Clinical trial NCT03151499
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-05-30; Completion date: 2017-07-11
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this trial is to investigate the relative bioavailability of BI 409306 tablets with prior 7-day intake of rifampicin tablets (Test, T) compared to BI 409306 tablets without prior administration of rifampicin (Reference, R) following oral administration in healthy male subjects.

The secondary objective is the evaluation and comparison of several pharmacokinetic parameters between the treatments. The secondary objectives will be assessed by descriptive statistics.

Detailed description:

Arms: arm 1: Subjects were administered during Period 1 on Day 1/Visit 2 a single dose of 50 milligrams (mg) of BI 409306 film-coated tablet orally with 240 millilitre (mL) of water (reference treatment, R).

On Days -7 to -1 /Visit 3 of Period 2 participants were administered rifampicin 600 mg Eremfat® film-coated tablet orally with 240 mL of water once per day during the evenings. Afterwards on Day 1/Visit 3, participants were administered a single dose of 50 mg BI 409306 orally approximately 14 hours after the last rifampicin dose (test treatment, T).

Due to the short half-life of BI 409306, trial period 2 directly followed trial period 1 without a wash-out period.
Interventions: intervention 1: BI 409306 intervention 2: Rifampicin
Intervention descriptions: intervention 1: Reference and Test Treatment intervention 2: Test Treatment

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c13704479-01
EudraCT No.:
BI Trial No.:
2016-004828-37
1289-0044
BI Investigational
Product:
BI 409306 
Title:
Effect of rifampicin on the pharmacokinetics of BI 409306 following 
oral administration in healthy male subjects 
(an open-label, two-period, fixed sequence trial)
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version: 1.0 
Date: 30 Jan 2017
Page 1 of 55
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:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
Not applicable
30 Jan 2017
1289-0044
Title of trial:
Effect of rifampicin on the pharmacokinetics of BI 409306 following oral 
administration in healthy male subjects 
(an open-label, two-period, fixed sequence trial)
Principal Investigator:
Trial site:
Clinical phase:
I
Objective:
To investigate whether and to what extent co-administration of multiple 
doses of rifampicin affect single dose pharmacokinetics of BI 409306 in 
healthy male subjects
Methodology:
Open-label, two-period, fixed sequence
No. of subjects: 
total entered:
16
each treatment:
16
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 55 years, body mass index (BMI) of 
18.5 to 29.9 kg/m2
Trial product 1:
BI 409306 film-coated tablets
dose:
50 mg as single dose in treatments R and T
mode of admin.:
Oral  with 240 mL of water under fasted conditions 
Trial product 2:
Eremfat® 600 mg film-coated tablet (1 tablet containing 600 mg 
rifampicin)
dose:
600 mg once daily (QD) for 7 days in treatment T
mode of admin.:
Oral with 240 mL of water


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
Not applicable
30 Jan 2017
1289-0044
Duration of treatment: Period 1:
Period 2:
50 mg BI 409306 as single dose (Reference - R)
600 mg of rifampicin as single dose for 7 days (Day -7 to -1)
50 mg BI 409306 as single dose (Day 1) (Test -T)
Period 2 directly follows Period 1 without washout period due to the short 
half-life of BI 409306. 
Criteria for 
pharmacokinetics:
Primary endpoints: AUC0-tz and Cmax of BI 409306
Secondary endpoints: AUC0-of BI 409306
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the 
physical examination, safety laboratory tests, 12-lead electrocardiogram 
(ECG), vital signs (blood pressure [BP], pulse rate [PR])
Statistical methods:
Relative bioavailability will be estimated based on the point estimators of 
the intra-subject ratio (test to reference treatments) of the geometric means 
(gMeans) of the primary endpoints. Additionally their corresponding two-
sided 90% confidence intervals will be provided.
The statistical model will be a (mixed effects) ANOVA on log transformed 
parameters, including effects for 'subjects' and 'treatment'. Confidence 
intervals will be based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to first drug 
administration [h:min]
Approximate clock time  of actual day [h:min]
Event and comment
Safety laboratory
PK blood BI 409306
PK blood rifampicin
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and concomitant therapy 6
SCR
1
-21 to -1
n.a.
n.a.
Screening (SCR)1
x
x
x
1
2
1
-02:00
06:00
Admission to trial site 
Assignment of subject numbers2
x2,5
x2
x2
x2
x2
0:00
08:00
Drug administration BI 409306
0:20
08:20
x
0:30
08:30
x
0:45
08:45
x
1:00
09:00
x
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
6:00
14:00
x
8:00
16:00
Snack3 (voluntary)
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x 
2
24:00
08:00
Discharge from trial site
Breakfast 3(voluntary)
x
x
2
37
-7
-158:30
17:30
Admission to trial site2
x2
-158:00
18:00
Rifampicin administration
-157:00
19:00
Dinner
-156:00
20:00
Discharge from trial site
x
-6
-134:00
18:00
Ambulatory visit. Rifampicin administration
x
-5
-110:00
18:00
Ambulatory visit. Rifampicin administration
x
-4
-86:00
18:00
Ambulatory visit. Rifampicin administration 
x2,8
x
-3
-62:00
18:00
Ambulatory visit. Rifampicin administration 
x
-2
-38:00
18:00
Ambulatory visit. Rifampicin administration 
x
-1
-15:00
17:00
Admission to trial site
x2,9
x
-14:00
18:00
Rifampicin administration
-13:30
18:30
Dinner
-12:00
20:00
x


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FLOW CHART (cont.)
Period
Visit
Day
Planned time (relative to first drug 
administration [h:min]
Approximate clock time  of actual day [h:min]
Event and comment
Safety laboratory
PK blood BI 409306
PK blood rifampicin
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and concomitant therapy 6
2
3
1
-02:00
06:00
x2
x2
x2
x2
x2
0:00
08:00
Drug administration BI 409306
0:20
08:20
x
0:30
08:30
x
0:45
08:45
x
1:00
09:00
x
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
6:00
14:00
x
8:00
16:00
Snack3 (voluntary)
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x 
2
24:00
08:00
Discharge from trial site
Breakfast3  (voluntary)
x
x
EOT
4
7 to 14
End of trial (EOT) examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within 3 h prior to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs and 
concomitant therapies. 
5.
Including urine drug screening and alcohol breath test.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Start of Visit 3 (day-7) follows directly after day 2 of Visit 2
8.
AST, ALT, AP, GGT, LDH, total and direct bilirubin only. This safety lab does not require fasting. 
9.
Urine drug screening and alcohol breath test only


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.............................................................................................9
1.2.2
Rifampicin .............................................................................................15
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 18
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................18
3.1.1
Administrative structure of the trial...................................................18
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................19
3.3
SELECTION OF TRIAL POPULATION ......................................................19
3.3.1
Main diagnosis for study entry............................................................20
3.3.2
Inclusion criteria...................................................................................20
3.3.3
Exclusion criteria ..................................................................................20
3.3.4
Removal of subjects from therapy or assessments.............................21
3.3.4.1
Removal of individual subjects................................................21
3.3.4.2
Discontinuation of the trial by the sponsor..............................22
4.
TREATMENTS........................................................................................ 23
4.1
TREATMENTS TO BE ADMINISTERED....................................................23
4.1.1
Identity of BI investigational product and comparator product......23
4.1.2
Method of assigning subjects to treatment groups ............................23
4.1.3
Selection of doses in the trial................................................................23
4.1.4
Drug assignment and administration of doses for each subject .......24
4.1.5
Blinding and procedures for unblinding ............................................24
4.1.6
Packaging, labelling, and re-supply ....................................................24
4.1.7
Storage conditions.................................................................................25


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4.1.8
Drug accountability ..............................................................................25
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................26
4.2.1
Other treatments and emergency procedures....................................26
4.2.2
Restrictions............................................................................................26
4.2.2.1
Restrictions regarding concomitant treatment .........................26
4.2.2.2
Restrictions on diet and life style.............................................26
4.3
TREATMENT COMPLIANCE.......................................................................27
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 28
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................28
5.1.1
Endpoints of efficacy.............................................................................28
5.1.2
Assessment of efficacy...........................................................................28
5.2
SAFETY..............................................................................................................28
5.2.1
Endpoints of safety................................................................................28
5.2.2
Assessment of adverse events...............................................................28
5.2.2.1
Definitions of adverse events...................................................28
5.2.2.2
Adverse event collection and reporting ...................................31
5.2.3
Assessment of safety laboratory parameters......................................33
5.2.4
Electrocardiogram................................................................................35
5.2.5
Assessment of other safety parameters...............................................36
5.2.5.1
Vital signs ................................................................................36
5.2.5.2
Medical examinations..............................................................36
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................37
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................37
5.5.1
Pharmacokinetic endpoints..................................................................37
5.5.1.1
Primary endpoints....................................................................37
5.5.1.2
Secondary endpoints................................................................37
5.5.2
Methods of sample collection...............................................................38
5.5.2.2
Plasma sampling for analysis of rifampicin concentrations ....39
5.5.3
Analytical determinations ....................................................................40
5.5.3.1
Analytical determination of analyte plasma concentration......40
6.
INVESTIGATIONAL PLAN.................................................................. 41
6.1
VISIT SCHEDULE............................................................................................41
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................41


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6.2.1
Screening period....................................................................................41
6.2.2
Treatment periods.................................................................................41
6.2.3
End of trial period.................................................................................42
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 43
7.1
STATISTICAL DESIGN – MODEL ...............................................................43
7.1.1
Objectives...............................................................................................43
7.1.2
Endpoints...............................................................................................43
7.1.3
Model......................................................................................................43
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................44
7.3
PLANNED ANALYSES....................................................................................44
7.3.1
Primary analyses...................................................................................44
7.3.2
Secondary analyses ...............................................................................45
7.3.3
Safety analyses.......................................................................................46
7.3.4
Interim analyses ....................................................................................46
7.3.5
Pharmacokinetic analyses ....................................................................46
7.4
HANDLING OF MISSING DATA ..................................................................47
7.4.1
Safety......................................................................................................47
7.4.2
Plasma drug concentration - time profiles..........................................47
7.4.3
Pharmacokinetic parameters...............................................................47
7.5
RANDOMISATION ..........................................................................................47
7.6
DETERMINATION OF SAMPLE SIZE ........................................................47
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 49
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................49
8.2
DATA QUALITY ASSURANCE .....................................................................49
8.3
RECORDS..........................................................................................................50
8.3.1
Source documents .................................................................................50
8.3.2
Direct access to source data and documents.......................................50
8.3.3
Storage period of records.....................................................................50
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................51
8.5
STATEMENT OF CONFIDENTIALITY.......................................................51
8.6
COMPLETION OF TRIAL..............................................................................51
9.
REFERENCES......................................................................................... 52
9.1
PUBLISHED REFERENCES...........................................................................52
9.2
UNPUBLISHED REFERENCES.....................................................................53
10. APPENDICES .......................................................................................... 54
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 55


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ABBREVIATIONS
AD
Alzheimer's Disease
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
APS
Attenuated Psychosis Syndrome
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CGMP
cyclic guanosine monophosphate
CI
Confidence interval
CIAS
Cognitive impairment associated with schizophrenia
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EM
Extensive metabolizer
EOT
End of trial
F
Absolute bioavailability factor
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation


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GI
Gastro-intestinal
gMean
Geometric mean
HPC
Human Pharmacology Centre
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LTP
Long term potentiation
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body after oral administration
NC
Not calculated
NMDA
N-methyl-D-aspartate
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PDE9
Phosphodiesterase-9
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PM
Poor metabolizer
PR
Pulse rate
q.d.
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
R
Reference treatment
REP
Residual effect period
RNA
Ribonucleic acid
SAE
Serious adverse event
SCR
Screening
SPC
Summary of product characteristics
SRD
Single-rising dose
Ss
(at) steady state
T
Test product or treatment


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tz,start(end)
Lower (upper) limit on time for values to be included in the calculation of 
z
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
tz
Time of last measurable concentration of the analyte in plasma
TDMAP
Trial Data Management and Analysis Plan
TS
Treated Set
TSAP
Trial statistical analysis plan
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration


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1.2.2
Rifampicin
Rifampicin is a broad-spectrum antibiotic that can be used to treat many infectious agents of 
clinical importance. Rifampicin inhibits bacterial RNA polymerase by blocking the path of 
the elongating RNA. Rifampicin is used mainly in the treatment of tuberculosis, but it is also 
a useful orally active alternative in the treatment of other infections such as those caused by 
methicillin-sensitive or methicillin-resistant staphylococcus [P03-08008]. The dosage of 
rifampicin in adults in the treatment of tuberculosis is usually between 450 and 600 mg/day.
Pharmacokinetics
Rifampicin is readily absorbed from the gastrointestinal tract. Two hours after a single 
600 mg oral dose of rifampicin in healthy adults, the mean peak serum concentration was 
7 μg/mL (range: 4 to 32 μg/mL). Absorption of rifampicin was reduced by about 30% when 
the drug was ingested with food. Rifampicin has a large volume of distribution, and 
approximately 80% is plasma-protein bound. Most of the unbound fraction is ionized and, 
therefore, diffuses freely into tissues. Rifampicin is rapidly eliminated in the bile and is 
circulated enterohepatically. Up to 30% of a dose is excreted in the urine, with about half of 
this being unchanged drug. 
In healthy adults, the mean biological half-life of rifampicin in serum averaged 3.4± 0.7 h 
after a 600 mg oral dose [R11-0197]. 
Rifampicin induces a number of drug-metabolising enzymes, having the greatest effects on 
the expression of CYP3A4 in the liver and in the small intestine. It induces several other CYP 
enzymes as well including CYP2C19 and 1A2. In addition, rifampicin induces some drug 
transporter proteins, such as intestinal and hepatic P-gp. 
Full induction of drug-metabolising enzymes is reached in about 1 week after starting 
rifampicin treatment and the induction dissipates in roughly 2 weeks after discontinuing 
rifampicin [P03-08008].
Safety
Very common adverse reactions to rifampicin are asymptomatic elevations of liver enzymes. 
In some patients hyperbilirubinaemia can occur in the early days of treatment. This results 
from competition between rifampicin and bilirubin for hepatic excretion. Hepatitis can be 
caused by rifampicin and monitoring of liver function tests is recommended.
Common adverse reactions are gastro-intestinal reactions including anorexia, nausea, 
vomiting, abdominal pain, meteorism, and diarrhoea as well as mild hypersensitivity 
reactions such as flushing, itching with or without skin rash, and urticaria. More serious 
hypersensitivity cutaneous reactions have been reported but are uncommon. Exfoliate 
dermatitis, pemphigoid reaction, erythema multiforme including Stevens-Johnson syndrome, 
Lyells syndrome and vasculitis have been reported rarely. Pseudomembranous colitis has 
been reported with rifampicin therapy in very rare cases. 
For a complete listing of adverse reactions including frequency of occurrence please refer to 
the current version of the summary of product characteristics (SPC) [R16-5180].


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This clinical phase I study will be conducted as an open-label, two period, fixed-sequence 
trial with 2 treatments in order to compare the test treatment (T) to the reference treatment 
(R) in a single centre.
The trial will consist of 4 visits. Visit 1 will be the screening investigation.
Each subject will receive treatment R (reference) in Visit 2 and treatment T (test) in Visit 3. 
The two treatments are described below. The administrations of the single dose of BI 409306
in the first period (Visit 2) will be followed directly by the combined treatment period 
(Visit 3) without wash-out period. This is owed to the short half-life of BI 409306. For details 
refer to Section 4.1.
Visit 4 will be the end-of-trial examination.
Reference treatment (BI 409306 alone):
One tablet of 50 mg BI 409306 will be given as a single dose on Day 1 of Visit 2 
(treatment R).
Test treatment (rifampicin + BI 409306):
During the second period of the study (Visit 3, treatment T) one tablet of 600 mg rifampicin 
will be given once daily on Days -7 to Day -1. One tablet of 50 mg BI 409306 will be given 
as a single dose on day 1, approximately 14 h after the last rifampicin administration. 
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.


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A log of all subjects enrolled into the trial (i.e. having given 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 study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections


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10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Current smoker or ex-smoker who quit smoking less than 30 days prior to screening.
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events, or diseases)
4. The subject shows 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 sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.


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A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported that is
considered to be unacceptable.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and comparator product
The characteristics of trial product 1 are given below:
Substance:
BI 409306
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg
Posology:
1-0-0 on day 1 of period 1 and 2
Route of administration:
p.o.
Duration of use:
single dose in treatment T and R
The characteristics of trial product 2 are given below:
Name:
Eremfat® 600 mg
Substance:
Rifampicin
Pharmaceutical formulation: Film-coated tablet
Source:
Riemser Pharma GmbH, Germany
Unit strength:
600 mg
Posology:
0-0-1 on day -7 to day -1 of period 2
Route of administration:
p.o.
Duration of use:
7 days (in treatment T only)
4.1.2
Method of assigning subjects to treatment groups
This is an open-label, two-period, fixed-sequence trial.
The allocation of subjects to study subject numbers will be performed prior to the first 
administration of trial medication in the morning of Day1 (Visit 2). For this purpose, the 
subjects will be allocated to a study subject number by drawing lots. Once a subject number 
has been assigned, it cannot be reassigned to any other subject.
4.1.3
Selection of doses in the trial
Rifampicin given at a dosage of 600 mg once daily reflects standard clinical doses and is 
considered sufficient to yield significant CYP2C19 induction.
 


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4.1.4
Drug assignment and administration of doses for each subject
All subjects will receive the two treatments in a fixed sequence order. The treatments to be 
evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total  dose
R (Reference)
BI 409306
Tablet
50 mg
1 tablet (50 mg) as single dose 
on day 1 of Visit 2
50 mg
T (Test)
BI 409306
Tablet
50 mg
1 tablet (50 mg) as single dose 
on day 1 of Visit 3
50  mg
Rifampicin
Tablet
600 mg
1 tablet (600 mg) once daily over
7 days
(i.e. from day -7 to day -1 of Visit 3)
4200 mg
The medication will be administered together with about 240 mL of water to a subject in the 
standing position under supervision of the investigating physician or an authorised designee. 
The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication and – if applicable – its preparation (e.g. reconstitution), if correct dosage 
cannot be ensured otherwise. BI 409306 administration will be performed in the morning of 
day 1(of period 1 and period 2) following an overnight fast starting no later than 10 h before 
scheduled dosing. 
For rifampicin, subjects are advised to fast for at least 2 hours before and at least 30 minutes 
after drug administrations.
 
.
For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
No blinding was performed because the treatments are distinguishable from each another. 
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct, 
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
4.1.6
Packaging, labelling, and re-supply
BI 409306 drug supply will be provided by the Department of Pharmaceutical Development 
of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. The clinical trial supply 
containers for BI 409306 will be labelled with:

BI trial number

Name of product and strengths or identification code


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
Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
Rifampicin (Eremfat® 600 mg tablets) will be ordered by the investigator from local 
pharmacy and used as marketed, without repackaging or additional labelling. Documentation 
on the commercial drug product according to [001-MCS-40-302_RD-24] must be available 
on-site in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained 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, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator 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 

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
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 


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These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the sponsor. At the time of disposal, the investigator must verify that all unused or partially 
used drug supplies have been returned by the clinical trial subject and that no remaining 
supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy (for restrictions see below). In those cases, subjects will be 
treated as necessary and, if required, kept under supervision at the trial site or transferred to a 
hospital until all medical evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Paracetamol and diclofenac must be avoided as symptomatic therapy of AEs due to its 
potential liver toxicity. Acetylsalicylic acid and dexamethasone is not allowed due to 
potential for CYP2C19 induction. Ibuprofen may be used as analgetic drug if need be.
Cimetidine, allicin, indomethacin, ketoconazole (non-topical), voriconazole (non-topical), 
fluconazole (non-topical), esomeprazole, lansoprazole, pantoprazole, or omeprazole are not 
allowed due to potential for CYP2C19 inhibition.
Ciprofloxacin, enoxacin, rofecoxib, and zafirlukast are not allowed due to potential for 
CYP1A2 inhibition.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardized meals will be served at the time points 
described in the Flow Chart.
On day 1 of period 1 and 2 the following applies:
No food is allowed for at least 4 h after intake of BI 409306 administration. 
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.


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For rifampicin, subjects are advised to fast for at least 2 hours before and at least 30 minutes 
after drug administrations (day-7 to –day -1). The restriction refers to food, water intake is 
allowed.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the first administration of trial medication until after the last 
PK sample of the trial is collected.
Smoking is not allowed in this trial. 
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during hospitalisation periods. 
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety and tolerability of the investigational drug will be assessed based on: 

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3). 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
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.
Adverse drug reaction
An adverse drug reaction is defined as a response to a medicinal product which is noxious 
and unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. Adverse drug 
reactions may arise from use of the product within or outside the terms of the marketing 
authorisation or from occupational exposure. Conditions of use outside the marketing 
authorization include off-label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death, 

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

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 jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as given 
above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system, a remote data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
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, please see above.


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The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters: 
o
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 sample, and/or
o
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.
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 sign(s) or symptom(s) 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
The definition of an adverse drug reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse drug 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
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.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).


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
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards through the residual effect period (REP), 
until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs. 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 


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these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report relevant SAEs and relevant AESIs of which he may 
become aware of.
 
The REP for 
rifampicin is defined as 6 days after the last administration of rifampicin.
Therefore, all AEs which occurred through the treatment phase and throughout the REP will 
be considered as on treatment; please see Section 7.3.3. 
The follow-up period describes the period of time from the last administration of trial 
medication including the REP until the end of trial examination (last per protocol contact).
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 of 
awareness) to the sponsor’s unique entry point (country specific contact details will be 
provided in the ISF). In specific occasions the Investigator could inform the sponsor upfront 
via telephone. The same timeline applies if follow-up information becomes available. This 
does not replace the requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication. 


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The following should also be recorded as an (S)AE in the CRF and on the 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 subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests and for safety labs taken in the evening prior to rifampicin administration.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis,
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
SCR
Within 
period*
End-of- trial
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
White blood cell count (WBC)
Platelet count
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Automatic WBC 
differential 
(relative and absolute)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
x
x
x
x
x
-
-
-
-
-
x
x
x
x
x
Manual WBC differential 
(if automatic is abnormal)
Polymorphnuclear neutrophils (segs)
Band neutrophils (stabs)
Eosinophils
Basophils
Monocytes
Lymphocytes
x
x
x
x
x
x
-
-
-
-
-
-
x
x
x
x
x
x
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT) 
Lactate dehydrogenase (LDH)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hormones
Thyroid stimulating hormone (TSH)
x
-
-
Substrates
Plasma glucose
Serum creatinine 
eGFR (CKD-EPI for creatinine) 
Total bilirubin 
Direct bilirubin
Total protein
C-Reactive Protein (CRP) 
x
x
x
x
x
x
x
-
-
-
x
x
-
x
x
x
x
x
x
x
x
Electrolytes
Sodium
Potassium
Calcium
x
x
x
-
-
-
x
x
x
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
x
x
x
x
x
x
x
x
x
-
-
-
-
-
-
-
-
-
x
x
x
x
x
x
x
x
x
Urine sediment
(microscopic examination 
if erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported 
(for instance, the presence of sediment 
bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
x
-
x
* on day -4 of visit 3: safety lab without haematology and CRP.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and at the times indicated in the Flow Chart.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed in each treatment period, and may be 
repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
 
. These tests will be performed at the trial site using e.g. AccuSign
DOA 10 test.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart. 
All ECGs will be recorded for 10-sec duration after the subjects have rested for at least 5 min 
in a supine position. ECG assessment will always precede all other study procedures of the 
same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists).
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons. 


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Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm 
if possible.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECGC, laboratory tests, and a physical examination.


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded.
Exact time points of plasma sampling will be derived from the study management system 
ClinBase™ and documented in the CRFs by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined for BI 409306

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated for BI 409306:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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5.5.2
Methods of sample collection


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The sample tube labels should list at least the following information: study number, subject
number, visit, planned time and aliquot. Further information such as matrix and analyte may
also be given.
After completion of the study the plasma samples may be used for methodological 
investigations, e.g. for stability testing, assessment of other metabolites, or further biomarker 
investigations. However, only data related to BI 409306, rifampicin and their metabolites
including anti-drug antibodies (if applicable) will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the final study report has been signed.
5.5.2.2
Plasma sampling for analysis of rifampicin concentrations
For quantification of rifampicin plasma concentrations 2.7 mL of blood will be taken from an 
antecubital or forearm vein into a K3-EDTA (tripotassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will be 
withdrawn by means of either an indwelling venous catheter or by venipuncture with a metal 
needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 2000 
g to 4000 g and 4 to 8 °C. Two plasma aliquots will be obtained and stored in polypropylene 
tubes. The first aliquot should contain at least 0.5 mL plasma whereas the second aliquot 
should contain the remaining plasma (0.5 mL or less). Within a maximum time of 2 hours 
after sampling at room temperature, the samples should be stored in a freezer. Until shipment 
on dry ice to the analytical laboratory, plasma samples will be stored frozen in an upright 
position at about –20°C or below. The second aliquot will be shipped after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory the plasma samples 
will be stored at about –20°C or below until analysis.
The sample tube labels should list at least the following information: study number, subject 
number, visit, planned time and aliquot. Further information such as matrix and analyte may 
also be given.
Backup samples (aliquot 3) from BI 409306 PK might be used for measurement of rifampicin 
concentrations if need be.


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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
 
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany, G144
Birkendorfer Straße 65, 88397 Biberach/ Riß, Germany
Analysis of CD 13896 and CD 14084 in PK plasma study samples (aliquot 2) will be 
performed using validated liquid chromatography tandem mass spectrometry assays (LC-
MS/MS) in the laboratory of:
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany, G144
Birkendorfer Straße 65, 88397 Biberach/ Riß, Germany
.
Covance Laboratories Limited
Otley Road, Harrogate HG3 1PY 
United Kingdom
Email :


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day -4, Day -1, and Day 1 are to be performed and completed within a 3 h-
period prior to the trial drug administration. 
The acceptable deviation from the scheduled time for vital signs and laboratory tests will be ± 
60 min.
The time window for rifampicin administration from Day -7 to Day -2 is  ± 60 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling and vital signs 
have to be done first. Furthermore, if several measurements including venipuncture are 
scheduled for the same time, venipuncture should be the last of the measurements due to its 
inconvenience to the subject and possible influence on physiological parameters.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Pharmacogenomic genotyping will be performed in those volunteers whose genotypes are not 
known (for details see Section 5.3).
6.2.2
Treatment periods
Each subject is expected to participate in two treatment periods (days 1 and 2) in period 1, 
days -7 to day 2 in period 2. 
 
On Day 1 of period 1 and Day – 1 of period 2 study participants will be admitted to the trial 
site and kept under close medical surveillance for at least 24 h following BI 409306 drug 


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administration. On Day -7 of period 2 study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 2 h following rifampicin administration.
The subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. On all other study days, the study will be performed in an 
ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2.
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. The end of the trial as a whole is defined by the ‘last regular visit completed 
by last subject’ or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of 
an AE has been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the relative bioavailability of 50 mg of 
BI 409306 tablets with prior 7-day intake of 600 mg rifampicin tablets  (Test, T) compared to 
50 mg of BI 409306 tablets without prior administration of rifampicin (Reference, R) 
following oral administration in healthy male subjects. The trial is designed to allow intra-
subject comparisons and will be evaluated statistically by use of an appropriate linear model.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between the treatments. The secondary objectives will be assessed by descriptive 
statistics.
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics.
7.1.2
Endpoints
Relative bioavailability is to be determined on the basis of the primary and secondary 
pharmacokinetic endpoints (see Section 5.5.1).
Safety and tolerability will be determined on the basis of the parameters specified in Section 
5.2.1.
7.1.3
Model
The statistical model used for the analysis of primary endpoints will be an ANOVA (analysis 
of variance) model on the logarithmic scale. This model will include effects accounting for 
the following sources of variation: ‘subjects’ and ‘treatment’. The effect ‘subjects’ will be 
considered as random, whereas the treatment effect will be considered as fixed. The model is 
described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response (endpoint, see Section 7.1.3) measured on subject m 
receiving treatment k,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received
treatment k.


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7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 409306 50 mg tablet after pre-administration of rifampicin
600 mg tablet for 7 days compared to BI 409306 50 mg tablet without pre-administration will 
be estimated by the ratios of the geometric means (test/reference) for the primary and 
secondary PK endpoints. Additionally, their two-sided 90% confidence intervals (CIs) will be 
provided. This method corresponds to the two one-sided t-tests procedure, each at the 5% 
significance level. Since the main focus is on estimation and not testing, an acceptance range 
was not specified, that is, no hypothesis will be tested.
Confidence intervals and p-values will be computed, but have to be interpreted in the 
perspective of the exploratory character of the study, i.e. confidence intervals are considered 
as interval estimates for effects, while p-values are considered as an exploratory measure of 
evidence for effects in the present data.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The primary and secondary pharmacokinetic endpoints listed in Section 5.5.1 will be 
calculated according to the BI Standard Operating Procedure (SOP) ‘Standards and processes 
for analyses performed within Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-
472].
Primary and secondary pharmacokinetic parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma  concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

the subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

a pre-dose concentration is >5% of the Cmax value of that subject 

missing samples/concentration data at important phases of PK disposition curve.


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The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one primary or secondary PK parameter that was not excluded according to 
the description above. Thus, a subject will be included in the PKS, even if he/she contributes 
only one PK parameter value for one period to the statistical assessment. 
Subjects who are not included in the PKS (refer to Section 7.3.1.) will be reported with their 
individual plasma concentrations and individual pharmacokinetic parameters; however, they 
will not be included in descriptive statistics for plasma concentrations, pharmacokinetic 
parameters or other statistical assessment.
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 and actual 
sampling times will be used for the calculation of PK parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the 
drug plasma concentration-time tables. For the presentation of the mean profiles, the 
arithmetic mean, geometric mean and the planned blood sampling times will be used.
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
Point estimates of bioavailability, the intra-subject ratios of the geometric means 
(test/reference) for the primary and secondary endpoints (see 5.5.1.1, 5.5.1.2), and their two-
sided 90% confidence intervals (CIs) will be provided.
To this end, the PK endpoints will be log-transformed (natural logarithm) prior to fitting the 
ANOVA model (cf. Section 7.1.3). For each endpoint, the difference between the expected 
means for log(T)-log(R) will be estimated by the difference in the corresponding adjusted 
means (Least Squares Means), and a two-sided 90% confidence interval based on the 
t-distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% CIs for each endpoint.
7.3.2
Secondary analyses
As sensitivity analysis, the ANOVA performed as primary analysis will be repeated with 
subject as fixed effect instead of random effect. The results will be presented in the same 
manner as for primary analyses.
The following descriptive statistics will be calculated for primary and secondary PK 
parameters and for further endpoints: N, arithmetic mean, standard deviation, minimum, 
median, maximum, arithmetic coefficient of variation, geometric mean, and geometric 
coefficient of variation. The data format for descriptive statistics of concentrations will be 


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identical with the data format of the respective concentrations. 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 3 significant digits in the clinical trial report.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is, 
all subjects who received at least one dose of study drug), will be included in the safety 
evaluation. Safety analyses will be descriptive in nature and will be based on BI standards.
The analyses will be done by ‘treatment at onset’.
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used for the evaluation of categorical (qualitative) data, and tabulations of descriptive 
statistics will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until next intake or the 
end of trial visit will be assigned to the preceding treatment. Therefore, measurements 
planned or AEs recorded prior to first intake of trial medication will be assigned to 
'screening', those between first trial medication intake until end of the residual effect period 
(see 5.2.2.2) will be assigned to the treatment period. Events after the residual effect period 
but prior to next intake or end of trial examination will be summarized as ‘follow-up’. These 
assignments including the corresponding time intervals will be defined in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, intensity and causal relationship of AEs will be tabulated by 
treatment, primary system organ class and preferred term. SAEs and other significant AEs 
(according to ICH E3), and AESIs will be listed separately (see Section 5.2.2.1). 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged. Additionally, differences from baseline (day 1 of period 1) will be 
evaluated.
For vital signs, the differences from baseline will be evaluated.
Relevant ECG findings will be reported as AEs.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
For the analysis of pharmacokinetic parameters please refer to Section 7.3.1.


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7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure of the Sponsor (001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
[001-MCS-36-472].
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. 
7.5
RANDOMISATION
Randomization is not applicable in this open-label and single group clinical study. All 
subjects will receive the same treatment. A list of consecutive subject numbers for non-PM 
subjects  will be provided (see Section 4.1.2 for details of allocation of subject numbers to 
subjects).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 16 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. 


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These calculations were performed as described by Kupper and Hafner [R12-0972] with R 
Version 3.0.2 and the package PowerTOST.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
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 or of ICH GCP.
As a general rule, no trial results should be published prior to finalisation of the CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’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 subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, 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.
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.


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8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the Human Pharmacology Centre (HPC) – Boehringer Ingelheim's Phase I unit – the 
validated ClinBaseTM system is operated for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data is entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
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. CRFs and 
all source documents, including progress notes (if applicable) 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/on site monitor and auditor may review all CRFs, 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 and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’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 i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC / competent authority in each participating EU member state needs to be notified
about the end of the trial (last subject / subject out, unless specified differently in Section
6.2.3 of the CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P03-08008
Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT. 
Pharmacokinetic interactions with rifampicin: clinical relevance. Clin 
Pharmacokinet 2003. 42(9):819-850.
R10-5092
Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain 
R10-5102
Reymann KG, Frey JU. The late maintenance of hippocampal LTP: 
requirements, phases, 'synaptic tagging', 'late-associativity' and 
implications. Neuropharmacology 52, 24 - 40 (2007)
R11-0197
Rifadin (rifampin capsules USP) and Rifadin iv (rifampin for injection 
USP) (sanofi-aventis U.S.), Rx only (prescribing information, revised: 
November 2010). 2010.
R12-0972
Kupper LL, Hafner KB. How appropriate are popular sample size 
formulas? Am Stat 1989. 43(2):101-105.
R13-4518
Hu NW, Ondrejcak T, Rowan MJ. Glutamate receptors in preclinical
research on Alzheimer's disease: update on recent advances. 
Pharmacol Biochem Behav 100, 855 - 862 (2012)
R13-4521
Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology 
and therapy of schizophrenia. 
Pharmacol Biochem Behav 100, 665 - 677 (2012)
R15-1457
Mathalon DH, Perkins D, Walker E, Addington J, Bearden C, Cadenhead 
K, Cornblatt B, McGlashan T, Seidman L, Tsuang M, Woods S, Cannon T, 
NAPLS, Consortium. Impaired synaptic plasticity, synaptic over-pruning, 
inflammation, and stress: a pathogenic model of the transition to psychosis 
in clinical high risk youth. 69th Ann Sci Convention and Mtg of the Society 
of Biological Psychiatry (SOBP), New York, 8 - 10 May 2014. Biol 
Psychiatry, 2014;75(9)(Suppl)
R15-3327
Perez VB, Woods SW, Roach BJ, Ford JM, McGlashan TH, Srihari VH, et 
al. Automatic auditory processing deficits in schizophrenia and clinical 
high-risk patients: forecasting psychosis risk with mismatch negativity.
Biol Psychiatry 2014. 75(6):459-469
R16-5180
Eremfat 600 mg Filmtabletten (Riemser), verschreibungspflichtig  
(Fachinformation (Zusammenfassung der Merkmale des 
Arzneimittels/SPC), Stand der Information: 12.2015). 2015.
R16-5274
Zhou HH, Anthony LB, Wood AJJ, Wilkinson GR. Induction of 
polymorphic 4'-hydroxylation of S-mephenytoin by rifampicin. 
Br J Clin Pharmacol 1990. 30:471-475
R16-5275
Zhou HH. CYP2C19 genotype determines enzyme activity and inducibility 
of S-mephenytoin hydroxylase. Clin Chim Acta 2001. 313:203-208
R16-5276
Feng HJ, Huang SL, Wang W, Zhou HH. The induction effect of rifampicin 
on activity of mephenytoin 4-hydroxylase related to M1 mutation of 
CYP2C19 and gene dose. Br J Clin Pharmacol 1998. 45:27-29


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R17-0138
Dymond AW, So K, Martin P, Huang Y, Severin P, Mathews D et al. 
Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and 
induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy 
subjects: results from two clinical trials. Eur J Clin Pharmacol 2017. 
73:175-184
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
001-MCS-40-302 Reference document No. 24 (RD-24). Investigational Medicinal Product
(IMP) and Auxiliary Medicinal Product (AMP) Manual. Current version. 
c02098989-02
 Safety, tolerability and 
pharmacokinetics of single oral doses of BI 409306 (tablet) in healthy 
Chinese and Japanese male volunteers and multiple oral doses of BI 409306 
(tablet) in healthy Japanese male volunteers (randomized, double-blind, 
placebo-controlled within dose groups), 1289.4, 13 March 2014
c09564954-01
: A study to investigate the 
pharmacokinetic drug-drug interaction following oral administration of 
BI 409306 and donepezil in healthy male and female subjects. 
Clinical Trial Report 29-Nov-2016.
U12-1034-01
. A randomized, double-blind, 
placebo-controlled (within dose groups) Phase I study to assess the safety, 
tolerability and pharmacokinetics of single rising doses 0.5 mg to 500 mg 
of BI 409306 administered orally in healthy male volunteers, Clinical Trial 
Report 1289.1, 19 Jan 2012


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13704479
1.0
clinical-trial-protocol
Effect of rifampicin on the pharmacokinetics of BI 409306 following oral
administration in healthy male subjects (an open-label, two-period, fixed sequence
trial)
Author-Trial Clinical Monitor
30 Jan 2017 16:35 CET
Approval-Therapeutic Area 
31 Jan 2017 08:22 CET
Verification-Paper Signature
Completion
31 Jan 2017 09:40 CET
Author-Trial Clinical
Pharmacokineticist
02 Feb 2017 11:18 CET
Author-Trial Statistician
03 Feb 2017 09:18 CET
Approval-Team Member Medicine
06 Feb 2017 14:26 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13704479
1.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c19227171-01
BI Trial No.:
1289-0044
Title:
Effect of rifampicin on the pharmacokinetics of BI 409306 
following oral administration in healthy male subjects (an open-
label, two-period, fixed sequence trial)
Investigational
Product:
BI 409306
Responsible trial 
statisticians:
Phone:
Fax:
Phone: 
Fax: 
Date of statistical 
analysis plan:
18 AUG 2017 SIGNED 
Version:
FINAL
Page 1 of 26
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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
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINT .................................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
..........................................9
........................................10
........................................10
........................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................14
......................................................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINTS...................................................................................19
7.5
SECONDARY ENDPOINT ...............................................................................20
7.5.1
Key secondary endpoint .....................................................................................20
7.5.2
Secondary endpoint.............................................................................................20
...................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21
7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................23
7.8.5
Others...................................................................................................................23
8.
REFERENCES....................................................................................................24


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...............................................................................25
10.
HISTORY TABLE..............................................................................................26


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the Clinical Trial Report (CTR).....................11
Table 6.2: 1
Important protocol violations ...........................................................................14
Table 6.3: 1
Subject sets analysed ........................................................................................15
Table 10: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis Data Set
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANOVA
Analysis of Variance
AST
Aspartate Aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BWU
Bioavailability/Bioequivalence, within-subject design, time-uncontrolled
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
DBLM
Database Lock Meeting
ECG
Electrocardiogram
ES
Entered Set
EudraCT
European Union Drug Regulating Authorities Clinical Trials
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
ICH
International Conference On Harmonisation
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number non-missing observations
O*C
Oracle Clinical


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Term
Definition / description
PK
Pharmacokinetics
PKS
PK Parameter Analysis Set
PT
Preferred Term
PV
Protocol Violation
qd
Quaque Die, Once Daily
R
Reference Treatment
REP
Residual Effect Period
RPM
Report Planning Meeting
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
T
Test Treatment
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP). 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.”
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE,
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 5.5.1.1 of the CTP: The following primary endpoints will be determined for 
BI 409306

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint
As no key secondary endpoint has been specified in the CTP, this section is not applicable.
5.2.2
Secondary endpoint
Section 5.5.1.2 of the CTP: The following secondary endpoint will be evaluated for BI 
409306:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)
Safety:
There is no specific endpoint regarding safety. The safety assessments, see CTP Section 5.2.1,
will be evaluated in a descriptive way only.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment, and 
selection of doses, please see CTP, Sections 3 and 4.
Section 3 of the CTP: This clinical phase I study will be conducted as an open-label, two 
period, fixed-sequence trial with 2 treatments in order to compare the test treatment (T) to the 
reference treatment (R) in a single centre.
[…] It is planned that 16 healthy male subjects will enter the study.
For details of dosage and formulation see Table 6.1: 1 below.
Table 6.1: 1
Labels for treatments for use in the Clinical Trial Report (CTR)
Treatment
Short label
R
BI 409306, 50 mg tablet, qd
BI 
T
BI 409306, 50 mg tablet, qd + Rifampicin, 
600 mg tablet, qd
BI + Rifa
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from day of informed consent until first administration of study 
drug)

BI treatment 
 

Follow-up BI (ranging from end of BI treatment period until next drug administration 
or alternatively, trial-termination date in case of no further treatment)

Rifa treatment (ranging from the time of first administration of rifampicin until time 
of second administration of BI 409306 and 
ranging from end of BI+Rifa treatment period until last Rifa administration + 6 days 
(Rifa REP))
OR
in case of study discontinuation, until last Rifa administration + 6 days (Rifa REP)

BI+Rifa treatment (ranging from time of BI 409306 administration in Visit 3 until 24 
hours thereafter (BI REP))

Follow-up Rifa (ranging from end of Rifa treatment period until trial termination date 
+ one day)


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Displays of AEs will be presented separately for the following treatments during on treatment 
phase:

BI 409306, 50 mg tablet, qd (labelled “BI“)

Rifampicin, 600 mg tablet, qd (labelled “Rifa“)

BI 409306, 50 mg tablet, qd + Rifampicin, 600 mg tablet, qd (labelled “BI + Rifa“)
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.9.2.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening, Follow-up BI and Follow-up Rifa will not be included in 
this analysis.
The following total will be provided in addition (Section 15.3 only):

a total over all on treatment phases involving BI (“Total BI”)

a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.9.2.8 (except for ClinicalTrials.gov and EudraCT) of the 
CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))

Follow-up BI (labelled “FU BI”)

Follow-up Rifa (labelled “FU Rifa”)
In Section 16.1.9.2.8 AE tables, the following totals will be provided in addition:

a total over all study phases ("Total")
Tables of vital signs and laboratory values will present results by the above mentioned on
treatment phase.
For detailed information on the handling of the treatments in the O*C views refer to Technical 
TSAP ADS (analysis data set) plan.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects.
Listings of protocol deviations and of unresolved discrepancies will be provided to be 
discussed at the combined report planning and database lock meeting (RPM/DBLM), e.g. 
deviations in drug administration, in blood sampling etc. At this meeting, it will be decided 
whether the discrepant data can be used as they are or whether the data have to be corrected in 
the clinical database.


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Each protocol deviation must be assessed to determine whether it is an important protocol 
violation. A protocol violation (PV) is important if it affects the rights or safety of the study 
subjects or if it can potentially influence the primary outcome measure(s) for the respective 
subjects in a way that is neither negligible nor in accordance with the study objectives. This 
last category of important PV forms the basis for the decision of whether a subject does or 
does not belong to an analysis set. PVs that do not influence the subject's rights and safety or 
the evaluability of the subjects for the main study objectives are called non-important PVs.
These are only considered when checking the trial quality in general.
If any important PVs are identified, they are to be summarized into categories and will be 
captured in the RPM/DBLM minutes via an accompanying Excel spreadsheet [001-MCS-50-
413_RD-02] (2). The following table contains the categories which are considered to be 
important protocol violations in this trial. If the data show other important PVs, this table will 
be supplemented accordingly by the time of the combined RPM/DBLM.


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Table 6.2: 1
Important protocol violations
Category
/Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomization
C1
Incorrect trial medication taken
C2
Non-compliance
C3
Incorrect intake of trial medication
D
Concomitant medication
D1
Prohibited medication use 
E
Missing data 
E1
Certain violations of procedures used to measure primary and secondary data
F
Incorrect timing1
F1
Certain violations of time schedule used to measure primary and secondary data
G
Other trial specific IPVs
G1
PVs affecting safety and rights
1 Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set
Source: ‘Protocol Violation Handling Definitions’ [001-MCS-50-413_RD-01] (3)
6.3
SUBJECT SETS ANALYSED
Entered set (ES):
This subject set includes all entered subjects, whether treated or not.
Treated set (TS):
This subject set includes all subjects from the ES who were dispensed study medication and 
were documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for safety 
analysis.
Section 7.3.1 of the CTP: Primary and secondary pharmacokinetic parameters of a subject 
will be included in the statistical pharmacokinetic (PK) analyses if they are not flagged for 
exclusion due to a protocol violation relevant to the evaluation of PK (to be decided no later 


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than in the Report Planning Meeting) or due to PK non-evaluability (as revealed during data 
analysis, based on the criteria specified below). Exclusion of a subject’s data will be 
documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

the subject experienced emesis that occurred at or before two times median tmax of the
respective treatment (Median tmax is to be determined excluding the subjects
experiencing emesis),

a pre-dose concentration is >5% of the Cmax value of that subject

missing samples/concentration data at important phases of PK disposition curve.
PK parameter analysis set (PKS):
The PK parameter analysis set (PKS) includes all subjects in the TS who provide at least one 
primary or secondary PK parameter that was not excluded according to the description above. 
Thus, a subject will be included in the PKS, even if he/she contributes only one PK parameter 
value for one period to the statistical assessment.
It is used for the PK analysis.
The descriptive analysis of PK concentrations will be based on the analysis data set (ADS)
ADPC as described at the beginning of Section 7.
Table 6.3: 1
Subject sets analysed
Analysis set
Class of endpoint
ES
TS
PKS
Analyses of primary and secondary
PK endpoints 
X
Safety endpoints 
X
Demographic/baseline endpoints
X
Important PVs
X
Disposition
X


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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
Handling of missing data and outliers will be performed as described in the CTP, Section 7.4.
The only exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-36-
472_RD-01 (5)).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement prior to study drug administration, i.e. 
the measurement on day 1 of period 1.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and end of trial examination 
are given in the CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day -4, Day -1, and Day 1 are to be performed and completed within a 3 h-
period prior to the trial drug administration.
The acceptable deviation from the scheduled time for vital signs and laboratory tests will be 
±60 min.
The time window for rifampicin administration from Day -7 to Day -2 is ± 60 min.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendices 16.2 and 16.1.9.2.
Inferential statistical analyses of PK endpoints (refer to Section 7.5.2) will also be performed 
by 
 and will be presented in Section 15.5 of the CTR and in 
Appendix 16.1.9.3.
Descriptive data analysis of PK endpoints will be performed by BI and will be presented in 
Section 15.6 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of clinical trials and project summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations.
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number, visit and actual treatment (if appropriate). The listings will be included in Appendix 
16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations as well as for all PK parameters, the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, P10, P90, Q1 and Q3 will be calculated.
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. 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.
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 (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 


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subjects in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS will include parameters if they are not flagged for exclusion;
that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO 
is set to ‘HALF LIFE’ the value will be excluded from half-life calculation only; the value is 
included for all other analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (7).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.


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The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations will provide additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
To investigate whether and to what extent co-administration of multiple doses of rifampicin 
affect single dose pharmacokinetics of BI 409306 in healthy male subjects, point estimates of 
the intra-subject ratios of the geometric means (test/reference) for the primary endpoints (see 
Section 5.1), and their two-sided 90% confidence intervals (CI) will be provided.
Section 7.1.3 of the CTP: The statistical model used for the analysis of primary endpoints 
will be an ANOVA (analysis of variance) model on the logarithmic scale. This model will
include effects accounting for the following sources of variation: ‘subjects’ and ‘treatment’. 
The effect ‘subjects’ will be considered as random, whereas the treatment effect will be 
considered as fixed. The model is described by the following equation:
ykm = µ + sm + τk + ekm, where
ykm = logarithm of response (endpoint, see Section 5.1) measured on subject m
receiving treatment k,
µ = the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
τk = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k.
The analysis will be accomplished by using the XPKISTAT macro, based on PKS (design 
BWU).
In addition, a sensitivity analysis will be performed by fitting the model described above, but
using all effects as fixed. This analysis will be done using PROC GLM.
The PK endpoints will be log-transformed (natural logarithm) prior to fitting the ANOVA 
model.
Section 7.3.1 of the CTP: For each endpoint, the difference between the expected means for 
log(T)-log(R) will be estimated by the difference in the corresponding adjusted means (Least 


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Squares Means), and a two-sided 90% confidence interval based on the t-distribution will be 
computed. These quantities will then be back-transformed to the original scale to provide the 
point estimate and 90% CIs for each endpoint.
7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoint
The secondary PK parameter will be analysed in the same manner as the primary endpoints 
(see Section 7.4).
Safety:
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 409306.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by actual treatment.
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and presentation of adverse event data from 
clinical trials” [001-MCG-156], (9).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs).
For analysis multiple AE occurrence data on the case report form (CRF) will be collapsed into 
an AE provided that all of the following applies:
•
All AE attributes are identical (lower level term (LLT), intensity, action taken, therapy
required, seriousness, reason for seriousness, relationship, outcome, AE of special 
interest).
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 occurrences 
is given if the second occurrence started within one hour after end of the first occurrence).
For further details on summarization of AE data, please refer to (4, 9).
Section 5.2.2.1 of the CTP: The following are considered as adverse events of special 
interest (AESI) in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory
parameters:
o
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 sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. 
Section 5.2.2.2 of the CTP:
 
. The REP for rifampicin is defined as 6 days after the last administration of 
rifampicin. Therefore, all AEs which occurred through the treatment phase and throughout 
the REP will be considered as on treatment; please see Section 7.3.3 of CTP.


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All adverse events occurring prior to drug administration will be assigned to ‘screening’,
those between intake of trial medication and end of the REP will be assigned to the 
corresponding treatment. AEs occurring after the REP but prior to next treatment or to 
termination date will be assigned to the corresponding follow-up phase. For more detail see 
the TSAP ADS plan.
For details on the treatment definition, see Section 6.1.
According to ICH E3 (10), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting.
An overall summary of adverse events will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (10), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency (within system organ class). The MedDRA 
version number will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[001-MCG-157] (11).
Section 7.3.3 of the CTP: Laboratory data will be compared to their reference ranges. 
Values outside the reference range will be flagged. Additionally, differences from baseline 
(day 1 of period 1) will be evaluated.
With respect to evaluations of laboratory data, ‘baseline’ is understood as last measurement 
before first drug administration. The ‘last value on treatment’ is defined as the last 


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measurement before the end of the 6 days REP for rifampicin and ‘post examination’ is the 
measurement at the end-of-trial examination.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the eCRF or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). In the listing the difference from baseline will also be 
displayed. With respect to evaluations of vital signs, baseline is understood as last 
measurement before the first drug administration.
7.8.4
ECG
ECG findings will be reported as relevant medical history/baseline condition (i.e., a condition 
already existent before intake of study drug) or as AE and will be summarised as such. No 
separate listing or analysis of ECG findings will be prepared.
7.8.5
Others
Physical examination 
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
10. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, current 
version


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
18 Aug 2017
None
This is the final TSAP