Clinical trial NCT03934203
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-05-09; Completion date: 2019-09-06
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this trial is to assess the effect of BI 409306 on the QT/QTc interval in healthy male and female volunteers as measured by the QTcF change from baseline compared with placebo.

Secondary objectives are to show the assay sensitivity of the trial, by reproducing the typical effect of the positive control moxifloxacin on the QT/QTc interval, and to assess the effect of BI 409306 on heart rate.

Detailed description:

Arms: arm 1: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 2: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 3: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 4: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 5: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 6: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 7: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 8: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 9: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 10: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 11: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 12: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 13: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 14: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2. arm 15: In this randomized, placebo-controlled, 5-period crossover trial participants were randomized to one of 15 possible treatment sequences based on a balanced, Prescott triple Latin square design. Treatments administered were 50 mg BI 409306 administered orally as a single dose (1 film-coated tablet plus 4 film-coated placebo tablets), 250 mg BI 409306 administered orally as a single dose (5 film-coated tablets), 400 mg moxifloxacin administered orally as a single dose (1 film-coated tablet), Placebo 1 and Placebo 2 both administered orally as a single dose (5 film-coated tablets). In all treatment periods tablets were taken with 240 milliliter of water after an overnight fast of at least 10 hours on day 1 of the treatment period. The trial was double-blind for placebo and BI 409306, but open-label for moxifloxacin. A washout period of least 6 days was adhered to between drug administrations. L=50 mg BI 409306, H=250 mg BI 409306, M= 400 mg moxifloxacin, P=Placebo 1/Placebo 2.
Interventions: intervention 1: BI 409306 intervention 2: Moxifloxacin intervention 3: Placebo matching to BI 409306
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet intervention 3: Film-coated tablet

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:
c09109536-07
EudraCT No.:
BI Trial No.:
2018-001335-44
1289-0038
BI Investigational
Product:
BI 409306
Title:
Thorough QT study to evaluate the effects of BI 409306 as single 
doses on cardiac safety parameters in healthy male and female subjects.
A randomized, placebo controlled, double-blind, five-period crossover 
study with (open-label) moxifloxacin as positive control.
Lay Title:
This study in healthy men and women tests whether BI 409306 has an 
effect on the ECG (thorough QT study)
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date:
Version: 4.0
Date: 23 April 2019
Page 1 of 89
Proprietary confidential information
© 2019 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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BI Trial No.: 1289-0038
c09109536-07
Trial Protocol
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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:
23 April 2019
08 February 2019
1289-0038
Title of trial:
Thorough QT study to evaluate the effects of BI 409306 as single doses on cardiac 
safety parameters in healthy male and female subjects. A randomized, placebo 
controlled, double-blind, five-period crossover study with (open-label) moxifloxacin 
as positive control
Principal Investigator:
Trial site:
Clinical phase:
I
Objective(s):
To evaluate the effect of a single therapeutic and a single supra-therapeutic dose of
BI 409306 on the QT/QTc interval and other ECG parameters
Methodology:
Double-blind (moxifloxacin: open-label), randomised, placebo controlled, crossover 
with five treatment periods: 50 mg BI 409306, 250 mg BI 409306, 
400 mg moxifloxacin (positive control) and placebo (2 periods).
There will be a washout period of at least 6 days between treatments.
Cardiac safety assessment will be performed based on triplicate 10-second ECGs as 
extracted at selected time points from 24 hours post-dose Holter recording as well as 
overall Holter assessment in each treatment period. For each treatment period, three 
triplicate baseline 10-second ECGs will be extracted at pre-defined time points from 
pre-dose Holter recording. 
No. of subjects: 
total entered:
45
each treatment:
45 (at least 10 subjects of each gender)
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male/female subjects, age of 18 to 50 years, body mass index (BMI) of 18.5 
to 29.9 kg/m2
Test product 1:
BI 409306 film-coated tablets (treatments 1 and 2)
Dose:
50 mg and 250 mg
Mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h


Boehringer Ingelheim
23 Apr 2019
BI Trial No.: 1289-0038
c09109536-07
Trial Protocol
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001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
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:
23 April 2019
08 February 2019
1289-0038
Reference product 1:
Dose:
Mode of admin.:
Reference product 2:
Dose:
Mode of admin.:
Moxifloxacin (Avalox®) film-coated tablets (treatment 3)
400 mg
Oral with 240 mL of water after an overnight fast of at least 10 h
Placebo matching to BI 409306 50 mg tablets (treatment 4)
Not applicable
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment: One day (single dose) for each treatment
Criteria for
pharmacokinetics:
 
Criteria for safety:
Primary endpoints:
The maximum mean difference between BI 409306 and placebo in the QTcF changes
from baseline between 20 min to 24 hours after drug administration, for each dose of 
BI 409306.
Secondary endpoints:

The maximum mean difference between moxifloxacin and placebo in the QTcF
changes from baseline for the time points 2, 3, and 4 hours after dosing (for 
assessment of assay sensitivity). 

The maximum mean difference between BI 409306 and placebo in heart rate
(HR) changes from baseline between 20 min to 24 hours after drug 
administration, for each dose of BI 409306. 

The minimum mean difference between BI 409306 and placebo in HR changes
from baseline between 20 min to 24 hours after drug administration, for each 
dose of BI 409306.


Boehringer Ingelheim
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BI Trial No.: 1289-0038
c09109536-07
Trial Protocol
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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:
23 April 2019
08 February 2019
1289-0038
Statistical methods:
For the analysis of QTcF changes from baseline (ΔQTcF) at each time point between 
20 min to 24 hours post drug administration, a linear mixed-effects model for repeated 
measurements will be used. The comparison between each dose of BI 409306 and 
placebo will be performed pairwise, i.e. data not relevant for the comparison of 
interest will be excluded. The model includes the covariates ‘period baseline’ and 
‘subject baseline’ (defined as the arithmetic mean of the respective period baselines), 
the fixed categorical effects ‘treatment’, ‘period’, and ‘time’, the interaction terms 
‘period baseline-by-time’, ‘subject baseline-by-time’, ‘treatment-by-time’, and 
‘period-by-time’. For comparisons between BI 409306 and placebo, two-sided 90% 
confidence intervals (CI) for the mean differences per time point and corresponding 
point estimators will be computed.
For assessment of assay sensitivity, the same model will be used to compare QTcF
changes from baseline between moxifloxacin and placebo including all time points 
between 20 min to 24 hours post drug administration.
Changes from baseline in heart rate for BI 409306 as compared to placebo will be 
analysed in the same way as described for QTcF.


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BI Trial No.: 1289-0038
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FLOW CHART (A)
Period
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory 13
 
 
Holter ECG 7
12-lead ECG
Continuous  ECG 
monitoring
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-25
to
-5
Screening (SCR)1
xA
x8
x
1/2/3/4/5 (5 periods with a wash-out of at least 6 days)
2/3/4/5/6
-7 
to 
-3
Ambulatory visit for run-in ECGs 
(including in-house stay over at least 
8 hours), in Visit 2 only10,14
▲
│
▼
10,14
x14
-1
-12:00
20:00
Admission to trial site12
x5
x
1
-2:00
06:00
Allocation to treatment2 (Visit 2 only)
x2,B
x2
    ▲2
x2,8
x2
x2
x2
-0:50
07:10
├
-0:35
07:25
├
-0:20
07:40
├
0:00
08:00
Drug administration
  │*
▲
0:20
08:20
x
├
│
0:40
08:40
x
├
│
1:00
09:00
x
├
x8
│
x
x
1:30
09:30
x
├
│
2:00
10:00
240 mL fluid intake
xB
x
├
x8
│
2:30
10:30
x
├
│
3:00
11:00
x
├
│
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
├
▼
x
x
8:00
16:00
Snack (voluntary)3
x
├
10:00
18:00
Dinner3
│
12:00
20:00
x
├
x
x 
2
24:00
08:00
xC
x
├
  ▼11
24:15
08:15
Breakfast (voluntary)3,
discharge from trial site
  
x8
x
x
EOT
7
5 to 
12
End-of-trial (EOT) examination4
xD
x8
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, 12-lead single ECG, safety laboratory (including drug 
screening and pregnancy test in women), demographics (including determination of body height and weight, smoking 
status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within 3 h prior to drug administration
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End-of-trial examination includes physical examination, vital signs, ECG, safety laboratory, pregnancy test in women,
recording of AEs and concomitant therapies
5.
Only urine drug screening, alcohol breath test, and pregnancy test in women will be done at this time point.
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.
Holter ECG (◄––│––│––►). The arrows refer to start (►) and end (◄) of Holter ECG recording.
The sign ├ indicates that trigger points will be set at the Holter device for extraction of triplicate 12-lead 10 second 
ECGs. The time is an approximate. For acceptable time deviations please refer to Section 6.1.
The sign * indicates that a trigger point will be set at the Holter device at the time point of drug administration.   
8.
Single 12-lead ECG for clinical evaluation by the investigator only
9.
No BI 409306 PK samples after open-label moxifloxacin administration


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10. 12-lead Holter ECG is performed at Visit 2 and will be used for extraction of 7 drug-free 10-second run-in ECGs (over 
at least 8 hours as shown in Flow Chart (B)) and for analyses of arrhythmic events (at least 24 h recording as shown in 
Flow Chart (B)). The start of Holter ECG recording on Day -7 to -4 can be no earlier than 1 day after screening.
11. 12-lead Holter ECG recording on Day 1 and 2; recording to be stopped no earlier than 24 h after drug administration
12. Admission to the trial site should not be later than 10 hours prior to drug administration
13. Letters A, B, C and D describe different sets of safety laboratory examinations (see Table 5.2.3: 1)
14. in Visit 2 only
FLOW CHART (B) FOR AMBULATORY VISIT (RUN-IN), 
IN VISIT 2 ONLY
Period
Visit
Day
Planned time (relative to 
drug administration 
[h:min]5
Approximate clock time  
of actual day [h:min]
Event and comment
Holter ECG 3
Bed rest
Questioning for AEs and 
concomitant therapy 
1
2
-7
to
-4
-170:00
06:00
Admission to trial site, start of Holter 
recording 
    
  ▲1
│
x1
-168:50
07:10
├
-168:35
07:25
├
-168:20
07:40
├
-168:00
08:00
240 mL fluid intake
  │*
▲
-167:40
08:20
├
│
-167:20
08:40
├
│
-167:00
09:00
├
│
-166:30
09:30
├
│
-166:00
10:00
240 mL fluid intake
├
│
-165:30
10:30
├
│
-165:00
11:00
├
│
-164:00
12:00
240 mL fluid intake, thereafter lunch2
├
▼
-163:00
13:00
├
-162:00
14:00
├
-161:00
15:00
├
-160:00
16:00
Snack (voluntary)2, discharge
├
-6
to
-3
-144:00
08:00
Ambulatory visit (stop Holter 
recording)
│
▼4
x
1.
The time is approximate; the procedure is to be performed and completed within 3 h prior to planned time -168:00.
2.
If several actions are indicated at the same time point, the intake of meals will be the last action.
3.
Holter ECG (◄––│––│––►). The arrows refer to start (►) and end (◄) of Holter ECG recording.
 
 
  
4.
12-lead Holter ECG recording to be stopped no earlier than -144:00 planned time.
5.
Planned times for Holter ECG are placeholders, applicable for the time window Day -7 to -3.


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BI Trial No.: 1289-0038
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Trial Protocol
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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART (A) ............................................................................................5
FLOW CHART (B) FOR AMBULATORY VISIT (RUN-IN), ......................
IN VISIT 2 ONLY...............................................................................................6
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................16
1.2.1
BI 409306 nonclinical data...................................................................16
1.2.1.1
Efficacy....................................................................................16
1.2.1.2
Toxicology...............................................................................16
1.2.1.3
Preclinical Pharmacokinetics and Metabolism........................16
1.2.1.4
hERG-assay..............................................................................17
1.2.1.5
Cardiovascular function...........................................................17
1.2.2
BI 409306 clinical data..........................................................................18
1.2.2.1
Ongoing studies/ studies under evaluation ..............................18
1.2.2.2
Completed studies....................................................................18
1.2.2.3
Clinical Pharmacology.............................................................18
1.2.2.4
Clinical Pharmacokinetics and Metabolism.............................18
1.2.2.5
Clinical Safety..........................................................................20
1.2.3
Moxifloxacin drug profile.....................................................................24
1.2.4
Residual Effect Period..........................................................................24
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 25
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................25
2.2
TRIAL OBJECTIVES.......................................................................................25
2.3
BENEFIT - RISK ASSESSMENT ...................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.1.1
Administrative structure of the trial...................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for study entry............................................................31
3.3.2
Inclusion criteria...................................................................................31
3.3.3
Exclusion criteria ..................................................................................32


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3.3.4
Removal of subjects from therapy or assessments.............................33
3.3.4.1
Removal of individual subjects................................................33
3.3.4.2
Discontinuation of the trial by the sponsor..............................34
3.3.5
Replacement of subjects .......................................................................34
4.
TREATMENTS........................................................................................ 36
4.1
TREATMENTS TO BE ADMINISTERED....................................................36
4.1.1
Identity of BI investigational products ...............................................36
4.1.2
Method of assigning subjects to treatment groups ............................37
4.1.3
Selection of doses in the trial................................................................37
4.1.4
Drug assignment and administration of doses for each subject .......37
4.1.5
Blinding and procedures for unblinding ............................................38
4.1.5.1
Procedures for emergency unblinding .....................................39
4.1.6
Packaging, labelling, and re-supply ....................................................39
4.1.7
Storage conditions.................................................................................40
4.1.8
Drug accountability ..............................................................................40
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................41
4.2.1
Other treatments and emergency procedures....................................41
4.2.2
Restrictions............................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment .........................41
4.2.2.2
Restrictions on diet and life style.............................................42
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 43
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................43
5.1.1
Endpoints of efficacy.............................................................................43
5.1.2
Assessment of efficacy...........................................................................43
5.2
SAFETY..............................................................................................................43
5.2.1
Endpoints of safety................................................................................43
5.2.1.1
Primary safety endpoints..........................................................43
5.2.1.2
Secondary safety endpoints......................................................43
5.2.1.3
Further safety endpoints...........................................................43
5.2.1.3.2 Further criteria of interest ......................................................................45
5.2.2
Assessment of adverse events...............................................................45
5.2.2.1
Definitions of adverse events...................................................45
5.2.2.2
Adverse event collection and reporting ...................................48
5.2.3
Assessment of safety laboratory parameters......................................50
5.2.4
Electrocardiogram................................................................................53
5.2.4.1
12-lead continuous (Holter) ECG recording at the clinical site...
.................................................................................................53
5.2.4.2
12-lead triplicate ECG evaluation at the central ECG laboratory
.................................................................................................54


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5.2.4.3
12-lead Holter ECG evaluation at the central ECG laboratory55
5.2.4.4
Safety 12-lead single standard ECG and run-in (Holter) ECG55
5.2.4.5
Continuous 3-lead ECG monitoring ........................................56
5.2.4.6
Adverse events assessment from ECG ....................................56
5.2.5
Assessment of other safety parameters...............................................56
5.2.5.1
Vital signs ................................................................................56
5.2.5.2
Medical examinations..............................................................57
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................57
5.6
BIOMARKERS..................................................................................................60
6.
INVESTIGATIONAL PLAN.................................................................. 61
6.1
VISIT SCHEDULE............................................................................................61
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................62
6.2.1
Screening period....................................................................................62
6.2.2
Run-in Holter ECGs in Visit 2 only.....................................................62
6.2.3
Treatment periods.................................................................................62
6.2.4
End-of-trial period................................................................................62
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 64
7.1
STATISTICAL DESIGN – MODEL ...............................................................64
7.1.1
Objectives...............................................................................................65
7.1.2
Endpoints...............................................................................................65
7.1.3
Model......................................................................................................66
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................67
7.3
PLANNED ANALYSES....................................................................................68
7.3.1
Primary analyses...................................................................................69
7.3.2
Secondary analyses ...............................................................................69
7.3.2.1
Assessment of assay sensitivity...............................................69
7.3.2.2
Analyses of the heart rate.........................................................70


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7.3.2.5
Heart rate corrections of QT interval.......................................70
7.3.3
Safety analyses.......................................................................................73
7.3.4
Interim analyses ....................................................................................73
7.4
HANDLING OF MISSING DATA ..................................................................74
7.4.1
Safety......................................................................................................74
7.5
RANDOMISATION ..........................................................................................75
7.6
DETERMINATION OF SAMPLE SIZE ........................................................75
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 78
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................78
8.2
DATA QUALITY ASSURANCE .....................................................................78
8.3
RECORDS..........................................................................................................79
8.3.1
Source documents .................................................................................79
8.3.2
Direct access to source data and documents.......................................79
8.3.3
Storage period of records.....................................................................79
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................80
8.5
STATEMENT OF CONFIDENTIALITY.......................................................80
8.6
COMPLETION OF TRIAL..............................................................................80
9.
REFERENCES......................................................................................... 81
9.1
PUBLISHED REFERENCES...........................................................................81
9.2
UNPUBLISHED REFERENCES.....................................................................82
10. APPENDICES .......................................................................................... 85
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 86


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AE/CT
Adverse event / Concomitant therapy
AESI
Adverse events of special interest
APS
Attenuated psychosis syndrome
AUC0-24h
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 – 24 h
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
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC,ss
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval at steady state                         
%AUCtz-∞
Percentage of AUC0-∞ obtained by extrapolation
BI
Boehringer Ingelheim
bid
Bis in die, twice daily
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
bpm
Beats per minute (beats/min)
BRPM
Blinded report planning meeting
CA
Competent authority
cAMP
Cyclic adenosine monophosphate
CDISC
Clinical Data Interchange Standards Consortium
cGMP
Cyclic guanosine monophosphate
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical trial supplies unit
CV
Cardiovascular


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CYP
Cytochrom P450
QTc
Change from baseline in QTc
DDI
Drug drug interaction
DILI
Drug induced liver injury
DMET
Drug metabolism enzymes and transporters
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECGS
Electrocardiogram set
EDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EM
Extensive metabolizer
EOT
End of trial
FDA
Food and Drug Administration
FEP
First episode of psychosis
FIM
First in human
GCP
Good clinical practice
GLP
Good laboratory practice
gMean
Geometric mean
HEK293
Human embryonic kidney cells 293
hERG
human Ether-à-go-go-Related Gene
HPC
Human Pharmacology Centre
HR
Heart rate
IB
Investigator’s brochure
IC50
half maximal inhibitory concentration
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LTP
Long term potentiation
MATE1
Multidrug and toxin extrusion 1
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed effects Model for Repeated Measurements
MRD
Multiple-rising dose


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MRTpo
msec
Mean residence time of the analyte in the body after oral administration
Milliseconds
NMDA
N-methyl-D-aspartate
OAT
Organic anion transporter
PDE
Phosphodiesterase
PDE9
Phosphodiesterase-9
PK
Pharmacokinetic(s)
PM
Poor metabolizer
popPK
Population pharmacokinetic
PR
Pulse rate
PR interval
ECG interval from the onset of P wave to the beginning of the QRS 
complex
PTM
Planned time
qd
Quaque die, once daily
QRS duration
Combination of the Q, R, and S waves
QT interval
ECG interval from the beginning of the QRS complex to the end of the 
T wave
QTc
Generic term for QTcF, QTcI and QTcN intervals
QTcF
QT interval corrected using Fridericia’s formula
REP
Residual effect period
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
SAE
Serious adverse event
SCR
Screening
sd
Single dose
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
t1/2
Terminal half-life of the analyte in plasma


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TDMAP
Trial Data Management and Analysis Plan
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TMF
Trial master file
tQT
Thorough QT
TS
Treated set
TSAP
Trial statistical analysis plan
tz
Time of last measurable concentration of the analyte in plasma
UGT
UDP glucuronosyltransferase
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration


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1.
INTRODUCTION
BI 409306 is a Phosphodiesterase-9 (PDE9) inhibitor that is being developed for relapse 
prevention in patients with schizophrenia (REX indication), and for the prevention of first 
episode of psychosis (FEP indication) in subjects with Attenuated Psychosis Syndrome 
(APS).
1.1
MEDICAL BACKGROUND
Schizophrenia is a chronic, severe, and disabling brain disorder affecting both men and 
women. Existing treatment options for schizophrenia (i.e. first- and second-generation 
antipsychotics) are primarily efficacious in treating positive symptoms and have limited, if 
any efficacy for the prevention of FEP or relapse in the chronic disorder. No pharmacologic 
therapies have been approved to delay or prevent a first episode of psychosis, and none are 
indicated for the symptomatic treatment of the cognitive impairment seen in patients with 
APS. 
Schizophrenia is characterized by abnormalities in glutamatergic pathways related to N-
methyl-D-aspartate (NMDA) receptor hypofunction in cortical and hippocampal brain areas 
[R13-4521]. These abnormalities are hypothesized to lead to negative symptoms and 
cognitive impairment in schizophrenia. NMDA receptor activation triggers a cascade of 
intracellular, post-synaptic signalling events through elevation of second messengers such as 
cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) with 
subsequent activation of protein kinases and manifestation of synaptic plasticity determined 
by long term potentiation (LTP), key processes underlying learning and memory formation 
[R10-5092, R10-5102].
PDE9 hydrolyses cGMP with the highest affinity of all PDEs and is highly expressed in the 
neocortex and hippocampus. Therefore it is likely to be a significant determinant of 
intracellular basal cGMP levels in these brain regions. In addition, increasing evidence 
suggests that glutamatergic dysfunction may play a key role in mediating risk for conversion 
to psychosis in individuals with attenuated psychosis syndrome [R15-3327; R15-1457]. 
Dysregulated NMDA receptor-dependent synaptic plasticity may be a proximal cause of 
disrupted functional connectivity seen in those who convert to first episode psychosis 
presumably via over-pruning of weak synapses during adolescence [R15-1457]. 
Consequently, inhibition of PDE9 should restore cGMP levels and thus NMDA receptor 
signalling to physiological levels and translate into memory improvement via strengthening 
of synaptic plasticity/LTP in patients. Moreover, PDE9 inhibition also represents a rational 
approach for improvement and potentially normalization of those processes dysfunctional in 
individuals with APS, leading to the delay or even prevention of FEP via decreasing synaptic 
over-pruning and strengthening the NMDA-receptor signalling and synaptic plasticity
[c01694347-10].


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1.2
DRUG PROFILE
1.2.1
BI 409306 nonclinical data
1.2.1.1
Efficacy
BI 409306 showed
1.2.1.2
Toxicology
In the nonclinical safety program, the No Observed Adverse Effect Level (NOAEL) after oral 
administration was as follows (Table 1.2.1.2: 1):
1.2.1.3
Preclinical Pharmacokinetics and Metabolism


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1.2.1.4
hERG-assay
1.2.1.5
Cardiovascular function


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For a more detailed description of the BI 409306 non-clinical profile please refer to the 
current Investigator’s Brochure (IB) [c01694347-10].
1.2.2
BI 409306 clinical data
1.2.2.1
Ongoing studies/ studies under evaluation
BI 409306 is currently in Phase II clinical development with ongoing studies in the 
indications ‘relapse prevention’ in patients with schizophrenia (REX indication) and 
‘prevention of first episode of psychosis’ (FEP indication) in subjects with APS.
1.2.2.2
Completed studies
In the current IB, data from fourteen Phase I studies in healthy volunteers (one of which also 
includes data from patients with schizophrenia and AD), one Phase I study and one Phase II 
study in patients with schizophrenia, and two Phase II studies in patients with AD are 
included. A total of 385 healthy volunteers (including 53 subjects age 65 years or older and 
64 PM subjects) have been treated with BI 409306. 
 
 Moreover, 393 patients 
with schizophrenia, and 324 patients with AD have been treated with BI 409306. To date, a 
good safety and tolerability profile has been observed with BI 409306 [c01694347-10].
1.2.2.3
Clinical Pharmacology
1.2.2.4
Clinical Pharmacokinetics and Metabolism


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Table 1.2.2.4: 1 gives an overview about exposure levels reached after single dose or multiple 
dose administration of BI 409306 in selected studies.
Table 1.2.2.4: 1
Overview about BI 409306 exposure levels in selected clinical studies 
in the BI 409306 clinical development program
Source: Tables 15.6.3: 1 of the respective clinical trial reports [U12-1034-01; U13-1182-01; c02098989-02; 
c03808525-02; c13128239-01]; FIM, first-in-human; sd, single dose; qd, once daily; CV, cardiovascular; DDI, 
drug-drug-interaction; ss, steady state; 


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1.2.2.5
Clinical Safety


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For a more detailed description of the clinical profile of BI 409306 please refer to the current 
Investigator’s Brochure [c01694347-10].
1.2.3
Moxifloxacin drug profile
Moxifloxacin is a fourth-generation fluoroquinolone antibacterial agent. It is marketed 
worldwide for treatment of a number of infections including respiratory tract infections, 
cellulitis, anthrax, intraabdominal infections, endocarditis, meningitis, and tuberculosis. 
Moxifloxacin has been used in several QT trials in healthy volunteers as a positive control 
due to its modest QT-prolonging properties at a dose of 400 mg. Moxifloxacin was shown to 
induce a mean increase in the QTc interval of between 7.5-12.5 msec with a median tmax of 
2 h after a single oral dose of 400 mg [R10-0867]. Because the magnitude of the QT 
prolongation is small after 400 mg, there is minimal risk of moxifloxacin-induced torsade de 
pointes. The pattern of side effects of moxifloxacin is well established, with the most 
common adverse effects being headache, light-headedness, nausea, vomiting, diarrhea, 
gastrointestinal/abdominal pain and aspartate transaminase (AST)/alanine transaminase 
(ALT) increase. For details about adverse events occurring after moxifloxacin administration 
please refer to Section 2.3.
Following oral administration moxifloxacin is rapidly and almost completely absorbed. The 
absolute bioavailability amounts to approximately 91%. Following a 400 mg oral dose peak 
concentrations of 3.1 mg/l are reached within 0.5-4 h post administration. Moxifloxacin 
undergoes Phase II biotransformation and is excreted via renal and biliary/faecal pathways as 
unchanged drug as well as in the form of a sulpho-compound and a glucuronide. 
Moxifloxacin is eliminated from plasma with a mean terminal half-life of approximately 12 
hours.  
For a more detailed description of the clinical profile moxifloxacin please refer to [R19-0482].
1.2.4
Residual Effect Period
The Residual Effect Period (REP) of BI 409306 is 24 hours. The REP of moxifloxacin is 
4 days.
The REP is the period after the last dose with measurable drug levels and/or pharmaco-
dynamic effects still likely to be present.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
According to the guideline ICH E14 (CHMP/ICH/2/04 2005) “The clinical evaluation of
QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs”
(2005) [R07-4722] and the respective Questions and Answers Document (2017) [R17-2903] 
concerning the evaluation of QT/QTc-interval prolongation, a randomized study with 
concurrent placebo control and positive control should be conducted in order to investigate 
the effect of a drug (here BI 409306) on the QT/QTc-interval in healthy volunteers. The 
conduct of such a study in healthy volunteers is preferred, as these provide a stable signal 
without influence of concurrent diseases or concomitant therapies. While a balanced 
recruitment of male and female volunteers is aimed at, a minimum of 10 subjects of each 
gender is mandatory. This is considered acceptable since recruitment of women is anticipated 
to be challenging due to exclusion of WOCBP using hormonal contraception.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to assess the effect of BI 409306 on the QT/QTc interval
in healthy male and female volunteers as measured by the QTcF change from baseline 
compared with placebo.
Secondary objectives are to show the assay sensitivity of the trial, by reproducing the typical 
effect of the positive control moxifloxacin on the QT/QTc interval, and to assess the effect of 
BI 409306 on heart rate.
The assessment of safety and tolerability of BI 409306 particularly with regard to cardiac 
safety are additional objectives of this trial.
A detailed description of the study endpoints is provided in Sections 5 and 7.1.2.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance for the further clinical 
development of BI 409306. The assessment of the potential of BI 409306 to induce QTc 
prolongation will contribute to a safe clinical use of this PDE9 inhibitor in patients with 
schizophrenia or APS. The subjects in this trial are exposed to the risks of the study 
procedures and the risks related to the exposure to the trial medication.
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 


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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 (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
Risks related to BI 409306 administration
Thus, for this trial the assumed therapeutic dose of 50 mg and a supra-therapeutic dose of 250
mg were selected. 
 
 
Risks related to moxifloxacin administration
In all clinical trials and derived from post-marketing reports with moxifloxacin 400 mg (used 
as an antibiotic), the following adverse reactions are reported [R19-0482]. Apart from nausea 
and diarrhea all adverse reactions were observed at frequencies below 3%.
Common (≥1/100 to <1/10): 
-
Superinfections (due to resistant bacteria or fungi, e.g. oral and vaginal candidiasis)
-
Headache, dizziness
-
QT prolongation (in patients with hypokalaemia)
-
Nausea, vomiting, gastrointestinal and abdominal pains, diarrhoea
-
Increase in transaminases
Uncommon (≥1/1,000 to <1/100):
-
Anaemia, leucopenia(s), neutropenia, thrombocytopenia, thrombocythemia, blood 
eosinophilia, prothrombin time prolonged/INR increased
-
Allergic reaction
-
Hyperlipidemia
-
Anxiety reactions, psychomotor hyperactivity/agitation
-
Par- and dysaesthesia, taste disorders (incl. ageusia in very rare cases), confusion and 
disorientation, sleep disorders (predominantly insomnia), tremor, vertigo, somnolence
-
Visual disturbances, incl. diplopia and blurred vision (especially in the course of CNS 
reactions)
-
QT prolongation, palpitations, tachycardia, atrial fibrillation, angina pectoris


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-
Vasodilatation
-
Dyspnea (incl. asthmatic conditions)
-
Decreased appetite and food intake, constipation, dyspepsia, flatulence, gastritis, 
increased amylase
-
Hepatic impairment (incl. LDH increase), increased bilirubin, gamma-glutamyl-
transferase and blood alkaline phosphatase
-
Pruritus, rash, urticaria, dry skin
-
Arthralgia, myalgia
-
Dehydration
-
Feeling unwell (predominantly asthenia or fatigue), painful conditions (incl. pain in 
back, chest, pelvic and extremities), sweating
Rare (≥1/10,000 to <1/1,000):
-
Anaphylaxis (incl. very rarely life-threatening shock), allergic oedema/angioedema 
(incl. laryngeal oedema, potentially life-threatening)
-
Hyperglycemia, hyperuricemia
-
Emotional lability, depression (in very rare cases potentially culminating in self-
injurious behaviour, such as suicidal ideations/thoughts, or suicide attempts), 
hallucination
-
Hypoaesthesia, smell disorders (incl. anosmia), abnormal dreams, disturbed 
coordination (incl. gait disturbances, esp. due to dizziness or vertigo), seizures (incl. 
grand mal convulsions), disturbed attention, speech disorders, amnesia, peripheral 
neuropathy and polyneuropathy
-
Photophobia
-
Tinnitus, hearing impairment incl. deafness (usually reversible)
-
Ventricular tachyarrhythmias, syncope (i.e., acute and short lasting loss of 
consciousness)
-
Hypertension, hypotension
-
Dysphagia, stomatitis, antibiotic associated colitis (incl. pseudo-membranous colitis, 
in very rare cases associated with life-threatening complications)
-
Jaundice, hepatitis (predominantly cholestatic)
-
Tendonitis, muscle cramp, muscle twitching, muscle weakness
-
Renal impairment (incl. increase in blood urea nitrogen and creatinine), renal failure
-
Oedema
Very rare (<1/10,000):
-
Prothrombin level increased/INR decreased, agranulocytosis
-
Hypoglycaemia
-
Depersonalization, psychotic reactions (potentially culminating in self-injurious 
behaviour, such as suicidal ideations/thoughts, or suicide attempts)
-
Hyperaesthesia
-
Transient loss of vision (especially in the course of CNS reactions), uveitis and 
bilateral acute iris transillumination
-
Unspecified arrhythmias, Torsade de Pointes, cardiac arrest
-
Vasculitis
-
Fulminant hepatitis potentially leading to life-threatening liver failure (incl. fatal 
cases)


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-
Bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis 
(potentially life-threatening)
-
Tendon rupture, arthritis, muscle rigidity, exacerbation of symptoms of myasthenia 
gravis
For a more detailed description of the profile of Moxifloxacin please refer to the ‘Summary 
of Product Characteristics’ (SmPC) for Avalox® 400 mg film-coated tablets [R19-0482].
Safety measures
To ascertain the safety and minimise the risk for healthy volunteers, several safety measures 
and investigations will be implemented in this trial:

A thorough screening examination will ensure that only suitable healthy subjects will
enter the study; 
 a marked baseline 
prolongation of QT/QTc interval, a history of additional risk factors for torsade de pointes 
or arrhythmic events in Holter ECG recording during run-in will be excluded from study 
participation (see Section 3.3.3).

To reduce the risk of undesirable effects, only single doses of trial medication will be 
given in each treatment period.

The subjects will be closely monitored through assessment of adverse events, safety lab, 
ECG and vital signs as well as through continuous ECG monitoring for 4 hours post 
treatment in each treatment period.

The subjects will maintain under close medical surveillance for at least 24 hours post 
dosing in each treatment period.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1, subsection “Adverse events of special interest”.
In summary, the information gained from this trial will provide the basis for further clinical 
development of the PDE9 inhibitor BI 409306, which is expected to become a valuable 
therapeutic option for patients with schizophrenia and APS. BI 409306 has a favorable 
benefit-risk-assessment based on a thorough preclinical data package as well as knowledge 
gained from previous clinical studies using BI 409306, which justifies further testing in 
humans. Considering the medical need regarding the treatment of schizophrenia and APS, the 
sponsor considers that the benefit outweighs the potential risks and justifies exposure of 
healthy human volunteers to the trial medication.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, placebo controlled, double-blind, five-period, 
four treatment crossover trial with two placebo periods and (open-label) moxifloxacin as 
positive control in healthy male and female subjects. The replicate design with respect to 
placebo allows for estimating the treatment contrasts of each active drug to placebo more 
precisely than with only one single placebo period, thus enabling a reduced sample size (see 
[R12-0517] and Section 7.6).
The treatments will be:

Treatment 1 ([L] – low): 
50 mg BI 409306 (1x 50 mg tablet + 4x placebo matching to 50 mg tablet) in the fasting 
state, single dose

Treatment 2 ([H] – high): 
250 mg BI 409306 (5x 50 mg tablet) in the fasting state, single dose

Treatment 3 ([M] – moxifloxacin): 
400 mg moxifloxacin (1 tablet) in the fasting state, single dose

Treatment 4 ([P1] – 1st placebo period and [P2] – 2nd placebo period):
Matching placebo (5x placebo matching to 50 mg tablet) in the fasting state, single dose
For details refer to Section 4.1.
The subjects will be randomly allocated to the 15 treatment sequences (3 subjects per
sequence) planned in this trial (see Section 7.1). 
There will be a washout phase of at least 6 days between the treatments.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.


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BI 409306 and matching placebo trial medication will be provided by the Clinical Trial 
Supplies Unit (CTSU), BI Pharma GmbH & Co. KG, Biberach, Germany. Moxifloxacin 
(Avalox®) will be ordered by the trial site from a local pharmacy.
The trial will be conducted at the 
 
, under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
The analyses of the concentrations of BI 409306 and metabolites in plasma will be performed 
at the contract research organisation 
. The pre-specified 
 will be performed at the
 
The digitally recorded Holter ECGs in Visits 2-6 will be sent to a specialised contract 
research organisation (
) for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
According to the guideline ICH E14 (CHMP/ICH/2/04 2005) “The clinical evaluation of
QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs”
(2005) [R07-4722] and the respective Questions and Answers Document (2017) [R17-2903]
concerning the evaluation of QT/QTc-interval prolongation, a randomised study with 
concurrent placebo control and a positive control will be conducted in order to investigate the 
effect of a drug (BI 409306) on QT/QTc-interval in healthy volunteers.
As positive control, the subjects will receive a single dose of moxifloxacin 400 mg, which is
known to induce moderate QT/QTc-prolongation (see Section 2.1) and will therefore verify
the ability of the study to detect relevant changes in the QT/QTc-interval.
For thorough QT trials, the crossover design is preferred due to its efficiency: since each 
subject serves as his/her own control, the comparison between treatments is based on a 
comparison within subjects rather than between subjects. This trial design therefore removes 
intersubject variability from the comparison between treatments [R94-1529]. Moreover, with 
proper randomisation of subjects to the different sequences of treatment administrations, it 
provides the best unbiased estimates for the differences between treatments. Additionally, the 
total number of subjects needed to participate in this trial is minimised compared to a parallel 


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group design trial. Since all assessments in tQT trials are based on the comparisons between 
active treatment and placebo, these treatment contrasts should be estimated with the highest 
statistical efficiency. To account for this, the selected crossover design for this trial will 
include a second placebo period instead of only one. The sample size for the resulting 
4-treatment 5-period crossover design can be determined as 3/4 of the sample size of the 
corresponding 4-period crossover design (see also Section 7.6).
Blinding with regard to the study drug substances to be investigated versus their matching 
placebos is essential in such a study. ECG profiles will be performed for BI 409306 and 
placebo in a double-blind fashion. The positive control (moxifloxacin) will be administered 
open-label. This is not expected to bias results, since moxifloxacin is known to robustly 
induce a mean increase in the QTc interval of between 7.5 – 12.5 msec with a median tmax of
2 hours after a single oral dose of 400 mg [R10-0867]. The technicians and cardiologists at 
the ECG laboratory performing the ECG interval measurements and assessments will remain 
blinded in this study with regard to all treatments, including moxifloxacin and placebo (see 
Section 5.2.4).
3.3
SELECTION OF TRIAL POPULATION
It is planned that 45 healthy male and female subjects (at least 10 subjects of each gender)
will enter the study. They will be recruited from the volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (that is, having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male or female subjects according to the assessment of the investigator, based on 
a complete medical history including a physical examination, vital signs (BP, PR), 
12-lead single ECG and 12-lead Holter ECG, and clinical laboratory tests
2. Age of 18 to 50 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5. Male subjects, or 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


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A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in
questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and 
estradiol below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 100 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
 
14. Inability to refrain from smoking 
15. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for
males)
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


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20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 msec) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
23. For female subjects, positive pregnancy test, pregnancy or plans to become pregnant 
within 30 days after study completion
24. For female subjects, lactation period
25. For female subjects, concomitant use of hormonal replacement therapy or hormonal 
contraceptives 
27. Findings from run-in Holter ECG recording judged to be clinically relevant 
28. Subjects with any condition that would preclude administration of moxifloxacin (i.e. 
contraindicated as per SmPC), such as but not limited to history of tendon disease/damage 
as a result of quinolone therapy, clinically relevant bradycardia, clinically relevant heart 
failure with reduced left ventricular ejection fraction or a history of symptomatic cardiac 
arrhythmia.
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:
1. If the subject withdraws consent for trial treatment or trial participation, without the need 
to justify the decision
2. If the subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. If the subject is no longer able to participate for other medical reasons (such as 
pregnancy, surgery, AEs, or diseases)
4. If 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.
5. If the subjects shows an elevation of AST and/or ALT ≥3-fold ULN.
6. In case of relevant individual QT prolongations in safety ECG recordings, i.e. absolute 
QT or QTc > 500 msec and/or QTc increase > 60 msec from baseline (i.e., pre-dose), as 
confirmed by a repeat ECG recording. 
7. In case of a serious adverse reaction, or in case of a severe non-serious adverse reaction
not listed in Table 7.6: 1 of the current Investigator’s brochure.


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In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgement.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end-of-trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 1.2), the discontinued subject should if possible be questioned for AEs and 
concomitant therapies at or after the end of the REP in order to ascertain collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject. These discontinuations will be discussed in the CTR.
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 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% 
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.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
3.3.5
Replacement of subjects
In case some subjects do not complete the trial as per protocol, 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 maximum of 5 subjects will be replaced. Thus, the total 
number of subjects entered and dosed in this trial will not exceed 50. A replacement subject 


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will be assigned a unique study subject number, and will be assigned to the same treatment
sequence as the subject he or she replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
BI 409306 and matching placebos will be manufactured by BI Pharma GmbH & Co. KG. 
Moxifloxacin (Avalox®) 400 mg tablets produced by Bayer Vital, Leverkusen, Germany, 
will be sourced from a local pharmacy. 
4.1.1
Identity of BI investigational products
The characteristics of the test product are given below:
Substance:
BI 409306
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg
Posology:
1-0-0 on Day 1 of treatment 1 [L],
5-0-0 on Day 1 of treatment 2 [H]
Route of administration:
p.o.
Duration of use:
Single dose in treatments 1 [L] and 2 [H]
The characteristics of the reference products are given below:
Name:
Avalox®
Substance:
Moxifloxacin
Pharmaceutical formulation: Film-coated tablet
Source:
Bayer Vital, Leverkusen, Germany
Unit strength:
400 mg
Posology:
1-0-0 on Day 1 of treatment 3 [M]
Route of administration:
p.o.
Duration of use:
Single dose in treatment 3 [M]
Substance:
Placebo matching to BI 409306 50 mg tablet
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
4-0-0 on Day 1 of treatment 1 [L], 
5-0-0 on Day 1 of treatment 4 ([P1] and [P2])
Route of administration:
p.o.
Duration of use:
Single dose in treatments 1 [L] and 4 ([P1] and [P2])


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4.1.2
Method of assigning subjects to treatment groups
According to the calculated sample size, 5 cohorts are planned. Prior to start of the study, 
subjects willing to participate will be recruited to cohorts according to their temporal 
availability. Since the study includes healthy volunteers from a homogenous population, 
relevant imbalances between the treatment sequences are not expected.
The list of study subject and medication numbers will be provided to the trial site in advance.
The allocation of subjects to study subject numbers will be performed prior to the first 
administration of trial medication. For this purpose, the subjects will be allocated to a study
subject number by drawing lots. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
The overall number of 45 subjects is planned to be split into 5 cohorts. In case subjects need 
to be replaced an additional cohort may be added or replacement subjects may be added to 
existing cohorts allowing up to 12 subjects on treatment days. The planned cohort size allows 
a timely conduct of the study with reasonable duration minimizing seasonal impact on trial 
data while at the same time still allows adequate medical surveillance of the subjects. Within 
one cohort, subjects will be treated on the same calender day. No minimal time interval 
between dosing is defined. This is acceptable from a safety point of view (for safety margin 
margins refer to Section 1.2.2.4; for discussion of study-associated risk and safety measures 
see Section 2.3).
4.1.3
Selection of doses in the trial
The dose of 50 mg was selected in order to measure the effect of the anticipated therapeutic 
dose of BI 409306. The dose of 250 mg was selected in order to measure the effect of a 
tolerable supra-therapeutic dose of BI 409306 on cardiac safety (see Section 1.2).
 
4.1.4
Drug assignment and administration of doses for each subject
This trial is a five-period crossover study. All subjects will receive the 4 treatments (two
placebo periods) in randomised order. The treatments to be evaluated are outlined in Table 
4.1.4: 1 below. 


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Table 4.1.4: 1
Dosage and treatment schedule, oral administration
Treatment
Substance
Formulation Unit strength
Number 
of units
Total  dose
1 [L]
BI 409306
Placebo to BI 409306 50 mg
Tablet
Tablet
50 mg
---
1
4
50 mg
2 [H]
BI 409306
Tablet
50 mg
5
250 mg
3 [M]
Moxifloxacin
Tablet
400 mg
1
400 mg
4 ([P1] and [P2])
Placebo to BI 409306 50 mg
Tablet
---
5
---
The medication will be administered as a single oral dose together with about 240 mL of 
water to a subject in a 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 if correct dosage cannot be ensured otherwise. 
Administration will be performed following an overnight fast which is to start no later than 
10 h before scheduled dosing. 
Subjects will be kept under close medical surveillance until at least 24 h following 
BI 406309, moxifloxacin and placebo administration. Holter ECG will be recorded from up 
to 3 hours prior to drug administration until at least 24 hours after drug administration. 
During the first 2 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture) except for
medical examinations, single ECG recordings and triplicate ECG extraction time points and 
preceding resting time. For restrictions with regard to diet see Section 4.2.2.2.
The treatments will be separated by a wash-out phase of at least 6 days.
4.1.5
Blinding and procedures for unblinding
The two doses of BI 409306 and matching placebos will be administered double-blind with 
regard to the subjects and the investigators (as well as the research staff at the trial site) in 
order to eliminate observer or performance bias; moxifloxacin will be administered open-
label. This means avoiding systematic differences in assessments regarding the subject’s 
treatment (active or placebo). Persons directly involved in the clinical conduct or statistical 
analysis of the trial will not have access to the treatment allocation prior to database lock.
At the sponsor, access to the randomisation schedule is restricted to the Clinical Trial Support 
group, who generates the randomisation code and labels, to the Pharmaceutics Department, 
where the packaging takes place, to the independent programmer as described below, and to 
the trial bioanalyst.
Prior to trial initiation, the randomisation codes will be provided to an independent 
programmer, who will generate a list indicating the moxifloxacin treatment period for each 
subject in the form of e.g. X-X-M-X-X or M-X-X-X-X. This list will be provided to the 


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clinical site to enable study set up. The independent programmer will confirm that the 
original randomisation codes will be treated confidentially.
Prior to unblinding of the trial database, the randomisation codes will be provided to 
bioanalytical staff to allow them to exclude from the bioanalytical analyses PK samples taken 
from placebo-treated subjects. Bioanalytics will not disclose the randomisation code or the 
results of their measurements until the trial is officially unblinded.
The trial will only be unblinded after locking of the database.
Within the central ECG lab, the staff involved with interval measurements and morphological 
analyses will be blinded with respect to the treatment and also with regard to the recording
date and time as well as planned time points of the ECGs. The interval measurements for a 
given subject will be performed in a random and blinded sequence by a single technician.
4.1.5.1
Procedures for emergency unblinding
For this blinded trial, the investigator will be supplied with a set of sealed envelopes 
containing the medication codes for each subject according to the randomisation scheme. The 
envelopes will be kept unopened at the trial site until the end of data collection. An envelope 
may only be opened in emergency situations when the identity of the trial drug must be 
known to the investigator in order to provide appropriate medical treatment or to assure 
safety of trial participants. If the envelope for a subject is opened, the sponsor must be 
informed immediately. The reason for opening the code break must be documented on the 
envelope or appropriate CRF page along with the date and the initials of the person who 
broke the code. At the close-out visit all envelopes are collected.
4.1.6
Packaging, labelling, and re-supply
BI 406309 and matching placebos will be provided by the Department of Pharmaceutical 
Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Each container will 
contain 2 blisters with 7 tablets each of either BI 409306 50 mg or matching placebo. The 
containers will be labelled with:

BI trial 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

Subject or medication number

Visit number

Batch number


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At the trial site, drug will be dispensed by the investigator or authorised designee according 
to medication and visit numbers (table 4.1.6: 1):
Table 4.1.6: 1
Content of the blisters containing trial medication for treatments 
1 [L], 2 [H], and 4 ([P1] and [P2])
Treatment
Blister 
Number 
of units (tablets) 
to be dispensed#
Blister containing *
Unit strength
Total  dose
1 [L]
Blister 1
Blister 2
1
4
BI 409306 50 mg tablet
Matching placebo tablet
50 mg
---
50 mg
2 [H]
Blister 1
Blister 2
1
4
BI 409306 50 mg tablet
BI 409306 50 mg tablet
50 mg
4x 50 mg
250 mg
4 ([P1] and [P2])
Blister 1
Blister 2
1
4
Matching placebo tablet
Matching placebo tablet
---
---
---
---
* The information about blister content will not be provided to the clinical site
# Each blister contains 7 tablets; only 1 tablet (of blister 1) and 4 tablets (of blister 2) will be used
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
Moxifloxacin (Avalox®) will be sourced from a local pharmacy. It will not be labelled. The 
original packaging (German commodity) will be used for the open-label part of the trial.
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 ensure that the drug supplies are stored at the correct 
temperature. If the storage conditions are found to be outside the specified range, the local 
clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee 

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol


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Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator will maintain records that document adequately that the subjects were provided 
the amounts of tablets specified by the CTP, and that reconcile all investigational products 
received from the sponsor. At the time of disposal, the investigator must verify that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Ibuprofen may be used as an analgesic drug if needed. 


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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.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL. For 
fasting requirements see Section 4.1.4.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products including St. John's wort (Hypericum perforatum) are not permitted starting 
7 days before the first administration of trial medication until after the last PK sample in the 
study is collected.
Smoking is not allowed starting from 30 days prior to screening until end-of-trial 
examination.
Alcoholic beverages are not allowed from 48 h before administration of trial medication until 
the end of hospitalisation period in each treatment period.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during in-house confinement.
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 (that is, sunbathing) or exposure to solarium radiation should be 
avoided during the entire study.
If female subjects of child-bearing potential are included, 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. 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
5.2.1.1
Primary safety endpoints
The primary endpoint will be the maximum mean difference between each single dose of
either 50 mg or 250 mg BI 409306 and placebo in QTcF changes from baseline between 20 
min to 24 hours after drug administration. QTcF is the heart rate corrected QT interval 
according to Fridericia (see Section 7.3.2.5).
5.2.1.2
Secondary safety endpoints

The maximum mean difference between moxifloxacin and placebo in QTcF changes from 
baseline between 20 min to 24 hours after drug administration.

The maximum mean difference between each single dose of either 50 mg or 250 mg 
BI 409306 and placebo in HR changes from baseline between 20 min to 24 hours after 
drug administration. HR will be derived from the RR interval (see Section 7.3).

The minimum mean difference between each single dose of either 50 mg or 250 mg
BI 409306 and placebo in HR changes from baseline between 20 min to 24 hours after 
drug administration.
5.2.1.3
Further safety endpoints


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5.2.1.3.2
Further criteria of interest
Safety and tolerability of the investigational drugs will be assessed based on:

AEs (including clinically relevant findings from physical examination)

Safety laboratory tests

12-lead single ECGs or Holter ECG recordings

Vital signs (blood pressure, pulse rate)
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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable): 

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they are 
judged clinically relevant by the investigator 
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death 

is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe

requires inpatient hospitalisation  

requires prolongation of existing hospitalisation

results in persistent or significant disability or incapacity 

is a congenital anomaly/birth defect 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse.
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.2.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
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 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest 
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.2.2.
The following is considered as AESI:


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


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
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
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs 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 carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
If subjects report a change in perception or any vision-related AE, site staff must record the 
subject’s verbatim description in the source documents to be reported in the eCRF.
A local ophthalmology assessment will be required if any visual AE is rated as severe by the 
subject or at the discretion of the investigator. The ophthalmologist will act as a consultant to 
the investigator and may offer advice on the proper management and treatment for the 
reaction.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial:
o
All AEs (serious and non-serious) and all AESIs 
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 


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screening failures prior to administration of any trial medication. In these cases, 
the subjects’ data must be collected at trial site but will not be entered in the CRF 
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 new AEs but 
should only report any occurrence of cancer and related SAEs and related
AESIs of which the Investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
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 the initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as “chronic” or “stable”, 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 Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical 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.


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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. Over-night fasting is not required for drug screening and pregnancy test at 
admission and at the discretion of the investigator or designee for re-tests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis,
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes
X
--
--
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
--
--
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils Bands;  
Neutrophils Bands, absol.; Eosinophils/Leukocytes; Eosinophils, 
absol.; Basophils/ Leukocytes; Basophils, absol.; Monocytes/ 
Leukocytes; Monocytes, absol.; Lymphocytes/Leukocytes; 
Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalization Ratio)
X
X
X
--
--
--
--
--
--
X
X
X
Enzymes
AST (Aspartate transaminase) /GOT, SGOT 
ALT (Alanine transaminase) /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl-Transferase 
Amylase
Lipase
X
X
X
X
X
X
--
--
--
--
--
--
X
X
--
X
--
--
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X
--
--
--
X
X
X


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment (microscopic 
examination if erythrocytes, 
leukocytes nitrite or protein 
are abnormal in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: Parameters to be determined at Visit 1 (screening examination) 
B: Parameters to be determined prior to dosing and at 2:00 PTM on Day 1 of Visits 2 to 6
C: Parameters to be determined on prior to discharge on Day 2 of Visits 2 to 6
D: Parameters to be determined at Visit 7 (end-of-trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy test and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
each treatment period (on Days -1 or 1), and as part of the end-of-trial examination. Drug 
screening will be performed at screening and prior to each treatment period (on Days -1 or 1).
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qual)
Hepatitis B core antibody (qual)
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to each treatment period (on Days -1 


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or 1), and may be repeated at any time during the study at the discretion of an investigator or 
designee. The results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
 with the exception of 
the drug screening and pregnancy tests. These tests will be performed at the trial site using 
M-10/14-PDT test and HCG-K20 test, respectively, or comparable test kits.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead continuous (Holter) ECG recording at the clinical site 
To determine potential effects of BI 406309 on cardiac safety parameters, 12-lead continuous 
24-hour Holter ECG recordings will be used to extract 10-second triplicate ECGs for cardiac 
interval and heart rate analysis (see Section 5.2.4.2) as well as to analyse heart rhythm and 
conduction (see Section 5.2.4.3).
The 12-lead continuous 24-hour Holter ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be 
recorded using Holter devices (e.g. CardioMem® CM 3000, GETEMED AG, Berlin, 
Germany) provided by the core lab. Recordings will be started within 3 h prior to drug 
administration and will last at least until 24 h post drug administration in each treatment 
period. Prior to each Holter recording, the device will be initialized with subject ID and visit 
number. The exact starting time of the Holter recordings will be documented on a provided 
housekeeping list. Moreover, at dosing a trigger button will be pressed on the Holter recorder
to electronically mark the time point of drug administration on the Holter recordings. 
A lead system with modified Einthoven/Goldberger leads (the so called Mason/Likar lead 
system) and precordial leads according to Wilson will be applied. Electrode placement will 
be performed by trained personnel according to established anatomical landmarks to ensure 
individual placement of electrodes will be identical throughout all 5 treatment periods. 
Before and at the planned time points at which resting ECGs are to be extracted from 24-hour 
Holter ECG recordings, the subjects should be kept in a relaxed and quiet environment. Thus, 
at least 5 minutes prior to the triplicate ECG extraction time points (see Flow Chart), the 
subjects will take a supine position to ensure a stable heart rate at rest and high ECG quality
during the recordings. These resting periods and ECG recordings will always precede all 
other study procedures planned for the same time point to avoid compromising ECG quality. 
To guide the extraction of the ECGs by the core lab, the study staff will be instructed to press 
a trigger button twice on the recorder after the intended 3-minute extraction period (which 
was preceded by a 5-minute resting period) to electronically mark the end of the 3-minute 
extraction period. Triplicate 10-second ECGs will be extracted by the core lab (see Section 
5.2.4.2) during the 3-minute time window preceding the electronic marks.
The Holter ECG recordings from each treatment period will be transmitted to the central 
ECG laboratory using a provided secure transfer program. The ECG data will be checked by 
the core lab for any timing inconsistencies prior to the evaluation of the ECGs.


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5.2.4.2
12-lead triplicate ECG evaluation at the central ECG laboratory
At the core lab, the evaluation of the triplicate 10-second ECGs extracted per ECG time point
from the 24-hour Holter ECG recordings on Days 1 and 2 of Visits 2-6 comprises the 
determination of cardiac axis (measured automatically) as well as the intervals RR, PR, QRS 
and QT measured semi-automatically. All semi-automatic interval measurements in an 
individual subject will be performed on the same lead. The intervals will be measured from 4
cardiac cycles (beats) in Lead II. If Lead II shows a flat T wave or is not measurable for any 
reason, Lead V5 will be used, or if that lead is not measurable, then Lead I will be used. The 
lead actually used will be reported in the CTR. HR and the QT interval corrected for HR 
(QTc, e.g. QTcF) will be determined by BI (see TSAP for details). For the run-in ECGs on 
Day -7 of Visit 2 only QT and RR will be determined semi-automatically.
Morphological analyses of the extracted triplicate ECGs will be performed by a board-
certified cardiologist or equivalent for 1 randomly selected ECG per extraction time point
(exception: No morphological analysis for run-in ECGs). The cardiologists’ assessments will 
include an overall assessment (classifications are: ‘normal’, ‘abnormal, clinically relevant’, 
‘abnormal, clinically not relevant’, ‘not evaluable’) as well as qualitative ECG findings with 
respect to e.g. rhythm, conduction and morphological abnormalities, presence of myocardial 
infarction, ST segment deviations, T wave morphology and presence of U-wave. Basis of the 
terminology used for the evaluation is the most current published version of CDISC 
controlled terms at the time of the final ECG transfer. Abnormalities detected during 
centralised ECG evaluation will be entered as AEs if assessed as clinically relevant based on 
the investigator’s judgement.
For blinding arrangements see Section 4.1.5. Within the ECG laboratory, the staff involved 
with ECG interval measurements and morphological analyses will be blinded with regard to 
treatment, date and time as well as time points of the ECG measurements. No more than two 
blinded readers will evaluate all ECGs of the study. The interval measurements for a given 
subject will be performed in random and blinded sequence by a single reader. For quality 
assurance and control of the measurements, all ECGs of an individual subject will be 
subsequently reviewed by the ECG technician supervisor or his/her designee to assess the 
overall variance of the measured intervals and to detect accidental switching of leads and/or 
false subject assignments of the ECGs. After quality control, the fiducial point markings will 
be reviewed by the cardiologist assigned to the study.


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Evaluation of extracted triplicate ECGs will comply with the ICH E14 guidance document 
and supplements [R07-4722, R17-2903] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
5.2.4.3
12-lead Holter ECG evaluation at the central ECG laboratory
In addition to the interval measurements on extracted triplicate ECGs, also Holter arrhythmia 
analysis (as defined in the TSAP) will be performed for the complete recording period of 24 h 
post dosing in each of the 5 treatment periods (at Visits 2 to 6). Holter arrhythmia analysis 
will also be performed for the run-in Holter (as defined in the TSAP). These analyses will be 
performed by the same board-certified cardiologist or equivalent who is reviewing the 
extracted 10-sec ECGs. Run-in Holter ECG recording will be evaluated by the core lab and 
the results will be relevant for subject In/Exclusion (see Section 3.3.3).
All ECG recordings will be stored at the central ECG laboratory for later additional analyses 
if needed. Recording and transmission procedures will be explained in detail in a study 
specific “ECG manual” which will be given to the site and stored in the ISF.
5.2.4.4
Safety 12-lead single standard ECG and run-in (Holter) ECG

For immediate cardiac safety assessment, a single standard 12-lead ECG will be recorded 
o
at the screening examination (Visit 1)
o
prior to drug administration, at PTM 1:00 and at PTM 2:00 in each treatment 
period (Visits 2 to 6),
o
once on Day 2 in each treatment period (Visits 2 to 6) prior to discharge from the 
site
o
at the end-of-trial examination (Visit 7)
These 12-lead single ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded for
10 seconds each using a computerised electrocardiograph (CardioSoft EKG System, GE 
Medical Systems, Freiburg, Germany) provided by the site. Electrode placement will be 
performed adjacent to the Holter ECG electrodes according to the method of Wilson, 
Goldberger and Einthoven modified by Mason and Likar (hips and shoulders instead of 
ankles and wrists). All ECGs will be stored electronically on the Muse CV Cardiology 
System (GE Medical Systems, Freiburg, Germany). For each time point, a printout should 
be obtained and filed at the investigational site. All locally printed ECGs will be 
evaluated by the investigator or a designee. These ECGs will not be sent to the central 
ECG laboratory responsible for evaluation of the Holter recordings (refer to Sections
5.2.4.2 and 5.2.4.3). ECGs may be repeated for quality reasons (like alternating current 
artefacts, muscle movements, electrode dislocation). The repeat ECGs are assigned to the 
respective scheduled time point. Additional (unscheduled) ECGs may be collected by the 
investigator for safety reasons.


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
To exclude clinically relevant cardiac arrhythmia and to generate drug-free RR/QT data 
for the derivation of QTcI, a 12-lead run-in Holter ECG recording over at least 24 h (for 
arrhythmia analysis; at least 22 h of recorded ECG data need to be evaluable) and at least 
8 h (for drug-free RR/QT data) will be performed as described in Section 5.2.4.1
o
at Visit 2 only
and evaluated by the core lab.   
The purpose of the ECGs at screening (single standard 12-lead ECG) and the run-in 12-lead 
Holter ECG recording is to obtain information about the subjects’ baseline condition that may 
not have been elicited in obtaining the medical history. Therefore, abnormal clinically 
relevant findings from ECG as judged by the investigator will be recorded in the medical 
history. The investigator will decide about subject inclusion in case of findings in the 
screening and run-in ECGs, thoroughly taking into account the exclusion criteria. Moreover, 
the 12-lead run-in Holter ECG will be used to extract multiple drug-free 10-second ECGs for 
proper QTcI derivation.
5.2.4.5
Continuous 3-lead ECG monitoring
In each treatment period, cardiac rhythm (including heart rate) will be monitored by means of 
continuous 3-lead ECG recording using the CARESCAPE Monitor B450 (GE Healthcare, 
Freiburg, Germany) for at least 10 min before drug administration (for baseline assessment) 
until 4 h after dosing. This continuous ECG monitoring supports the early detection of 
adverse events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the trial 
site. Beyond this clinical evaluation at the trial site, no further data collection or analyses are 
performed based on continuous 3-lead ECG monitoring at the site. ECG data from continuous 
3-lead ECG recording will not be transferred to the clinical trial database. 
5.2.4.6
Adverse events assessment from ECG
Abnormal findings from safety 12-lead single ECGs, Holter recordings or 3-lead continuous 
ECG monitoring, irrespective of whether they originate from central or local evaluation, will 
be reported as AEs (during the trial) or recorded in the subject’s medical history (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 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 (Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm if possible.


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5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination.
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 and 


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pharmacodynamic 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.


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5.6
BIOMARKERS
Not applicable.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. 
Time windows are permitted as follows:

The acceptable time windows for screening and end-of-trial examination are given in the 
Flow Chart.

Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3-hour period prior 
to the trial drug administration. 

The acceptable deviation from the scheduled time for vital signs and single safety 12-lead 
ECGs will be ± 30 min on Day 1 and 2 of each treatment period except for procedures 
which are to be completed within 3 h prior to drug administration as outlined in the Flow 
Chart.

The timing of ECG extractions from 24-hour Holter recordings (see Flow Chart) is of
particular importance in this study. Thus, triplicate ECG extraction from Holter ECG 
recordings will always precede PK sampling and measurements of vital signs if scheduled 
for the same time point. The acceptable time windows for ECG triggering in Holter ECG 
recordings to mark the end of the extraction periods (see Section 5.2.4) are ± 5 minutes up 
to 2 hours after dosing (or after planned time -168:00 in case of run-in Holter ECG) and
± 10 minutes from more than 2 hours to 24 hours after dosing (or after planned time 
-168:00 in case of run-in Holter ECG).

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. Acceptable deviations from nominal times are ± 5 minutes for up to 2 hours 
after dosing and ± 10 min from more than 2 hours to 24 hours after dosing.

If scheduled in the Flow Chart at the same time as a meal, blood sampling or vital signs
assessment, the end of the extraction periods from Holter ECG recordings have to be 
triggered 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, 
including ECG time intervals.

For a particular subject, the clock time of dosing should be similar in all 5 treatment 
periods (60 minutes).
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 
Blinded Report Planning Meeting.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening, and 
pregnancy test in females), ECG, vital signs, and physical examination, refer to Sections 
5.2.3 to 5.2.5.
Pharmacogenomic genotyping will be performed in those volunteers whose genotypes are not 
known (for details see Section 5.3).
6.2.2
Run-in Holter ECGs in Visit 2 only
Each subject who successfully passed the screening period is expected to participate in an 
ambulatory visit (Visit 2 only) for run-in ECG Holter recording prior to randomisation. This 
will be used for generation of drug-free Holter ECG data to assess the cardiac rhythm over at 
least 24 hours
 
During this ambulatory visit, subjects will enter the trial site in the morning and stay in 
the trial site for at least 8 hours to allow triggering for ECG extraction. Subjects will then be 
allowed to leave the trial site. They will return the next morning and the Holter ECG 
recording will then be stopped after at least 24 h recording (for arrhythmia analysis at least 
22 h of recorded ECG data need to be evaluable).
6.2.3
Treatment periods
Each subject is expected to participate in 5 treatment periods (that are each comprised of 
Days -1, 1 and 2). The treatment periods will be separated by at least 6 days wash-out 
between drug administrations.
On Day -1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration in all 
treatment periods. The subjects will then be allowed to leave the trial site after formal 
assessment and confirmation of their fitness.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.5.2. After administration of moxifloxacin no blood samples 
for pharmacokinetic analysis will be taken. 
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.
6.2.4
End-of-trial period
For AE/CT assessment, laboratory tests (including pregnancy test in females), recording of 
ECG and vital signs, and physical examination during the end of trial period, see


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Sections 5.2.2 to 5.2.5. Subjects who discontinue treatment before the end of the planned 
treatment period should undergo the end-of-trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The study will be performed as a randomised, double-blind, 5-period crossover of single dose 
treatments including BI 409306 50 mg and 250 mg, as well as open-label moxifloxacin. The 
placebo (matching to BI 409306) will be given twice in two separate periods. This choice of 
BI 409306 doses allows subjects to reach BI 409306 exposure levels at and above the 
anticipated daily exposure of BI 409306 in the target population. The replicate design with 
respect to placebo allows for estimating the treatment contrasts of each active drug to placebo 
more precisely than with only a single placebo period, thus enabling a reduced sample size 
(see [R12-0517] and Section 7.6).
The treatment sequences are based on a Prescott triple Latin square design for five treatments
and 5 periods, which is a balanced, efficient design [R14-5088]. Fifteen sequences will be 
formed according to the following scheme:
Table 7.1: 1
Prescott triple Latin square crossover design for 5 treatments and 5 
periods
Sequence
Treatment Period
1
2
3
4
5
1
2
3
4
5
A
B
C
D
E
B
C
D
E
A
D
E
A
B
C
E
A
B
C
D
C
D
E
A
B
6
7
8
9
10
A
B
C
D
E
C
D
E
A
B
E
A
B
C
D
D
E
A
B
C
B
C
D
E
A
11
12
13
14
15
A
B
C
D
E
E
A
B
C
D
D
E
A
B
C
B
C
D
E
A
C
D
E
A
B
The allocation of the codes (A, B, C, D, E) to the 4 treatments L, H, M, P ([P1] and [P2]), 
(see Section 3.1) will be done prior to the randomisation in a way that the knowledge of the 
open-label treatment M does not unblind the other 3 treatments.
Throughout the study protocol, the term “baseline” (if not specified further) refers to the 
3 pre-dose triplicate ECG measurements at Visits 2-6 (i.e. a separate baseline for each period 


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will be derived from the 9 ECG recordings that comprise 4 cardiac cycles each). Each ECG 
measurement per time point on treatment is derived from the 3 single ECGs with 4 cardiac 
cycles each. For further details on the derivation rules refer to Section 7.3. All ECGs used for 
the evaluation of QT/QTc (and additional ECG time intervals) are extracted from 12-lead 24-
hour Holter recordings.
Since it is not expected that the mean of the placebo-corrected HR change from baseline will 
be larger than 10 beats/min for both doses of BI 409306, QTcF will be selected as the 
primary correction method for the present trial. 
 
 
 
7.1.1
Objectives
The objective of this trial is to assess the effect of BI 409306 on the QT/QTc interval. As per 
ICH E14, this thorough QT trial will be deemed as negative if the maximum upper limit of 
the two-sided 90% confidence bound for the mean difference between BI 409306 and 
placebo in QTcF changes from baseline after single dose administration is less than 10 msec; 
this applies to both doses of BI 409306 (50 mg and 250 mg).
Secondary objectives are to show the assay sensitivity of the trial, by reproducing the typical 
effect of the positive control moxifloxacin on the QT/QTc interval, and to assess the effect of 
BI 409306 on the heart rate.
The assessment of safety and tolerability of BI 409306 particularly with regard to cardiac 
safety are additional objectives of this trial.
7.1.2
Endpoints
The primary endpoint will be derived based on the changes from baseline in QTcF at each 
time point between 20 min to 24 hours after drug administration of BI 409306 and placebo. 
For each of the 2 doses of BI 409306, the relevant outcome is the maximum mean difference 
between BI 409306 and placebo in the QTcF changes from baseline (see also Section 
5.2.1.1).
The secondary endpoints are based on (see also Section 5.2.1.2):

The QTcF changes from baseline at each time point between 20 min to 24 hours after 
drug administration of moxifloxacin and placebo (for assessment of assay sensitivity). 
The relevant outcome is the maximum mean difference between moxifloxacin and
placebo in the QTcF changes from baseline for the time points 2, 3, and 4 hours after 
dosing.

The changes from baseline in HR at each time point between 20 min to 24 hours after 
drug administration of BI 409306 and placebo. For each dose of BI 409306, the relevant 
outcomes are the maximum and the minimum mean differences between BI 409306 and
placebo in HR changes from baseline after dosing. HR will be derived from the RR 
interval (see Section 7.3).


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Safety and tolerability will be determined on the basis of further safety endpoints specified in 
Section 5.2.1.3.
7.1.3
Model
For the analysis of the QTcF changes from baseline at each time point between 20 min to 
24 hours after dosing, a linear mixed-effects model for repeated measurements (MMRM) will 
be used. 
The comparison between each dose of BI 409306 and placebo will be performed pairwise, 
i.e. data not relevant for the comparison of interest will be excluded. Data from both placebo 
periods per subject will be included simultaneously in the analysis, using the same treatment 
code ‘placebo’ but differentiated by the respective period numbers. This means that the 
model defined below can directly be used for estimating the treatment contrast between the 
active drug under consideration and placebo, using the observations from both placebo 
periods. In the following, the ‘subject baseline’ is defined as the arithmetic mean of the 
period baselines per subject (only from the periods involved in the comparison, i.e. the period 
baseline of the active treatment period and those of the 2 placebo periods).
The MMRM is based on Schall and Ring [R10-5353] and includes the fixed categorical 
effects of ‘treatment’, ‘period’ and ‘time’, the ‘treatment-by-time’ interaction and ‘period-by-
time’ interactions, as well as the continuous fixed covariates ‘period baseline’ and ‘subject 
baseline’, and the ‘period baseline-by-time’ interaction and ‘subject baseline-by-time’ 
interaction. Subject is included as a random effect on the intercept. For the repeated effect 
‘time’, an unstructured covariance pattern is chosen, using the blocking factor ‘subject-by-
period’. Note that the ‘subject baseline’ is included in the model to avoid cross-level bias 
affecting treatment comparisons; see Kenward and Roger [R10-4391].
More precisely, the model is given by
(	) =  +  +  +  + 	 +  +  + 
 + ()
+ ()	 +  + ,
~(0, 
), (, … ,  ) ~ (!, "),
where i=1,...,I indicates the subject, k=1,…,# the time point within period, m=1,…,M the 
period and j=1,2 the treatment,
(	)
the QTcF change from period baseline for subject i receiving treatment j in period 
m at repeated measures time point k,

the overall intercept, 

the baseline value for subject i in period m (period baseline),

the associated covariate effect of period baseline,


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
the subject baseline value (mean of 3 period baselines) for subject i,

the associated covariate effect of subject baseline,

the effect of period m,
	
the effect of treatment j,

the effect of time k,

the interaction effect of period baseline and time,


the interaction effect of subject baseline and time,
()
the interaction effect of period and time,
()	
the interaction effect of treatment and time,

the random effect of subject i on intercept, assumed mutually independent across 
subject,

the random error associated with subject i for time k and period m, assumed 
independent across period and subject (indices m, i), and
Ψ
an unstructured K-by-K covariance matrix.
The random subject effects  and the random errors  are assumed to be independent of 
one another.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The primary objective of this study will be assessed by testing for each dose of BI 409306 the 
null hypothesis that the mean difference in the QTcF changes from baseline between 
BI 409306 and placebo is greater than or equal to 10 msec at least for one time point after 
dosing, against the alternative hypothesis that the mean difference is below the threshold of 
10 msec for all time points.
The conclusion that this tQT trial is negative as per ICH E14 (see Section 7.1.1) will be based
on the rejection of this null hypothesis for each of the two doses of BI 409306. This testing 
procedure is considered to be confirmatory, as the power calculations are based on this 
endpoint and the non-inferiority margin of 10 msec (see Section 7.6). The one-sided tests will 
be performed at the 5% level, which is equivalent to the estimation of two-sided 90% 
confidence intervals because of the symmetry of the normal distribution.
For the assessment of assay sensitivity of the trial, the null hypothesis that the mean 
difference in the QTcF changes from baseline between moxifloxacin and placebo is less than
or equal to 5 msec for all of the time points 2, 3, and 4 hours after dosing will be tested at the 
5 % level, against the alternative hypothesis that the mean difference is above the threshold of 
5 msec for at least one of the three time points. The Hochberg correction will be used for 
adjusting for multiplicity (see Section 7.3.2.1). 


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7.3
PLANNED ANALYSES
For the analysis of the ECG variables QT, RR, PR, and QRS, a 2-step averaging procedure 
will be performed. In the first step, the 4 cardiac cycles per 10-second ECG will be averaged. 
For each 10-second ECG, heart rate will then be derived from the calculated RR value as
HR[bpm]=60000/RR[msec].
Likewise, for each ECG the heart rate corrected QT intervals QTcF and QTcI will be derived 
from the mean values of the 4 cardiac cycles for RR and QT, respectively (see Section 
7.3.2.5).
In the second step, for obtaining one ECG variable value per subject per time point, the 
calculated values of the three 10-second ECGs (triplicate ECGs extracted from the Holter 
recordings) will be averaged. 
For all quantitative ECG variables derived from the 10-second ECGs, further analyses are 
then performed on these aggregated data on time point level. Period baseline values are 
calculated as the means of the values derived for the 3 baseline time points per period.
Important protocol deviations (iPDs) will be defined in the Integrated Quality and Risk
Management plan. 
The following analysis sets will be defined:

Treated Set (TS): This subject set includes all randomised subjects who have received 
at least one dose of any study drug.

ECG Set (ECGS): This subject set includes all subjects in the TS who have at least 
one on-treatment value for at least one ECG endpoint, which is not excluded due to 
ECG relevant iPDs. Such iPDs may be e.g. the use of pro-arrhythmic medications. 
Exclusion of single ECG values due to relevant iPDs is to be decided no later than in 
the Blinded Report Planning Meeting (BRPM) before data base lock and will be 
documented in the CTR.


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The ECGS will be used for all analyses of the centrally assessed ECG data, 
 
The TS will be used 
for all other safety summaries and all safety listings.
 
7.3.1
Primary analyses
The primary analyses use the MMRM described in Section 7.1.3 for the QTcF data from 
BI 409306 and placebo treatments, based on the ECG set. 
For the pairwise comparisons between each dose of BI 409306 and placebo, mean treatment 
differences in the QTcF changes from baseline at each time point will be estimated by the 
differences in the corresponding least-squares means. Two-sided 90% confidence intervals 
based on the t-distribution will also be computed for each time point. The null hypothesis will 
be rejected if the maximum upper confidence limit for the mean difference in the QTcF 
changes from baseline between BI 409306 and placebo is less than 10 msec.
7.3.2
Secondary analyses
7.3.2.1
Assessment of assay sensitivity
The effect of moxifloxacin on the QTcF changes from baseline in comparison with placebo 
will be assessed using the same MMRM as applied in the primary analysis. 
For this analysis, only the data from the moxifloxacin and placebo periods will be used.
For describing the time course of the effect of moxifloxacin on QTcF, 90% confidence 
intervals for the mean differences of the QTcF changes from baseline between moxifloxacin 
and placebo will be provided. 
For the formal test of assay sensitivity at level α=5%, the method by Hochberg [R97-1003]
will be applied. To this end, the three single hypotheses that the mean difference in the QTcF
change from baseline between moxifloxacin and placebo is less than or equal to 5 msec at a 
given time point (out of the three time points 2, 3, and 4 hours after drug administration) will 
be tested based on the results of the MMRM (fitted to the data for all time points). If the 
largest of the three p-values is less than 5% (=α), then all single hypotheses can be rejected. If 
the second largest p-value is less than 2.5% (=α/2), then the corresponding null hypothesis 
and the one regarding the test with the lowest p-value can be rejected. If the lowest p-value is 
less than 1.667% (=α/3), then only the null hypothesis corresponding to this p-value can be 
rejected. Note that it is sufficient to reject only one of the three single null hypotheses in 
order to reject the overall null hypothesis stated in Section 7.2 (i.e., the intersection of the 
three single hypotheses), and hence to show assay sensitivity.


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7.3.2.2
Analyses of the heart rate
For each dose of BI 409306, the HR changes from baseline at each time point between 
20 min to 24 hours after dosing will be analysed by applying the same model as in the 
primary analyses and calculating the corresponding 90 % CIs for the mean difference 
between BI 409306 and placebo. For these analyses, only the HR data from the respective 
BI 409306 dose and placebo will be used. 
7.3.2.5
Heart rate corrections of QT interval
Precise heart rate correction of the QT interval is one of the most important factors in 
increasing the precision for the detection of drug induced QT prolongation. In the absence of 
relevant effects of a drug on the heart rate, the Fridericia correction formula is accepted as the 
primary correction method (see e.g. the FDA “Scientific white paper on concentration-QTc 
modeling” [R18-0143]). For a given pair ($%, &&), it is defined as
$%'([msec] = $%[msec] ∗01000 msec
&&[msec] 2

3
.
QTcF will be selected as the primary correction method for the present trial, as it is not 
expected that the mean of the placebo-corrected HR change from baseline will be larger than 
10 beats/min for both doses of BI 409306.
 


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7.3.3
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 24 hours after the 
last dose of trial medication (in treatment periods with BI drug or placebo) or a period of 4 
days after the last dose of trial medication (in moxifloxacin treatment period), will be 
assigned to the on-treatment period for evaluation. The safety analysis will be done by 
‘treatment at onset’.
All treated subjects will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be listed only. Values outside the reference range as well as values 
defined as clinically relevant will be flagged.
Vital signs, physical examinations, or other safety-relevant data observed at screening, baseline, 
during the course of the trial and at the end-of-trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment.
7.3.4
Interim analyses
No interim analysis is planned.


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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.
If it is not possible to estimate an individual correction factor for a subject, e.g. if the range of 
observed off-drug heart rates is too narrow, the correction factor will be imputed by the 
correction factor estimated from the entire study population instead, referred to as QTcN 
correction method.


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7.5
RANDOMISATION
Subjects will be randomised to the 15 treatment sequences (see Section 7.1) in a balanced 
ratio. 
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to 3.3.5).
Access to the codes will be controlled and documented according to the standard procedures 
in place at BI.
7.6
DETERMINATION OF SAMPLE SIZE
The following sample size considerations are performed for the MMRM based analysis of the 
primary endpoint.
Based on the results of trial 1289.28 [c03808525-02], the maximum effect of BI 409306 on
the QTc interval can be expected within the first 3 hours after drug administration. Except for 
one outlier at 8 hours after drug administration, the maximum (over all remaining time 
points) estimated standard deviation of the mean difference between BI 409306 and placebo 
in QTc changes from baseline was 11.3 msec, and the estimated maximum difference (over 
all time points) was less than 5 msec for both QTcF and QTcN. 


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In case of a QT prolonging drug effect of BI 409306, the higher effect would be expected for 
the higher dose, while the effects of the two doses on QTc should be highly correlated, 
especially since all comparisons are done with the same comparator. Therefore, the sample 
size determination will be based on the assumptions for the higher dose. Hence, in the 
following, we focus only on one single testing problem (i.e. for only one dose).
Further, since the above worst case scenarios (maximum effect over time, maximum standard 
deviation of the difference over time) will be used, the following power calculations are 
performed only for the univariate testing problem of non-inferiority at a single time point.
Since all assessments in tQT trials are based on the comparisons between active treatment 
and placebo, these treatment contrasts should be estimated with the highest statistical 
efficiency. To account for this, the selected crossover design for this trial will include a 
second placebo period instead of only one, following the arguments in [R12-0517]. The 
sample size for the resulting 4-treatment 5-period crossover design can be determined as 3/4 
of the sample size for the corresponding 4-period crossover design (i.e., with the number of 
treatments and periods being equal); see formula (2) in [R12-0517].
Thus, in a first step the sample sizes for a crossover tQT trial with equal number of treatments 
and periods will be determined, which then lead to the sample size for the selected 5-period 
design through multiplication by 0.75 in a second step.
Using a one-sided confidence level of α = 0.05 and a power of 90%, Table 7.6: 1 displays the 
required sample sizes for showing that the mean difference between BI 409306 and placebo 
in the QTcF change from baseline is smaller than 10 msec under various assumptions for the 
within-subject variability and expected differences between the means.
Table 7.6: 1
Sample sizes assuming a power of 90% for concluding that the mean 
difference between BI 409306 and placebo is less than 10 msec 
LEL for difference
-999
-999
-999
-999
-999
-999
-999
-999
-999
UEL for difference
10
10
10
10
10
10
10
10
10
Expected difference
3
3
3
4
4
4
5
5
5
Standard deviation of 
differences
10
11
12
10
11
12
10
11
12
Total N
20
24
28
26
32
36
36
44
52
LEL: Lower equivalence limit, UEL: Upper equivalence limit (one-sided α = 0.05)
The calculations were performed using the MTE1co routine from commercial software nQuery Advisor7.0[R15-1331].
Therefore, in a standard crossover design with equal number of treatments and periods, a total 
sample size of 52 subjects will provide a power of 90% to conclude that the mean difference 
between BI 409306 and placebo in QTcF change from baseline is smaller than 10 msec, if the 
true difference is up to 5 msec and the standard deviation of the differences is at most 
12 msec. Accounting for up to 8 potential drop outs, a total of 60 subjects would be required.


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As the sample size for the 5-period crossover with 2 placebo periods can be determined as 3/4 
of the sample size of the corresponding 4-period crossover, the required sample size for this 
trial is 45 subjects. A power of roughly 90% will be achieved under the assumptions specified 
above, even if up to 6 subjects are to discontinue the trial prematurely.
Regarding the assessment of assay sensitivity, the maximum difference in the QTcF change 
from baseline between moxifloxacin and placebo can be expected to be around 12 msec, with 
a standard deviation of 10 msec, based on previous BI tQT trials. If just one single test (for 
one time point out of the three; see Section 7.3.2.1) was performed at level α/3=1.667%, and 
taking into account the design with 2 placebo periods, the power to reject the corresponding 
null hypothesis given a sample size of 45 would be 99.8%. If the true value of the maximum 
placebo-corrected change from baseline would be only 10 msec, still the power for the single 
test would be 93.3%. The power to reject the overall null hypothesis stated in Section 7.2
using the Bonferroni method would be larger than the above values in each scenario, since in 
that case all three single tests would be performed at level α/3, and only one would have to be 
significant. The power of the Hochberg method described in Section 7.3.2.1 is again larger 
than that of the Bonferroni method [R97-1003].


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


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8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5.1 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
In the 
 Phase I unit – the 
validated 
 is operated for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered into 
(that is, without prior written or electronic record) are 
considered to be source data. The place where data is entered first will be defined in a trial 
specific Source Data Agreement. The data in 
are available for inspection at any 
time.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER); 2005.
R08-0437
Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R, 
Stockbridge N, Tornoe CW, Wang Y, Zhu H, Gobburu JV. Concentration-
QT relationships play a key role in the evaluation of proarrhythmic risk 
during regulatory review. J Clin Pharmacol 2008;48:13-18.
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005). 
2005
R10-0867
Bloomfield DM, Kost JT, Ghosh K, Hreniuk D, Hickey LA, Guitierrez MJ, 
Gottesdiener K, Wagner JA. The effect of moxifloxacin on QTc and 
implications for the design of thorough QT studies. Clin Pharmacol Ther 
2008;84(4):475-480.
R10-4391 
Kenward MG, Roger JH The use of baseline covariates in crossover studies. 
Biostatistics 11 (1), 1 - 17 (2010)
R10-5092
Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain 
2006;129:1659-1673.
R10-5102
Reymann KG, Frey JU. The late maintenance of hippocampal LTP: 
requirements, phases, 'synaptic tagging', 'late-associativity' and 
implications. Neuropharmacology 2007;52:24-40.
R10-5353 
Schall R, Ring A. Mixed models for data from thorough QT studies: part 1. 
Assessment of marginal QT prolongation. Pharm Stat, (2010)
R12-0517
Ring A, Walter B, Larbalestier A, Chanter D. An efficient crossover design 
for thorough QT studies. GMS Med Inform Biometr Epidemiol 2010;
6(1):Doc05.
R13-4521
Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology 
and therapy of schizophrenia. Pharmacol Biochem Behav 2012;100:665-
677.
R14-5088
Jones B, Kenward MG. Design and analysis of cross-over trials. 
(Monographs on Statistics and Applied Probability; 138) 3rd ed. Boca 
Raton: CRC Press; 2015.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide. 
http://www.statsols.com/wp-
content/uploads/2013/10/nQ70_version2_manual.pdf (access date: 20 
March 2015) ; Los Angeles: Statistical Solutions; 2007.


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R15-1457
Mathalon DH, Perkins D, Walker E, Addington J, Bearden C, Cadenhead 
K, Cornblatt B, McGlashan T, Seidman L, Tsuang M, Woods S, Cannon T, 
NAPLS Consortium. Impaired synaptic plasticity, synaptic over-pruning, 
inflammation, and stress: a pathogenic model of the transition to psychosis 
in clinical high risk youth. 69th Ann Sci Convention and Mtg of the Society 
of Biological Psychiatry (SOBP), New York, 8 - 10 May 2014. Biol 
Psychiatry 2014;75(9)(Suppl)
R15-3327
Perez VB, Woods SW, Roach BJ, Ford JM, McGlashan TH, Srihari VH, 
Mathalon DH. Automatic auditory processing deficits in schizophrenia and 
clinical high-risk patients: forecasting psychosis risk with mismatch 
negativity. Biol Psychiatry 2014;75(6):459-469.
R17-2903
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs -
questions and answers (R3) (June 2017, ICH, revision 2). 
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/documen t/ucm073161.pdf (access date: 14 August 2017) ; 
U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER); 2017.
R18-0143
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific 
white paper on concentration-QTc modeling. J Pharmacokin Pharmacodyn 
(2017)
R19-0482
Avalox 400 mg film-coated tablets, broadspectrum antibiotic (Bayer), 
prescription only (product information (summary of product characteristics) 
date of revision of the text: 11/2018) 2018
R94-1529 
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
R97-1003
Hochberg Y. A sharper Bonferroni procedure for multiple tests of 
significance. Biometrika 75 (4), 800 - 802 (1988)
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c01694347-10
. Investigator's Brochure: BI 409306 in 
1. Prevention of first episode psychosis in subjects with attenuated 
psychosis syndrome and 2. reduction of relapse in patients with 
Schizophrenia. IB. Version 12. 26 Jun 2018.


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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 (randomised, double-blind, 
placebo-controlled within dose groups). CTR. Version 2. 1289.4. 
13 Mar 2014.
c03800738-01
 Randomised, parallel-group, 
double-blind study of systemic and ocular safety and pharmacokinetics of 
BI 409306 in patients with schizophrenia, Alzheimer’s disease, and age-
comparable healthy volunteers. CTR. Version 1. 1289.27. 19 April 2018.
c03808525-02
 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. Version 2. 1289.28. 
04 Sep 2017.
c13128239-01
 Influence of fluvoxamine on the 
pharmacokinetics of BI 409306 after oral administration (randomized, 
open-label, two-treatment, two-sequence, two-period crossover study). CTR. 
Version 1. 1289.35. 19 Jul 2017.
c22465310-01
 A multi-centre, double-blind, 
parallel-group, randomised controlled study to investigate efficacy, safety 
and tolerability of orally administered BI 409306 during a 12-week 
treatment period compared to placebo in patients with cognitive impairment 
due to Alzheimer’s Disease. CTR. Version 1. 1289.7. 11 June 2018.
c22514660-01
 A multi-centre, double-
blind, parallel-group, randomized controlled study to investigate the 
efficacy, safety and tolerability of orally administered BI 409306 during a 
12-week treatment period compared to placebo in patients with Alzheimer’s 
Disease. CTR. Version 1. 1289.5. 13 June 2018.
U12-1034-01
 A randomised, 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. CTR. 
Version 1. 1289.1. 19 Jan 2012.
U12-2165-01
 Randomised, 
double-blind, placebo-controlled, parallel-group proof of mechanism study 
to assess the pharmacokinetics and to evaluate the pharmacodynamic effect 
of different single oral doses of BI 409306 in healthy male volunteers. CTR. 
Version 1. 1289.3. 17 Sep 2012.


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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 (randomised, double-
blind, placebo-controlled within dose groups Phase I study). CTR. 
Version 1. 1289.2. 20 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
12 Feb 2019
EudraCT number
2018-001335-44
BI Trial number
1289-0038
BI Investigational Product(s)
BI 409306
Title of protocol
Thorough QT study to evaluate the effects of BI 
409306 as single doses on cardiac safety 
parameters in healthy male and female subjects. A 
randomized, placebo controlled, double-blind, 
five-period crossover study with (open-label) 
moxifloxacin as positive control.
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
2.3 Benefit-risk assessment
Description of change
Risks related to moxifloxacin administration were 
updated according to the current German SmPC 
for Avalox® [R19-0482]; a typing error was 
corrected.
Rationale for change
Version 1.0 of the CTP did not reference the 
currently valid version of the German SmPC for 
Avalox®.


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Number of global amendment
2
Date of CTP revision
25 Mar 2019
EudraCT number
2018-001335-44
BI Trial number
1289-0038
BI Investigational Product(s)
BI 409306
Title of protocol
Thorough QT study to evaluate the effects of BI 
409306 as single doses on cardiac safety 
parameters in healthy male and female subjects. 
A randomized, placebo controlled, double-blind, 
five-period crossover study with (open-label) 
moxifloxacin as positive control.
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
3.3.3
3.3.4.1
3.3.4.2
3.3.5
4.1.2
Exclusion criteria
Removal of individual subjects
Discontinuation of the trial by the sponsor
Replacement of subjects
Method of assigning subjects to treatment 
groups
Description of change
3.3.3
3.3.3
3.3.4.1
3.3.4.2
Changed the lower limit of systolic RR to 100 
mmHg (EX No. 2); added EX No. 28 
(contraindications for moxifloxacin 
administration)
Deleted “or run-in” in EX No. 20 
Added individual removal criterion No. 5
(AST/ALT increase), No. 6 (potential QT 
findings) and No. 7 (serious adverse reaction, 
non-serious severe adverse reaction)
Re-phrased discontinuation criterion No. 1 to 
address the case or potential serious adverse 
reaction or severe non-serious adverse reactions


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Number of global amendment
2
3.3.5
4.1.2
Number of replacement subjects have been 
specified
A description about the planned cohort number, 
cohort size and dosing regimen as well as 
justification has been added
Rationale for change
3.3.3
3.3.3
3.3.4.1
3.3.4.2
3.3.5
4.1.2
Request by competent authority (CA) and ethics 
committee (EC)
To reduce redundancy with EX No. 27.
Request by CA and EC
Request by CA and EC
Request by CA and EC
Request by CA and EC


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Number of global amendment
3
Date of CTP revision
23 Apr 2019
EudraCT number
2018-001335-44
BI Trial number
1289-0038
BI Investigational Product(s)
BI 409306
Title of protocol
Thorough QT study to evaluate the effects of BI 
409306 as single doses on cardiac safety 
parameters in healthy male and female subjects. 
A randomized, placebo controlled, double-blind, 
five-period crossover study with (open-label) 
moxifloxacin as positive control.
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
-
3.3.4.1
5.2.4.4
Flow Chart
Removal of individual subjects
Safety 12-lead single standard ECG and run-in 
(Holter) ECG
Description of change
-
3.3.4.1
5.2.4.4
Flow Chart: Inserted safety ECGs at PTM 2:00 
and 4:00
Amended individual removal criterion No. 6: 
Individual subjects will be removed from the 
trial in case of a QTc increase > 60 msec from 
baseline in safety ECGs
Added the two time-points for additional safety 
ECGs at PTM 2:00 and 4:00; added information 
about electrode placement 
Rationale for change
-
3.3.4.1
5.2.4.4
Request from health authority to implement an 
individual stopping criterion based on changes 
of QTc from baseline > 60 msec


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09109536
7.0
clinical-trial-protocol-revision-3
Thorough QT study to evaluate the effects of BI 409306 as single doses on cardiac
safety parameters in healthy male and female subjects. A randomized, placebo
controlled, double-blind, five-period crossover study with (open-label) moxifloxacin
as positive control.
Author-Trial Clinical
Pharmacokineticist
23 Apr 2019 16:04 CEST
Approval-Team Member Medicine
23 Apr 2019 16:09 CEST
Verification-Paper Signature
Completion
24 Apr 2019 08:09 CEST
Author-Trial Statistician
25 Apr 2019 09:33 CEST
Approval-Therapeutic Area 
26 Apr 2019 13:48 CEST
Author-Clinical Trial Leader
30 Apr 2019 08:20 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09109536
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26650906-01
BI Trial No.:
1289-0038
Title:
Thorough QT study to evaluate the effects of BI 409306 as single 
doses on cardiac safety parameters in healthy male and female 
subjects. A randomized, placebo controlled, double-blind, five-
period crossover study with (open-label) moxifloxacin as positive 
control
Investigational
Product(s):
BI 409306
Responsible trial 
statistician(s):
Phone: 
Fax: 
Phone: 
Date of statistical 
analysis plan:
18 NOV 2019 SIGNED
Version:
“Final”
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................14
6.1
TREATMENTS...................................................................................................14
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................16
6.3
SUBJECT SETS ANALYSED...........................................................................17
6.5
POOLING OF CENTRES .................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................18
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................21
6.7.1
Baseline ................................................................................................................21
6.7.2
Time windows......................................................................................................21
7.
PLANNED ANALYSIS......................................................................................24
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........24
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................24
7.3
TREATMENT COMPLIANCE........................................................................24
7.4
PRIMARY ENDPOINT(S) ................................................................................24
7.4.1
Primary analysis of the primary endpoint(s) ...................................................24
7.5
SECONDARY ENDPOINT(S) ..........................................................................27
7.5.1
Key secondary endpoint(s).................................................................................27
7.5.2
(Other) Secondary endpoint(s) ..........................................................................27
7.5.2.1
Assessment of assay sensitivity ............................................................................27
7.5.2.2
Analyses of the heart rate......................................................................................27


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7.7
EXTENT OF EXPOSURE.................................................................................32
7.8
SAFETY ANALYSIS..........................................................................................32
7.8.1
Adverse events.....................................................................................................32
7.8.2
Laboratory data ..................................................................................................34
7.8.3
Vital signs.............................................................................................................34
7.8.4
ECG......................................................................................................................34
7.8.5
Others...................................................................................................................34
8.
REFERENCES....................................................................................................35
10.
HISTORY TABLE..............................................................................................44


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs ................................................14
Table 6.2: 1
Handling of iPDs..............................................................................................17
Table 6.7.2: 2 Time schedule for extractions of triplicate ECGs from Holter recording 
during treatment periods...................................................................................22
Table 10: 1
History table .....................................................................................................44


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BRAVE
BI Rave system
CARE
Clinical data Analysis and Reporting Environment
CT
Concomitant Therapy
DBP
Diastolic blood pressure
ECGS
ECG analysis Set
HR 
Heart Rate 
IQRMP
Integrated Quality and Risk Management Plan
MMRM
Mixed effects Model for Repeated Measurements
PR interval
ECG interval from the onset of P wave to the beginning of the QRS
QRS duration
Duration of the QRS complex in the ECG (corresponding to the 
depolarization of the right and left ventricles) 
QT interval
ECG interval from the beginning of the QRS complex to the end of the T 
wave
QTcB [msec]
QT interval, heart rate corrected according to Bazett’s formula
QTcF [msec]
QT interval, heart rate corrected according to Fridericia’s formula


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Term
Definition / description
correction factor derived from individual subject data
Q1
Lower Quartile
Q3
Upper Quartile
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
SA
Statistical Analysis
SBP
Systolic Blood Pressure
SD
Standard Deviation
SDL
Subject Data Listings
SOC
System Organ Class
TS
Treated Set
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, 
randomization.
Study data will be stored in the BI Rave (BRAVE) system. 
The statistical analyses will be performed within the validated working environment Clinical 
data Analysis and Reporting Environment (CARE), including SASTM (current Version 9.4, by 
SAS Institute Inc., Cary, NC, USA), and a number of SASTM-based tools (e.g., macros for the 
analyses of AE data or laboratory data; Report Appendix Generator system (RAGe) for 
compilation/formatting of the CTR appendices). 
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version Phoenix 6.3, Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the CTP.


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5.
ENDPOINTS
No efficacy endpoints will be evaluated in this trial.
General remarks regarding ECG endpoints derived from interval measurements:
The derivation of HR, QTcI and QTcF endpoints is described in Section 9.1.
Throughout this section, the term “baseline” refers to the mean of the pre-dose ECG 
measurements at Visits 2-6 (i.e. a separate baseline for each period which is also denoted as 
“period baseline”; see Section 6.7). Each ECG measurement per time point is defined as the 
mean value of 3 single ECGs with 4 cardiac cycles each.
5.1
PRIMARY ENDPOINTS
CTP Section 5.2.1.1: The primary endpoint will be derived based on the changes from 
baseline in QTcF at each time point between 20 min to 24 hours after drug administration of 
BI 409306 and placebo. For each of the 2 doses of BI 409306, the relevant outcome is the 
maximum mean difference between BI 409306 and placebo in the QTcF changes from 
baseline.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable. There are no key secondary endpoints specified in the CTP.
5.2.2
Secondary endpoints
CTP Section 5.2.1.2:

The QTcF changes from baseline at each time point between 20 min to 24 hours after 
drug administration of moxifloxacin and placebo (for assessment of assay sensitivity). 
The relevant outcome is the maximum mean difference between moxifloxacin and placebo 
in the QTcF changes from baseline for the time points 2, 3, and 4 hours after dosing.

The changes from baseline in HR at each time point between 20 min to 24 hours after 
drug administration of BI 409306 and placebo. For each dose of BI 409306, the relevant 
outcomes are the maximum and the minimum mean differences between BI 409306 and 
placebo in HR changes from baseline after dosing. HR will be derived from the RR 
interval (see Section 9.1).


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic information on treatments to be administered and assignment of treatment groups, 
refer to Section 4 of the CTP.
For the statistical analysis of AEs, the following analysis phases specified in Table 6.1: 1 will 
be defined for each subject.
Table 6.1: 1
Analysis phases for statistical analysis of AEs
Study 
analysis 
phase
Label
Start
End
Screening
Screening
Date of informed consent
Date/time of first administration
of study drug in period 1
On-treatment
Placebo 1,
Placebo 2, 
BI 50 mg,
BI 250 mg,
or
Mox 400 mg,
respectively
Date/time of administration of 
study drug
Date/time of administration of 
study drug + residual effect 
period 
or
Date/time of administration of 
study drug in the next treatment 
period
or
12:00 a.m. on day after subject's 
end of study participation date,
whatever comes first
Follow-up
FUP Placebo 1,
FUP Placebo 2, 
FUP BI 50 mg,
FUP BI 250 mg,
or 
FUP Mox 400 mg,
respectively
End of the respective on-
treatment period (see line above)
Date/time of administration of 
study drug in the next treatment 
period, if applicable,
otherwise
12:00 a.m. on day after subject's 
end of study participation date
CTP Section 1.2.4: The Residual Effect Period (REP) of BI 409306 is 24 hours. The REP of 
moxifloxacin is 4 days.
For Placebo, the REP is set to 24 hours, i.e. equal to that of BI 409306. 
In CTR Section 15 and Appendix 16.1.13.1.8, AE displays will present results for the on-
treatment phase only.


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In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8 AE tables), the following 
totals will be provided in addition: 

"Total Pbo", defined as the total over all on-treatment phases involving treatment with 
placebo

“Total BI”, defined as the total over all on-treatment phases involving treatment with 
BI 409306

“Total”, defined as the total over all on-treatment phases
The treatments will be presented in Section 15 AE tables in the following sort order: 
Placebo 1, Placebo 2, BI 50 mg, BI 250 mg, Mox 400 mg, Total Pbo, Total BI, Total.
Statistical analyses of vital signs will be conducted by treatment (Placebo 1, Placebo 2, 
BI 50 mg, BI 250 mg, Mox 400 mg), with clear differentiation between baseline (see Section 
6.7) and on-treatment measurements.
Statistical analyses of ECG data will include the single periods involving BI treatment (or 
treatment with moxifloxacin, respectively) together with summarised Placebo and BI periods 
(see also Section 7.6.1).


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More details on the technical implementation of these analyses are provided in the Analysis 
Data Set Plan of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from pre-specified 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). At this 
meeting, it will be decided whether a discrepant data value can be used in the analyses or 
whether it must be corrected in the clinical database. Each protocol deviation must be 
assessed to determine whether it is an important protocol deviation (iPD). For definition of 
iPDs, and for the process of identification of these, refer to the BI reference document 
"Identify and Manage Important Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the minutes of the RPM. Categories which are considered to be iPDs in this trial are defined 
in the integrated quality and risk management plan (IQRMP). If the data show other iPDs, the 
definition in the IQRMP will be supplemented accordingly by the time of the RPM.
iPDs will be summarized and listed. Table 6.2: 1 below specifies which kind of iPDs could 
potentially lead to exclusion from which analysis set. The decision on exclusion of subjects 
from analysis sets will be made at the latest at the RPM, after discussion of exceptional cases 
and implications for analyses.
Decisions made at the RPM will be documented within the decision log and stored within the 
eTMF in the DMS.


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Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Potentially excluded from which 
analysis set
A1
Inclusion Criteria Not Met
ECGS, PKS
A2
Exclusion Criteria Met
ECGS, PKS
B1
Informed consent not available/not 
done
TS
B2
Informed consent too late
None
C1
Incorrect trial medication taken
ECGS, PKS
C2
Randomisation not followed
ECGS, PKS
C3
Non-compliance
ECGS, PKS
C4
Medication code broken 
inappropriately 
None
C5
Incorrect intake of trial medication
ECGS, PKS
C6
Improper washout between treatments
ECGS, PKS
D1
Prohibited medication use
ECGS, PKS
D3
Improper washout of concomitant 
medication
ECGS, PKS
E1
Certain violations of procedures used to 
measure primary or secondary data
ECGS
F1
Certain violations of time schedule 
used to measure primary or secondary 
data
ECGS
G1
Incorrect intake of meal
PKS
6.3
SUBJECT SETS ANALYSED
CTP Section 7.3: The following analysis sets will be defined:

Treated Set (TS): This subject set includes all randomised subjects who have received 
at least one dose of any study drug.

ECG Set (ECGS): This subject set includes all subjects in the TS who have at least 
one on-treatment value for at least one ECG endpoint, which is not excluded due to 
ECG relevant iPDs. Such iPDs may be e.g. the use of pro-arrhythmic medications. 
Exclusion of single ECG values due to relevant iPDs is to be decided no later than in 


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the Blinded Report Planning Meeting (BRPM) before data base lock and will be 
documented in the CTR.
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
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR. 
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) 
will be reported in the CTR as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded in the CTR.
CTP Section 7.4.1: With respect to safety evaluations, it is not planned to impute missing 
values.


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One exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
ECG
If single cardiac cycles (generally four) are missing, the arithmetic means per single ECG 
will be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If replicate ECG recordings (generally three) are missing, the arithmetic means per time-point 
will be computed with the reduced number (1 or 2) of recordings.
If a period baseline is missing the arithmetic mean of the remaining other period baselines
will be used.
In the repeated measures analyses, the subject baseline will be calculated based on the non-
missing period baselines used in the respective comparison. Imputed period baseline values 
will not be used for creation of subject baselines.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
6.7.1
Baseline
If not otherwise stated, baseline is defined as the last measurement prior to first drug 
administration.
ECG interval data:
CTP Section 7.1: Throughout the study protocol, the term “baseline” (if not specified 
further) refers to the 3 pre-dose triplicate ECG measurements at Visits 2-6 (i.e. a separate 
baseline for each period will be derived from the 9 ECG recordings that comprise 4 cardiac 
cycles each).
The mean of the values calculated for the 3 pre-dose time points per period is also denoted as 
‘period baseline’.  ‘Change from baseline’ always refers to the period baseline.  An additional 
’subject baseline’ is defined as the arithmetic mean of the period baselines per subject and 
will only be used in the context of MMRM analyses; for further details see Section 7.4. 
6.7.2
Time windows
Time windows are defined in Section 6.1 of the CTP. 
Adherence to time windows will be checked at the RPM.
The following tables summarize the time points of interval extractions from the 12-lead 
Holter recordings as well as the planned time intervals for Holter evaluations with regard to 
cardiac arrhythmia events. 


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Table 6.7.2: 2 Time schedule for extractions of triplicate ECGs from Holter recording during 
treatment periods
Planned times [hh:mm] relative to administration of study drug
Visit
Pre-dose
On treatment
2-6
-0:50, -0:35, -0:20
0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 8:00, 12:00, 24:00


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Q1 
(lower quartile) / Median / Q3 (upper quartile) / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject
set whether they have non-missing values or not).
The precision for percentages should be one decimal point. The category missing will be 
displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
CTP Section 7.1.3: For the analysis of the QTcF changes from baseline at each time point 
between 20 min to 24 hours after dosing, a linear mixed-effects model for repeated 
measurements (MMRM) will be used. The analyses will be based on the ECG set. 
The comparison between each dose of BI 409306 and placebo will be performed pairwise, 
i.e. data not relevant for the comparison of interest will be excluded. Data from both placebo 
periods per subject will be included simultaneously in the analysis, using the same treatment 
code ‘placebo’ but differentiated by the respective period numbers. This means that the 
model defined below can directly be used for estimating the treatment contrast between the 
active drug under consideration and placebo, using the observations from both placebo 
periods. In the following, the ‘subject baseline’ is defined as the arithmetic mean of the 
period baselines per subject (only from the periods involved in the comparison, i.e. the period 
baseline of the active treatment period and those of the 2 placebo periods).
The MMRM is based on Schall and Ring (14) and includes the fixed categorical effects of 
‘treatment’, ‘period’ and ‘time’, the ‘treatment-by-time’ interaction and ‘period-by-time’ 


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interactions, as well as the continuous fixed covariates ‘period baseline’ and ‘subject 
baseline’, and the ‘period baseline-by-time’ interaction and ‘subject baseline-by-time’ 
interaction. Subject is included as a random effect on the intercept. For the repeated effect 
‘time’, an unstructured covariance pattern is chosen, using the blocking factor ‘subject-by-
period’. Note that the ‘subject baseline’ is included in the model to avoid cross-level bias 
affecting treatment comparisons; see Kenward and Roger (13).
More precisely, the model is given by
(	) =  +  +  +  + 	 +  +  + 
 + ()
+ ()	 +  + ,
~(0, 
), (, … ,  ) ~ (!, "),
where i=1,...,I indicates the subject, k=1,…,# the time point within period, m=1,…,M the 
period and j=1,2 the treatment,
(	)
the QTcF change from period baseline for subject i receiving treatment j in 
period m at repeated measures time point k,

the overall intercept, 

the baseline value for subject i in period m (period baseline),

the associated covariate effect of period baseline,

the subject baseline value (mean of 3 period baselines) for subject i,

the associated covariate effect of subject baseline,

the effect of period m,
	
the effect of treatment j,

the effect of time k,

the interaction effect of period baseline and time,


the interaction effect of subject baseline and time,
()
the interaction effect of period and time,
()	
the interaction effect of treatment and time,

the random effect of subject i on intercept, assumed mutually independent 
across subject,

the random error associated with subject i for time k and period m, assumed 


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independent across period and subject (indices m, i), and
Ψ
an unstructured K-by-K covariance matrix.
The random subject effects  and the random errors  are assumed to be independent of 
one another.
CTP Section 7.3.1: For the pairwise comparisons between each dose of BI 409306 and 
placebo, mean treatment differences in the QTcF changes from baseline at each time point 
will be estimated by the differences in the corresponding least-squares means. Two-sided 
90% confidence intervals based on the t-distribution will also be computed for each time 
point. The null hypothesis will be rejected if the maximum upper confidence limit for the 
mean difference in the QTcF changes from baseline between BI 409306 and placebo is less 
than 10 msec.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
(Other) Secondary endpoint(s)
7.5.2.1
Assessment of assay sensitivity
CTP Section 7.3.2.1: The effect of moxifloxacin on the QTcF changes from baseline in 
comparison with placebo will be assessed using the same MMRM as applied in the primary 
analysis.
For this analysis, only the data from the moxifloxacin and placebo periods will be used.
For describing the time course of the effect of moxifloxacin on QTcF, 90% confidence 
intervals for the mean differences of the QTcF changes from baseline between moxifloxacin 
and placebo will be provided. 
For the formal test of assay sensitivity at level α=5%, the method by Hochberg (10) will be 
applied. To this end, the three single hypotheses that the mean difference in the QTcF change 
from baseline between moxifloxacin and placebo is less than or equal to 5 msec at a given 
time point (out of the three time points 2, 3, and 4 hours after drug administration) will be 
tested based on the results of the MMRM (fitted to the data for all time points). If the largest 
of the three p-values is less than 5% (=α), then all single hypotheses can be rejected. If the 
second largest p-value is less than 2.5% (=α/2), then the corresponding null hypothesis and 
the one regarding the test with the lowest p-value can be rejected. If the lowest p-value is less 
than 1.667% (=α/3), then only the null hypothesis corresponding to this p-value can be 
rejected. Note that it is sufficient to reject only one of the three single null hypotheses in 
order to reject the overall null hypothesis stated in CTP Section 7.2 (i.e., the intersection of 
the three single hypotheses), and hence to show assay sensitivity.
7.5.2.2
Analyses of the heart rate
For each dose of BI 409306, the HR changes from baseline at each time point between 
20 min to 24 hours after dosing will be analysed by applying the same model as in the 
primary analyses and calculating the corresponding 90 % CIs for the mean difference 
between BI 409306 and placebo. For these analyses, only the HR data from the respective 
BI 409306 dose and placebo will be used. 


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
CTP Section 7.3: The TS will be used for all other safety summaries and all safety listings.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
Unless otherwise specified, the analyses of adverse events 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 eCRF will be collapsed into an 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 at most 1 hour after the first
occurrence ended).
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (5) and "Handling of missing and incomplete AE 
dates" (3). 


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The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to screening, on-treatment or follow-up phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
In addition to the presentation of AEs in separate study periods, both the events in the two 
placebo periods, and the events of the two periods of (the different doses of) BI 409306 (see 
Section 6.1) will be added. The interpretation of this summary for “Total BI” is “events 
following a dose of at least the therapeutic dose level”. When comparing “Total Pbo” and 
“Total BI”, “time under risk” is similar.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (6) and for the class of 
AESIs.
CTP Section 5.2.2.1: The following is considered as AESI:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
o
an elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) ≥3-fold 
ULN combined with an elevation of total bilirubin ≥2-fold ULN measured in the same 
blood sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
According to ICH E3 (6), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting.
The frequency of subjects with adverse events will be summarised by treatment, primary 
system organ class and preferred term. Separate tables will be provided for subjects with 
other significant adverse events according to ICH E3 (6), for subjects with AESIs and for 
subjects with serious adverse events. The frequency of subjects with AEs and the frequency 
of subjects with AEs considered by the investigator to be drug related will also be 
summarised by maximum intensity, primary SOC and preferred term.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.


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For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
CTP: Laboratory data will be listed only. Values outside the reference range as well as 
values defined as clinically relevant will be flagged. Refer to the BI reference document 
"Display and Analysis of Laboratory Data” (7).
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
The statistical analyses of ECG endpoints selected as primary, secondary or further endpoints 
(see Sections 5.1, 5.2 and 5.3) are described in the respective sections of this TSAP (see 
Section 7.4, 7.5 and 7.6).
CTP Section 5.2.4.5: ECG data from continuous 3-lead ECG recording will not be 
transferred to the clinical trial database.
CTP Section 5.2.4.6: Abnormal findings from safety 12-lead single ECGs, Holter recordings 
or 3-lead continuous ECG monitoring, irrespective of whether they originate from central or 
local evaluation, will be reported as AEs (during the trial) or recorded in the subject’s 
medical history (at screening) if judged clinically relevant by the investigator.
Listing of individual ECG data
The listings of individual ECG data will be based on the treated set.
For all quantitative and qualitative endpoints, listings of individual data will be shown in 
Appendix 16.2. Occurrences of notable findings will be flagged.
For all subjects with any notable finding of quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in Appendix 
16.2) and the corresponding time profiles will be shown.
Comments regarding the ECGs will be listed.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized 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-40-413_1.0: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3.
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; KMED
4.
001-MCS-36-472: “Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics”, current version, Group “Biostatistics & Data
Sciences”, IDEA for CON.
5.
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data 
from Clinical Trials", current version; KMED 
6.
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
7.
KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED
8.
Guidance for industry: E14 clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs. Rockville: U.S. Department of 
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER), Center for Biologics Evaluation and Research (CBER); 2005.
[R07-4722]
9.
Guidance for industry: E14 clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs - questions and answers (R3) (June 
2017, ICH, revision 2). https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/documen t/ucm073161.pdf (access date: 14 August 2017) ; U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER); 2017. [R17-2903]
10. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 75 (4), 800 - 802 (1988) [R97-1003]
11. Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R, Stockbridge N, Tornoe 
CW, Wang Y, Zhu H, Gobburu JV Concentration-QT relationships play a key role in the 
evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol 48, 13 - 18 
(2008) [R08-0437]
12. Schall R, Ring A. Statistical characterization of QT prolongation. J Biopharm Stat 20 (3), 
543 - 562 (2010) [R10-2954]
13. Kenward MG, Roger JH. The use of baseline covariates in crossover studies. 
Biostatistics 11 (1), 1 - 17 (2010) [R10-4391]
14. Schall R, Ring A. Mixed models for data from thorough QT studies: part 1. Assessment 
of marginal QT prolongation. Pharm Stat, (2010) [R10-5353]


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15. Ring A, Walter B, Larbalestier A, Chanter D. An efficient crossover design for thorough 
QT studies. GMS Med Inform Biometr Epidemiol 2010; 6(1):Doc05. [R12-0517]
16. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokin Pharmacodyn (2017) [R18-0143]


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9.1
DERIVATION OF HR AND QTC INTERVAL ENDPOINTS
CTP Section 7.3: For the analysis of the ECG variables QT, RR, PR, and QRS, a 2-step 
averaging procedure will be performed. In the first step, the 4 cardiac cycles per 10-second 
ECG will be averaged. 
For each 10-second ECG, heart rate will then be derived from the calculated RR value as
HR[beats/min]=60000/RR[msec].
Likewise, for each ECG the heart rate corrected QT intervals QTcF and QTcI will be derived 
from the mean values of the 4 cardiac cycles for RR and QT, respectively (see Section 7.6.3).
In the second step, for obtaining one ECG variable value per subject per time point, the 
calculated values of the three 10-second ECGs (triplicate ECGs extracted from the Holter 
recordings) will be averaged. 
For all quantitative ECG variables derived from the 10-second ECGs, further analyses are 
then performed on these aggregated data on time point level. Period baseline values are 
calculated as the means of the values derived for the 3 baseline time points per period.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
18-NOV-19
 
None
This is the final TSAP