies. A final 
database lock will be done once the last patient 
treated with tiotropium+olodaterol FDC completes 
the extended follow-up visit. The final clinical trial 
report will include analysis results of all patients in 
both treatment groups.’
Was changed to
‘No interim analyses is planned.’
Rationale for change
Olodaterol 5µg treatment group is unnecessary for 
NDA application.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c07779972
3.0
clinical-trial-protocol-version-03
An open-label trial to assess pharmacokinetics and safety of tiotropium + olodaterol
fixed-dose combination (5 µg/ 5 µg) delivered by the RESPIMAT inhaler after single
and multiple dose treatment in Chinese patients with Chronic Obstructive Pulmonary
Disease (COPD)
Approval-Clinical Pharmacokinetics
20 Feb 2017 09:40 CET
Approval-Team Member Medicine
20 Feb 2017 20:41 CET
Approval–Clinical Monitor
21 Feb 2017 03:17 CET
Approval-Team Member Medicine
21 Feb 2017 05:56 CET
Approval-Biostatistics
21 Feb 2017 14:45 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c07779972
3.0

SAP_001.pdf: 
ABCD
Trial Statistical Analysis Plan
c16258258-02
BI Trial No.:
1237.30
Title:
An open-label trial to assess pharmacokinetics and safety of 
tiotropium + olodaterol fixed-dose combination (5 µg/ 5 µg)
delivered by the RESPIMAT inhaler after single and multiple dose 
treatment in Chinese patients with Chronic Obstructive Pulmonary 
Disease (COPD)
Including Protocol Amendment 2 [c07779972-03]
Investigational
Product:
Tiotropium + olodaterol fixed-dose combination solution for 
inhalation - RESPIMAT
Responsible trial 
statistician:
Phone: 
, Fax: 
Date of statistical 
analysis plan:
30 JUN 2017 SIGNED
Version:
Final
Page 1 of 18
Proprietary confidential information
2017 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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1.
TABLE OF CONTENTS
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 ..........................................................................................8
5.1
PRIMARY ENDPOINTS....................................................................................8
5.2
SECONDARY ENDPOINTS..............................................................................8
.................................................................................8
5.4
OTHER VARIABLES.........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS.............................................9
6.1
TREATMENTS....................................................................................................9
6.2
IMPORTANT PROTOCOL VIOLATIONS ....................................................9
6.3
PATIENT SETS ANALYSED..........................................................................12
6.4
SUBGROUPS .....................................................................................................12
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 ENDPOINTS..................................................................................13
7.5
SECONDARY ENDPOINTS............................................................................13
...............................................................................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.......................................................................................................15
7.8.4
ECG ................................................................................................................15
7.8.5
Others .............................................................................................................15
7.9
PK ANALYSIS...................................................................................................15
8.
REFERENCES.....................................................................................16
9.
ADDITIONAL SECTIONS ................................................................17
10.
HISTORY TABLE...............................................................................18


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LIST OF TABLES
Table 6.2: 1   Important protocol violations ............................................................................10
Table 10: 1  History table........................................................................................................18


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse event
BAC
Benzalkonium chloride
BI
Boehringer Ingelheim
bpm
beats per minute
COPD
Chronic Obstructive Pulmonary Disease
CTP
Clinical Trial Protocol
DBL
Database lock
ECG
Electrocardiogram
ECSC
European Community for Steel and Coal
EDTA
Ethylene diaminete taacetic acid
EX
Exclusion criterion
FEV1
Forced expiratory volume in one second
FVC
Forced vital capacity
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HR
Heart rate
ICF
Informed consent form
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
ms
milliseconds
O*C
Oracle Clinical
PK
Pharmacokinetics
PR interval
The ECG interval from the start of the P wave to the start of the 
QRS complex
PT
Preferred term
PV
Protocol violation
QRS complex
Combination of Q wave, R wave, and S wave
QT interval
The ECG interval from the start of the QRS complex to the end of 
the T wave


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Term
Definition / description
QTc interval
QT interval, heart rate corrected
QTcF interval
QT interval, corrected according to Fridericias formula
RPM
Report planning meeting
RR interval
The ECG interval from the peak of the R wave to the peak of the 
subsequent R wave
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System organ class
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9, 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 trial statistical analysis plan (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, randomisation.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There has been no change in the planned analyses from the statistical methods described in 
the CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
No efficacy endpoint is defined for this trial. The objective of this trial is to assess the 
pharmacokinetics (PK) and safety of tiotropium + olodaterol fixed dose combination (5 µg/ 
5 µg). The primary endpoints are specified as defined in the CTP, Sections 5.1.1.
5.2
SECONDARY ENDPOINTS
The secondary endpoints are specified as defined in the CTP, Sections 5.1.2.
5.4
OTHER VARIABLES
Demographic data:

Gender: Male, Female

Age [years]

Race

Height [cm]

Weight [kg]

Body mass index [kg/m2]

Smoking status: Never smoked, Ex-smoker, Currently smokes

Smoking history [pack years]
History of trial indication:

Trial diagnosis duration [days]
Treatment compliance:
Compliance [%] = (number of actual administered days) / (date of last trial drug 
administration – date of first trial drug administration + 1) × 100
Treatment exposure:
Extent of exposure [days] = date of last trial drug administration – date of first trial drug 
administration + 1 day
Pharmacokinetic:
The derivation of standard pharmacokinetic parameters will be performed according to 001-
MCS-36-472 (1).


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Analysing treatments will be used for safety analysis. Date from the first trial drug intake up 
to 21 days after the last trial drug intake will be considered as on-treatment.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Table 6.2: 1 gives the important protocol violations (PVs) for this trial. Patients with 
important PVs relevant to the evaluation of PK will be excluded from PK analysis. If data 
shows other important PVs, this table will be supplemented accordingly at the Database lock 
(DBL) meeting at latest.


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Table 6.2: 1   Important protocol violations
Category / 
Code
Description
Comment/Example
Excluded 
from
A
Entrance criteria not met
A1
Respiratory conditions
A1.1
Without diagnosis of COPD
IN 2 not met
Detected manually
None
A1.2
Age<40
IN 3 not met
Detected manually
None
A1.3
Never smoke or ex-smokers with a 
smoking history of less than 10 packs 
year
IN 4 not met
Detected automatically
None
A1.4
Patients are not capable to enter the trial
IN 5 not met
Detected manually
None
A1.5
Patients are unable to inhale medication
IN 6 not met
Detected manually
None
A1.6
Women of childbearing potential but are 
unable to use effective methods in birth 
control
IN 7 not met or EX 23 met
Detected manually
None
A2
Exclusion criteria met
A2.1
With significant disease other than 
COPD
EX1
Detected manually
None
A2.2
With clinically relevant abnormal 
baseline haematology, blood chemistry, 
or urinalysis
EX2
Detected manually
Detected automatically for 
SGOT, SGPT, bilirubin, 
creatinine
None
A2.3
With asthma
EX3
Detected manually
None
A2.4
Patients are under conditions specified in 
exclusion criteria 4-14
EX4-14
Detected manually
None
A2.5
Have undergone thoracotomy with 
pulmonary resection
EX15
Detected manually
None
A2.6
Treated with any oral β-adrenergics
EX16
Detected manually
None
A2.7
Treated with oral corticosteroid 
medication at unstable dose
EX17
Detected manually
None
A2.8
Regularly use daytime oxygen therapy
EX18
Detected manually
None
A2.9
Completed a pulmonary  rehabilitation 
program in the six weeks prior to visit 1 
or currently in the program
EX19
Detected manually
None
A2.10
Insufficient wash-out period
EX20
Detected manually
None


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Category / 
Code
Description
Comment/Example
Excluded 
from
A2.11
Hypersensitivity toβ-adrenergics and/or 
anticholinergic drugs, BAC, EDTA or 
any other component of the RESPIMAT 
inhalation solution
EX21
Detected manually
None
A2.12
Pregnant or nursing women
EX22
Detected manually
None
A2.13
Patients who were in this study or are 
currently participating another study
EX24
Detected manually
None
A2.14
Patients who are unable to comply with 
pulmonary medication restrictions prior 
to allocation
EX25
Detected manually
None
B
Informed consent
B1
Informed consent not available/not done
Informed consent date missing. 
No signature on ICF
Detected automatically/manually
All
B2
Informed consent too late
Date of informed consent was 
after the date of any study-related 
procedure. If date of informed 
consent equals to date of Visit 1, 
such cases will be discussed at 
MQRM/RPM/DBL meetings.
Detected automatically/manually
None
C
Trial medication and randomisation
C1
Study medication taken >2 weeks longer 
than planned
Study medication was 
documented to be taken for >5 
weeks
Detected automatically
case by 
case 
discussio
n before 
DBL if 
fraudulent 
data 
detected
C2
Serious non-compliance as reported in 
monitoring report
Detected manually
None
D
Concomitant Medication
D1
Prohibited medication use during study
Review concomitant therapies
Detected manually.
None
E
Incorrect timing
E1
Incorrect timing – visit
Only for PK endpoints
Detected manually
PK set
E2
Incorrect timing – examination
Only for PK endpoints
Detected manually
PK set
KEY:
EX = exclusion criterion, SGOT = serum glutamic oxaloacetic transaminase, SGPT = serum glutamic pyruvic 
transaminase, BAC = benzalkonium chloride, EDTA = ethylene diaminete taacetic acid, ICF = informed consent 
form, MQRM = medical quality review meeting, RPM = report planning meeting


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6.3
PATIENT SETS ANALYSED

Treated set:
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.

PK set:
This patient set includes all patients in the treated set with at least one evaluable PK 
parameter in the treatment period. The patients with important PVs related to PK will 
be excluded from PK set.
6.4
SUBGROUPS
No subgroup is defined in this trial.
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing safety data will not be imputed with the exception of missing adverse event (AE)
dates which will be imputed according to Boehringer Ingelheim (BI) standards (see 
“Handling of missing and incomplete AE dates”). (2)
Missing data and outliers of PK data are handled according to 001-MCS-36-472, RD-01 (1)
(6).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The definition of baseline values is described in the CTP, Section 7.1 ‘STATISTICAL 
DESIGN – MODEL’.


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7.
PLANNED ANALYSIS
Non-pharmacokinetic variables:
For End-Of-Text tables, the set of summary statistics is: N / Mean / SD / Minimum / Median 
/ 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 (%) (unless 
otherwise specified, all patients in the respective patient set whether they have non-missing 
values or not). Percentages will be rounded to one decimal place. The category missing will 
be displayed only if there are actually missing values.
Pharmacokinetic variables:
For all pharmacokinetic tables, the set of descriptive statistics is: N (number of subjects with 
nonmissing values) / Mean / geometric mean (gMean) / SD / coefficient of variation (CV) / 
geometric coefficient of variation (gCV) / Min / 10th percentile (P10) / Q1 (lower quartile) / 
Median / Q3 (upper quartile) / 90th percentile (P90) / Max.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. COPD background
characteristics will be listed only.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded similarly as the AEs based on the most recent version of 
Medical Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be 
coded according to the most recent version of World Health Organization Drug Dictionary.
Only descriptive statistics are planned for this section of the report.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINTS
No efficacy endpoint is defined in this trial.
Primary pharmacokinetic endpoints will be analysed as described in Sections 7.9.
7.5
SECONDARY ENDPOINTS
See Section 7.8 for safety analyses which are the secondary objectives of this trial.


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7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature and will be based on BI standards (see 
‘Handling and summarisation of adverse event data for clinical trial reports and integrated 
summaries’) (3). All analyses of AEs will be based on the number of patients with AEs (not 
the number of AEs).
For analysis of AE attributes such as duration, severity, etc. multiple AE occurrence data on 
the Case Report Form, will be collapsed into AE episodes provided that all of the following 
applies:
•
The same MedDRA lowest level term was reported for the occurrences
•
The occurrences were 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
For further details on summarization of AE data, please refer the BI guidelines. (2), (3).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs occurring between first drug intake till 21 days after last drug intake will be 
assigned to the treatment. All AEs occurring before first drug intake will be assigned to 
‘screening’ and all AEs occurring after last drug intake + 21 days will be assigned to ‘follow-
up’ (for listings only). 
According to ICH E3 (4), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant AEs with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting (MQRM).


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An overall summary of AEs will be presented.
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for patients with other 
significant AEs according to ICH E3 (4), for patients with AEs leading to death, for patients 
with AEs leading to treatment discontinuation, for patients with AEs of special interest, for 
patients with serious AEs, for patients with related serious AEs, and for patients with drug-
related AEs. The frequency of patients with AEs will also be summarised by intensity,
treatment, primary SOC and PT.
The SOCs will be sorted according to the standard sort order specified by European 
Medicines Agency. PTs will be sorted by frequency (within SOC).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (5).
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Not applicable as ECG measurement data are not collected in this study.
7.8.5
Others
Not applicable since no other endpoint was planned.
7.9
PK ANALYSIS
The analysis of standard PK parameters will be performed according to 001-MCS-36-472 
RD-01 (6), and also as described in CTP Section 7.3.


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8.
REFERENCES
1
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", version
1.0; IDEA for CON.
3
001-MCG-156: “Handling and summarization of adverse event data for clinical 
trial reports and integrated summaries”, version 5.0; IDEA for CON.
4
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.
5
001-MCG-157: “Display and Analysis of Laboratory Data”, current version, IDEA 
for CON.
6
001-MCS-36-472 RD-01: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; IDEA for CON.


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9.
ADDITIONAL SECTIONS
Not applicable as no additional information is needed.


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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
01-Mar-2017
None
This is the initial TSAP with necessary 
information for trial conduct
Final
30-Jun-2017
None
This is the final TSAP