Clinical trial NCT05155306
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2022-01-14; Completion date: 2022-05-16
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To investigate the relative bioavailability of the intended Commercial Formulation (iCF) (Test, T) compared with Trial Formulation 2 (TFII) (Reference, R) and to assess potential food effects following oral administration of BI 1358894.

Detailed description:

Arms: arm 1: A single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning following an overnight fast of at least 10 hours. arm 2: A single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning following a high-fat, high-calorie meal. arm 3: A single dose of 100 mg (milligram) BI 1358894 given orally as two 50 mg film-coated tablets in the morning following an overnight fast of at least 10 hours. arm 4: A single dose of 00 mg (milligram) BI 1358894 given orally as two 50 mg film-coated tablets in the morning following a high-fat, high-calorie meal.
Interventions: intervention 1: BI 1358894, intended Commercial Formulation (iCF) (T) intervention 2: BI 1358894, Trial Formulation 2 (TFII) (R)
Intervention descriptions: intervention 1: A single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning intervention 2: A single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning.

Protocol documents:
Prot_000.pdf: 

























































































































































SAP_001.pdf: 
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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
                     c38312926-01
BI Trial No.:
1402-0020
Title:
Relative bioavailability of two different tablet formulations of BI 
1358894 administered in healthy subjects in fasted and fed state 
(an open-label, randomised, single-dose, four-period, four-
sequence crossover study)
Investigational
Product(s):
BI 1358894
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
16 JUN 2022   SIGNED 
Version:
1
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................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 .........................................................................................................8
5.1
PRIMARY ENDPOINTS.....................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoints......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
5.3.2
Safety parameters .................................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENTS...................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................12
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY ENDPOINTS...................................................................................18
7.4.1
Primary analysis of the primary endpoints......................................................18
 
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoint .....................................................................................20
7.5.2
Other Secondary endpoint .................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20


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7.8.1
Adverse Events ....................................................................................................21
7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................22
7.8.4
ECG......................................................................................................................22
7.8.5
Others...................................................................................................................22
7.8.5.1
Physical examination ............................................................................................22
7.8.5.2
Body weight ..........................................................................................................23
7.8.5.3
C-SSRS .................................................................................................................23
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............24
9. 
REFERENCES....................................................................................................25
11.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................10
Table 6.1: 2
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data, vital signs and ECG..............................................11
Table 6.3: 1
Subject sets used for analysis of endpoints ......................................................14
Table 11: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
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
BMI
Body mass index
BP
Blood Pressure
CI
Confidence interval
CL
Confidence interval limit
Cmax
Maximum measured concentration of the analyte in plasma
CSD
Company Standard Displays
C-SSRS
Columbia-Suicidal Severity Rating Scale
CV
Arithmetic coefficient of variation
EDMS
Electronic Document Management System
F/U
Follow Up
gCV
Geometric coefficient of variation
gMean
Geometric mean
iCF
Intended Commercial Formulation
iPD
Important Protocol Deviation
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PD
Protocol deviation
PKS
PK parameter analysis set
PR
Pulse Rate


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Term
Definition / description
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
qd
Quaque die
R 
Reference treatment
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SD
Standard deviation
SOC
System organ class
T
Test treatment
TFII
Trial Formulation 2
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
Study data as collected in the eCRF will be stored in a trial database within the RAVE EDC 
system. All study data also including external data will then be uploaded to the CDR data 
warehouse.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 8.1.1 or higher, 
) or SAS Version 9.4 (or later 
version).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), 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.
5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: 
The following pharmacokinetic parameters will be determined for BI 1358894:

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 ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameter will be determined for BI 1358894:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
5.3.2
Safety parameters
Section 2.2.2.2 of the CTP:
Safety and tolerability of BI 1358894 will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests


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
12-lead ECG

Vital signs (blood pressure, pulse rate)

Prospective suicidality assessment (C-SSRS)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products and selection of doses, please see 
CTP Sections 3 and 4. 
The treatments will be one 100 mg tablet (iCF) of BI 1358894 (test, T) administered to 
subjects in the fasting (Tfasted) and fed (Tfed) state and two 50 mg tablets (TFII) of BI 1358894  
(reference, R) administered to subjects in the fasting (Rfasted) and fed (Rfed) state.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
Rfasted
BI 1358894, 2 tablets à 50mg (TFII), fasted
Rfasted
Rfed
BI 1358894, 2 tablets à 50mg (TFII), fed
Rfed
Tfasted
BI 1358894, 1 tablet à 100mg (iCF), fasted
Tfasted
Tfed
BI 1358894, 1 tablet à 100mg (iCF), fed
Tfed
 
The following study phases will be defined for the analysis of adverse events (AEs):


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Table 6.1: 2
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data, vital signs and ECG
Study analysis 
phase
Label
Start
End
Screening1
Screening
0:00h on date of informed 
consent
Date/time of administration of 
study drug in treatment period 1
On treatment
Rfasted,
Rfed,
Tfasted or
Tfed
respectively
Date/time of administration of 
study drug of respective 
treatment period
End of REP (
 
 
Date/time of next administration 
of study drug in the next 
treatment period, if applicable OR 
Date/time of trial termination,
whichever occurs first.
Follow-up
Follow-up
End of REP 
Date/time of administration of 
study drug in the next treatment 
period, if applicable OR
Date/time of trial termination,
whichever occurs first
1 See Section 6.7 for definition of baseline, which will be used in the statistical analyses of safety laboratory 
data, ECG and vital signs.
For each subject, the overall trial period lasts from signing informed consent until the last visit.
Section 7.2.5 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
The following AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) 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 and follow-up periods 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 included in this analysis ("Total")
B) Section 15.4 of the CTR displays:
Screening 
On-treatment (labelled with the name of the study treatment (short label))
Follow-up (labelled “F/U”)


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C) Appendix 16.2 of CTR: all AEs will be listed.
Measurements will be considered on-treatment, if they were taken within the on-treatment 
phases as defined in Table 6.1: 2.
For detailed information on the handling of the treatments refer to Technical TSAP ADS plan 
and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will
be provided to be discussed at the Report Planning Meeting. At this meeting, it will be
decided whether a discrepant data value can be used in analyses or whether it must be
corrected in the clinical database. Each protocol deviation must be assessed to determine
whether it is an important protocol deviation (iPD). For definition of iPDs, and for the process 
of identification of these, refer to the BI reference document "Identify and Manage Important
Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in
the decision log. Categories which are considered to be iPDs in this trial are defined in the
DV domain template. If the data show other iPDs, the definition in the DV domain template
will be supplemented accordingly by the time of the Report Planning Meeting.
iPDs will be summarized and listed in the CTR. Which kind of iPDs could potentially lead to 
exclusion from which analysis set is specified in the DV domain template. The decision on 
exclusion of subjects from analysis sets will be made at the latest at the Report Planning 
Meeting, after discussion of exceptional cases and implications for analyses.
Non-important COVID-19 related PDs will only be listed.
6.3
SUBJECT SETS ANALYSED
Section 7.2.1.1 of the CTP:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). 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. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.


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Section 7.2.1.2 of the CTP:
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation 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.
Important protocol deviations 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

Incorrect intake of meal prior to drug administration in treatment periods under fed 
condition

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 BI 1358894 predose concentration is >5% Cmax value for a subject for a specific 
treatment period, that specific treatment period will be excluded

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are flagged for exclusion will 
be reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.


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Table 6.3: 1
Subject sets used for analysis of endpoints
Subject set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Safety parameters 
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
Exposure
X
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 7.3.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
Missing and Incomplete AE Dates”) (3).
Missing data and outliers of PK data are handled according to BI standards (see “Standards 
and processes for analyses performed within Clinical Pharmacokinetics/Pharmacodynamics”
(4) and “Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses of Clinical 
Studies” (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For each treatment period, the baseline value is defined as the last available off-treatment 
measurement before administration of BI 1358894 of the respective treatment period. 
Section 6.1 of the CTP: Study measurements and assessments scheduled to occur ‘before’ 
trial medication administration on Day 1 are to be performed and completed within a 3 h-
period prior to the trial drug administration.
Up to 48 h after drug administration (planned time), the acceptable deviation from the 
scheduled time for adverse event/concomitant medication questioning, suicidality assessment, 


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vital signs, ECG, and laboratory tests will be ± 30 min, if not stated otherwise in the CTP
Flow Chart,
Starting from planned time of 48 hours until 168 hours (not inclusive) after drug 
administration (and beyond) a time window of +/- 120 minutes will be allowed for all 
procedures
Starting from a planned time of 168 hours after drug administration (and beyond) a time 
window of +/- 26 hours will be allowed for all procedures
In addition the following time windows will be considered acceptable for PK sampling up to 
48 hours after each study drug administration:
Starting from planned time of 0 hours until 2 hours (not inclusive) after drug administration a 
time window of +/- 5 minutes will be allowed. Starting from planned time of 2 hours until 48
hours (not inclusive) after drug administration a time window of +/- 10 minutes will be 
allowed.
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data, vital signs data, for adverse event/concomitant 
medication questioning, suicidality assessment and ECG data will be assumed to be repeat 
measurements of the most recent scheduled measurement (e.g. for follow-up or confirmation 
of a particular value). Therefore, unscheduled measurements will be assigned to the planned 
time point of the previous scheduled measurement. 


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by the
and will be presented in Sections 15.1 to 15.4 of the CTR and in 
Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4 and Section 7.5.2) will 
also be performed by the
 and will 
be presented in Section 15.5 of the CTR and in Appendix 16.1.13.3.
Descriptive data analysis of PK endpoints and concentrations will be performed by the 
and will be 
presented in Section 15.6 of the CTR and in Appendix 16.1.13.3.
The format of the listings and tables will follow the BI standards (see “Standards for 
Reporting of Clinical Trials and Project Summaries” (6)) with the exception of those 
generated for PK-calculations following BI standards for PK/PD analysis (7).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit, except for listings regarding PK, which will be sorted by treatment, subject
number and planned time. The listings will be included in Appendix 16.2 and for PK in 
Appendix 16.1.13 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, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The descriptive statistics of concentrations will be displayed with three significant digits. 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.


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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject 
set whether they have non-missing values or not). 
Percentages will be given in integer numbers due to the small sample size of <100. The 
category missing will be displayed only if there are actually missing values.
Main comparisons of interest
The main comparisons of interest in this trial to assess relative bioavailability are the 
following:
i) Tfasted versus Rfasted
ii) Tfed versus Rfed
iii) Tfed versus Tfasted
iv) Rfed versus Rfasted
In the remaining document treatment A represents the first, and treatment B the second 
treatment of each pairwise comparison stated above.
Exclusion of PK parameters
The ADS “ADPP” (PK parameters)  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 are based on PK parameter values which are not 
flagged for exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma 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. 

"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.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies"(5) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (8)


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
The data will be summarised by treatment sequence and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Descriptive statistics are planned for this section of the CTR.
Concomitant diseases and non-drug therapies will be coded according to the most recent 
version of the coding system of the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Concomitant medication will be coded according to the most recent version of 
the World Health Organization - Drug Dictionary (WHO-DD). The coding version number 
will be displayed as a footnote in the respective output.
In the remaining document ‘therapy’ will be used for non-drug therapies and concomitant 
medications.
Section 7.2.5 CTP: Previous and concomitant therapies will be presented per treatment
sequence group.
A therapy will be considered concomitant to a treatment, if it

is ongoing at the time of study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
The diagnoses and medications will be listed. Subjects without any concomitant disease or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed or listed as a specific endpoint, but judged by 
observed analyte concentrations. Any deviation from complete food and medication intake 
will be addressed in the RPM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
For BI 1358894, the relative bioavailability will be investigated on the basis of the primary 
PK endpoints AUC0-tz and Cmax (see Section 5.1) and using the PKS.
7.4.1
Primary analysis of the primary endpoints
Section 7.2.1.2 of the CTP: The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 
for drug BI 1358894 will be calculated according to the relevant BI internal procedures.


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Section 7.2.2 of the CTP:
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: sequence, subjects within sequences, 
period and treatment. The effect 'subjects within sequences' will be considered as random, 
whereas the other effects will be considered as fixed. The model is described by the following 
equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment  
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2, 3, 4
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., 6
j = the jth period effect, j = 1, 2, 3, 4
k = the kth treatment effect, k = 1, 2, 3, 4
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where  ~ (0, 
) i.i.d.,  ~ (0, 
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (treatment A / treatment B) for the 
comparisons as stated in Section 7 and the primary endpoints (see Section 5.1) with their 
two-sided 90% confidence intervals (CIs) will be provided.
For each endpoint, the difference between the expected means for log(A)-log(B) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally, their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.


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7.5
SECONDARY ENDPOINTS
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
Other Secondary endpoint
Section 7.2.3 of the CTP: The secondary endpoint […] AUC0-∞will be calculated according 
to the relevant BI internal procedures and will be assessed statistically using the same 
methods as described for the primary endpoints.
7.7
EXTENT OF EXPOSURE
Descriptive statistics of number of doses and calculated total dose are planned for this section 
of the CTR. Only aggregated exposure of BI 1358894 will be presented as all treatments have 
the same dose. The date and time of drug administrations will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
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.


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7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs. BI 
standards as presented in “Analysis and Presentation of Adverse Event Data from Clinical 
Trials – Display Template” (9) and “Analysis and Presentation of AE data from clinical trials”
(10) will be applied. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to ‘screening’, ‘on-treatment’ or ‘follow-up’ phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This will comprise summary statistics for the 
class of AESIs.
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:
Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined 
by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
According to ICH E3 (11), in addition to deaths and serious adverse events, ‘other significant’ 
AEs need to be listed in the CTR. These will be any non-serious adverse event that led to an 
action taken with study drug (e.g. discontinuation or dose reduced or interrupted).
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 
serious AEs, for subjects with drug-related AEs, for subjects with drug-related serious adverse 
events and for subjects with AESIs. In addition, the frequency of subjects with AEs will be 
summarised by treatment, worst intensity, SOC and PT.
The SOCs and PTs within SOCs will be sorted by descending frequency over all treatment 
groups. The MedDRA version number will be displayed as a footnote in the respective output.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs that had an incidence of > 5% (in preferred terms) for at least one treatment will be 
summarised by treatment, primary SOC and PT.


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For disclosure of AE data in the EudraCT register, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards
“Handling, Display and Analysis of Laboratory Data” (12).
Analyses will be based on normalised values, which means transforming to a standard unit
and a standard reference range. The original values will be analysed if the transformation into
standard unit is not possible for a parameter.
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possibly 
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such. It is the investigator's responsibility to decide whether a lab value is 
clinically significantly abnormal or not (at the RPM at the latest). 
Descriptive statistics of laboratory data over time including change from baseline (see Section 
6.7) will be calculated by planned time point based on the worst value of the subject at that 
planned time point (or assigned to that planned time point).
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature.
Descriptive statistics of vital signs over time and for the difference from baseline (see
Section 6.7) will be provided.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment), and will be analysed as such.
No separate ECG listing will be provided.
7.8.5
Others
7.8.5.1
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 


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summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.
7.8.5.2
Body weight
Analysis of body weight at screening time point will be descriptive in nature.
7.8.5.3
C-SSRS
Section 7.2.5 of the CTP: Reports of C-SSRS will be reported as AEs as described in Section 
5.2.6.2.4 and will be summarized as such. Results of the C-SSRS will be provided as listing.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database after completion of enrolment, 
i.e. the randomization has been completed.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”, IDEA for CON.
3.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
4.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
5.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
7.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and 
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
8.
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; KMED
9.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
10. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical trials”, 
current version, KMED.
11. 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, EMA webpage.
12. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1
16-JUN-22
None
This is the final TSAP