Clinical trial NCT03193307
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-06-29; Completion date: 2017-12-01
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this trial is to investigate the effect of multiple doses of ethinylestradiol / levonorgestrel (Microgynon®) on single dose pharmacokinetics of BI 409306 and the effect of single dose of BI 409306 on multiple dose pharmacokinetics of ethinylestradiol / levonorgestrel (Microgynon®)

Detailed description:

Arms: arm 1: Run in period: Microgynon alone Treatment period: Microgynon® 30 +BI 409306 then BI 409306 alone
Interventions: intervention 1: Microgynon® 30 intervention 2: BI 409306
Intervention descriptions: intervention 1: Run in period \& Treatment Period intervention 2: Day 18 \& 29 (Treatment Period)

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c13608215-02
BI Trial No.:
1289-0040
BI Investigational
Product:
BI 409306
Title:
A study to investigate the pharmacokinetic drug-drug interaction 
following oral administration of ethinylestradiol/levonorgestrel
(Microgynon®) and BI 409306 in healthy Korean 
premenopausal female subjects (an open-label, two-period, 
fixed-sequence study)
Lay Title:
This study tests in healthy Korean women which effects BI 
409306 and a birth-control pill have on each other.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone:
Fax: 
Status:
Final Protocol(Revised Protocol(based on global amendment1))
Version and Date:
Version: 2.0
Date: 14 Jul 2017
Page 1 of 68
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
14 Jul 2017
30 Mar 2017
1289-0040
Title of trial:
A study to investigate the pharmacokinetic drug-drug interaction following oral 
administration of ethinylestradiol/levonorgestrel (Microgynon®) and BI 409306 in 
healthy Korean premenopausal female subjects
(an open-label, two-period, fixed-sequence study)
Principal Investigator:
Phone:
Fax:
Trial site:
Clinical phase:
I
Objectives:
To investigate the effect of multiple dose of ethinylestradiol/levonorgestrel
(Microgynon®) on single dose pharmacokinetics of BI 409306 and the effect of single 
dose of BI 409306 on multiple dose pharmacokinetics of
ethinylestradiol/levonorgestrel (Microgynon®)
Methodology:
Open-label, run-in period, two treatment periods in a fixed-sequence
No. of subjects: 
total entered:
16
each treatment:
16
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy Korean premenopausal female subjects, age of 19 to 40 years, body mass 
index (BMI) of 18.5 to 25.0 kg/m2, CYP2C19 poor metabolizer (PM) status
Trial product 1:
BI 409306 film-coated tablets 
strength:
25 mg
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h on Days 18 and 29
Trial product 2:
Microgynon® 30
strength:
0.03 mg ethinylestradiol (EE) and 0.15 mg levonorgestrel (LNG)
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h on Days 17 and 18
On all other trial days no fasting is required


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
14 Jul 2017
30 Mar 2017
1289-0040
Duration of treatment: Run-in period (Day -49/-28 to Day -8)
Microgynon® QD for 21-42 days (until Day -8)
(depending on individual stage of menstrual cycle)
Treatment period
Days 1 to 17: Microgynon® QD for 17 days (R2 on Day 17)
Day 18: BI 409306 + Microgynon® (T1 and T2)
Days 19 to 21: Microgynon® QD for 3 days
Day 29: BI 409306 (R1)
Treatments:
BI 409306 as victim (part 1):
Reference 1 (R1): 1 tablet BI 409306 on Day 29.
Test 1 (T1):            1 tablet BI 409306 together with 
                               1 tablet Microgynon® QD on Day 18. 
Microgynon® as victim (part 2):
Reference 2 (R2): 1 tablet Microgynon® QD on Day 17
Test 2 (T2) :          1 tablet Microgynon® QD together with 
                              1 tablet BI 409306 on Day 18
Criteria for
pharmacokinetics:
Primary endpoints: 
(part 1) BI 409306 as victim
AUC0-tz and Cmax of BI 409306 in plasma for T1 compared with R1
(part 2) Microgynon® as victim
AUC0-24,ss and Cmax,ss of EE in plasma for T2 compared with R2
AUC0-24,ss and Cmax,ss of LNG in plasma for T2 compared with R2
Secondary endpoint:
(part 1) BI 409306 as victim
AUC0-of BI 409306 in plasma for T1 compared with R1
 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
14 Jul 2017
30 Mar 2017
1289-0040
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), vital signs 
(blood pressure [BP], pulse rate [PR]) 
Statistical methods:
The effect of Microgynon® on the pharmacokinetics of BI 409306 will be evaluated 
by estimating the ratios of the geometric means for the primary and secondary PK 
endpoints (part 1).
The effect of BI 409306 on the pharmacokinetics of Microgynon® will be evaluated 
by estimating the ratios of the geometric means for the primary PK endpoints (part 2).
For both parts, the two-sided 90% confidence intervals (CIs) will be provided. This 
method corresponds to the two one-sided t-tests procedure, each at the 5% 
significance level. Since the main focus is on estimation and not testing, an 
acceptance range was not specified. The statistical model used will be an ANOVA on 
the logarithmic scale including effects for ‘subject’ and ‘treatment’ in part 1 and part 
2. CIs will be calculated based on the residual error from ANOVA. Descriptive 
statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to  drug 
administration [h:min]
Approximate clock time  of actual 
day [h:min]
Event and comment
Safety laboratory
PKblood for EE and LNG
PKblood for BI 409306
12-lead ECG
Pregnancy test
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-70 to
-29
Screening (SCR)1
x5
x
x
x
Run-
in8
2
-49 to -8
Microgynon® intake9
x9
-3 to -1
Ambulatory visit
x
x
x
x
x
Treat
ment
3
1
-02:00
07:00
x
00:00
09:00
Drug administration (ambulatory): 
Microgynon®
x7
x
2
24:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
3
48:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
4
72:00
09:00
Drug administration (ambulatory):
Microgynon®
x
5
96:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
6
120:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
7
144:00
09:00
Drug administration (ambulatory):
Microgynon®
x
8
168:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
9
192:00
09:00
Drug administration (ambulatory):
Microgynon®
x
10
216:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
11
240:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
12
264:00
09:00
Drug administration (ambulatory):
Microgynon®
x
13
288:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
14
312:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
15
336:00
09:00
Drug administration (ambulatory):
Microgynon®
x


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FLOW CHART (Cont.)
Period
Visit
Day
Planned time (relative to  drug 
administration [h:min]
Approximate clock time  of actual 
day [h:min]
Event and comment
Safety laboratory
PKblood for EE and LNG
PKblood for BI 409306
12-lead ECG
Pregnancy test
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Treat
ment
3
16
360:00
09:00
Drug administration (ambulatory): 
Microgynon®
x
x7
x
367:00
16:00
Admission to the trial site10
x
x
17
382:00
07:00
384:00
09:00
Drug administration:
Microgynon®
x7
x
384:30
09:30
x
x
385:00
10:00
x
x
385:30
10:30
x
x
386:00
11:00
240 mL fluid intake (mandatory)
x
x
388:00
13:00
240 mL fluid intake (mandatory)
Lunch3
x
x
392:00
17:00
x
x
395:00
20:00
Dinner3
398:00
23:00
x
x
18
406:00
07:00
x2
x2
x2
x
408:00
09:00
Drug administration:
BI 409306 + Microgynon®
x7
x7
x
408:15
09:15
x
x
408:30
09:30
x
x
x
408:45
09:45
x
x
409:00
10:00
x
x
x
409:30
10:30
x
x
x
410:00
11:00
240 mL fluid intake (mandatory)
x
x
x
410:30
11:30
x
x
411:00
12:00
x
x
412:00
13:00
240 mL fluid intake (mandatory)
Lunch3
x
x
x
414:00
15:00
x
x
416:00
17:00
x
x
x
418:00
19:00
x
x
419:00
20:00
Dinner3
422:00
23:00
x
x
x
19
432:00
09:00
Drug administration:
Microgynon®
x7
x7
x
x
444:00
21:00
x
x
20
456:00
09:00
Drug administration:
Microgynon®
x7
x
21
480:00
09:00
Drug administration:
Microgynon®
x7
x
x
480:30
09:30
Discharge from trial site
  Breakfast3 (optional)


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FLOW CHART (Cont.)
Period
Visit
Day
Planned time (relative to  drug 
administration [h:min]
Approximate clock time  of actual 
day [h:min]
Event and comment
Safety laboratory
PKblood for EE and LNG
PKblood for BI 409306
12-lead ECG
Pregnancy test
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Treat
ment
3
28
655:00
16:00
Admission to the trial site10
x
x
29
670:00
07:00
x2
x2
x2
x
672:00
09:00
Drug administration:
BI 409306
x7
x7
x
672:15
09:15
x
x
672:30
09:30
x
x
672:45
09:45
x
x
673:00
10:00
x
x
673:30
10:30
x
x
674:00
11:00
240 mL fluid intake (mandatory)
x
x
674:30
11:30
x
x
675:00
12:00
x
x
676:00
13:00
240 mL fluid intake (mandatory)
Lunch3
x
x
678:00
15:00
x
x
680:00
17:00
x
x
682:00
19:00
x
x
683:00
20:00
Dinner3
686:00
23:00
x
x
30
696:00
09:00
x
x
x
708:00
21:00
x
x
31
720:00
09:00
x
x
32
744:00
09:00
x
x
x
744:30
09:30
Discharge from trial site
  Breakfast3 (optional)
EOT
4
33 to
35
End of trial (EOT) examination4
x
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status, alcohol history, and pregnancy test), 
relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will 
be collected for those subjects whose CYP2C19 genotype is not known.
2.
The time is approximate; the procedure is to be performed and completed within 2 h prior to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies. 
5.
Including urine drug screening and alcohol breath test
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
PK sample taken within 10 minutes before dose
8. 
Days -7 to -1 of the run-in period are Microgynon® free days.


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9.    The Microgynon® administration during the run-in period is done by the subjects at home. The subjects are advised to 
take the Microgynon® tablets with a cup of water at the same time each morning.
The intake of Microgynon® starts depending on the subjects’ actual menstruation cycle and at least -28 days before Day 
1 of treatment period. In the run-in period, the subjects will take one tablet of Microgynon® daily until Day -8. On Day -
7 to Day -1 no Microgynon® tablets will be given in order to induce withdrawal bleeding.
During run-in period, phone contacts are scheduled for AE reporting at least every week.
10.    Alcohol breath test will be performed prior to each admission.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 12
1.2.2
Microgynon (ethinylestradiol + levonorgestrel)...............................18
2.2
TRIAL OBJECTIVES.......................................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................25
3.1.1
Administrative structure of the trial...................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................26
3.3
SELECTION OF TRIAL POPULATION ......................................................26
3.3.1
Main diagnosis for study entry............................................................27
3.3.2
Inclusion criteria...................................................................................27
3.3.3
Exclusion criteria ..................................................................................27
3.3.4
Removal of subjects from therapy or assessments.............................29
3.3.4.1
Removal of individual subjects................................................29
3.3.4.2
Discontinuation of the trial by the sponsor..............................29
3.3.5
Replacement of subjects .......................................................................30
4.
TREATMENTS........................................................................................ 31
4.1
TREATMENTS TO BE ADMINISTERED....................................................31
4.1.1
Identity of BI investigational product and comparator product......31
4.1.2
Method of assigning subjects to treatment groups ............................31
4.1.3
Selection of doses in the trial................................................................31
4.1.4
Drug assignment and administration of doses for each subject .......32
4.1.5
Blinding and procedures for unblinding ............................................33
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................34
4.1.8
Drug accountability ..............................................................................34


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................35
4.2.2
Restrictions............................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment .........................35
4.2.2.2
Restrictions on diet and life style.............................................35
4.3
TREATMENT COMPLIANCE.......................................................................36
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 37
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................37
5.1.1
Endpoints of efficacy.............................................................................37
5.1.2
Assessment of efficacy...........................................................................37
5.2
SAFETY..............................................................................................................37
5.2.1
Endpoints of safety................................................................................37
5.2.2
Assessment of adverse events...............................................................37
5.2.2.1
Definitions of adverse events...................................................37
5.2.2.2
Adverse event collection and reporting ...................................40
5.2.3
Assessment of safety laboratory parameters......................................42
5.2.4
Electrocardiogram................................................................................45
5.2.5
Assessment of other safety parameters...............................................45
5.2.5.1
Vital signs ................................................................................45
5.3
OTHER...............................................................................................................46
5.3.1.2
Analytical determinations........................................................46
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................46
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................46
5.5.1
Pharmacokinetic endpoints..................................................................47
5.5.1.1
Primary endpoints....................................................................47
5.5.1.2
Secondary endpoints................................................................47
5.5.2
Methods of sample collection...............................................................48
5.5.2.2
Plasma sampling for pharmacokinetic analysis of 
ethinylestradiol and levonorgestrel..........................................48
5.5.3
Analytical determinations ....................................................................49
5.5.3.1
Analytical determination of analyte plasma concentration......49
6.
INVESTIGATIONAL PLAN.................................................................. 51
6.1
VISIT SCHEDULE............................................................................................51


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................51
6.2.1
Screening and run-in period ................................................................51
6.2.2
Treatment periods.................................................................................52
6.2.3
End of trial period.................................................................................52
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 53
7.1
STATISTICAL DESIGN – MODEL ...............................................................53
7.1.1
Objectives...............................................................................................53
7.1.2
Endpoints...............................................................................................53
7.1.3
Model......................................................................................................53
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................54
7.3
PLANNED ANALYSES....................................................................................54
7.3.1
Primary analyses...................................................................................54
7.3.2
Secondary analyses ...............................................................................55
7.3.3
Safety analyses.......................................................................................56
7.3.4
Interim analyses ....................................................................................56
7.3.5
Pharmacokinetic analyses ....................................................................56
7.4
HANDLING OF MISSING DATA ..................................................................57
7.4.1
Safety......................................................................................................57
7.4.2
Plasma drug concentration - time profiles..........................................57
7.4.3
Pharmacokinetic parameters...............................................................57
7.5
RANDOMISATION ..........................................................................................57
7.6
DETERMINATION OF SAMPLE SIZE ........................................................57
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 60
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................60
8.2
DATA QUALITY ASSURANCE .....................................................................60
8.3
RECORDS..........................................................................................................61
8.3.1
Source documents .................................................................................61
8.3.2
Direct access to source data and documents.......................................61
8.3.3
Storage period of records.....................................................................61
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................61
8.5
STATEMENT OF CONFIDENTIALITY.......................................................61
9.
REFERENCES......................................................................................... 63
9.1
PUBLISHED REFERENCES...........................................................................63
9.2
UNPUBLISHED REFERENCES.....................................................................64
10. APPENDICES .......................................................................................... 66
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 67


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
ATE
Analysis of variance
Presence or risk of arterial thromboembolism
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
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
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
BPM
Blood pressure
beats per minute
CA
CHC
Competent authority
Combined hormonal contraceptives
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
COC
Maximum measured concentration of the analyte in plasma
combined oral contraceptives
CRF
CSF
Case report form
Cerebrospinal fluid
CTMF
Clinical trial master file
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
DDI
Genotyping of cytochrome P450
Drug-drug interactions
DILI
Drug induced liver impairment
ECG
Electrocardiogram
EDTA
EE
Ethylenediaminetetraacetic acid
ethinylestradiol


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EOT
FDA
GCP
End of trial
Food and Drug Administration
Good clinical practice
gCV
Geometric coefficient of variation
HR
Heart rate
IB
ICH
Investigator’s brochure
Independent ethics committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
LNG
liquid chromatography tandem mass spectrometry assays
levonorgestrel
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body after oral administration
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetic(s)
PKS
PM
po
Pharmacokinetic set
Poor metabolizers
oral
PR
Pulse rate
q.d.
Quaque die, once daily
QT
QTc
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QT interval corrected for heart rate using the method of Fridericia (QTcF)
or Bazett (QTcB)
REP
RDC
Residual effect period
Remote Date Control
SAE
Serious adverse event
SmPC
SOP
Summary of Product Characteristics
Standard operating procedure
SRD
Single-rising dose


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t1/2
TDMAP
tmax
Terminal half-life of the analyte in plasma
Trial Data Management and Analysis Plan
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
tz
TS
Time of last measurable concentration of the analyte in plasma
Treated Set
TSAP
VTE
Trial statistical analysis plan
Presence or risk of venous thromboembolism


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1.2
DRUG PROFILE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.2
Microgynon® (ethinylestradiol + levonorgestrel)
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 is also used as an emergency contraceptive drug
combined with levonorgestrel or norgestrel. A combined preparation of ethinylestradiol with
the anti-androgen cyproterone is used for the hormonal treatment of acne and hirsutism,
particularly when contraception is also required. Ethinylestradiol has also been used for
hormone replacement therapy; doses of 10 to 20 μg daily are given (with a progestogen in
women with a uterus), but natural estrogens are usually preferred. 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 estradiol 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]. According to the FDA 


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DDI guidance, oral contraceptives are weak CYP2C19 inhibitors due to estradiol.[ P12-
05791]
For a more detailed description of ethinylestradiol, please refer to the SmPC of Microgynon®
(R17-0443).
Levonorgestrel
Norgestrel and its active (-)-isomer, levonorgestrel (LNG), are progestogens derived from
nortestosterone. They are more potent inhibitors of ovulation than norethisterone and have
androgenic activity. Levonorgestrel is more commonly used than norgestrel and is twice as
potent. Both are used as hormonal contraceptives. The typical daily levonorgestrel dose is 30
or 37.5 μg when used as an oral progestogen-only contraceptive, 100 to 250 μg when used for
the monophasic portion of combined oral contraceptives, and 50 to 125 μg when used in
triphasic preparations. Levonorgestrel is also used as a long-acting progestogen-only
contraceptive by subcutaneous implantation. An intrauterine device containing levonorgestrel
is available for contraception or menorrhagia. For emergency contraception, levonorgestrel
may be given alone or in combination with ethinylestradiol.
Progesterone and the progestogens may cause gastrointestinal disturbances, changes in
appetite or weight, fluid 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%).
Levonorgestrel is rapidly and almost completely absorbed after an oral dose and undergoes
little first-pass hepatic metabolism. Maximum plasma concentrations occur 1 to 2 hours after
oral administration. Levonorgestrel is highly bound to plasma proteins, with 42 to 68% bound
to sex hormone binding globulin and 30 to 56% bound to albumin. The proportion bound to
sex hormone binding globulin is higher when levonorgestrel is given with an oestrogen.
Levonorgestrel is metabolised in the liver to sulfate and glucuronide conjugates, which are
excreted in the urine (40 to 68% of dose) and to a lesser extent in the faeces (16 to 48% of
dose). Levonorgestrel distributes into breast milk. The terminal half-life of levonorgestrel is
approximately 25 hours [R13-3708]
For a more detailed description of levonorgestrel, please refer to the SmPC of Microgynon®
(R17-0443).
Safety
Combined hormonal contraceptives (CHC) including Microgynon® should not be used in the 
following conditions. Should any of the conditions appear for the first time during CHC use, 
the product should be stopped immediately.


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
Presence or risk of venous thromboembolism (VTE)

Presence or risk of arterial thromboembolism (ATE)

Presence or history of severe hepatic disease or liver tumours

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 combined oral 
contraceptives (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 Microgynon® are nausea, abdominal pain, increased 
weight, headache, depressed mood, altered mood, breast pain, and breast tenderness. They 
occur in more than 1% of users.
Less common adverse events are vomiting, diarrhea, fluid retention, migraine, libido 
decreased, breast hypertrophy, rash, and urticarial.
Serious adverse reactions are VTE and ATE. Special warnings are precautions for use in 
arterial or venous thromboembolic disorders, strokes, hypertension, and liver tumours.
For a complete listing of adverse reactions including frequency of occurrence please refer to 
the current version of the summary of product characteristics (SmPC) (R17-0443)


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2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the effect of multiple doses of 
ethinylestradiol / levonorgestrel (Microgynon®) on single dose pharmacokinetics of BI 
409306 and the effect of single dose of BI 409306 on multiple dose pharmacokinetics of 
ethinylestradiol / levonorgestrel (Microgynon®)
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
 
 
 
 


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Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (400 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
 
 
 
 
 
 
 
 
Risks related to Microgynon® administration
Microgynon® has been used for over 10 years and is generally well tolerated [R11-0385,
R11-0382]. The intake of combined oral contraceptives is associated with an increased risk of
serious side effects such as cardiovascular diseases (myocardial infarction, cerebrovascular
insult, venous thromboembolism) and tumors of breast and liver. The incidence of venous
thromboembolic events is 5-10 per 100.000 women in 1 year, if no hormonal contraceptives
are used. The incidence is increased to about 20/100.000 after intake of 2nd generation
combined oral contraceptives (containing levonorgestrel, e.g. Microgynon®). In contrast, the
intake of 3rd generation combined oral contraceptives (containing gestoden or desogestrel) is
associated with a higher risk (up to 40/100.000) of thrombembolic events [R12-0033]. 
The most frequent side effects (>10%) of Microgynon® are headache, spotting and 
intermenstrual bleeding. Furthermore the following undesirable effects have been observed: 
gastric upset, nausea, vomiting, breast tenderness, changes in body weight, changes in libido, 
and depression. In predisposed women, use of Microgynon® can sometimes cause chloasma 
which is exacerbated by exposure to sunlight. Women with a predisposition to pigment 
changes should avoid prolonged exposure to sunlight. Individual cases of poor tolerance of 
contact lenses have been reported with use of oral contraceptives; therefore, contact lens 
wearers who develop changes in lens tolerance should be assessed by an ophthalmologist. 


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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. Therefore, treatment with Microgynon® should be continued even if 
irregular bleeding occurs. If irregular bleeding is persistent, appropriate diagnostic measures 
to exclude an organic cause are indicated.
Although rare, a potential for drug-induced liver injury is under constant surveillance by
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and
follow-up of laboratory alterations of selected liver laboratory parameters to ensure subjects´
safety.
 
 
 
 
 
 
 
Safety measures
-
Close monitoring of adverse events, safety lab, ECG and vital signs 
-
To reduce the risk of cardiovascular events, subjects with additional risk factors 
(smoking, adipositas, hypertension) are not to be entered in the trial, per 
inclusion/exclusion criteria and study restrictions. 
-
Thrombophilic testing will be performed on each subject to detect a potential 
thrombophilic disposition (deficiency of antithrombin III, resistance to activated 
protein C, etc.).
-
In addition to the general inclusion examination, the suitability of subjects for taking 
this oral contraceptive will be assessed by a gynaecologist prior to trial entry.
-
Although rare, a potential for drug-induced liver injury is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, 
and follow-up of alterations in selected liver laboratory parameters to ensure subjects´ 
safety.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, run-in period, two treatment periods in a fixed-
sequence.
A total of 16 healthy Korean premenopausal female volunteers with CYP2C19 PM genotype 
will participate in the trial.
Run-in-period
All subjects will undergo a run-in period (Visit 2) that starts between Day -49 and Day -28. In
this period, the subjects will take one tablet of Microgynon® daily (for 21-42 days) until Day
-8. In the last 7 days of the run-in period (Day -7 to Day -1) no treatment will be given in 
order to induce withdrawal bleeding. The next day will be Day 1. Subjects who have already 
been using oral contraceptives before the study will start the run-in period after the usual 
tablet-free interval of 7 days. Subjects who have been using hormonal contraceptive vaginal 
rings before the study will start the run-in-period after the usual hormone-free interval of 7 
days.
Treatment period
Visit 3 follows directly after the run-in-period. Subjects will be treated as below.
1 tablet of Microgynon® QD with 240 mL water on Days 1 to 17 (R2 on Day 17)
1 tablet of BI 409306 and 1 tablet of Microgynon® with 240 mL water on Day 18 (T1 and T2)
1 tablet of Microgynon® QD with 240 mL water on Days 19 to 21
1 tablet of BI 409306 with 240 mL water on Day 29 (R1)
Period
Screening
Run-in
Treatment
End of Trial
Visit
1
2
3
4
Day
-70 to -29
-49 to -1
1 to 16
17
18
19 to 21
…
29
33 to 35
BI 409306
X
X
Microgynon®
X*
X
X
X
X
* depending on the subjects’ actual menstruation cycle. No Microgynon® on the Days -7 to -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 Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial will be conducted at the 
under the supervision of the Principal Investigator.


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The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany. 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
The analyses of BI 409306 concentrations in plasma will be performed at the Department of 
Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, Germany.
The analyses of ethinylestradiol and levonorgestrel concentrations in plasma will be 
performed at the laboratory of
Genotyping of cytochrome P450 (CYP) isoenzyme 2C19 will be performed at the study site.
Safety laboratory tests will be performed by the local laboratory of the trial site.
Electrocardiograms (ECG) are to be evaluated for subject safety at the study site by the 
investigator or 
 representative.
Data management and statistical evaluation will be done by BI according to BI SOPs.
The trial is sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The trial will be conducted as an open-label, two-period, fixed-sequence trial. 
The design of the study allows each subject to serve as her own control. The comparison
between treatments is based on a comparison within subjects rather than between subjects.
This means that the inter-subject variability is removed from the comparison between
treatments [R94-1529].
Considering possible variations of enzyme activities during the menstrual cycle [R09-5728],
a fixed-sequence design was chosen to ensure that pharmacokinetic parameters of the
respective investigational drugs would be determined in all subjects at the same time point of
the menstrual cycle. To exclude possible interaction with any preceding oral contraceptive
regime and to minimize the influence of adaptation to a newly administered oral
contraceptive, all participants will undergo a run-in period of at least 28 days (including
treatment with Microgynon® for at least 21 days) before the beginning of the first study
period. The duration of Microgynon® intake was chosen to ensure steady state condition for 
Microgynon®.The study design is considered appropriate to assess a possible influence of BI
409306 on the steady state pharmacokinetics of ethinylestradiol and levonorgestrel.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy Korean premenopausal female subjects with CYP2C19 poor 
metabolizer (PM) genotype will enter the study. The CYP2C19 PM genotype is defined by 


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the carriage of two non-functional alleles (*2 and *3) of the CYP2C19 gene. Subjects will be 
recruited from the volunteers' pool of the trial site.
A log of all subjects enrolled into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy female subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy CYP2C19 PM genotyped (defined 5.3.1) premenopausal female subjects
according to the investigator’s assessment, based on a complete medical history including 
a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests.
2. Korean ethnicity according to the following criteria
; be a current Korean passport or national identification card holder, and have parents and 
grandparents who were all born in Korea
3. Age of 19 to 40 years (incl.)
4. BMI of 18.5 to 25.0 kg/m2 (incl.)
5. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
6. Female subjects who meet any of the following criteria starting from at least 30 days
before the first administration of trial medication and until 30 days after trial completion:
-
Use of adequate contraception, e.g. non-hormonal intrauterine device plus condom 
-
Sexually abstinent
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)
-
Surgically sterilised (including hysterectomy)
3.3.3
Exclusion criteria
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator


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5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, 
oncologic or hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial (including bioequivalence trial) where an investigational 
drug has been administered within 3 months prior to planned administration of trial 
medication
13. Current smoker or ex-smoker who quit smoking less than 30 days prior to screening
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 20 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study.
21. Any relevant finding of the gynaecological examination
22. Thrombotic predisposition according to thrombophilic testing
23. Existing or history of arterial thrombotic or embolic processes, conditions which
predispose to them e.g. disorders of the clotting processes, valvular heart disease and
atrial fibrillation
24. Existing or history of confirmed venous thromboembolism, family history of venous
thromboembolism, and other known risk factors for venous thromboembolism.
25. Relevant varicosis
26. Use of hormone-containing intrauterine device, depot injection or contraceptive implants
 
 


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For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent, without the need to justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as pregnancy,
surgery, adverse events, or diseases)
4. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication in run-in period, the data of this subject will not be entered in the case report form 
(CRF) or trial database and will not be reported in the clinical trial report (CTR). If a subject 
is removed from or withdraws from the trial after first administration of trial medication in 
run-in period, this will be documented and the reason for discontinuation must be recorded in 
the CRF. In this case, the data will be included in the CRF/trial database and will be reported
in the CTR. At the time of discontinuation a complete end of trial examination will be 
performed if possible and the information will be recorded in the CRFs. These 
discontinuations will be discussed in the CTR.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication has to be stopped immediately, and the subject has to be removed from the trial. 
The subject is to be followed until she has given birth or until the end of pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the clinical trial report. For reporting of pregnancy and all related events refer to 
Section 5.2.2.2.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 


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of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported that is
considered to be unacceptable.
2. The expected enrolment goals overall are not met
3. Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and comparator product.
Trial Product 1
Substance:
BI 409306
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Days 18 and 29
Trial Product 2
Name:
Microgynon® 30
Substance:
ethinylestradiol (EE) and levonorgestrel (LNG)
Pharmaceutical formulation: coated tablet (sugar-coated)
Source:
Bayer plc, Bayer House
Unit strength:
0.03 mg EE and 0.15 mg LNG
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Maximum 42 days in run-in period, 21 days in treatment period
4.1.2
Method of assigning subjects to treatment groups
This is an open-label, two-period, fixed-sequence trial.
The allocation of subjects to study subject numbers will be performed after screening. Once a 
subject number has been assigned, it cannot be reassigned to any other subject.
4.1.3
Selection of doses in the trial
The ethinylestradiol/levonorgestrel (Microgynon®) doses of 0.03 / 0.15 mg QD are standard 
clinical doses and were selected to achieve a the relevant plasma exposure for evaluation of a 
possible drug-drug interaction (see section 1.2).


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4.1.4
Drug assignment and administration of doses for each subject
All subjects will receive the two treatments in a fixed sequence order. The treatments to be 
evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
R1
(Reference 1)
BI 409306
Film coated tablet
25 mg
1 tablet on Day 29
T1
(Test 1)
BI 409306
Film coated tablet
25 mg
1 tablet on Day 18
Microgynon®
Coated tablet
0.03 mg EE / 0.15 mg LNG
1 tablet on Day 18
R2
(Reference 2)
Microgynon®
Coated tablet
0.03 mg EE / 0.15 mg LNG
1 tablet on Day 17
T2
(Test 2)
Microgynon®
Coated tablet
0.03 mg EE / 0.15 mg LNG
1 tablet on Day 18
BI 409306
Film coated tablet
25 mg
1 tablet on Day 18
Run-in period:
The Microgynon® tablets for the run-in period (duration depends on the actual menstrual
cycle of the subject) will be dispensed to the eligible subjects. The administration during the
run-in period is done by the subjects and documented in a diary. The subjects are advised to


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take the Microgynon® tablets with a cup of water at the same in the morning. No
Microgynon® tablets are to be taken in the last 7 days of the run-in period.
Treatment period:
The medication will be administered as an oral dose together with about 240 mL of water to a 
subject in the standing position under supervision of the investigating physician or an 
authorised designee. The so-called four-eye principle (two-person rule) should be applied for 
administration of trial medication and – if applicable – its preparation (e.g. reconstitution), if 
correct dosage cannot be ensured otherwise. Administration in the morning of Days 17, 18
and 29 will be performed following an overnight fast starting no later than 10 h before 
scheduled dosing. For medication at all other time points no fasting is required. 
Subjects will be kept under close medical surveillance for at least 12 h post dose on Days 17, 
18 and 29. 
During the first 2 h after drug administration on these days, they are not allowed to lie down 
(i.e. no declination of the upper body of more than 45 degrees from upright posture, except 
for trial activities). For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
No blinding was performed because the treatments are distinguishable from each another. 
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, since all subjects receive the same dose of 
different formulations in an open label design.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The clinical trial supply containers for BI 409306 will be labelled 
with:

BI trial number

Batch number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date


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The blisters are labelled with reduced requirements.
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. Examples of the labels will be available in the 
ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre

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 or immediately imminent 
signing of the clinical trial protocol
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication must be returned to the sponsor. Receipt, usage 
and return must be documented on the respective forms in ISF. Account must be given for 
any discrepancies.
The investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each subject, and 
the returned to the sponsor of unused products. 
These records will include dates, quantities, batch / serial numbers and expiry (‘use-by’) 
dates. The investigator / pharmacist / investigational drug storage manager will maintain 
records that document adequately that the subjects were provided the doses specified by the
CTP, and that reconcile all investigational products received from the sponsor. At the time of
return to the sponsor, the investigator / pharmacist / investigational drug storage manager 
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.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. No additional treatment is planned. However, in case of 
adverse events in need of 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 medical evaluation results have returned to an 
acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed.
 
 
 
 
 
If a concomitant medication is required for treatment of adverse events the interaction 
potential with the trial drugs must be checked prior to administration. All concomitant or 
rescue therapies will be recorded (including time of intake on study days) on the appropriate 
pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake.
On Days 17, 18 and 29 the following applies:
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects). From lunch until 12 h post-dose, total fluid intake is restricted to 2000 mL.
 
 


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Smoking is not allowed.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 h before administration of trial medication until 24 h after 
the last PK sample of each study period is collected.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
Adequate contraception is to be maintained throughout the course of the trial (see Section 
3.3.2 for adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. This does not apply for dosing of 
Microgynon® in the run-in phase. The measured plasma concentrations will provide 
additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death, 

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 
or 

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as given 
above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system, a remote data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.


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The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab 
results (ALT, AST, total bilirubin) available, the Investigator should make sure these 
parameters are analysed, if necessary in an unscheduled blood test. Should the results 
meet the criteria of hepatic injury alert, the procedures described in the DILI checklist 
should be followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).


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


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these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report relevant SAEs and relevant AESIs of which 
 may 
become aware of.
 
The REP for 
Microgynon is defined as 10 days after the last administration of Microgynon®.
Therefore, all AEs which occurred through the treatment phase and throughout the REP will 
be considered as on treatment; please see Section 7.3.3. Events which occurred after the REP 
will be considered as post treatment events.
The follow-up period describes the period of time from the last administration of trial 
medication including the REP until the end of trial examination (last per protocol contact).
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours of 
awareness) to the sponsor’s unique entry point (country specific contact details will be 
provided in the ISF). In specific occasions the Investigator could inform the sponsor upfront 
via telephone. This does not replace the requirement to complete and fax the BI SAE form. 
The same timeline applies if follow-up information becomes available.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication


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The following should also be recorded as an (S)AE in the CRF and on the SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
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 Trials (Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and 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 Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designate 
for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is a clinically relevant abnormality in the automatic blood cell count or in 
the urinalysis, respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Set A1
Set B2
Set C3
Hematology
Hematocrit 
Hemoglobin 
Red blood cell count (RBC) 
Reticulocyte count
White blood cell count (WBC)
Platelet count  
x
x
x
x
x
x
x
x
x
-
x
x
x
x
x
-
x
x
Automatic WBC differential 
(relative)
Neutrophils, eosinophils, basophils, monocytes, 
lymphocytes
x
x
x
Manual differential WBC (if 
automatic differential WBC is 
clinically relevant abnormal)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
x
x
x
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Thrombophilic tests4
x
x
x
-
-
-
x
x
-
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (ALP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated
Lactate dehydrogenase (LDH)
Amylase
Lipase
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
-
-
x
x
x
x
x
x
x
-
-
Hormones
Thyroid stimulating hormone (TSH)
x
-
-
Substrates
Serum Glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Uric acid 
Total cholesterol 
Triglycerides
hs-CRP (high sensitivity C-Reactive Protein)
x
x
x
x
x
x
x
x
x
x
x
x
x
-
-
-
-
x
x
x
x
x
-
-
-
-
x
1
Parameters of Set A will be determined at the screening examination
2
Parameters of Set B will be determined during treatment periods at the time points given in the Flow Chart
3
Parameters of Set C will be determined at the end of trial examination
4
Thrombosis panel (Lupus anticoagulant / Anti-cardiolipin antibody (ACA) (IgM, IgG) / Protein C / Protein S / 
antithrombin III /anti-beta2 Glycoprotein I antibody (IgM, IgG) / Plasminogen)


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Table 5.2.3: 1
Routine laboratory tests (cont.).
Functional lab group
Test name 
Set A1
Set B2
Set C3
Electrolytes
Sodium
Potassium
Calcium
x
x
x
x
x
-
x
x
-
Urinalysis4 (Stix)
Urine nitrite
Urine protein (albumin)
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes (RBC)
Urine leukocytes (WBC)
Urine pH
x
x
x
1
Parameters of Set A will be determined at the screening examination
2
Parameters of Set B will be determined during treatment periods at the time points 
given in the Flow Chart
3
Parameters of Set C will be determined at the end of trial examination
4
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)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. 
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Set A1
Set B2
Set C3
Drug screening (urine)
Includes:
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis, Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates , Phencyclidine
Tricyclic antidepressants
x
-
-
Infectious serology (blood)
Includes:
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV 1+2-antibody
x
-
-
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-
HCG)
x
x
x
1
Parameters of Set A will be determined at the screening examination
2
Parameters of Set B will be determined during treatment periods at the time points given in the Flow Chart
3
Parameters of Set C will be determined at the end of trial examination


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To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
at screening and prior to each admission, and may be repeated at any time during the study at
the discretion of an investigator or designate. The results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at the trial site.
Laboratory data will be transmitted electronically from the trial site to BI.
5.2.4
Electrocardiogram
For safety monitoring 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded 
using a computerised electrocardiograph Mac 5500, GE Medical Systems, Milwauekee, USA
or Philips Pagewriter trim III). 
The ECGs will be recorded for 10 second duration after the subjects have rested for at least 5
min in a supine position. Electrode placement will be performed according to the method of 
Einthoven/Goldberger modified by Mason/Likar (hips and shoulders instead of ankles and 
wrists). At time points, indicated in the Flow Chart, single ECGs will be recorded.
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor at the times indicated in the Flow Chart, after subjects have rested for 
at least 5 min in a supine position. All recordings should be made using the same type of 
blood pressure recording instrument on the same arm if possible.
 
 


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5.3
OTHER
 
 
 
 
 
 
 
 
 
5.3.1.2
Analytical determinations
Genotyping will be performed at the trial site (
. Genomic DNA will be 
extracted from blood samples according to standard molecular genetics methods and 
analyzed by TaqMan-PCR or other standard genotyping technologies.
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in
the CRFs. 


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5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined for BI 409306

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
The following primary endpoints will be determined for ethinylestradiol and levonorgestrel:

AUC0-24,ss (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax, ss (maximum measured concentration of the analyte in plasma)
5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated for BI 409306:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
 
 
 


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Further pharmacokinetic parameters might be calculated as appropriate.
5.5.2
Methods of sample collection
 
 
 
 
 
 
 
 
 
5.5.2.2
Plasma sampling for pharmacokinetic analysis of ethinylestradiol and 
levonorgestrel
For quantification of ethinylestradiol and levonorgestrel, approximately 6 mL of blood will 
be taken from an antecubital or forearm vein into an EDTA (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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The EDTA-anticoagulated blood samples will be centrifuged for about 15 min at about 2100 
g and at 4 to 8 °C. If samples cannot be centrifuged immediately store them in an ice bath (up 
to 60 min) until centrifugation. Two plasma aliquots will be obtained and stored in
polypropylene tubes. The first aliquot should contain at least 1.5 mL plasma whereas the
second aliquot should contain the remaining plasma. Within a maximum time of 1 hour after
sampling at room temperature, the samples should be stored in a freezer. Until shipment on 
dry ice to the analytical laboratory, plasma samples will be stored frozen in an upright 
position at about –20°C or below. The second aliquot will be shipped after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory the plasma samples 
will be stored at about –20°C or below until analysis
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. 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 study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany, G144
Birkendorfer Straße 65, 88397 Biberach/ Riß, Germany
 
 
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany, G144
Birkendorfer Straße 65, 88397 Biberach/ Riß, Germany
Analysis of ethinylestradiol and levonorgestrel in plasma study samples will be performed 
using validated liquid chromatography tandem mass spectrometry assays (LC-MS/MS) in the 
laboratory:


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Days 17, 18 and 29 are to be performed and completed within a 2 h-period 
prior to the trial drug administration. 
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 60 min.
For PK sampling, pre-dose PK samples (nominal time, 0 hours) on Days 17, 18 and 29 have
to be performed within 10 minutes before each morning administration.
Acceptable deviations will be ± 5 minutes for collection of samples within 1 hour after drug
administration in the morning, ± 10 minutes for collection of samples within up to 12 hours
after drug administration in the morning, and ± 30 minutes for collection of samples within
up to 24 hours after drug administration in the morning and ± 60 minutes samples collected
after 24 hours after drug administration in the morning. Blood sampling for plasma trough
concentration is to be performed within 10 minutes before each morning administration.
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 individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, physical examination gynaecological examination including Pap smear, refer to 
Sections 5.2.3 to 5.2.5.
Pharmacogenomic genotyping will be performed in those subjects whose genotypes are not 
known (for details see Section 5.3).


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After passing the screening examination the subjects will be allocated to a subject number
and will be given a 2-month package of Microgynon® tablets for the run-in-period. The
intake of these tablets starts depending on the subjects’ actual menstruation cycle and at least
28 days before Day 1 of the treatment period (see Section 3.1). In the last 7 days of the run-in 
period, no Microgynon® tablets will be taken to induce a withdrawal bleeding.
6.2.2
Treatment periods
Each subject is expected to participate in the treatment periods (Days 1 to 32). 
On Days 16 and 28 study participants will be admitted to the trial site and kept under close 
medical surveillance for at least 12 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 study days, the study will be performed in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2. 
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period
For AE assessment, laboratory tests, recording of ECG and vital signs and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised. The end of the 
trial as a whole is defined by the ‘last regular visit completed by last subject’ or ‘end date of 
the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has been decided as 
sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate whether and to what extend BI 409306 
affects multiple dose pharmacokinetics of Microgynon® and whether and to what extend
Microgynon® affetcs single dose pharmacokinetics of BI 409306. The trial is designed to 
allow intra-subject comparisons and will be evaluated statistically by use of an appropriate 
linear model.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between the treatments. The secondary objectives will be assessed by descriptive 
statistics.
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics.
7.1.2
Endpoints
Relative bioavailability is to be determined on the basis of the primary and secondary 
pharmacokinetic endpoints (see Section 5.5.1).
Safety and tolerability will be determined on the basis of the parameters specified in Section 
5.2.1.
7.1.3
Model
The statistical model used for the analysis of primary and secondary endpoints will be an 
ANOVA (analysis of variance) model on the logarithmic scale. This model will include 
effects accounting for the following sources of variation:‘subjects’ and ‘treatment’. The effect 
‘subjects’ will be considered as a random effect, whereas the treatment effects will be 
considered as a fixed effect. The model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response (endpoint, see Section 7.1.3) measured on subject m 
receiving treatment k,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
k = the kth treatment effect, k = 1, 2, 
ekm = the random error associated with the mth subject who received
treatment k.


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7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of combined treatment of BI 409306 and Microgynon® compared 
to multiple treatment of Microgynon® and to single treatment of BI 409306 will be estimated 
by the ratios of the geometric means (test/reference) for the primary and secondary PK
endpoints. Additionally, their two-sided 90% confidence intervals (CIs) will be provided. 
This method corresponds to the two one-sided t-tests procedure, each at the 5% significance 
level. Since the main focus is on estimation and not testing, an acceptance range was not 
specified, that is, no hypothesis will be tested.
Confidence intervals will be computed, but have to be interpreted in the perspective of the 
exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The primary and secondary pharmacokinetic endpoints listed in Section 5.5.1 will be 
calculated according to the BI Standard Operating Procedure (SOP) ‘Standards and processes 
for analyses performed within Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-
472).
Primary and secondary pharmacokinetic parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

the subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

a pre-dose concentration is >5% of the Cmax value of that subject 

missing samples/concentration data at important phases of PK disposition curve.


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


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


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


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All calculations were performed as described by Kupper and Hafner [R12-0972] using R 
Version 3.2.2.


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


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The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the CTMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.


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Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P12-05791
U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER).
Guidance for industry: drug interaction studies - study design, data analysis, 
implications for dosing, and labeling recommendations (draft guidance, 
February 2012 (this guidance document is being distributed for comment 
purposes only)). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo
rmation/Guida nces/ucm292362.pdf (access date: 14 May 2012) ; 
U.S.Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2012
R09-5728
Salmon J, Coussediere D, Cousty C, Raynaud JP. Pharmacokinetics and 
metabolism of moxestrol in humans. J Steroid Biochem 1983. 18(5):565-
573
R10-5092
Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain 
129, 1659 - 1673 (2006)
 
 
R11-0382
Ragueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does not alter the 
pharmacokinetics of an oral contraceptive in healthy women. Epilepsia 
2002. 43(7):697-702
R11-0385
Kelly S, Davies E, Fearns S, McKinnon C, Carter R, Gerlinger C, Smithers 
A. Effects of oral contraceptives containing ethinylestradiol with either 
drospirenone or levonorgestrel on various parameters associated with well-
being in healthy women: a randomized, single-blind, parallel-group, 
multicentre study. Clin Drug Invest 2010. 30(5):325-336.
R12-0033
Yasmin 0,03 mg/3 mg Filmtabletten (Bayer Vital), verschreibungspflichtig 
(Fachinformation (Zusammenfassung der Merkmale des Arzneimittels), 
Stand der Information: Mai 2011). 2011
R12-0972
Kupper LL, Hafner KB. How appropriate are popular sample size 
formulas? Am Stat 43 (2), 101 - 105 (1989)
R13-3708 
Microgynon® 0,03 mg/0,15 mg ueberzogene Tabletten (Bayer Vital), 
verschreibungspflichtig (Fachinformation (Zusammenfassung der 
Merkmale des Arzneimittels), Stand der Informationen: November 2012).
 
 


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R17-0443 
Microgynon 30 (Bayer plc) (summary of product characteristics updated
06-Jul-2015). http://www.medicines.org.uk/emc/print-
document?documentId=1827 (access date: 7 February 2017) 2015 
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
001-MCS-36-472Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
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. 511.93. 23 Apr 2008
U09-1393
16.1.9 Documentation of statistical - bioanalytical 
and pharmacokinetic analysis. 1218.44. 
U12-1031
16.1.9 Documentation of statistical -
bioanalytical and pharmacokinetic analysis. 1245.41
U12-1034-01
A randomized, double-blind, 
placebo-controlled (within dose groups) Phase I study to assess the safety, 
tolerability and pharmacokinetics of single rising doses 0.5 mg to 500 mg of 
BI 409306 administered orally in healthy male volunteers, Clinical Trial 
Report 1289.1, 19 Jan 2012
U13-1182-01
 Safety, tolerability, 
pharmacokinetics, and pharmacodynamics of multiple-rising doses of BI 
409306 film-coated tablets given orally q.d. or BID for 14 days in young 
healthy and elderly healthy male/female volunteers (randomized, double-
blind, placebo-controlled within dose groups Phase I study), Clinical Trial 
Report 1289.2., 20 Feb 2013
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. 1220.56. 19 Feb 2013.


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c02098989-02
 Safety, tolerability and 
pharmacokinetics of single oral doses of BI 409306 (tablet) in healthy 
Chinese and Japanese male volunteers and multiple oral doses of BI 409306 
(tablet) in healthy Japanese male volunteers (randomized, double-blind, 
placebo-controlled within dose groups), Clinical Trial Report 1289.4, 13 
March 2014.
c03131799-01
. Open, randomized, two-way 
crossover study to assess the effect of a high fat, high caloric meal on the 
pharmacokinetics of BI 409306, followed by a fixed sequence period to 
investigate the pharmacokinetics of BI 409306 after a single oral dose given 
at bed time in healthy male and female volunteers. 1289.22. Clinical Trial 
Report 1289.22, 10 Sep 2015..
c03183204-01
 Open-label, randomized, two-way 
crossover study to assess the effect of once daily Itraconazole on the 
pharmacokinetics of BI 409306 after a single oral dose in healthy male 
volunteers genotyped as poor and extensive metabolisers of CYP2C19, ctr-
1289-0023, 14 Aug 2015
с03808525
 A randomized, double-blind, double 
dummy, placebo-controlled, three-way crossover study to assess cardiac 
effects after single oral doses of BI 409306 under resting and exercise 
conditions in healthy male volunteers, ctr-1289-0028, 08 Jun 2016
n00249464
 Investigations on the in vitro metabolism of 
BI 409306 using LC-MS analytics. A382/15LU. 24 Mar 2016
c09564954-01
: A study to investigate the 
pharmacokinetic drug-drug interaction following oral administration of 
BI 409306 and donepezil in healthy male and female subjects. Clinical Trial 
Report 29-Nov-2016.
U13-1303-01
Safety, tolerability, 
pharmacokinetics, and pharmacodynamics of multiple-rising doses of BI 
409306 film-coated tablets given orally q.d. or BID for 14 days in young 
healthy and elderly healthy male/female volunteers (randomized, double-
blind, placebo-controlled within dose groups Phase I study), Clinical Trial 
Report 1289.17, 22 Feb 2013.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
14 Jul 2017
EudraCT number
BI Trial number
1289-0040
BI Investigational Product(s)
BI 409306
Title of protocol
A study to investigate the pharmacokinetic drug-
drug interaction following oral administration of 
ethinylestradiol/levonorgestrel (Microgynon®) 
and BI 409306 in healthy Korean premenopausal 
female subjects (an open-label, two-period, fixed-
sequence study)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Flow Chart
2. Section 1.2.1
3. Section 3.3.4.1
4. Section 4.1.4
5. Section 5.2.3
6. Section 5.5.3.1
7. Section 5.5.2.2
8. Section 7.3.1
Description of change
1. Remove ‘Assignment of medication numbers’
on Day 1
Change ‘684:00’ and ’21:00’ ‘686:00’ and 
‘23:00’
2. Change ‘visual blurred’ ‘vision blurred’
3. Remove ‘The only exception to this rule is 
when the subject had an AESI and/or SAE 


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Number of global amendment
1
that the investigator considers related to the 
screening procedure.’
Change ‘first administration of trial 
medication’ ‘first administration of trial 
medication in run-in period’
4. Change ‘No Microgynon® tablets are to be 
taken in the last 6 days of the run-in period.’
‘No Microgynon® tablets are to be taken in 
the last 7 days of the run-in period.’
5. Change ‘Plasma glucose’ ‘Serum glucose’
Add punctuation and ‘Anti-cardiolipin 
antibody’ in thrombosis panel
6. Delete the name of analysts
7. Change ‘The second aliquot will be shipped 
after the bioanalyst has acknowledged safe 
arrival of the first and second aliquots.’
‘The second aliquot will be shipped after 
the bioanalyst has acknowledged safe arrival 
of the first aliquot.’
8. Change ‘plasma and urine’ ‘plasma’
Rationale for change
1. Correction
2. Correction
3. To avoid confliction with section 5.2.2.2
4. Correction
5. To clarify the safety lab test
6. Correction
7. To avoid further amendment
8. Correction


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13608215
2.0
clinical-trial-protocol-revision-01
A study to investigate the pharmacokinetic drug-drug interaction following oral
administration of ethinylestradiol/levonorgestrel (Microgynon®) and BI 409306 in
healthy Korean premenopausal female subjects (an open-label, two-period,
fixed-sequence study)
Author-Statistician
19 Jul 2017 04:43 CEST
Approval-Clinical Pharmacokinetics
19 Jul 2017 09:37 CEST
Approval-Therapeutic Area 
19 Jul 2017 14:14 CEST
Author-Clinical Monitor
20 Jul 2017 04:45 CEST
Approval-Team Member Medicine
21 Jul 2017 20:59 CEST
Verification-Paper Signature
Completion
24 Jul 2017 04:26 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13608215
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c20737022-01
BI Trial No.:
1289-0040
Title:
A study to investigate the pharmacokinetic drug-drug interaction 
following oral administration of ethinylestradiol/levonorgestrel 
(Microgynon®) and BI 409306 in healthy Korean premenopausal 
female subjects (an open-label, two-period, fixed-sequence study)
Protocol Amendment 1 1289-0040-protocol-amendment-1
[c13608215-02]
Investigational
Product:
BI 409306
Responsible trial 
statistician:
Address:
Phone:
 Fax:
Date of statistical 
analysis plan:
05 JAN 2018 SIGNED
Version:
Final
Page 1 of 26
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2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINT(S).......................................................................................................8
5.1
PRIMARY ENDPOINT(S) ..................................................................................8
5.2
SECONDARY ENDPOINT(S) ............................................................................8
5.2.1
Key secondary endpoint(s)...................................................................................8
5.2.2
Secondary endpoint(s) ..........................................................................................8
.................................................................................8
..........................................9
..........................................9
..........................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENT(S)................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................15
..................................................................................................16
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........20
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINT(S) ................................................................................20
7.5
SECONDARY ENDPOINT(S) ..........................................................................20
7.5.1
Key secondary endpoint(s).................................................................................20
7.5.2
(Other) Secondary endpoint(s) ..........................................................................20
..............................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................23
7.8.5
Others...................................................................................................................23
8.
REFERENCES....................................................................................................24


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


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................10
Table 6.2: 1
Important Protocol violations...........................................................................14
Table 6.3: 1
Subject sets analysed........................................................................................16
Table 10: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse event
BMI
Body mass index
CTP
Clinical trial protocol
CTR
Clinical trial report
DBL
Data base lock
ES
Entered set
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
O * C
Oracle ClinicalTM
PK
Pharmacokinetic
PKS
Pharmacokinetic set
PV
Protocol violation
RAGe
Report Appendix Generator system
REP
Residual effect period
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
TS
Treated set
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per International Conference on Harmonisation (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, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a 
number of SASTM-based tools (e.g., macros for the analyses of adverse event (AE) data or 
laboratory data; Report Appendix Generator system (RAGe) for compilation/formatting of 
the clinical trial report (CTR) appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There will be no changes in the planned analysis of the study.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
Primary PK endpoints as defined in Section 5.5.1.1 of the CTP:
The following primary endpoints will be determined for BI 409306 

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
The following primary endpoints will be determined for ethinylestradiol and levonorgestrel:

AUC0-24,ss (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax,ss (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
There are no key secondary endpoints in this trial.
5.2.2
Secondary endpoint(s)
Section 5.5.1.2 of the CTP:
The following secondary endpoints will be evaluated for BI 409306:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on investigational products, assignments of treatment, and 
selection of doses, please see CTP, Sections 3 and 4. For details of dosage and formulation
see Table 6.1: 1 below.
Table 6.1: 1
Labels for treatments for use in the CTR
Treatment
Substance
Formulation
Unit strength
Dosage
Short label
R1
(Reference 1)
BI 409306
Film coated tablet 25 mg
1 tablet on 
Day 29
BI
T1
(Test 1)
BI 409306
Film coated tablet 25 mg
1 tablet on 
Day 18
BI+Microgynon®
Microgynon® Coated tablet
0.03 mg EE / 
0.15 mg LNG
1 tablet on 
Day 18
R2
(Reference 2)
Microgynon® Coated tablet
0.03 mg EE / 
0.15 mg LNG
1 tablet on 
Day 17
Microgynon®
T2
(Test 2)
Microgynon® Coated tablet
0.03 mg EE / 
0.15 mg LNG
1 tablet on 
Day 18
BI+Microgynon®
BI 409306
Film coated tablet 25 mg
1 tablet on 
Day 18
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from day of informed consent until first administration of study 
drug)

Microgynon® treatment (ranging from the time of first intake of Microgynon® until 
the time of first administration of BI 409306 or last intake of Microgynon® + 
Microgynon® REP (10 days), whatever occurs earlier)

BI 409306 + Microgynon® treatment (ranging from the first administration of 
BI 409306 + Microgynon® until end of Microgynon® REP (10 days)) 

BI 409306 treatment 
 

Follow up BI 409306 treatment 
 
The residual effect period (REP) for BI 409306, when measurable drug levels or PD effects 
are still likely to be present, 
 The REP for 
Microgynon® is considered to be 10 days.


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Displays of AEs will be presented separately for the following treatments during on treatment
phase:

BI 409306, tablet, qd (labelled “BI“)

Microgynon®, tablet, qd (labelled “Microgynon“)

BI 409306, tablet, qd + Microgynon®, tablet, qd (labelled “BI + Microgynon“)
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.9.2.8 (for ClinicalTrials.gov) of the CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening and Follow-up BI will not be included in this analysis.
The following total will be provided in addition (Section 15.3 only):

a total over all on treatment phases involving BI (“Total BI”)

a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.9.2.8 (except for ClinicalTrials.gov) of the CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))

Follow-up BI (labelled “FU BI”)
In Section 16.1.9.2.8 AE tables, the following totals will be provided in addition:

a total over all study phases ("Total")
Tables of vital signs and laboratory values will present results by the following separate study 
phases which will be defined for the analyses of vital signs and laboratory values:

Screening (ranging from day of informed consent until first administration of study 
drug)

Microgynon® treatment (ranging from first intake of Microgynon® until first 
administration of BI 409306 or last intake of Microgynon® + Microgynon® REP (10 
days), whatever occurs earlier)

BI 409306 + Microgynon® treatment (ranging from first administration of BI 409306 
+ Microgynon® until administration of BI 409306 + 

Microgynon® treatment (ranging from end of 
until last 
intake of Microgynon® + Microgynon® REP (10 days))

BI 409306 treatment (ranging from first administration of BI 409306 alone until EOT 
or last intake of BI 409306 + 
 whatever occurs earlier)


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
Follow up BI 409306 treatment (ranging from end of last BI 409306 treatment + 
 
For detailed information on the handling of the treatments in the O*C views refer to 
Technical TSAP analysis data set (ADS) plan.


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6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects in the 
database (i.e., treated subjects and subjects with serious AE (SAE) which the investigator 
considered related to the screening procedure). Consistency check listings (for identification 
of violations 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 at the report 
planning meeting (RPM) and data base lock meeting (RPM/DBL). At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation (PV). For definition of important PVs, and for the process of identification of these, 
refer to the Boehringer Ingelheim reference document 'Protocol Violation Handling 
Definitions' (2). 
If any important PVs are identified, they are to be summarised into categories and will be 
captured in the RPM minutes via accompanying Excel spreadsheet (3). The following table 
contains the categories which are considered to be important PVs in this trial. If the data 
show other important PVs, this table will be supplemented accordingly by the time of the 
RPM. If substantial numbers of PVs are reported at the RPM, a decision about summarising 
the PVs in a tabular format will be made. Otherwise, only a PV listing will be provided.
The following Table 6.2: 1 gives the important PVs for this trial.


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Table 6.2: 1
Important Protocol violations
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomization
C1
Incorrect trial medication taken
C2
Non-compliance
C3
Incorrect intake of trial medication
D
Concomitant medication
D1
Prohibited medication use
E
Missing data
E1
Certain violations of procedures used to measure primary or secondary data
F
Incorrect timing
F1
Certain violations of time schedule used to measure primary or secondary data.
G
Other trial specific important violations
G1
Incorrect intake of meal


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6.3
SUBJECT SETS ANALYSED

Entered set (ES):
This subject set includes all entered subjects, whether treated or not.

Treated set (TS):
This subject set includes all subjects from the ES who were dispensed study medication 
and were documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for safety 
analysis.
Section 7.3.1 of the CTP:
Primary and secondary pharmacokinetic parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol violation relevant to the evaluation of PK (to be decided no later than in the 
Report Planning Meeting) or due to PK non-evaluability (as revealed during data 
analysis, based on the criteria specified below). Exclusion of a subject’s data will be 
documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

the subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

a pre-dose concentration is >5% of the Cmax value of that subject 

missing samples/concentration data at important phases of PK disposition curve.

Pharmacokinetic set (PKS):
The PK parameter analysis set (PKS) includes all subjects in the TS who provide at least 
one primary or secondary PK parameter that was not excluded according to the 
description above. Thus, a subject will be included in the PKS, even if she contributes 


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only one PK parameter value for one period to the statistical assessment. It is used for the 
PK analysis.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to populations will be made at latest at the RPM.
The following table summarizes which subject sets will be used for the different analyses.
Table 6.3: 1
Subject sets analysed
Class of endpoint
ES
TS
PKS
Disposition, exposure
X
Important PVs
X
Primary endpoints 
X
Secondary endpoints and further 
parameters of interest in PK analyses
X
Safety endpoints
X
Demographic/baseline endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data will be according to the CTP, Section 7.4. Additionally, handling 
information of missing data is shown as follows:

Missing data and outliers of PK data are handled according to (4).

Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (5).


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline values of laboratory data and value of vital sign for safety analysis will be 
defined as the last values before first drug administration. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


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7.
PLANNED ANALYSIS
In general, a set of descriptive statistics to be displayed for continuous variables in the 
clinical trial report will be as follows:
Non-pharmacokinetic variables:
For End-Of-Text tables, the set of summary statistics is: N, mean, standard deviation (SD), 
min, median, and max.
Tabulation of frequencies for categorical or categorised data will include all possible 
categories and display number of observations (subjects) with the percentage relative to the 
respective treatment sequence / regimen. Percentages will be rounded to one decimal place. 
The category missing will be displayed if and only if there are actually missing values. 
Percentages will be based on all subjects in the respective subject set whether they have non-
missing values or not.
Pharmacokinetic variables:
The analysis of standard PK parameters will be performed according to (4).
Safety analysis (refer to Section 7.8) will be presented in Sections 15.1 to 15.4 of the CTR 
and in Appendices 16.2 and 16.1.9.2. 
Inferential statistical analyses of PK endpoints (refer to Section 7.5.2) will be presented in 
Section 15.5 of the CTR and in Appendix 16.1.9.3.
Descriptive data analysis of PK endpoints will be performed by BI and will be presented in
Section 15.6 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate
guideline “Reporting of clinical trials and project summaries” [001-MCG-159] (6) with the
exception of those generated for PK calculations.
The individual values of all subjects will be listed, sorted by treatment sequence, subject
number, visit and actual treatment (if appropriate). The listings will be included in Appendix
16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is:
N 
number non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For analyte concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:


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CV 
arithmetic coefficient of variation
gMean 
geometric mean
gCV 
geometric coefficient of variation
For PK parameters, P10, P90, Q1 and Q3 will be calculated.
The data format for descriptive statistics of concentrations will be identical with the data
format of the respective concentrations. The descriptive statistics of PK parameters will be
calculated using the individual values with the number of decimal places as provided by the
evaluation program. Then the individual values as well as the descriptive statistics will be
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will
display the number of observations in a category, as well as the percentage (%) for each
treatment group. Percentages will be rounded to one decimal place and will be based on all
subjects in the respective subject set whether they have non-missing values or not. The
category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO).
All analyses based on the PKS will include parameters if they are not flagged for exclusion;
that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’ the value will be excluded from half-life calculation only; the value is
included for all other analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic /
Pharmacodynamic Analyses of Clinical Studies” (4) and 001-MCS-36-472_RD-03
“Description of Analytical Transfer Files and PK/PD Data Files” (7).


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report based on the TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medication will be coded 
according to the most recent version of the World Health Organisation – Drug Dictionary.
Only listing is planned for this section of the report. The data will be summarised in total.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later
than at the RPM/DBLM.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of this treatment, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM and described in the CTR.
7.4
PRIMARY ENDPOINT(S)
The analysis will be performed as defined in the CTP, Sections 7.3.1-2.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
There are no key secondary endpoints in this trial.
7.5.2
(Other) Secondary endpoint(s)
The analysis will be performed as defined in the CTP, Sections 7.3.1-2.


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7.7
EXTENT OF EXPOSURE
Only listing is planned for this section of the report.
7.8
SAFETY ANALYSIS
The analysis will be performed as defined in the CTP. All safety analyses will be performed 
on the TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA. The analyses of AEs will be 
descriptive in nature. All analyses of AEs will be based on the number of subjects with AEs 
and not on the number of AEs.
For analysis multiple AE occurrence data on the case report form (CRF) will be collapsed 
into one AE provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest).

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started within one hour after end of the 
first occurrence).


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For further details on summarisation of AE data, please refer to (5, 8).
Section 5.2.2.1 of the CTP: 
The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The analysis of AEs will be based on the concept of treatment emergent AEs.
Section 5.2.2.2 of the CTP:
 
 The REP for 
Microgynon is defined as 10 days after the last administration of Microgynon®.
Therefore, all AEs which occurred through the treatment phase and throughout the REP will 
be considered as on treatment; please see Section 7.3.3 of CTP. Events which occurred after 
the REP will be considered as post treatment events.
For details on the treatment definition, see Section 6.1.
According to ICH E3 (9), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious with
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a RPM/database lock (DBL) 
meeting. 
An overall summary of AEs will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class and preferred term (MedDRA levels to be displayed in the tables). 
Separate tables will be provided for subjects with other significant AEs according to ICH E3 
(9), for subjects with significant non-serious AEs (only if these are defined for the project) 
and for subjects with serious AEs, for subjects with drug-related AEs, for subjects with drug 
related SAEs and for subjects with AESIs.
The table for the subject with non-serious AEs occurring with incidence in preferred term 
greater than 5 % will be provided. Additionally, occurred AEs will be listed.


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The system organ classes will be sorted by default alphabetically. Preferred terms will be 
sorted by frequency (within system organ class).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (10), descriptive statistics with original values will be provided for baseline, on-
treatment values and for changes from baseline. Clinically relevant findings in laboratory 
data will be reported as AEs and will be analysed as part of AE analysis. Laboratory values 
will be compared to their reference ranges and frequency tables will be provided for the 
number of subjects within and outside the reference range at baseline and the last 
measurement on treatment. 
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the eCRF or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
7.8.3
Vital signs
Only descriptive statistics by planned visit are planned for this section of the report for 
absolute values and changes from baseline. Clinically relevant findings in vital signs data will 
be reported as AEs and will be analysed as part of AE analysis.
7.8.4
ECG
ECG data will not be listed but clinically relevant abnormal findings will be reported as AEs.
7.8.5
Others
Physical examination 
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", current 
version; IDEA for CON.
3
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", 
current version; IDEA for CON.
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON;
5
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version IDEA for CON;
6
001-MCG-159: “Reporting of clinical trials and project summaries”, current 
version;IDEA for CON.
7
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; IDEA for CON.
8
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", Version 5; IDEA for CON.
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
10
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
05-JAN-18
None