Clinical trial NCT05934942
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2023-09-08; Completion date: 2024-02-08
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study aims to investigate the effect of multiple doses of BI 1358894 on pharmacokinetics of ethinylestradiol (EE) and drospirenone (DRSP) (Yasmin®)

Detailed description:

Arms: arm 1: All female participants were treated with 1 daily tablet of the contraceptive Yasmin® (ethinylestradiol and drospirenone) during the run-in period (Day-56 to Day-8).

Since the study was discontinued as per protocol after the run-in period, none of the participants received the intended treatments for periods 1 and 2.
Interventions: intervention 1: Yasmin® intervention 2: BI 1358894
Intervention descriptions: intervention 1: Ethinylestradiol (EE) and Drospirenone (DRSP) intervention 2: BI 1358894

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
 
Document Number:
c41232811-04
EU Trial No.
2022-502861-78-00
BI Trial No.
1402-0019
BI Investigational
Medicinal Product
BI 1358894
Title
An open-label, fixed-sequence cross-over, two-period, phase I 
trial to evaluate the effect of multiple doses of BI 1358894 on 
the pharmacokinetics of a combination of ethinylestradiol and 
drospirenone in healthy female subjects
Lay Title
A study in healthy women to test whether BI 1358894 
influences the amount of a contraceptive in the blood
Clinical Phase
I
Clinical Trial Leader
Phone: +
Investigator
Phone: +
Current Version, Date
Version 4.0, 19 Oct 2023
Original Protocol Date
06 Mar 2023
Page 1 of 84
Proprietary confidential information
© 2023 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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Test product 1
BI 1358894, film-coated tablets, dose strength 
and
dose
mode of 
administration
Oral with 240 mL of water after a continental breakfast
Test product 2
Yasmin®, film-coated tablets
dose
30 microgram ethinylestradiol + 3 milligram drospirenone q.d.
mode of admin.
Oral with 240 mL of water after a continental breakfast
Duration of treatment
Run-in period:

1 tablet of Yasmin® q.d. for 21-49 days 
Reference treatment (Period 1):

1 tablet of Yasmin® q.d on study days 1 – 21 
Test treatment (Period 2):

1 tablet of Yasmin® q.d. +1
 
on study days 1 – 21
Statistical methods
The effect of multiple doses of BI 1358894 on COC Yasmin® (EE+ DRSP) will be 
estimated by the ratios of the geometric means (test/reference) for the primary 
endpoints AUCτ,ss, Cmax,ss and secondary endpoint Cmin,ss (of EE and DRSP
separately). Additionally, two-sided 90% confidence intervals (CIs) will be 
provided. This method corresponds to the two one-sided t-test procedure, each at a 
5% significance level. Since the main focus is on estimation and not testing, a 
formal hypothesis test and associated acceptance range will not be specified. The 
statistical model will be an analysis of variance (ANOVA) on the logarithmic scale 
including effects for “subjects” and “treatment”. CIs will be calculated 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 plasma, BI 1358894
PK plasma, COC
Exploratory PD serum11
12-lead ECG
Vital signs (BP, PR)
Suicidality Assesessment10
Questioning for AEs and concomitant therapy 5
SCR
1
-91 to -
35
Screening (SCR)1
A6
x
x
x
Run
-in7
2
-56 to -
8
Self-administration of COC
x8
x
-7 to -1
Follow up call (COC free 
interval)
x
Period 1
3
1
0:00
08:00
Dosing COC12
B8
x9
x9
x
2
24:00
08:00
Dosing COC12
x
3
48:00
08:00
Dosing COC12
x
4
72:00
08:00
Dosing COC12
x
5
96:00
08:00
Dosing COC12
x
6
120:00
08:00
Dosing COC12
x
7
144:00
08:00
Dosing COC12
x
8
168:00
08:00
Dosing COC12
x
9
192:00
08:00
Dosing COC12
x
10
216:00
08:00
Dosing COC12
x8
x
11
240:00
08:00
Dosing COC12
x
12
264:00
08:00
Dosing COC12
x
13
288:00
08:00
Dosing COC12
x
14
312:00
08:00
Dosing COC12
x
15
336:00
08:00
Dosing COC12
x
16
360:00
08:00
Dosing COC12
x
17
384:00
08:00
Dosing COC12
x
18
408:00
08:00
Dosing COC12
x
19
432:00
08:00
Dosing COC12
x
20
456:00
08:00
Dosing COC12
x
466:00
18:00
Admission to trial site
x8
x
x
21
479:30
07:30
Start of continental breakfast
x
480:00
08:00
Dosing COC12
x9
x9
x
480:30
08:30
x
x
481:00
09:00
x
x
481:30
09:30
x
x
482:00
10:00
240 mL fluid intake 
x
x
482:30
10:30
x
x
483:00
11:00
x
x
483:30
11:30
x
x
484:00
12:00
240 mL fluid intake, Lunch3
x
x


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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 plasma, BI 1358894
PK plasma, COC
Exploratory PD serum11
12-lead ECG
Vital signs (BP, PR)
Suicidality Assesessment10
Questioning for AEs and concomitant therapy 5
485:00
13:00
x
x
486:00
14:00
x
x
488:00
16:00
Snack (voluntary)3
x
x
490:00
18:00
x
x
492:00
20:00
Dinner3
x
x
22
504:00
08:00
Breakfast3, discharge from trial 
site
x
x
x
x
23-28
Follow-up call (COC free 
interval)
x
Period 2
4
1
0:00
08:00
Dosing COC + BI 1358894 12
B8
x9
x9
x2
x
2
24:00
08:00
Dosing COC + BI 1358894 12
x
3
48:00
08:00
Dosing COC + BI 1358894 12
x
4
72:00
08:00
Dosing COC + BI 1358894 12
x
5
96:00
08:00
Dosing COC + BI 1358894 12
x
6
120:00
08:00
Dosing COC + BI 1358894 12
x
7
144:00
08:00
Dosing COC + BI 1358894 12
x2
x
8
168:00
08:00
Dosing COC + BI 1358894 12
x
9
192:00
08:00
Dosing COC + BI 1358894 12
x
10
216:00
08:00
Dosing COC + BI 1358894 12
x8
x
11
240:00
08:00
Dosing COC + BI 1358894 12
x
12
264:00
08:00
Dosing COC + BI 1358894 12
x
13
288:00
08:00
Dosing COC + BI 1358894 12
x
14
312:00
08:00
Dosing COC + BI 1358894 12
x2
x
15
336:00
08:00
Dosing COC + BI 1358894 12
x
16
360:00
08:00
Dosing COC + BI 1358894 12
x
17
384:00
08:00
Dosing COC + BI 1358894 12
x
18
408:00
08:00
Dosing COC + BI 1358894 12
x9
x
19
432:00
08:00
Dosing COC + BI 1358894 12
x9
x
20
456:00
08:00
Dosing COC + BI 1358894 12
x9
x
466:00
18:00
Admission to trial site
x8
x
x2
x
21
479:30
07:30
Start of continental breakfast
x
480:00
08:00
Dosing COC + BI 1358894 12
x9
x9
x9
x
480:30
08:30
x
x
481:00
09:00
x
x
481:30
09:30
x
x
482:00
10:00
240 mL fluid intake
x
x
482:30
10:30
x
x
483:00
11:00
x
x
483:30
11:30
x
x
484:00
12:00
240 mL fluid intake, Lunch3
x
x
485:00
13:00
x
x


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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 plasma, BI 1358894
PK plasma, COC
Exploratory PD serum11
12-lead ECG
Vital signs (BP, PR)
Suicidality Assesessment10
Questioning for AEs and concomitant therapy 5
486:00
14:00
x
x
488:00
16:00
Snack (voluntary)3
x
x
490:00
18:00
x
x
492:00
20:00
Dinner3
x
x
22
504:00
08:00
Breakfast3, discharge from trial 
site
x
x
x
x
x
23-28
Follow-up call (COC free 
interval)
x
x
EoS
5
42 to 
52
End of study (EoS) examination4
C6
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 and 
cotinine test), demographics (including determination of body height and weight, smoking status and alcohol history), 
relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. In addition, a gynaecological 
examination will be performed prior to trial entry.
2.
Pre-dose
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, body weight, vital 
signs, ECG, safety laboratory, recording of AEs and concomitant therapies. 
5.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
6.
Including hematology, biochemistry, coagulation, urinalysis, drug screen (only at screening), cotinine test (only at 
screening) and serum pregnancy test. 
7.
The intake of Yasmin® starts depending on the subjects’ actual menstruation cycle and at least -28 days before Day 1 
of first treatment period. In the run-in period, the subjects will take one tablet of COC daily until Day -8. On Day - 7 to 
Day -1 no COC tablets will be given in order to induce withdrawal bleeding. Self-administration in the morning with 
no requirement of fasting. Self-administration to be documented in the diary. A negative urine pregnancy test should 
be performed at the site 1 to 7 days before start of the run-in. Details are outlined in Section 4.1.4
8.
Urine pregnancy test. Additional urine drug screening on day 20 of each period.
9.
Blood collection takes place within 10 minutes before dosing. 
10.
Suicidality assessment using the Columbia-Suicidal Severity Rating Scale (C-SSRS): ‘Screening/Baseline’ version at 
Visit 1, and ‘since last visit’ version at other visits.
11.
Measurement of exploratory pharmacodynamic parameters: estradiol, luteinizing hormone (LH), follicle stimulating 
hormone (FSH), and progesterone. The samples will be taken in duplicate.
12.
Dosing at the trial site after a continental breakfast (for details see Section 4.1.4).


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS AND DEFINITIONS..................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
1.2.1
BI1358894 ..............................................................................................15
1.2.2
Yasmin® (ethinylestradiol + drospirenone)........................................17
1.2.2.1
Ethinylestradiol........................................................................17
1.2.2.2
Drospirenone............................................................................17
1.2.2.3
Safety
...................................................................................18
1.2.3
Residual Effect Period..........................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................19
1.4
BENEFIT - RISK ASSESSMENT ...................................................................20
1.4.1
Benefits...................................................................................................20
1.4.2
Risks .......................................................................................................20
1.4.3
Discussion...............................................................................................24
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......26
2.1.1
Main objective.......................................................................................26
2.1.2
Primary endpoints ................................................................................26
2.1.3
Secondary endpoint ..............................................................................26
2.2.2.3
Safety and tolerability..............................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 28
3.1
OVERALL TRIAL DESIGN............................................................................28
3.2
DISCUSSION OF TRIAL DESIGN.................................................................28
3.3
SELECTION OF TRIAL POPULATION ......................................................29
3.3.1
Main diagnosis for trial entry..............................................................29
3.3.2
Inclusion criteria...................................................................................29
3.3.3
Exclusion criteria ..................................................................................30
3.3.4
Withdrawal of subjects from treatment or assessments ...................32


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3.3.4.1
Withdrawal from trial treatment ..............................................33
3.3.4.2
Withdrawal of consent to trial participation ............................34
3.3.4.3
Discontinuation of the trial by the sponsor..............................34
3.3.5
Replacement of subjects .......................................................................34
4.
TREATMENTS........................................................................................ 36
4.1
INVESTIGATIONAL TREATMENTS ..........................................................36
4.1.1
Identity of the Investigational Medicinal Products ...........................36
4.1.2
Selection of doses in the trial................................................................36
4.1.3
Method of assigning subjects to treatment groups ............................36
4.1.4
Drug assignment and administration of doses for each subject .......37
4.1.5
Blinding and procedures for unblinding ............................................38
4.1.6
Packaging, labelling, and re-supply ....................................................38
4.1.7
Storage conditions.................................................................................39
4.1.8
Drug accountability ..............................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................40
4.2.1
Other treatments and emergency procedures....................................40
4.2.2
Restrictions............................................................................................40
4.2.2.1
Restrictions regarding concomitant treatment .........................40
4.2.2.2
Restrictions on diet and life style.............................................40
4.2.2.3
Contraception requirements.....................................................40
4.3
TREATMENT COMPLIANCE.......................................................................41
5.
ASSESSMENTS....................................................................................... 42
5.1
ASSESSMENT OF EFFICACY.......................................................................42
5.2
ASSESSMENT OF SAFETY............................................................................42
5.2.1
Physical examination ............................................................................42
5.2.2
Vital signs...............................................................................................42
5.2.3
Safety laboratory parameters..............................................................42
5.2.4
Electrocardiogram................................................................................45
5.2.5
Other safety parameters.......................................................................46
5.2.5.1
Suicidality assessment .............................................................46
5.2.6
Assessment of adverse events...............................................................47
5.2.6.1
Definitions of adverse events...................................................47
5.2.6.1.1 Adverse event ............................................................47
5.2.6.1.2 Serious adverse event ................................................48
5.2.6.1.3 AEs considered ‘Always Serious’.............................48
5.2.6.1.4 Adverse events of special interest .............................48
5.2.6.1.5 Intensity (severity) of AEs.........................................49
5.2.6.1.6 Causal relationship of AEs ........................................49
5.2.6.2
Adverse event collection and reporting ...................................50


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5.2.6.2.1 AE collection.............................................................50
5.2.6.2.2 AE reporting to the sponsor and timelines ................51
5.2.6.2.3 Pregnancy ..................................................................51
5.2.6.2.4 AE reporting from suicidality assessment.................51
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................52
5.3.1
Assessment of pharmacokinetics .........................................................52
5.3.2
Methods of sample collection...............................................................52
5.3.2.1
Blood sampling for pharmacokinetic analysis of 
ethinylestradiol and drospirenone............................................52
5.3.2.2
Blood sampling for pharmacokinetic analysis of BI 1358894.52
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................53
5.4
ASSESSMENT OF BIOMARKERS................................................................53
5.4.1
Drug-Drug Interaction Biomarkers ....................................................53
5.4.2
Exploratory pharmacodynamic biomarkers......................................54
5.4.2.1
Methods of sample collection..................................................54
5.4.3
Pharmacogenomic biomarkers............................................................54
5.5
BIOBANKING ...................................................................................................54
5.6
OTHER ASSESSMENTS .................................................................................54
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................54
6.
INVESTIGATIONAL PLAN.................................................................. 55
6.1
VISIT SCHEDULE............................................................................................55
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................55
6.2.1
Screening and run-in period ................................................................55
6.2.2
Treatment periods.................................................................................56
6.2.3
Follow-up period and trial completion ...............................................56
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 57
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................57
7.2
PLANNED ANALYSES....................................................................................57
7.2.1
General considerations.........................................................................57
7.2.1.1
Analysis sets.............................................................................57
7.2.1.2
Pharmacokinetics.....................................................................58
7.2.2
Primary endpoint analyses...................................................................59
7.2.3
Secondary endpoint analyses ...............................................................59


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7.2.5
Safety analyses.......................................................................................60
7.2.6
Interim analyses ....................................................................................61
7.3
HANDLING OF MISSING DATA ..................................................................62
7.3.1
Safety......................................................................................................62
7.3.2
Pharmacokinetics..................................................................................62
7.4
RANDOMISATION ..........................................................................................62
7.5
DETERMINATION OF SAMPLE SIZE ........................................................62
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 64
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................64
8.2
DATA QUALITY ASSURANCE .....................................................................65
8.3
RECORDS..........................................................................................................65
8.3.1
Source documents .................................................................................65
8.3.2
Direct access to source data and documents.......................................66
8.3.3
Storage period of records.....................................................................66
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................67
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......67
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................67
8.6
TRIAL MILESTONES .....................................................................................68
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................68
9.
REFERENCES......................................................................................... 70
9.1
PUBLISHED REFERENCES...........................................................................70
9.2
UNPUBLISHED REFERENCES.....................................................................72
10. APPENDICES .......................................................................................... 74
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................74
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 80
11.1
GLOBAL AMENDMENT 1 .............................................................................80
11.2
GLOBAL AMENDMENT 2 .............................................................................82
11.3
GLOBAL AMENDMENT 3 .............................................................................84


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ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC
Area under curve
AUC0-24h
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to 24 hours
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at 
steady state over a uniform dosing interval τ
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
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline personality disorder
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady 
state
Cmin
Minimum measured concentration of the analyte in plasma
Cmin,ss
Minimum measured concentration of the analyte in plasma at steady state
COC
Combined oral contraceptive
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
C-SSRS
Colombia-Suicidal Severity Rating Scale
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450
DDI
Drug-drug interaction
DILI
Drug induced liver injury
DRSP
Drospirenone
ECG
Electrocardiogram
eCRF
Electronic case report form
EE
Ethinylestradiol
eDC
Electronic data capture 


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EDTA
Ethylenediaminetetraacetic acid
EoS
End of Study (synonym for End of Trial)
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLP
Good Laboratory Practice
gMean
Geometric mean
IB
Investigator’s brochure
ICH
International Council for Harmonisation
iCF
Intended commercial formulation
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LH
Luteinizing hormone
MDA
Methylenedioxyamphetamine
MDD
Major depressive disorder
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NOAEL
No observed adverse effect level
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PTSD
Post-traumatic stress disorder
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
ss
(at) steady state










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1.2.2
Yasmin® (ethinylestradiol + drospirenone)
1.2.2.1
Ethinylestradiol
Ethinylestradiol (EE) is a synthetic estrogen with actions similar to those of estradiol. It is
frequently used as the estrogenic component of combined oral contraceptives; a typical daily
dose is 20 to 40 μg. Ethinylestradiol has also been used for hormone replacement therapy. 
Ethinylestradiol is also used for the treatment of female hypogonadism and the palliative 
treatment of prostate cancer and malignant breast cancer.
The adverse effects of EE and other estrogens are related, in part, to dose and duration of 
therapy, and to the sex and age of the recipient. In addition, adverse effects may be modified 
by administration of progestogen in combined oral contraceptives or hormone replacement 
therapy. Whether adverse effects of natural and synthetic estrogens differ, and whether the 
route of administration has an effect, is less clear. The use of estrogens in girls may cause 
premature closure of the epiphyses resulting in decreased final adult height. Large doses of 
estrogens used in palliative care have also been associated with nausea, fluid retention, 
venous and arterial thrombosis, and cholestatic jaundice. In men, large doses of estrogen 
cause impotence and feminising effects such as gynaecomastia. In women, uterine bleeding 
may occur after the cessation of estrogen therapy.
Ethinylestradiol is rapidly and well absorbed from the gastrointestinal tract with maximum
plasma concentrations occurring after 1 h. The presence of an ethinyl group at the 17-position
greatly reduces hepatic first-pass metabolism compared with estradiol, enabling the
compound to be much more active after oral dosing, but there is some initial conjugation by
the gut wall and systemic bioavailability is only about 45% (20-65%). Ethinylestradiol is
highly protein bound (98%), but unlike naturally occurring estrogens which are mainly bound
to sex-hormone binding globulin, it is principally bound to albumin. The apparent volume of
distribution is 2.8 to 8.6 L/kg. It is metabolised in the liver by hydroxylation (mediated by
CYP3A4) followed by glucuronidation (UGT1A1) and sulfatation of metabolites that
undergo enterohepatic recycling. Metabolites are excreted via urine (40%) and bile (60%).
The terminal half-life of ethinylestradiol is 10 to 20 h [R13-3708].
For a more detailed description of ethinylestradiol, please refer to the SmPC of Yasmin®
[R23-0484].
1.2.2.2
Drospirenone
Drospirenone (DRSP) is a synthetic progestin used in oral contraceptives for the prevention 
of pregnancy. It is commonly found in combination with EE in combined oral contraceptives 
(COC). Aside from its contraceptive effects, DRSP is used with estrogens to control acne and 
premenstrual dysphoric disorder. DRSP and EE in combination inhibit the release of follicle 
stimulating hormone (FSH) and luteinizing hormone (LH), resulting in ovulation suppression. 
Other changes include changes in the cervical mucus consistency, hindering sperm movement 
and preventing embryo implantation. DRSP is an analog of the diuretic spironolactone, which 
means that DRSP has ant mineralocorticoid activity. Therefore, DRSP should not be used in 
patients with renal or hepatic impairment or adrenal insufficiency. Progesterone and the 
progestogens may cause gastrointestinal disturbances, changes in appetite or weight, fluid 


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retention, oedema, acne, chloasma (melasma), allergic skin rashes, urticaria, mental 
depression, breast changes including discomfort or occasionally gynaecomastia, changes in 
libido, hair loss, hirsutism, fatigue, drowsiness or insomnia, fever, headache, premenstrual 
syndrome-like symptoms, and altered menstrual cycles or irregular menstrual bleeding. 
Anaphylaxis or anaphylactoid reactions may occur rarely (<0.01%).
After an oral dose DRSP is rapidly absorbed, with a bioavailability of about 76% due to first-
pass effect. It is about 97% bound to plasma proteins, likely to albumin. The maximum 
concentration occurs within 1 to 2 hours. It is heavily metabolized with a terminal half-life of 
about 30 to 40 hours. DRSP undergoes oxidative metabolism via the hepatic cytochrome 
enzyme CYP3A4. The metabolites are excreted in urine and faeces. [R23-0688].
For a more detailed description of drospirenone, please refer to the SmPC of Yasmin®
[R23-0484].
1.2.2.3
Safety
Combined oral contraceptives (COC) including Yasmin® should not be used in the following 
conditions. Should any of the conditions appear for the first time during COC use, the 
product should be stopped immediately.

Presence or risk of venous thromboembolism (VTE)

Presence or risk of arterial thromboembolism (ATE)

Presence or history of severe hepatic disease or liver tumors

Current or history of breast cancer

Hypersensitivity to the active substances or to any of the excipients
The frequency of diagnosis of breast cancer is very slightly increased among COC users. As 
breast cancer is rare in women under 40 years of age the excess number is small in relation to 
the overall risk of breast cancer. Causation with COC use is unknown.
The most common adverse events with Yasmin® are nausea, headache, migraine, depressed 
mood, menstrual cycle alteration, breast tenderness, vaginal discharge and candidiasis 
vulvovaginal altered mood, breast pain, and breast tenderness. 
Less common adverse events are changes in the libido, hypertension, hypotension, vomiting, 
diarrhoea, acne, eczema, pruritus, alopecia, breast hypertrophy, vaginal infections, fluid 
retention and weight changes.
Rare adverse events are hypersensitive reactions, asthma, hearing loss, venous and arterial 
thromboembolism, erythema nodosum, erythema multiforme and discharge of the mammary 
glands.
Drospirenone, as many other progestogens, has been linked to increased risk of venous 
thromboembolism [R23-0501] A statement from FDA concluded that the increase in the risk 
of thromboembolism resulting from the use of drospirenone remains unclear; in its statement, 
the FDA mentioned that increased risk of venous thromboembolism with oral contraceptives 
such as drospirenone exists but remains lower than the risk of this condition during 
pregnancy and during the postpartum period [R23-0680].








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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: Yasmin®
Increased risk of tumors
Some epidemiologic data 
suggest the presence of 
increased incidence of cervix
carcinoma. The data is not 
clear in this respect (SmPC of 
Yasmin).
A metanalysis of 54 
epidemiologic studies showed 
a light increase risk (RR = 
1.24) in breast cancer in 
women who take COC. The 
risk goes back to baseline 
within 10 years of stopping the 
COC [R23-0484]. 
In rare cases it was observed
the presence of malignant liver 
neoplasms in women taking 
COCs [R23-0484].
- Close monitoring of signs and 
symptoms that suggest the 
presence of malignancy
- Subjects with a recent history 
of malignancy within 5 years 
(except appropriately treated 
basal cell carcinoma of the skin) 
will be excluded from 
participation. Subjects with any 
history of breast cancer will be 
excluded from the trial.
Risk of hyperkalaemia
Due to the aldosterone 
agonism of drospirenone
possible increase in the kalium 
concentration can occur. This 
is particularly important in 
patients with mild to moderate 
renal insufficiency 
[R23-0484].
- Only subjects with normal 
kidney function will be allowed 
in the trial
The most frequent side 
effects of Yasmin® are:
- Headache
- Migraine
- Nausea
- Spotting and intermenstrual
bleeding
- Irregularities of menstrual
cycle 
- Breast tenderness
- Depressive mood
- Vulvovaginal candidiasis
Menstrual changes associated 
with the use of oral 
contraceptives include 
reduction of menstrual flow 
and missed menstruation. 
Intermenstrual bleeding may 
occur but normally ceases 
spontaneously.
Based on SmPC of Yasmin®
[R23-0484]
- Symptomatic treatment of 
headache and breast tenderness 
if required
- Treatment of vulvovaginal 
candidiasis if required
- Treatment with Yasmin®
should be continued even if
irregular bleeding occurs as it 
normally ceases spontaneously
- If irregular bleeding is
persistent, appropriate diagnostic 
measures to exclude an organic 
cause are indicated
- Women with history of 
migraine or major depressive
disorder will be excluded


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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: Yasmin®
The following undesirable 
effects have been observed: 
- Changes in libido
- Hypertension
- Hypotension
- Vomiting
- Diarrhea
- Acne, Eczema, pruritus,
alopecia
- Breast hypertrophy
- Vaginal infection
- Fluid retention
- Weight changes
Based on SmPC of Yasmin®
[R23-0484]
- Increased awareness of 
symptoms
- Symptomatic treatment if 
required
- If required, further diagnostics 
and treatment have to be initiated 
according to local standard of 
care
Drug-drug interaction 
between Yasmin® and other 
drugs
CYP3A4 inhibitors or inducers 
may impact the exposure of 
oral contraceptives. Whereas 
an increase of exposure may 
increase the number and 
intensity of side effects, a 
decrease would result in 
reduced efficacy.
Subjects will not be allowed to 
use other drugs which may 
interfere with Yasmin® in 
accordance to the SmPC within 
30 days before start of run-in 
period (including moderate and 
strong CYP3A4 inhibitors, 
CYP3A4 inducers, grapefruit 
juice, St. John’s wort 
(Hypericum perforatum), etc.)






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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objective
The main objective of this trial is to investigate the effect of multiple oral doses of BI 
1358894 on pharmacokinetics of ethinylestradiol (EE) and drospirenone (DRSP) (Yasmin®).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for ethinylestradiol and 
drospirenone:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over the uniform dosing interval τ),

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over
the uniform dosing interval τ)
2.1.3
Secondary endpoint

Cmin,ss (minimum measured concentration of the analyte in plasma at steady state over
the uniform dosing interval τ)


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2.2.2.3
Safety and tolerability
Safety and tolerability of BI 1358894 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)

Suicidality assessment (C-SSRS)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a non-randomised, open-label, two-period, fixed sequence trial 
with run-in period in healthy female subjects in order to compare the test treatment (T) to the 
reference treatment (R).
Reference (R): one tablet of Yasmin® q.d. after a continental breakfast on Days 1-21 in 
Period 1.
Test (T): one tablet of Yasmin® q.d. + one tablet of BI 1358894 25 mg q.d. + two tablets of 
BI 1358894 50 mg q.d. after a continental breakfast on Days 1-21 in Period 2.
The Reference Treatment will always be followed by the Test Treatment in a fixed sequence. 
There will be no wash-out period between the treatments.
All subjects will undergo a run-in period that starts between Day -56 and Day -28. In this 
period, the subjects will take one tablet of Yasmin® daily until Day -8.
In the last 7 days of each treatment period (i.e., Day 22 to Day 28) and the run-in period (i.e. 
Day -7 to Day -1) no treatment will be given in order to induce bleeding.
For details, refer to Section 4.1.
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 Section 6.1 and 6.2, respectively.
Figure 3.1: 1 Trial design
3.2
DISCUSSION OF TRIAL DESIGN
For this DDI-trial, a fixed-sequence design was chosen to ensure that pharmacokinetic 
parameters of the respective investigational drugs would be determined in all subjects at 
approximately the same time point of the menstrual cycle. In this regard BI 1358894 is 




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1. Healthy premenopausal female subjects according to the assessment of the 
investigator, as based on a complete medical history including a physical and 
gynaecological examination, vital signs (BP, PR), 12-lead ECG, and clinical 
laboratory tests
2. Age of 18 to 35 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
5. Female subject who meet any of the following criteria for a highly effective 
contraception from at least 30 days before the first administration of trial 
medication until 30 days after trial completion:
-
Use of an oral hormonal contraception method in combination with a barrier
contraception method and willing to stop the hormonal method and to continue 
using the barrier method plus Yasmin® for the duration of the trial
-
Use of non-hormonal intrauterine device (IUD)
-
Sexually abstinent
-
Female subject who underwent tubal ligation
-
A vasectomised sexual partner who received medical assessment of the 
surgical success (documented absence of sperm) and provided that partner is the 
sole sexual partner of the trial participant
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) deviating from 
normal and assessed as clinically relevant by the investigator (e.g. pronounced 
varicosis, thrombophlebitis, and evidence of peripheral circulatory disturbances)
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 50 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 assessed as clinically relevant by the 
investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, 
immunological or hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere 
with the pharmacokinetics of the trial medication (except appendectomy or simple 
hernia repair)


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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. Relevant chronic or acute infections
10. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma of the 
skin
11. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients) 
12. Use of drugs within 30 days prior to treatment allocation that might reasonably 
influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
13. Intake of an investigational drug in another clinical trial within 60 days prior to
treatment allocation, or concurrent participation in another clinical trial in which 
investigational drug is administered
14. Smoker (former smokers must have stopped smoking at least 6 months before 
screening) or positive cotinine test at screening
15. Alcohol abuse (consumption of more than 12 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days prior to treatment allocation
or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to 
treatment allocation or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked prolongation of QT/QTcF interval (such as QTcF intervals that are 
repeatedly greater than 470 ms in females) or any other relevant ECG finding at 
screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance,
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the 
study 
23. Lactation or pregnancy within the last 6 months, or plans to become pregnant 
during the trial or within 30 days after trial completion
24. Positive pregnancy test
In addition, the following trial-specific exclusion criteria apply:


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25. Use of drugs which may interfere with Yasmin® in accordance to the SmPC within 
30 days prior to treatment allocation (including moderate and strong CYP3A4 
inhibitors, CYP3A4 inducers, St. John’s wort, etc.)
26. Use of other hormone-containing methods of contraception except Yasmin® per 
trial protocol, e.g. hormone-containing intrauterine device, depot injection or 
contraceptive implants. Subjects taking oral contraceptives other than Yasmin®
will be allowed to participate as long as they agree to stop their current oral 
contraceptive and accept taking Yasmin® for the duration of the trial. 
27. History of confirmed venous thromboembolism, family history of venous 
thromboembolism, and other known risk factors for venous thromboembolism
28. History of malignancy within 5 years (except appropriately treated basal cell 
carcinoma of the skin). Any history of breast cancer will lead to exclusion.
29. History or evidence of arterial thrombotic or embolic processes, conditions which 
predispose to them (such as disorders of the clotting processes, valvular heart 
disease, atrial fibrillation, autoimmune diseases, dyslipidaemia, etc.)
30. History of migraine in the past 5 years
31. History of relevant liver diseases (e.g. disturbances of liver function, jaundice or 
persistent itching during a previous pregnancy, Dubin-Johnson syndrome, Rotor 
syndrome, or previous or existing liver tumours)
32. History of bipolar mood disorder, bulimia or anorexia
33. History of suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. 
active suicidal thought, active suicidal thought with method, active suicidal 
thought with intent but without specific plan, or active suicidal thought with plan 
and intent) or any suicide attempt in the past 24 months (i.e. actual attempt, 
interrupted attempt) prior to screening
34. History of major depressive disorder
35. Clinically relevant finding in the gynaecological anamnesis, gynaecological 
examination which in the opinion of the gynaecologist oppose the prescription of 
Yasmin®
36. Clinically relevant result of the cervical smear
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Section 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).


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If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.3), the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to 
explain the reasons but has the right to refuse to answer
2. The subject has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of both, the investigator and sponsor representative,
the safety of the subject cannot be guaranteed as she is not willing or able to adhere 
to the trial requirements in the future. For details regarding missed visits see 
Section 6.1.
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as 
pregnancy, surgery, adverse events (AEs), or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and 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
6. Suicidal ideation (type 2-5) or any suicidal behaviour based on C-SSRS 
questionnaires during the trial
7. The subject experiences a drug-related adverse event of severe intensity or a 
serious adverse event
8. In addition to these criteria, the investigator may discontinue subjects at any time 
based on his or her clinical judgment.
9. If it is known that a subject becomes pregnant during the trial, administration of the 
trial medication is to be stopped immediately, and the subject is to be removed 
from the trial. The subject is to be followed until she has given birth or until the 
end of the pregnancy. The subject’s data are to be collected until the end of the trial 
(last visit of last subject) and reported in the CTR. For reporting of pregnancy and 
associated events, refer to Section 5.2.6.2.3.
10. If new efficacy or safety information becomes available, Boehringer Ingelheim 
will review the benefit-risk-assessment and, if needed, pause or discontinue the 




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replacements (after starting period 1) may not exceed 1/3 of the total number of evaluable 
subjects anticipated to complete the trial. A replacement subject will be assigned a unique 
trial subject number (or Subject Identification Number).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product 1 are given below:
Substance:
BI 1358894
Pharmaceutical formulation:
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
 
Posology:
Mode of administration:
Duration of use:
21 days q.d. (once daily) in Period 2
The characteristics of the test product 2 are given below:
Name:
Yasmin®
Substance:
ethinylestradiol (EE) and drospirenone (DRSP)
Pharmaceutical formulation: Film-coated tablet
Source:
Unit strength:
30 ug EE + 3 mg DRSP
Posology:
1-0-0
Mode of administration:
Oral
Duration of use:
21 days q.d. followed by 7 days of no treatment in of Periods 1 
and 2. In the run-in period, up to 49 days q.d. followed by 7 
days of no treatment. For details, refer to Section 3.1 and 4.1.4.
4.1.2
Selection of doses in the trial
The dose of 30 μg EE and 3 mg DRSP selected for this trial is the standard clinical dose and 
is sufficient to achieve the relevant plasma exposure for evaluation of a possible drug-drug 
interaction.
The dose of 
of BI 1358894 is the highest dose currently tested in Phase II clinical 
trials.
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in this trial, and each subject will be 
allocated to the same treatment sequence (R-T). The subjects will be allocated to a trial 




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medication, and – if applicable – its preparation, if correct dosage cannot be ensured 
otherwise. The composition of the continental breakfast is detailed in Table 4.1.4: 2. For 
restrictions with regard to diet, see Section 4.2.2.2.
Table 4.1.4: 2
Composition of the light (standard continental) breakfast
Ingredients
kcal
1 bread roll
164
15 g butter 
113
1 slice of Gouda cheese (approximately 40g)
146
20 g of curd cheese (approximately)
33
1 cup of decaffeinated coffee or tea (without sugar)
2
Sum1
458
1
The total caloric content was supplied approximately as following: 88 kcal as protein, 133 kcal 
as carbohydrate, and 237 kcal as fat.
During the in-house stays subjects will be kept under close medical surveillance until 24 h 
after drug administration. During the first 4 h after drug administration on day 21 of both 
periods, subjects are not allowed to lie down (i.e. no declination of the upper body of more 
than 45 degrees from upright posture).
There will be no wash-out phase between the run-in period and both treatment periods. No 
Yasmin® tablets are to be taken in the last 7 days of each of Period 1 and Period 2 in order to 
induce bleeding.
4.1.5
Blinding and procedures for unblinding
This non-randomised open-label Phase I trial will be handled in an open fashion throughout. 
The treatment assignment will be available to all involved parties.
4.1.6
Packaging, labelling, and re-supply
BI 1358894
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).
The label will be prepared according to Regulation (EU) No 536/2014, Annex 6, Section D.8. 
omitting certain particulars with the following justifications:
The investigator name was omitted from the label because it is included on the Trial 
Identification Card (TIC), which will be issued to each trial participant.
The "keep out of reach of children" statement was omitted from the label because the product 
will remain at the clinical site.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EU Trial number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 


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No re-supply is planned.
Yasmin®
Yasmin® tablets are manufactured by 
and have a 
market authorisation. Yasmin® will be obtained by the clinical trial site from a public
pharmacy. The drug will be dispensed out of the original, unmodified packages.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If 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 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor or 
delegate and the investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Delegation List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee 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.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.


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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, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. 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 results of medical 
evaluations are acceptable.
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 trial days) on the appropriate pages of the CRF.
Occasional use of paracetamol or ibuprofen to treat pain could be allowed after consultation 
with the investigator. 
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
On day 21 of each treatment period additional 240 mL of water at 2 h and 4 h post-dose will 
be provided (mandatory for all subjects). From lunch until 24 h post-dose, total fluid intake is 
restricted to 3000 mL.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of the second trial period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during in-house confinement in both treatment periods.
Smoking is not allowed.
Excessive physical activity (such as competitive sport) is not allowed from 7 days before the 
first administration of trial medication until the end of trial examination.
4.2.2.3
Contraception requirements
Since all participants in this trial will be female subjects of child-bearing potential, adequate 
contraception is to be maintained throughout the course of the trial (see Section 3.3.2 for the 
definition of adequate measures).


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in periods 1 and 2 in the 
trial centre under supervision of the investigating physician or a designee. The measured 
plasma concentrations of trial medication 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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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
Erythrocyte Sedimentation Rate 1 h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalization Ratio)
X
X
X 
--
--
--
--
--
--
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
--
--
Hormones
Thyroid Stimulating Hormone
Estradiol
LH (Luteinizing hormone)
FSH (follicle stimulating hormone)
Progesterone
X
X
X   
X
X
--
--
--
--
--
--
--
--
--
--


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
Uric Acid 
Cholesterol, total
Cholesterol, HDL
Cholesterol, LDL
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
X
X
X
X
--
--
--
--
--
X
X
--
X
X
X
X
--
--
--
--
--
Electrolytes
Sodium
Potassium
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine HGB (qual)
Urine leukocyte esterase (qual)
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)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined on Day 1 of each period (for time points refer to Flow Chart)
C: parameters to be determined at Visit 5 (end of trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that 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 pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing will be performed at screening, prior to run-in, prior 
to each treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and on day 20 of each treatment period.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
THC
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Morphine (MOP)
Phencyclidine
Tricyclic antidepressants
Cotinine test (urine)
Cotinine (metabolite of nicotine) in urine
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (blood/urine)1
Beta human chorionic gonadotropin (beta-HCG)
Cervical smear
Papanicolaou test
1 Pregnancy test in serum at screening and EoS and in urine at the beginning of run-in, at the beginning of 
each period and on days 10 and 20 of each period.
To encourage compliance with alcoholic restrictions, a breath alcohol test (
 Alcotest®, 
) will be performed prior to admission to trial site on day 20 and 
may be repeated at any time during the trial at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
, with the exception of drug screening, cotinine test and urine pregnancy 
tests. These tests will be performed at the trial site using SURESTEP Urine Drug Test, 
Cotinine SureStep Test by 
 TestPackTM Plus hCG Urine Test with OBC, 
respectively, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4).
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, 
 
 at the times provided in the Flow Chart. 


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To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
. Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Suicidality assessment
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behaviour and ideation [R08-1147]. 
The C-SSRS interview may be administered by a physician or a study nurse with C-SSRS 
training. It has a typical duration of five minutes, and causes only a low burden on subjects. 
At a minimum, the interview consists of 2 screening questions related to suicidal ideation and 
4 related to suicidal behaviour, and may be expanded to up to 17 items in case of positive 
responses. Free text entries are allowed.
The C-SSRS has been widely used in large multinational CTs. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and 
behaviour will also be recorded. See Section 10.1 for the original English C-SSRS. For this 
trial, the paper version of the respective German translation will be used. After the screening 
visit, the ‘since last visit’ version is used for the suicidality assessment at the time points 
indicated in the Flow Chart.
Positive reports are generated for any of the following findings:
Suicidal ideation

Suicidal ideation with intention to act (type 4)


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
Suicidal ideation with specific plan and intent (type 5)
Suicidal behavior

Completed suicide

Suicide attempt

Interrupted attempt

Aborted attempt

Preparatory actions toward imminent suicidal behaviors.
Negative reports of suicidal ideation are defined as reports when there are no indications of 
the above, i.e. suicidal ideation of type 1-3.
The investigator is to review positive and negative reports for plausibility and clinical
relevance. Doubtful reports may be repeated or reports may be validated by a consulting
psychiatrist.
If there is a confirmed positive report of suicidal behaviour or suicidal ideation type 4 or 5
after start of trial, the investigator is to immediately interview the subject during the clinic
visit, and/or is to consult a psychiatrist. If the positive report is confirmed, appropriate actions
for the subject’s safety have to be initiated.
For details regarding AE reporting see section 5.2.6.2.4
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.


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5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
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. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in Section 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI


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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
These lab findings constitute a hepatic injury alert and the subjects 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 that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, 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)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)


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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

There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
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. 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 carefully 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, intensity of the event, and 
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 until an individual subject’s end of trial
(the End of Study (EoS) visit): 
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 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.


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
After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific reporting process will be 
provided in the ISF. The same timeline applies if follow-up information becomes available. 
On specific occasions, the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send 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. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.2.6.2.4
AE reporting from suicidality assessment
All positive reports from C-SSRS suicidality assessment (see Section 5.2.5.1), i.e. reports of 
suicidal ideation type 4 or 5 and all reports of suicidal behaviour must be reported as separate 
SAEs by the investigator.
Negative reports (i.e. suicidal ideation type 1, 2 or 3) can be reported as AEs, at the discretion
of the investigator. All negative reports should be reviewed by the Investigator for clinical
relevance and determination if an AE report is warranted


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis of ethinylestradiol and
drospirenone
For quantification of ethinylestradiol and drospirenone concentrations in plasma, for each 
analyte, 2.7 mL of blood will be drawn from an antecubital or forearm vein into an K2-EDTA 
(dipotassium 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 approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.8 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 1 h, with interim storage of blood samples and aliquots in ice water or on 
ice. The time each aliquot was placed in the freezer will be documented. Until transfer on dry 
ice to the analytical laboratory, the aliquots will be stored upright at approximately -20°C or 
below at the trial site. The second aliquot will be transferred to the analytical laboratory after 
the bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory,
the plasma samples will be stored at approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, and planned sampling time. 
After analysis, the plasma samples may be used for further methodological investigations
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.
5.3.2.2
Blood sampling for pharmacokinetic analysis of BI 1358894
For quantification of BI 1358894 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
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.




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5.4.2
Exploratory pharmacodynamic biomarkers
The following hormone concentrations will be determined: luteinizing hormone, follicle-
stimulating hormone, estradiol and progesterone.
5.4.2.1
Methods of sample collection
For quantification of luteinizing hormone, follicle-stimulating hormone, estradiol and 
progesterone concentrations in serum, 4.9 mL of blood will be drawn from an antecubital or 
forearm vein into a Serum-Monovette® 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 blood samples will be allowed to clot for 30 minutes at room temperature and then 
centrifuged for approximately 10 min at 2500 x g at room temperature. Until transfer the 
same day the samples will be stored ambient. If the samples cannot be sent on the same day 
they should be stored at 2 – 8 °C until shipment.
5.4.3
Pharmacogenomic biomarkers
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
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 5.3 are 
generally used assessments of drug exposure. The pharmacodynamic biomarkers
measurements outlined in Section 5.4 are of exploratory nature only.


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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 the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration are to be performed and completed within a 2 h-period prior to the trial drug 
administration.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, ECG, and laboratory tests will be ± 30 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings 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 blood 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 
the determination of pharmacokinetic parameters.
During the run-in period, administration of Yasmin® tablets must be done by the subjects at
home. The subjects are advised to take Yasmin® tablets with a cup of water at the same time 
each day, approximately between 06.00 and 10.00 am local time.
Ambulatory dosing in periods 1 and 2 should be performed between 06.00 and 10.00 am
local time.
If a subject misses an ambulatory visit in weeks 1 or 2 of any period all efforts should be 
made for the subject to attend the visit as soon as possible. In such case dosing of Yasmin®
can occur at any time of the day or can even be taken together with the next planned dose. 
. If a subject 
misses 2 visits they must be separated by at least 7 days. Subjects who miss a visit in weeks 1 
or 2 will be reminded of the importance of using additional contraception methods. All visits 
in week 3 must be attended. 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 and run-in period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.


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In addition, a gynaecological examination will be performed in order to assess the suitability 
of subjects for taking the oral contraceptive prior to trial entry.
After eligibility has been confirmed subjects will come to the site to perform an urine 
pregnancy test and they will be given 1-2 packages of Yasmin® tablets for the run-in-period. 
The start and end of the run-in will be decided by the investigator depending on the subjects 
actual menstrual cycle duration (see Section 3.1). In the last 7 days of the run-in period, 
subjects will be instructed to stop taking Yasmin® in order to induce a withdrawal bleeding.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days 1 to 28 in each period).
There will be no wash-out period between the treatments.
On Day 1 of the first study period the subjects will be asked to return unused tablets of 
Yasmin®, including packages and blisters. On Day 20 of each treatment period, trial 
participants will be admitted to the trial site and kept under close medical surveillance for at 
least 24 h following drug administration. The subjects will then be allowed to leave the trial 
site after formal assessment and confirmation of their fitness. On all other trial days in 
treatment periods (Days 1 to 20), subjects will be treated ambulatorily. In the last 7 days of 
each treatment period (i.e., Days 22 to Day 28) no treatment will be given in order to induce 
withdrawal bleeding.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as 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 a subject’s EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.




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‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if 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.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be suggested in the iPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for EE and DRSP 
(components of COC Yasmin® ) will be calculated according to the relevant BI internal 
procedures. 
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

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), 

The subject experiences emesis at any time during the labelled dosing interval. 

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.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic 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). 


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7.2.2
Primary endpoint analyses
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 and will be applied to each analyte (EE, 
DRSP) separately. 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: subjects and treatment. The effects 'subjects’ and ‘treatment’ will be 
considered as fixed. The model is described by the following equation:
ykm = + γm + k + ekm, where
ykm = logarithm of response measured on subject m in receiving treatment k,
= the overall mean,
γm = the effect associated with the mth subject, m = 1, 2, ..., 32,
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k.
where e ~ N(0, σ
 ) i.i.d. and ekm is an independent random variable.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
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). 
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.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but the 
effect 'subjects’ will be considered as random, whereas the effect ‘treatment’ will be 
considered as fixed.” 
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) 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.


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7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.3. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.


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For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the assigned treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate 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 time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period. Those occurring in the run-in period will be assigned to the 
run-in period, while all others -from first trial medication intake in respective treatment 
period to end of REP (see Section 1.2.3) will be assigned to the respective treatment period. 
Events occurring after the REP but prior to end of study examination date will be assigned to 
follow-up’. In case of two or more treatments, the follow-up will be summarized according to 
the previous treatment. These assignments including the corresponding time intervals will be 
defined in detail in the TSAP. 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.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented without consideration of time intervals 
and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
In general, unless otherwise specified in the TSAP, the last non-missing measurement prior to 
first trial medication intake will be used as baseline for safety variables (laboratory data, 
ECG, vital signs).
Relevant ECG findings will be reported as AEs.
Results regarding the C-SSRS will only be listed.
7.2.6
Interim analyses
No interim analysis is planned.


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7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures. 
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.4
RANDOMISATION
Since no randomisation will be performed in this trial, this Section is not applicable.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned that approximately 32 subjects (including up to 8 drop-outs or non PK evaluable 
subjects) will participate in the trial and start period 1. This is considered sufficient to achieve 
the aims of this exploratory trial. With this sample size, the following precision in estimating 
the ratio of geometric means (test/reference) can be expected with 95% probability. Precision 
is defined as the ratio of upper CI limit to the relative BA estimate. Note that the precision is 
independent of the actual ratio of geometric means.
The observed intra-individual coefficient of variation (gCV) for EE in previous trials 
[U13-1189; U12-1031; U09-1393; U07-1867; U03-3408] was roughly 13-20% for Cmax and
8-15% for AUC. The intra-individual coefficient of variation (gCV) for DRSP reported in the 
literature [R23-0502]was roughly 16% for Cmax and 23% for AUC.
Therefore, the following Table 7.5: 1 provides a summary of the precision that is expected 
with a 95% probability and two-sided 90% confidence interval of various gCVs and gMean 
ratios (T/R) using sample sizes of 20, 24 and 28.


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Table 7.5: 1
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs in a fixed-sequence 
crossover trial (N=20, 24, 28).
N
gCV 
[%]
Precision 
upper CL** 
/ relative BA 
estimate
90% CI [%] of respective ratio*
94
100
107
20
15
1.11
(84.82; 104.17)
(90.24; 110.82)
(96.55; 118.58)
20
20
1.15
(82.01; 107.74)
(87.25; 114.61)
(93.36; 122.64)
20
25
1.19
(79.34; 111.37)
(84.40; 118.48)
(90.31; 126.77)
24
15
1.1
(85.80; 102.98)
(91.28; 109.56)
(97.67; 117.22)
24
20
1.13
(83.27; 106.11)
(88.59; 112.88)
(94.79; 120.78)
24
25
1.16
(80.85; 109.28)
(86.02; 116.26)
(92.04; 124.40)
28
15
1.09
(86.53; 102.11)
(92.06; 108.63)
(98.50; 116.23)
28
20
1.12
(84.22; 104.92)
(89.59; 111.62)
(95.87; 119.43)
28
25
1.15
(82.00; 107.76)
(87.23; 114.64)
(93.34; 122.66)
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
**Confidence interval limit
The expected 90% confidence interval limits in the table were derived by
CI limit"##$%,&'($% = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.1.2.
Thus, based on a sample size of N=24 evaluable subjects and assuming a gCV of 25% for the 
PK endpoints of EE + DRSP (= COC Yasmin®), the precision of the 90% CI would be 1.16. 
Accounting for up to 8 drop-outs or non PK evaluable subjects, a total of N = 32 ( 24 + 8) 
subjects are planned to be entered into the trial.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national 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 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 retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.


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For the CRF, data must be derived from source documents, for example:

Subject identification: gender, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject into a clinical trial, there must be documented evidence 
in the source data (e.g. medical records) that the trial participant meets all inclusion 
criteria and does not meet any exclusion criteria. The absence of records (either 
medical records, verbal documented feedback of the subject or testing conducted 
specific for a protocol) to support inclusion/exclusion criteria does not make the 
subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a participant identification number instead of the trial 
participant’s name. The code is only available at the site and must not be forwarded to the 
sponsor. In case participant’s records will be forwarded e.g. for SAE processing or 
adjudication committees, personal data that can identify the trial participant will be redacted 
by the site prior to forwarding. Access to the participant files and clinical data is strictly 
limited: personalised treatment data may be given to the subject’s personal physician or to 
other appropriate medical personnel responsible for the subject’s welfare. Data generated at 
the site as a result of the trial need to be available for inspection on request by the 
participating physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory 
authorities.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs/IECs and trial 
participants will be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data


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
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
 
, under the supervision of the Principal Investigator. Relevant documentation on the 
participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the ISF. The 
investigators will have access to the BI web portal Clinergize to access documents provided 
by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local Clinical Trial Mangers 
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites


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The trial medication will be provided by the 
, or will be obtained by the clinical trial site from public
pharmacy (Yasmin®).
Safety laboratory tests and exploratory PD biomarkers measurements will be performed by 
the local laboratory of the trial site (
).
Analyses of ethinylestradiol and drospirenone concentrations in plasma will be performed at 
Address:
Analyses of BI 1358894 concentrations in plasma will be performed at 
. 
Address:
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P05-12887
Shelepova T Nafziger AN Victory J Kashuba ADM Rowland E Zhang Y 
Sellers E Kearns G Leeder JS Gaedigk A Bertino JS. Effect of a triphasic 
oral contraceptive on drug-metabolizing enzyme activity as measured by 
the validated Cooperstown 5 + 1_cocktail. J Clin Pharmacol; 45(12), p. 
1413-1421; 2005.
P06-11895
Rush AJ Trivedi MH Wisniewski SR Nierenberg AA Stewart JW Warden 
D Niederehe G Thase ME Lavori PW Lebowitz BD McGrath PJ 
Rosenbaum JF Sackeim HA Kupfer DJ Luther J Fava M. Acute and 
longer-term outcomes in depressed outpatients requiring one or several 
treatment steps: a STAR*D report. Am J Psychiatry; 163(11), p. 1905-
1917; 2006
R03-1002
Belle DJ Callaghan JT Gorski JC Maya JF Mousa O Wrighton SA Hall 
SD. The effects of an oral contraceptive containing ethinyloestradiol and 
norgestrel on CYP3A activity. Br J Clin Pharmacol; 53, p. 67-74; 2002.
R03-1128
Palovaara S Kivisto KT Tapanainen P Manninen P Neuvonen PJ Laine K. 
Effect of an oral contraceptive preparation containing ethinylestradiol and 
gestodene on CYP3A4 activity as measured by midazolam 1'-
hydroxylation. Br J Clin Pharmacol; 50, p. 333-337; 2000.
R06-2872
Trivedi MH Rush AJ Wisniewski SR Warden D McKinney W Downing 
M Berman SR Farabaugh A Luther JF Nierenberg AA Callan JA Sackeim 
HA. Factors associated with health-related quality of life among 
outpatients with major depressive disorder: a STAR*D report. J Clin 
Psychiatry; 67(2), p. 185-195; 2006.
R08-1147
Posner K. State of the science: measurement of suicidal adverse events and 
the Columbia Suicide Severity Rating Scale.; 2007.
R08-4516
Kessler RC Chiu WT Demler O Walters EE. Prevalence, severity, and 
comorbidity of 12-month DSM-IV diorders in the national comorbidity 
survey replication. Arch Gen Psychiatry; 62, p. 617-627; 2005.
R09-5728
Salmon J Coussediere D Cousty C Raynaud JP. Pharmacokinetics and 
metabolism of moxestrol in humans. J Steroid Biochem; 18(5), p. 565-
573; 1983.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R12-0031
Garg V Heeswijk R van Yang Y Kauffman R Smith F Adda N. The 
pharmacokinetic interaction between an oral contraceptive containing 
ethinyl estradiol and norethindrone and the HCV protease inhibitor 
telaprevir. J Clin Pharmacol; 2011.




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R23-0484
Yasmin 0,03 mg/3 mg Filmtabletten (Jenapharm c), 
verschreibungspflichtig, (Fachinformation, Stand der Information: 
November 2022).
R23-0501
Oedingen C Scholz S Razum O. Systematic review and meta-analysis of 
the association of combined oral contraceptives on the risk of venous 
thromboembolism: the role of the progestogen type and estrogen dose. 
Thromb Res; 165, p. 68-78; 2018.
R23-0502
Blode H Kowal K Roth K Reif S. Pharmacokinetics of drospirenone and 
ethinylestradiol in Caucasian and Japanese women. Eur J Contracept 
Reprod Health Care; 17, p. 284-297; 2012
R23-0680
U.S. Food and Drug Administration (FDA). FDA drug safety 
communication: updated_information about the risk of blood clots in 
women taking birth control pills containing drospirenone. Website: 
fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communic 
ation-updated-information-about-risk-blood-clots-women-taking-birth-
control (access date: 2023-02-21); 2012
R23-0688
Martindale: the complete drug reference. In: Martindale: the complete 
drug reference. 36th ed. Sweetman SC, London and Grayslake: 
Pharmaceutical Press; 2009.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c10354149
 Investigator's Brochure BI 1358894 in Major Depressive, 
Disorder and Borderline Personality Disorder. Current version
c28667517
. Safety, tolerability, and 
pharmacokinetics of multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebocontrolled, parallel-group design) and 
evaluation of midazolam interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects. CTR 1402-0002. 2020
U03-3408
. A single 
centre, open-label, randomized, parallel group, multiple dose comparison 
of the effect of Tipranavir 750 mg and Ritonavir 200 mg or Tipranavir 500 
mg and Ritonavir 100 mg, administered twice daily, on the 
pharmacokinetic characteristics of Noret. CTR 1182.22. 2005
U07-1867
 An open, randomised, two-way cross-over trial to evaluate the effect of 
multiple doses of flibanserin on the single dose pharmacokinetics of a 
combination of ethinylestradiol and levonorgestrel. CTR 511.93.2008


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U09-1393
. An open, two-period, 
fixed-sequence, phase I trial to evaluate the effect of multiple doses of BI 
1356 on the multiple-dose pharmacokinetics of a combination of 
ethinylestradiol and levonorgestrel. CTR 1218.11. 2009
U12-1031
. An open-label, two-
period, fixed-sequence trial to evaluate the effect of multiple doses of BI 
10773 on the multiple-dose pharmacokinetics of a combination of 
ethinylestradiol and levonorgestrel in healthy premenopausal female 
volunteers. CTR 1245.41. 2012
U13-1189
. An open-label, two-period, 
fixed-sequence, phase I trial to evaluate the effect of multiple doses of 240 
mg BI 201335 QD on the multiple-dose pharmacokinetics of a 
combination of ethinylestradiol and levonorgestrel in healthy 
premenopausal female volunteers. CTR 1220.56. 2013




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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
08 May 2023
EU Trial number
2022-502861-78-00
BI Trial number
1402-0019
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
An open-label, fixed-sequence cross-over, two-
period, phase I trial to evaluate the effect of 
multiple doses of BI 1358894 on the 
pharmacokinetics of a combination of 
ethinylestradiol and drospirenone in healthy female 
subjects
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment
Non-substantial Global Amendment
Section to be changed
Flow Chart
Description of change
Follow up to take place on Days 42 - 52
Rationale for change
Request from competent authorities
Section to be changed
Flow Chart, section 5.2.3 Safety laboratory 
parameters
Description of change
Cotinine test at screening included
Rationale for change
Request from competent authorities
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
Exclusion criterion 14 was changed to exclude all 
smokers from the study. The following exclusion 
criterion was removed since it is not applicable: 
“Inability to refrain from smoking on specified trial 
days”
Rationale for change
Request from competent authorities
Section to be changed
Section 4.1.2 Selection of doses in the trial 
Description of change
Sentence to the justification of dose selection added
Rationale for change
Request from competent authorities
Section to be changed
Section 8.1 Trial approval, subject information, 
informed consent 
Description of change
Wording referring to the subjects’ legally 
representative deleted
Rationale for change
Request from competent authorities
Section to be changed
Section 8.5 Statement of confidentiality and subject 
privacy


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Description of change
A description of the arrangements to comply with 
the applicable rules on the protection of
personal data was added
Rationale for change
Request from competent authorities


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11.2
GLOBAL AMENDMENT 2
Date of amendment
12 Jul 2023
EU Trial number
2022-502861-78-00
BI Trial number
1402-0019
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
An open-label, fixed-sequence cross-over, two-
period, phase I trial to evaluate the effect of 
multiple doses of BI 1358894 on the 
pharmacokinetics of a combination of 
ethinylestradiol and drospirenone in healthy female 
subjects
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment
Non-substantial Global Amendment
Section to be changed
Flow Chart
Description of change
Footnote 8 added at Period 2, Visit 4, Day 1
Rationale for change
Inconsistency
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criteria number 12, 13, 17, 18 and 25 will 
have as reference time point the treatment 
allocation. 
Rationale for change
To correct an inconsistency in the previous version 
of the protocol. Since start of run-in marks the first 
administration of trial medication, a reference to 
treatment allocation was necessary.
To clarify that the run-in period belongs to the trial 
per se and, as a consequence, patients need to start 
adhering to study restrictions already at that time.
Section to be changed
Section 3.3 Selection of trial population, Section 
3.3.4 Withdrawal of subjects from treatment or 
assessments, Section 3.3.5 Replacement of subjects, 
Section 7.5 Determination of sample size
Description of change
Clarification about the necessity that at least 32 
subjects start period 1. Instructions about how to 
proceed with subjects who stop the trial before 
starting period 1.
Rationale for change
An adaptation of the description was necessary 
because it is imperative that at least 32 subjects start 
period 1 to reach the objectives of the trial and it 
has consequences on the replacement strategy.


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Section to be changed
4.1.1 Identity of the Investigational Medicinal 
Products
Description of change
Yasmin® is listed as test product 2
Rationale for change
Inconsistency
Section to be changed
Section 4.3 Treatment compliance
Description of change
Compliance will only be checked in treatment 
periods 1 and 2
Rationale for change
Clarification
Section to be changed
Section 4.1.3 Method of assigning subjects to 
treatment groups 
Description of change
Adaption of text for allocation of Subject 
Identification Number and implementation of a re-
check of inclusion/exclusion criteria prior to run-in
Rationale for change
In line with other changes in this amendment, the 
allocation will take place prior to run-in and after a 
re-check of relevant inclusion/exclusion criteria.
Section to be changed
Section 5.3.2.1 Blood sampling for pharmacokinetic 
analysis of ethinylestradiol and drospirenone
Description of change
Adaption of volume of first aliquot
Rationale for change
Lab request
Section to be changed
Section 5.3.2.2 Blood sampling for pharmacokinetic 
analysis of BI 1358894
Description of change
Adaption of volume of first aliquot
Rationale for change
Lab request


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11.3
GLOBAL AMENDMENT 3
Date of amendment
19 Oct 2023
EU Trial number
2022-502861-78-00
BI Trial number
1402-0019
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
An open-label, fixed-sequence cross-over, two-
period, phase I trial to evaluate the effect of
multiple doses of BI 1358894 on the 
pharmacokinetics of a combination of 
ethinylestradiol and drospirenone in healthy female 
subjects
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment
Non-substantial Global Amendment
Section to be changed
Title page, synopsis
Description of change
Change of PI
Rationale for change
 will take over the function as 
PI in the trial
Section to be changed
Section 1.2.1 B I1358894
Description of change
Number of participants in phase I and II updated
Rationale for change
New numbers according to recent update of IB


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c41232811
4.0
clinical-trial-protocol-version-04
An open-label, fixed-sequence cross-over, two-period, phase I trial to evaluate the
effect of multiple doses of BI 1358894 on the pharmacokinetics of a combination of
ethinylestradiol and drospirenone in healthy female subjects
Author-Trial Statistician
23 Oct 2023 15:05 CEST
Approval-Clinical Program
23 Oct 2023 15:06 CEST
Approval-Clinical Trial Leader
23 Oct 2023 15:47 CEST
Verification-Paper Signature
Completion
24 Oct 2023 11:18 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c41232811
4.0

SAP_001.pdf: 
ABCD
TRIAL STATISTICAL ANALYSIS PLAN
 
Document No.:
c44020208-01
BI Trial No.:
1402-0019
Title:
An open-label, fixed-sequence cross-over, two-period, phase I trial 
to evaluate the effect of multiple doses of BI 1358894 on the 
pharmacokinetics of a combination of ethinylestradiol and 
drospirenone in healthy female subjects
(Revised Protocol including Amendments 1-3 [c41232811-04])
Investigational
Product:
BI 1358894
Responsible trial 
statistician:
Phone:
+
Fax:
+
Date of statistical 
analysis plan:
19 MAR 2024
Version:
1.0
Page 1 of 20
Proprietary confidential information
© 2024 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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Date: 19 MAR 2024, Version 1.0
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
LIST OF TABLES
Table 6.1: 1 
Treatments and labels used in the analysis.......................................................10
Table 11: 1
History table .....................................................................................................20


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Date: 19 MAR 2024, Version 1.0
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http: //glossary
Term
Definition / description
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
BMI
Body mass index
Cmax
Maximum measured concentration of the analyte in plasma 
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
Cmin,ss
Minimum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
COC
Combined oral contraceptives
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic Coefficient of Variation
DBL
Data base lock
DILI
Drug induced liver injury
DRSP
Drospirenone
EE
Ethinylestradiol
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
Max
Maximum
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
Q1
1st quartile
Q3
3rd quartile
REP
Residual effect period


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BI-VQD-12681-S-G_50-415_AD-01 (5.0)
Term
Definition / description
RPM
Report Planning Meeting
RAGe
Report Appendix Generator system
SD
Standard Deviation
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
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), 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 (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
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
This trial has been prematurely terminated during the run-in period as Boehringer Ingelheim 
decided not to continue with trial execution due to strategic reasons. None of the subjects has 
started with treatment period 1. Therefore, not all analyses as planned in the CTP will be 
performed. For all study endpoints listings will be provided. Tables will only be provided for 
adverse events (AEs). For variables regarding disposition, demography, medical history, 
concomitant medication and non-drug procedures, exposition, protocol deviations, laboratory 
data, vital signs and C-SSRS suicidality, only listings will be provided and no descriptive 
analysis will be carried out. An additional analysis set, the Entered set, will be defined as a 
base for the disposition listings.
The descriptive and model-based analysis of pharmacokinetic endpoints will not be performed 
as well, in line with the CTP no PK samples were collected in the run-in period.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
This section is not applicable as no plasma concentrations are collected since the trial has 
been prematurely terminated. The primary endpoints originally defined in the CTP were:
Section 2.1.2 of the CTP:
The following pharmacokinetic parameters will be determined for ethinylestradiol and
drospirenone:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
This section is not applicable as no plasma concentrations are collected since the trial has 
been prematurely terminated. The secondary endpoint originally defined in the CTP was:

Cmin,ss (minimum concentration of the analyte in plasma at steady state over a uniform 
dosing interval τ)
5.3
FURTHER ENDPOINTS
Safety and tolerability endpoints
Section 2.2.2.3 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

12-lead ECG

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
selection of doses, refer to CTP Sections 3 and 4. 
This is a Phase I trial in healthy female subjects between 18 and 35 years of age. A total of 
32 subjects was planned to be entered to the trial.
Section 3.1 of the CTP:
The trial will be performed as a non-randomised, open-label, two-period, fixed sequence trial
with run-in period in healthy female subjects in order to compare the test treatment (T) to the
reference treatment (R).
Reference (R): one tablet of Yasmin® q.d. after a continental breakfast on Days 1-21 in
Period 1.
Test (T): one tablet of Yasmin® q.d. + one tablet of BI 1358894 25 mg q.d. + two tablets of BI 
1358894 50 mg q.d. after a continental breakfast on Days 1-21 in Period 2.
The Reference Treatment will always be followed by the Test Treatment in a fixed sequence.
There will be no wash-out period between the treatments.
All subjects will undergo a run-in period that starts between Day -56 and Day -28. In this
period, the subjects will take one tablet of Yasmin® daily until Day -8.In the last 7 days of 
each treatment period (i.e., Day 22 to Day 28) and the run-in period (i.e.Day -7 to Day -1) no 
treatment will be given in order to induce bleeding.
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
R
Yasmin tablet (30ug Ethinylestradiol + 3mg Drospirenone), qd
COC
T
BI 1358894, 1*25 + 2*50mg tablet + Yasmin tablet (30ug 
Ethinylestradiol + 3mg Drospirenone), qd
BI+COC
The study was prematurely terminated after the run-in period, with n=28 subject treated in the 
run-in period. Therefore, all analyses will be performed for the run-in period only.


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Section 1.2.3 of the CTP: 
Based on an effective half-life of 50-70 hours, the Residual Effect Period (REP) of BI 
1358894 is 17 days. This is the period after the last dose during which relevant drug levels 
and/or pharmacodynamic effects are still likely to be present.
The REP of ethinylestradiol is 5 days based on a minimum observation period of at least 5-
fold estimated t½ (i.e. 5 x 20 h, or 4.2 days, rounded to 5 days). 
The REP of drospirenone is 9 days based on a minimum observation period of at least 5-fold 
estimated t½ (i.e. 5 x 40 h, or 8.3 days, rounded up to 9 days).
Overall, the REP of 17 days will be considered for evaluation of adverse events in the trial.
The study was prematurely terminated after run-in period. Therefore, the subjects received 
combined oral contraceptives (COC), but none of the subjects was treated with BI 1358894. 
Consequently, the REP of ethinylestradiol and drospirenone was 9 days. 
Based on this, the following study phases will be defined for the analysis of AEs:

Screening
o
Ranging from 0:00h on day of informed consent until time of first 
administration of COC.

On treatment (labelled “COC (run-in)”)
o
Ranging from the time of first administration of COC until last administration 
of COC plus 9 days (216 h) thereafter OR until trial termination (0:00 h on the 
day after trial termination), whatever occurs first.

Follow-up (labelled “Follow-up (run-in)”)
o
Ranging from the end of REP until trial termination (0:00 h on the day after 
trial termination).
Section 7.2.5 of the CTP:
Note that AEs occurring after the last per protocol contact but entered before 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:

In Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov only) of the CTR 
displays, the on treatment phase will be analysed (labelled with the short label of the 
study treatment). The screening and follow-up phases will not be included in this 
analysis.

In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, the screening 
period, as well as the follow-up phases will additionally be included and no totals will 
be provided.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of 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 prior to Data base lock (DBL). All manual deviations identified at 
the sites by the CRAs and deviations too complex to program will be reviewed by the trial 
team to decide which are considered important. For definition of important protocol 
deviations (iPD), and for the process of identification of these, refer to the Boehringer 
Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" (2).
Important protocol deviation (iPD) categories are pre-specified in the iPD specification file 
(DV domain) (3). IPDs will be identified no later than DBL, and the iPD categories will be 
updated as needed.
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the iPD specification file (DV domain) (3) and in the decision log (4). Both documents will be
stored within the TMF in EDMS.
The iPDs will be summarized and listed in the CTR.
6.3
INTERCURRENT EVENTS
This section is not applicable.
6.4
SUBJECT SETS ANALYSED
Section 7.2.1.1 of the CTP:
Statistical analyses will be based on the following analysis sets:

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.
The study was prematurely terminated after run-in period. No PK parameter values were 
assessed. Therefore, the pharmacokinetic parameter analysis set as defined in the CTP is not 
applicable. 
An additional analysis set will be defined for listings of disposition:

Entered set (ES): The entered set includes all subjects who were entered to the trial.


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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:
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035) (5).
6.7 BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline is defined as the last measurement before first administration of COC.
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 the end of trial examination are provided in the
CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration are to be performed and completed within a 2 h-period prior to the trial drug
administration.
If not stated otherwise in the CTP Flow Chart, the acceptable deviation from the scheduled
time for vital signs, ECG, and laboratory tests will be ± 30 min.
If scheduled in the CTP Flow Chart at the same time as a meal, blood sampling, vital signs, 
and 12-lead ECG recordings 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.
During the run-in period, administration of Yasmin® tablets must be done by the subjects at
home. The subjects are advised to take Yasmin® tablets with a cup of water at the same time
each day, approximately between 06.00 and 10.00 am local time.
Adherence to time windows will be checked via the consistency check listings prior to DBL.
Unscheduled measurements of laboratory data and vital signs 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
 and 
will be presented in Sections 15.3 and 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
The study was prematurely terminated after run-in period. Therefore, in 15.3 and 15.4 only 
AEs will be presented. In addition, no descriptive data analysis of PK endpoints and 
concentrations will be performed.
The format of the listings and tables will follow the BI standards (see “Standards for 
Reporting of Clinical Trials and Project Summaries” (6)).
The individual values of all subjects will be listed, sorted by subject number and visit. The 
listings will be included in Appendix 16.2 of the CTR.
Units of variables should be given in the titles or column/row descriptors in brackets (e.g. 
(mg)).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only listings are planned for this section of the report, based on the TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only listings are planned for this section of the report, based on the TS.
Concomitant diseases and non-drug therapies will be coded according to the version defined 
in the decision log (4) of the coding system of the Medical Dictionary for Drug Regulatory 
Activities (MedDRA). Concomitant medications 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.
Section 7.2.5 of the CTP:
Previous and concomitant therapies will be presented without consideration of time intervals 
and treatment periods.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies will be marked with a “No” in the respective column.
7.3
TREATMENT COMPLIANCE
Only listings are planned for this section of the report, based on the TS.
It is not intended to list the compliance separately.


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7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis 
The study was prematurely terminated after run-in period. No PK parameter values were 
assessed. Therefore, no primary or secondary endpoint analyses will be performed.
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary objective has been specified in the 
protocol.
7.5.2
Secondary objective analysis
This section is not applicable as no secondary objective has been specified in the protocol.
7.6
FURTHER OBJECTIVE ANALYSIS
Pharmacokinetic endpoints
The study was prematurely terminated after run-in period. No PK parameter values were 
assessed. Therefore, no descriptive analyses of PK endpoints will be performed.
Safety endpoints
For a description of the analysis of safety and tolerability, please refer to Section 7.8. 
7.7
EXTENT OF EXPOSURE
The date and time of drug administration will be listed for each subject. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.


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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 using MedDRA. The coding version number will be displayed as a 
footnote in the respective output.
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” (7) and “Analysis and Presentation of AE data from clinical trials”
(8) 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.
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
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:

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

Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN 
These lab findings constitute a hepatic injury alert and the subjects 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 that 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.
According to ICH E3 (9), in addition to Deaths and serious adverse events, ‘other significant’ 
AEs need to be listed in the clinical trial report. These will be any non-serious adverse events


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that led to an action taken with study drug (e.g. discontinuation or dose reduced or 
interrupted).
An overall summary of adverse events will be presented. 
The frequency of subjects with AEs will be summarised by 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 
worst intensity, primary system organ class (SOC) and preferred term (PT).
The system organ classes will be sorted by default alphabetically, PTs will be sorted by 
descending frequency (within SOC).
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by primary SOC and PT.
7.8.2
Laboratory data
Only listings will be provided for laboratory data and will be based on BI standards as 
presented in “Handling, Display and Analysis of Laboratory Data” (10). 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 (prior to DBL).
7.8.3
Vital signs
Only listings will be presented for vital signs (blood pressure and pulse rate). The change 
from baseline will also be displayed.
Clinically relevant findings 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.
7.8.4
ECG
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.


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7.9
OTHER ANALYSIS
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of trial drug) or as AE and will be summarised 
as such.
No separate listing or analysis of physical examination findings will be prepared.
Columbia Suicide Severity Rating Scale (C-SSRS)
Suicidality assessment with the C-SSRS will be assessed as additional safety parameter, 
measured at screening and at the end of study, due to the premature termination of trial. The
results will be listed only. If applicable, the following sentence will be sufficient: No subjects 
with suicidal ideation, suicidal behaviour, or self-injurious behaviour without suicidal intent.
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION
Not applicable due to open label fashion of the trial as described in the CTP section 4.1.5.


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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-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED.
4.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) Decision 
Log”, current version, Group “Biostatistics & Data Sciences”, IDEA for CON.
5.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version; KMED.
7.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
8.
BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical trials”, 
current version, KMED.
9.
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.
10. 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
1.0
19-Mar-24
None
This is the final TSAP.