Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 40
Healthy volunteers: no

Brief summary:
The main objective of this trail is to investigate if and to what extent BI 409306, BI 425809 and lamotrigine attenuate ketamine induced cognitive deficits.

Detailed description:

Arms:
arm 1: Treatments:

T1: Lamotrigine T2: BI 409306 T3: BI 425809 R: Placebo arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None arm 11: None arm 12: None arm 13: None arm 14: None arm 15: None arm 16: None arm 17: None arm 18: None

Interventions: intervention 1: Lamotrigine intervention 2: BI 409306 intervention 3: Placebo intervention 4: BI 425809
Intervention descriptions: intervention 1: Tablet intervention 2: Film-coated tablet intervention 3: Tablet, Film-coated tablet intervention 4: Film-coated tablet

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26985010-03
BI Trial No.
1289-0057
BI Investigational
Medicinal Products
BI 409306, BI 425809
Title
A randomized, placebo controlled, double-blind, double-dummy three-
way cross over trial to investigate the effect of BI 409306, BI 425809
and lamotrigine on ketamine-induced cognitive deficits in healthy male 
subjects
Lay Title
A study in healthy men to test whether BI 409306, BI 425809 or 
lamotrigine can reverse the memory problems caused by ketamine
Clinical Phase
I
Clinical Trial Lead
Phone: 
Fax: 
Principal Investigators
1.
Phone/Fax:
2.
Phone/Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 12 November 2021
Page 1 of 133
Proprietary confidential information
© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
30 January 2020
Revision date
12 November 2021
BI trial number
1289-0057
Title of trial
A randomized, placebo controlled, double-blind, double-dummy three-way cross 
over trial to investigate the effect of BI 409306, BI 425809 and lamotrigine on 
ketamine-induced cognitive deficits in healthy male volunteers
Principal Investigators
1.
2.
Trial sites
1.
      
      
      
2.
      
      
Clinical phase
I
Trial rationale
To investigate the effect of BI 409306 (a PDE 9 inhibitor in clinical development) 
and BI 425809 (a GlyT1 inhibitor in clinical development) on ketamine-induced 
cognitive deficits. Lamotrigine that has been reported to attenuate ketamine-induced 
cognitive deficits will be used as a technical control.
Trial objective
To investigate if and to what extent BI 409306, BI 425809 and lamotrigine 
attenuate ketamine induced cognitive deficits
Trial design
Randomized, placebo controlled, double-blind, double-dummy, three-way cross 
over trial
Trial endpoints
Primary endpoint: 

PAL Total Errors Adjusted (PALTEA28) on ketamine
Secondary endpoints:

SWM Between Errors (SWMBE468) on ketamine

RVP A’ Prime (RVPA) on ketamine
Number of subjects 
total entered
N = 36
each treatment
N = 36 (placebo; R) 
N = 24 (each active treatment; T1, T2 and T3)


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Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, 
Age of 18 to 55 years (inclusive), 
Body mass index (BMI) of 18.5 to 32 kg/m2 (inclusive), 
CYP2C19 non-poor metabolizers, 
Normative performance within 2 SD (compared against an age matched sample) on 
CANTAB PALTEA28 at screening V1 and V2 (pre-ketamine),
Ketamine-responders (defined as ≥ 10 errors change on CANTAB PALTEA28 
from baseline (pre-ketamine) to ketamine challenge (on ketamine) at screening V2
Test product 1
Lamotrigine,
100 mg tablets
Dose
300 mg 
Mode of admin.
Oral with 240 mL of water after a light snack
Test product 2
BI 409306, 
 tablets 
Dose
 
Mode of admin.
Oral with 240 mL of water after a light snack
Test product 3
BI 425809, 
 tablets 
Dose
 
Mode of admin.
Oral with 240 mL of water after a light breakfast
Reference product 1
Matching placebo to lamotrigine
Dose
NA
Mode of admin.
Oral with 240 mL of water after a light snack
Reference product 2
Matching placebo to 
 BI 409306 tablets 
Dose
NA
Mode of admin.
Oral with 240 mL of water after a light snack
Reference product 3
Matching placebo to 
 BI 425809 tablets 
Dose
NA
Mode of admin.
Oral with 240 mL of water after a light breakfast
Challenge agent
Ketamine hydrochloride,
, 500 mg/10 ml
Dose
0.26 mg/kg over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 
89 min (reduced by 10% (or 0.00073 mg/kg/min) every 15 min)
Mode of admin.
Intravenous 1-minute bolus followed by an intravenous infusion over 89 minutes


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Duration of treatment
Screening: 
SCR KET:
Intravenous ketamine infusion (administered as a bolus of 0.26 mg/kg over 1 
min, followed by continuous infusion of 0.0073 mg/kg/min over 89 minutes
(reduced by 10% every 15 min))*
4 Treatments**:
Lamotrigine Treatment (T1) = Ketamine + 300 mg Lamotrigine + Placebo to BI 
409306 + Placebo to BI 425809:
Day 1 of Period 1 or 2 or 3
o
Single dose of 300 mg lamotrigine, 2h prior to ketamine infusion
o
Single dose of placebo to 
 BI 409306, 2h prior to ketamine infusion
o
Single dose of placebo to 
 BI 425809, 5h prior to ketamine infusion
o
Intravenous ketamine infusion (administered as a bolus of 0.26 mg/kg 
over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 
89 min (reduced by 10% every 15 min))*
BI 409306 
 Treatment (T2) = Ketamine + Placebo to Lamotrigine + 
 
BI 409306 + Placebo to BI 425809:
Day 1 of Period 1 or 2 or 3
o
Single dose of placebo to lamotrigine, 2h prior to ketamine infusion
o
Single dose of 
 BI 409306, 2h prior to ketamine infusion
o
Single dose of placebo to 
 BI 425809, 5h prior to ketamine infusion
o
Intravenous ketamine infusion (administered as a bolus of 0.26 mg/kg 
over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 
89 min (reduced by 10% every 15 min))*
BI 425809 
 Treatment (T3) = Ketamine + Placebo to Lamotrigine + 
Placebo to BI 409306 + 
 BI 425809:
Day 1 of Period 1 or 2 or 3
o
Single dose of placebo to lamotrigine, 2h prior to ketamine infusion
o
Single dose of placebo to 
 BI 409306, 2h prior to ketamine infusion
o
Single dose of 
 BI 425809, 5h prior to ketamine infusion
o
Intravenous ketamine infusion (administered as a bolus of 0.26 mg/kg 
over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 
89 min (reduced by 10% every 15 min))*
Placebo Treatment (R) = Ketamine + Placebo to Lamotrigine + Placebo to BI 
409306 + Placebo to BI 425809:
Day 1 of Period 1 or 2 or 3
o
Single dose of placebo to lamotrigine, 2h prior to ketamine infusion
o
Single dose of placebo to 
 BI 409306, 2h prior to ketamine infusion
o
Single dose of placebo to 
 BI 425809, 5h prior to ketamine infusion
o
Intravenous ketamine infusion (administered as a bolus of 0.26 mg/kg 
over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 
89 min (reduced by 10% every 15 min))*
* infusion can be prolonged for a maximum of 15 min, i.e. to 105 min in total, in 
case of delays from the planned time of the assessments on ketamine, or terminated 
earlier if the planned assessments on ketamine are completed or any test drops out


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** each subject will receive R treatment and 2 of 3 randomly allocated T1 or T2 or 
T3; each treatment period is separated by a washout of at least 11 days between 
study drug administrations
Statistical methods
The differences between Lamotrigine and Placebo as well as BI 409306 and 
Placebo, and BI 425809 and Placebo will be evaluated for the primary endpoint 
based on a linear mixed effects model. The statistical model will include fixed 
effects for treatment, sequence, period and baseline values (pre and on ketamine at 
Visit 2), whereas “subject within sequence” will be included as a random effect. 
Formal hypotheses tests will not be performed, instead the adjusted mean 
differences and their 95% confidence intervals will be shown.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART A (SUMMARY)
Period
Visit
Day
Planned time (relative to
Drug administration (1) [h:min]
Approximate clock time of actual 
day [hh:min]
Event and comment
Safety laboratory26
Targeted physical examination29
DSST, MOAA/S, CADSS, SFST30
C-SSRS31
CANTAB (RVP, SWM, PAL)8,19
12-lead ECG32
Continuous ECG monitoring32
Vital signs (BP, PR, SaO2)24
AEs and concomitant therapy33
Screening6
1
-28 
to -9
Screening Examination1
x1
x1 x1,31 x1
x1
x1
2
-22
to -3
-12:00 20:005 Admission to trial site9 for  
Screening Ketamine 
Challenge2
x7
x
-21 
to -2
-2:00 06:002
x2
x2
x2
x2
-0:30 07:30
Light breakfast10
0:008 08:00
240 mL fluid intake
2:55
10:55
Light snack (clear liquid)10
3:00
11:00
240 mL fluid intake
3:25
11:25
3:36
11:36
4:20
12:20
CANTAB19,
┬
4:55
12:55
┴
x
x14
x
5:00
13:00
Start of ketamine infusion11
┬
┬25
5:06
13:06
CANTAB19,
│
│
│
│
x
┬
5:26
13:26
│
│
│
5:40
13:40
┴
│
│
│
│
x
6:00
14:00
│
│
6:20
14:20
│
│
x
6:30
14:30
Stop of ketamine infusion12
│
│
7:00
15:00
x
│
│
x
7:30
15:30
Confirmation of recovery13, 
240 mL fluid intake, 
thenafter lunch
┴
┴
x
10:00 18:00
x
x
11:00 19:00
Dinner
-20 
to -1
24:00 08:00
Breakfast (voluntary)15,
discharge from trial site16
x
x
x
x
x
x
1/2/3
3/4/5
-1
-12:00 20:005 Admission to trial site9
x7
x
1
-2:00 06:003 Allocation to treatment3
(visit 3 only)
x3
x3
x3
x3
x3
-0:30 07:30
Light breakfast10
0:00
08:00
Drug administration (1)17,
240 mL fluid intake
0:30
08:30
1:00
09:00
x
x
2:00
10:00


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. For details 
of screening procedures at Screening Examination (V1), refer to Flow Chart B.
2.
The time is approximate; the procedure is to be performed and completed before light breakfast, within 2 h prior to 
planned time 0:00. For details of screening procedures at Screening Ketamine Challenge (V2), refer to Flow Chart C.
3.
The time is approximate; the procedure is to be performed and completed before light breakfast, within 2 h prior to 
Drug administration (1). For details of procedures at each Treatment Day (V3, V4, V5), refer to Flow Chart D.
4.
End of Trial (EoT) Examination includes physical examination (incl. targeted examination), visual acuity test, C-SSRS, 
vital signs, ECG, safety laboratory, recording of AEs and concomitant therapies. For details, refer to Section 6.2.3.
2:55
10:55
Light snack (clear liquid)10
Period
Visit
Day
Planned time (relative to 
Drug administration (1) [h:min]
Approximate clock time of actual 
day [hh:min]
Event and comment
Safety laboratory26
Targeted physical examination29
DSST, MOAA/S, CADSS, SFST30
C-SSRS31
CANTAB (RVP, SWM, PAL)8,19
 
 
 
 
tamine27
12-lead ECG32
Continuous ECG monitoring32
Vital signs (BP, PR, SaO2)24
AEs and concomitant therapy33
1/2/3 (3 identical periods with a washout of at least 11 days)
3/4/5
1
3:00
11:00
Drug administration (2)18, 
240 mL fluid intake
3:25
11:25
3:36
11:36
4:00
12:00
x
x
4:20
12:20
CANTAB19,
┬
4:30
12:30
│
4:55
12:55
┴
x
x14
x
5:00
13:00
Start of ketamine infusion11
┬
┬25
5:06
13:06
CANTAB19,
│
│
│
│
x
┬
5:26
13:26
│
│
│
5:40
13:40
┴
│
│
│
│
x
6:00
14:00
│
│
6:20
14:20
│
│
x
6:30
14:30
Stop of ketamine infusion12
│
│
7:00
15:00
x
│
│
x
7:30
15:30
Confirmation of recovery13, 
240 mL fluid intake, 
thenafter lunch
┴
┴
x
8:00
16:00
9:00
17:00
10:00 18:00
x
x
x
11:00 19:00
Dinner
2
24:00 08:00
Breakfast (voluntary)15
x
x
x
27:00 11:00
Discharge from trial site16
x
x
x
x
x
x
4
Follow-Up Phone call
x
6
Follow-Up Phone call
x
9
Follow-Up Phone call
x
EoT
6
12 to 
19
End of trial (EoT) 
examination4
x
x
x
x
x
x


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5.
The time is approximate; admission is to be performed no later than 10 h prior to planned time 0:00. At discretion of the 
investigator or designee, admission on the next morning no later than 2 h prior to planned time 0:00 is possible.
6.
Screening period consists of Screening Examination (V1) and (if applicable) Screening Ketamine Challenge (V2). Only 
subjects who have already passed all applicable eligibility criteria at Screening Examination (incl. confirmation on 
CYP2C19 status, except not yet determined response to ketamine) will be invited to Screening Ketamine Challenge that 
has to be scheduled on a different day. For details regarding screening period, refer to Section 6.2.1.
7.
Only urine drug screening and alcohol breath test will be done at this time.
8.
CANTAB tests,
at Screening Ketamine Challenge have to occur time-matched to 
these assessments in each treatment period. Therefore, planned time 0:00 at Screening Ketamine Challenge (V2) should 
equal planned time 0:00 relative to Drug administration (1) on Day 1 (V3, V4 and V5). Before ketamine infusion, the 
planned time for these tests should be adhered as closely as possible. During ketamine infusion, time intervals between 
these tests should be minimized, i.e. if any test completed earlier or dropped out, the next test should start straight away.
The assessments will occur in environmentally controlled rooms, only one subject per room is allowed.
9.
SARS-CoV-2 PCR test will be performed within 72 h prior to admission to trial site. For details, refer to Appendix 10.7.
10. For details of light breakfast and light snack composition, refer to Section 4.1.4.
11. If ketamine infusion is interrupted for a technical reason, the reason to be eliminated as soon as possible, before start of 
a new test, after the ongoing test has been completed (if applicable). An interruption of maximum of 15 min for 
technical reasons is allowed. For details, refer to Section 4.1.2.
12. Ketamine infusion can be prolonged for a maximum of 15 min, i.e. to 105 min in total, in case delays from the planned 
time occur for CANTAB tests, 
; or terminated earlier, if the above assessments on 
ketamine are completed (or any test drops out) 
13. Confirmation of recovery from ketamine must be confirmed via criteria of recovery from ketamine after a minimum of 
60 min of recovery follow up. For details, refer to Section 5.2.5.6.
14. Vital signs at 5 min prior to start of ketamine infusion include recording of respiratory rate and effort, and will serve as 
baseline for confirmation of recovery from ketamine. For details, refer to Section 5.2.5.6
15. If several actions are indicated at the same time point, the intake of meal will be the last action.
16. Discharge after assessment of fitness by the investigator or designee.
17. Drug administration (1) at planned time 0:00: BI 425809 or Placebo to BI 425809. For details, refer to Section 4.1.4.
18. Drug administration (2) at planned time 3:00: BI 409306 + Placebo to Lamotrigine, or Lamotrigine + Placebo to BI 
409306, or Placebo to BI 409306 + Placebo to Lamotrigine. For details, refer to Section 4.1.4.
19. The selected tests from the CANTAB test battery will be done with a 4 min break in between each test in the following 
sequence: Rapid Visual Information Processing (RVP), Spatial Working Memory (SWM), Paired Associates 
Learning (PAL). For details, refer to Section 5.4.1.
24. For details of vital signs evaluation, refer to Section 5.2.2, Flow Chart C and Flow Chart D.
25. From start of ketamine infusion until confirmation of recovery from ketamine, oxygen saturation (SaO2) will be 
monitored continuously. For other details of vital signs recording, refer to Flow Chart C and Flow Chart D.
26. For details of safety laboratory evaluation, refer to Section 5.2.3.
29. Targeted physical examination includes skin inspection for signs of rash, check for lymphadenopathy and neurological 
examination (mental status, motor examination, reflexes, sensory, gait and cranial nerves).
30. For details of DSST, MOAA/S, CADSS and SFST, refer to Section 5.2.5.5 and Appendices 10.3, 10.4, 10.5 and 10.6.
31. C-SSRS will be administered at Screening Examination (V1) using the ‘screening/baseline’ version. After Screening 
Examination, the assessment ‘since last visit’ will be performed at each time point as per the Flow Chart above. For 
details, refer to Section 5.2.6.1.7 and Appendix 10.2.
32. For details of 12-lead ECG and Continuous ECG monitoring, refer to Section 5.2.4.


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33. 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.


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FLOW CHART B (SCREENING EXAMINATION)
Day -28 to -9 (Visit 1)
Planned time
[h:min] 
Approximate 
clock time 
[hh:min]
Event(s)
Comment(s)
Informed Consent
Subject must be informed and written informed consent 
obtained prior to starting any screening procedures
Demographics
Medical History
Smoking and Alcohol History
Concomitant Medications
Questioning for COVID-19
Body Temperature
Body Height and Weight
Physical Examination
Vital Signs
BP and PR incl. orthostatic testing, SaO2
DSST, MOAA/S, CADSS, SFST
C-SSRS ‘screening/baseline’
Review Inclusion Exclusion Criteria
If subject remains eligible based on above assessments, 
proceed with additional testing indicated below.
Visual Acuity Test
For details, refer to Section 5.2.5.4.
12-lead ECG
CANTAB RVP
CANTAB SWM
CANTAB PAL
In the end of PAL, eligibility results will be displayed 
Review Inclusion Exclusion Criteria
If subject remains eligible based on above assessments, 
proceed with additional testing indicated below.
Drug and Tobacco Screening (urine)
Safety Laboratory (blood, urine)
Hematology, Biochemistry, Hormones, Coagulation,
Urinalysis, Infectious Serology
SARS CoV-2 PCR Test (nasal swab sample)
PGx sampling for CYP2C19 (blood)
For details, refer to Section 5.6.1.
Review Inclusion Exclusion Criteria
(after results of Safety Laboratory, SARS 
CoV-2 PCR test and confirmation of 
CYP2C19 status are available)
If subject remains eligible based on above assessments,
invite to Screening Ketamine Challenge (V2) that will 
be scheduled on a different day.


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FLOW CHART C (SCREENING KETAMINE CHALLENGE)
Day -21 to -2 (Visit 2)
Planned time*
[h:min] 
Approximate 
clock time 
[hh:min]
Event(s)
Comment(s)
-12:001
20:001
Admission to trial site2
Questioning for AEs and concomitant therapy
Questioning for COVID-19
Body Temperature
Drug Screening (urine)
Alcohol Breath Test
1 The time is approximate; admission is to be 
performed no later than 10 h prior to planned time 
0:00. At discretion of the investigator or designee, 
admission on the next morning no later than 2 h 
prior to planned time 0:00 is possible.
2 SARS-CoV-2 PCR test will be performed shortly 
(within 72 h) prior to admission
-2:001
06:001
Questioning for AEs and concomitant 
therapyC-SSRS ‘since last visit’
Targeted Physical Examination2
Vital Signs (BP, PR, SaO2)
12-lead ECG
1 the time is approximate; the procedures are to be 
performed and completed before light breakfast, 
within 2 h prior to PT 0:00
2 incl. skin inspection for signs of rash, check for 
lymphadenopathy and neurological examination
-0:30
07:30
Light breakfast
0:00
08:00
240 mL fluid intake
2:55
10:55
Light snack (clear liquid)
3:00
11:00
240 mL fluid intake
3:25
11:25
11:35
1 min break
3:36
11:36
11:49
1 min break
11:50
11:55
12:00
1 min break
12:01
12:12
1 min break
12:13
12:19
1 min break
4:20
12:20
CANTAB RVP
12:27
12:31
CANTAB SWM
12:37
12:41
CANTAB PAL
Review In-/ Exclusion Criteria
in the end of PAL, eligibility results will be displayed
12:53
2 min break
4:55
12:55
Questioning for AEs
Vital Signs (BP, PR, SaO2 +Resp.Rate/Effort)
12-lead ECG
instructing study subjects before ketamine infusion;
4:59
12:59
5:001
13:001
Start of ketamine infusion1
Start of continuous ECG and SaO2 monitoring
1 if ketamine infusion is interrupted for a technical 
reason, the reason to be eliminated as soon as 
possible, before start of a new test, after the ongoing 
test has been completed (if applicable)
13:03
Questioning for AEs1
 right 
before CANTAB RVP


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* planned time 0:00 at Screening Ketamine Challenge (V2) should equal planned time 0:00 relative to Drug administration
(1) on Day 1 (V3, V4 and V5).
Vital Signs (BP, PR, SaO2)1
5:06
13:06
CANTAB RVP
13:13
Vital Signs (BP, PR, SaO2)1
 right 
before CANTAB SWM
13:17
CANTAB SWM
13:23
Vital Signs (BP, PR, SaO2)1
PK blood (ketamine)1
 right 
before CANTAB PAL
13:27
CANTAB PAL 
Review In-/ Exclusion Criteria
in the end of PAL, eligibility results will be displayed
13:39
Questioning for AEs
Vital Signs (BP, PR, SaO2) 
5:40
13:40
13:53
Vital Signs (BP, PR, SaO2)
13:54
13:57
14:00
Vital Signs (BP, PR, SaO2)
14:01
14:12
Vital Signs (BP, PR, SaO2)
14:13
14:19
Questioning for AEs
6:20
14:20
6:301
14:301
Vital signs (BP, PR, SaO2)
Stop of ketamine infusion1
Stop of continuous ECG and SaO2 monitoring
1 can be prolonged for a maximum of 15 min, in case 
delays from PT occur for CANTAB, 
 
 or terminated earlier, if the above tests are 
completed (or any test drops out)
6:45
14:45
Vital Signs (BP, PR, SaO2)
7:00
15:00
Questioning for AEs
Vital Signs (BP, PR, SaO2)
12-lead ECG
7:15
15:15
Vital Signs (BP, PR, SaO2)
7:301
15:301
Questioning for AEs
Vital Signs (BP, PR, SaO2)
Confirmation of recovery from ketamine2,3
240 mL fluid intake
1 a minimum of 60 min of recovery follow up
2 as per Criteria of recovery from ketamine 
3 lunch will be served after confirmation of recovery
10:00
18:00
Questioning for AEs
Vital Signs (BP, PR)
dinner will be served in the evening
24:001
08:001
Questioning for AEs
Vital Signs (BP, PR)
12-lead ECG
C-SSRS ‘since last visit’
DSST, MOAA/S, CADSS, SFST
Targeted Physical Examination2
Discharge from trial site3,4
1 Day -20 to -1 at V2. The time is approximate; the 
procedures to be performed and completed ± 2 h.
2 incl. skin inspection for signs of rash, check for 
lymphadenopathy and neurological examination
3 after confirmation of fitness by the investigator
4 breakfast will be served before discharge


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FLOW CHART D (TREATMENT KETAMINE CHALLENGE)
Day 1 of each Treatment Period (Visits 3, 4 and 5)
Planned time*
[h:min] 
Approximate 
clock time 
[hh:min]
Event(s)
Comment(s)
-12:001
20:001
Admission to trial site1,2
Questioning for AEs and concomitant therapy
Questioning for COVID-19
Body Temperature
Drug Screening (urine)
Alcohol Breath Test
1 Day -1 at V3, V4 and V5. The time is approximate; 
admission is to be performed no later than 10 h prior 
to first study drug administration. At discretion of 
the investigator or designee, admission in the 
morning of Day 1 no later than 2 h prior to planned 
time 0:00 is possible.
2 SARS-CoV-2 PCR test will be performed shortly 
(within 72 h) prior to admission
-2:001
06:001
Allocation to treatment (only at V3)
Questioning for AEs
C-SSRS ‘since last visit’
Targeted Physical Examination2
Vital Signs (BP, PR, SaO2)
12-lead ECG
1 the time is approximate; the procedures are to be 
performed and completed before light breakfast, 
within 2 h prior to first study drug administration
2 incl. skin inspection for signs of rash, check for 
lymphadenopathy and neurological examination
-0:30
07:30
Light breakfast
0:00
08:00
Drug administration (1)1
240 mL fluid intake
1 BI 425809 or Placebo to BI 425809
1:00
09:00
Questioning for AEs
Vital Signs (BP, PR)
P
2:00
10:00
2:55
10:55
Light snack (clear liquid)
3:00
11:00
Drug administration (2)1
240 mL fluid intake
1 BI 409306 + Placebo to Lamotrigine, or
Lamotrigine + Placebo to BI 409306, or
Placebo to BI 409306 + Placebo to Lamotrigine
3:25
11:25
11:35
1 min break
3:36
11:36
11:49
1 min break
11:50
12:00
Questioning for AEs
Vital Signs (BP, PR)
12:01
 
12:12
1 min break
12:13
 
12:19
1 min break
4:20
12:20
CANTAB RVP 
12:27
 
12:31
CANTAB SWM
12:37


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12:41
CANTAB PAL
12:53
2 min break
4:55
12:55
Questioning for AEs
Vital Signs (BP, PR, SaO2 +Resp.Rate/Effort)
12-lead ECG
instructing study subjects before ketamine infusion;
4:59
12:59
5:001
13:001
Start of ketamine infusion1
Start of continuous ECG and SaO2 monitoring
1 if ketamine infusion is interrupted for a technical 
reason, the reason to be eliminated as soon as 
possible, before start of a new test, after the ongoing 
test has been completed (if applicable)
13:03
Questioning for AEs1
Vital Signs (BP, PR, SaO2)1
1
, right 
before CANTAB RVP
5:06
13:06
CANTAB RVP
13:13
Vital Signs (BP, PR, SaO2)1
, right 
before CANTAB SWM
13:17
CANTAB SWM
13:23
Vital Signs (BP, PR, SaO2)1
, right 
before CANTAB PAL
13:27
CANTAB PAL
13:39
Questioning for AEs
Vital Signs (BP, PR, SaO2)
5:40
13:40
13:53
Vital Signs (BP, PR, SaO2)
13:54
13:57
14:00
Vital Signs (BP, PR, SaO2)
14:01
14:12
Vital Signs (BP, PR, SaO2)
14:13
14:19
Questioning for AEs
Vital Signs (BP, PR, SaO2)
6:20
14:20
6:301
14:301
Vital signs (BP, PR, SaO2)
Stop of ketamine infusion1
Stop of continuous ECG and SaO2 monitoring
1 can be prolonged for a maximum of 15 min, in case 
delays from PT occur for CANTAB, 
 
 or terminated earlier, if the above tests are 
completed (or any test drops out)
6:45
14:45
Vital Signs (BP, PR, SaO2)
7:00
15:00
Questioning for AEs
Vital Signs (BP, PR, SaO2)
12-lead ECG
7:15
15:15
Vital Signs (BP, PR, SaO2)
7:301
15:301
Questioning for AEs
Vital Signs (BP, PR, SaO2)
Confirmation of recovery from ketamine2,3
240 mL fluid intake
1 a minimum of 60 min of recovery follow up
2 as per criteria of recovery from ketamine 
3 lunch will be served after confirmation of recovery
8:00
16:00
9:00
17:00


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* planned time relative to Drug administration (1) on Day 1 (V3, V4 and V5).
10:00
18:00
Questioning for AEs
Vital Signs (BP, PR)
12-lead ECG
dinner will be served in the evening
24:001
08:001
Questioning for AEs
Vital Signs
12-lead ECG
Safety Laboratory (blood, urine)2,3
1 Day 2 at V3, V4 and V5. The time is approximate; 
the procedures to be performed and completed ± 2 h.
2 Hematology, Biochemistry, Coagulation,
Urinalysis
3 breakfast will be served after blood sampling
27:001
11:001
Questioning for AEs
Vital Signs
C-SSRS ‘since last visit’
DSST, MOAA/S, CADSS, SFST
Targeted Physical Examination2
Discharge from trial site3
1 time is approximate; the procedures to be performed 
and completed within 2 h prior to discharge
2 incl. skin inspection for signs of rash, check for 
lymphadenopathy and neurological examination
3 after confirmation of fitness by the investigator, and 
at least 24h after the last study drug administration


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART A (SUMMARY)......................................................................6
FLOW CHART B (SCREENING EXAMINATION).................................. 10
FLOW CHART C (SCREENING KETAMINE CHALLENGE) .............. 11
FLOW CHART D (TREATMENT KETAMINE CHALLENGE) ............ 13
TABLE OF CONTENTS ................................................................................ 16
ABBREVIATIONS.......................................................................................... 21
1.
INTRODUCTION.................................................................................... 24
1.1
MEDICAL BACKGROUND............................................................................24
1.2
DRUG PROFILE...............................................................................................25
1.2.3
Lamotrigine ...........................................................................................33
1.2.3.1
Clinical pharmacokinetics........................................................34
1.2.3.2
Clinical experience in humans.................................................35
1.2.4
Ketamine................................................................................................38
1.2.4.1
Use of ketamine as a challenge agent ......................................39
1.2.4.2
Clinical pharmacokinetics........................................................41
1.2.4.3
Clinical safety ..........................................................................41
1.2.5
Residual Effect Period..........................................................................42
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................42
1.4
BENEFIT - RISK ASSESSMENT ...................................................................43
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 47
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......47
2.1.1
Main objectives......................................................................................47
2.1.2
Primary endpoint..................................................................................47
2.1.3
Secondary endpoints.............................................................................47


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2.2.2.3
Safety and tolerability..............................................................48
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 49
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................49
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................50
3.3
SELECTION OF TRIAL POPULATION ......................................................50
3.3.1
Main diagnosis for trial entry..............................................................51
3.3.2
Inclusion criteria...................................................................................51
3.3.3
Exclusion criteria ..................................................................................52
3.3.4
Withdrawal of subjects from treatment or assessments ...................53
3.3.4.1
Discontinuation of trial treatment............................................54
3.3.4.2
Withdrawal of consent to trial participation ............................55
3.3.4.3
Discontinuation of the trial by the sponsor..............................55
3.3.5
Replacement of subjects .......................................................................55
4.
TREATMENTS........................................................................................ 56
4.1
INVESTIGATIONAL TREATMENTS ..........................................................56
4.1.1
Identity of the Investigational Medicinal Products ...........................56
4.1.2
Selection of doses in the trial and dose modifications........................58
4.1.3
Method of assigning subjects to treatment groups ............................60
4.1.4
Drug assignment and administration of doses for each subject .......60
4.1.5
Blinding and procedures for unblinding ............................................62
4.1.6
Packaging, labelling, and re-supply ....................................................63
4.1.6.1
BI 409306, BI 425809, placebo to BI 409306, placebo to 
425809, placebo to Lamotrigine ..............................................63
4.1.6.2
Lamotrigine, Ketamine ............................................................63
4.1.7
Storage conditions.................................................................................64
4.1.8
Drug accountability ..............................................................................64
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................64
4.2.1
Other treatments and emergency procedures....................................64
4.2.2
Restrictions............................................................................................65
4.2.2.1
Restrictions regarding concomitant treatment .........................65
4.2.2.2
Restrictions on diet and life style.............................................66
4.3
TREATMENT COMPLIANCE.......................................................................67
5.
ASSESSMENTS....................................................................................... 68
5.1
ASSESSMENT OF EFFICACY.......................................................................68
5.2
ASSESSMENT OF SAFETY............................................................................68


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5.2.1
Physical examination, incl. targeted examination..............................68
5.2.2
Vital signs...............................................................................................68
5.2.3
Safety laboratory parameters..............................................................69
5.2.4
Electrocardiography.............................................................................72
5.2.4.1
12-lead ECG.............................................................................72
5.2.4.2
Continuous ECG monitoring ...................................................73
5.2.5
Other safety parameters.......................................................................73
5.2.5.2
Suicidality monitoring .............................................................73
5.2.5.4
Visual acuity test (near visual acuity)......................................75
5.2.5.5
Safety tests (DSST, MOAA/S, CADSS and SFST) ................75
Digit Symbol Substitution Test (DSST)....................75
Modified Observer's Assessment of 
Alertness/Sedation (MOAA/S)..................................75
Clinician Administered Dissociative States Scale 
(CADSS)....................................................................75
Standardized Field Sobriety Test (SFST)..................76
5.2.5.6
Criteria of recovery from ketamine..........................................76
5.2.6
Assessment of adverse events...............................................................76
5.2.6.1
Definitions of adverse events...................................................76
Adverse event ............................................................76
Serious adverse event ................................................77
AEs considered ‘Always Serious’.............................77
Adverse events of special interest .............................78
Intensity (severity) of AEs.........................................78
Causal relationship of AEs ........................................78
Suicidality assessment...............................................79
5.2.6.2
Adverse event collection and reporting ...................................80
AE collection.............................................................80
AE reporting to the sponsor and timelines ................81
Information required..................................................81


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5.4
ASSESSMENT OF BIOMARKERS................................................................84
5.4.1
Cambridge Neuropsychological Test Automated Battery 
(CANTAB).............................................................................................84
5.4.1.1
Paired Associates Learning (PAL)...........................................85
5.4.1.2
Spatial Working Memory (SWM) ...........................................85
5.4.1.3
Rapid Visual Information Processing (RVP)...........................86
5.5
BIOBANKING ...................................................................................................88
5.6
OTHER ASSESSMENTS .................................................................................88
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................89
6.
INVESTIGATIONAL PLAN.................................................................. 90
6.1
VISIT SCHEDULE............................................................................................90
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................91
6.2.1
Screening period....................................................................................91
6.2.2
Treatment periods.................................................................................92
6.2.3
Follow-up period and trial completion ...............................................93
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 94
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................94
7.2
PLANNED ANALYSES....................................................................................94
7.2.1
General considerations.........................................................................94
7.2.2
Primary endpoint analyses...................................................................95
7.2.3
Secondary endpoint analyses ...............................................................95
7.2.5
Safety analyses.......................................................................................95
7.2.6
Interim analyses ....................................................................................96
7.3
HANDLING OF MISSING DATA ..................................................................96
7.4
RANDOMISATION ..........................................................................................96
7.5
DETERMINATION OF SAMPLE SIZE ........................................................96
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 98
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................98
8.2
DATA QUALITY ASSURANCE .....................................................................99


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8.3
RECORDS..........................................................................................................99
8.3.1
Source documents .................................................................................99
8.3.2
Direct access to source data and documents.....................................100
8.3.3
Storage period of records...................................................................100
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ...............................100
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.....100
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .............................................................................101
8.6
TRIAL MILESTONES ...................................................................................101
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ................................101
9.
REFERENCES....................................................................................... 103
9.1
PUBLISHED REFERENCES.........................................................................103
9.2
UNPUBLISHED REFERENCES...................................................................108
10. APPENDICES ........................................................................................ 110
10.2
COLUMBIA-SUICIDE SEVERITY RATING SCALE ..............................113
10.3
DIGIT SYMBOL SUBSTITUTION TEST (DSST)......................................119
10.4
MODIFIED OBSERVER'S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) ..........................................................120
10.5
CLINICIAN ADMINISTERED DISSOCIATIVE STATES SCALE 
(CADSS)............................................................................................................121
10.6
STANDARDIZED FIELD SOBRIETY TEST (SFST) ................................126
10.7
SARS-COV-2/ COVID-19 RELATED BENEFIT-RISK ASSESSMENT 
AND RISK MITIGATION MEASURES ......................................................128
10.7.1 Introduction.........................................................................................128
10.7.2 Benefit-Risk Assessment in Context of COVID-19 Pandemic........128
10.7.3 Risk Mitigation Measures in Context of COVID-19 Pandemic......129
10.7.3.1 Screening Period....................................................................129
10.7.3.2 Treatment Periods..................................................................130
10.7.4 Assessment of Adverse Events related to COVID-19......................130
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 131
11.1
GLOBAL AMENDMENT 1 ...........................................................................131
11.2
GLOBAL AMENDMENT 2 ...........................................................................133


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ABBREVIATIONS
AD
Alzheimer disease
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine transaminase
APS
Attenuated Psychosis Syndrome
AST
Aspartate transaminase
 
 
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CADSS
Clinician Administered Dissociative States Scale
CANTAB
Cambridge Neuropsychological Test Automated Battery
cAMP
Cyclic adenosine monophosphate
cGMP
Cyclic guanosine monophosphate
CI
Confidence interval
CIAS
Cognitive impairment in schizophrenia
 
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
C-SSRS
Columbia Suicidal Severity Rating scale
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
DDI
Drug drug interaction
DILI
Drug induced liver injury
DRESS
Drug reaction with eosinophilia and systemic symptoms
DSST
Digit Symbol Substitution Test
ECG
Electrocardiography


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eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoT
End of trial
ERP
Event-Related Potential
ET
Eye tracking
FEP
First episode of psychosis
FU
Follow-up
GCP
Good Clinical Practice
GlyT1
Glycine transporter 1
HLH
Hemophagocytic Lymphohistiocytosis
HR
Heart rate
HV
Hyperventilation
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IQRMP
Integrated Quality and Risk Management Plan 
IRB
Institutional Review Board
ISF
Investigator site file
i.v.
Intravenous
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LTP
Long term potentiation
MOAA/S
Modified Observer's Assessment of Alertness/Sedation
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MMN
Mismatch-Negativity
NMDA
N-methyl-D-aspartate
NMDAR
N-methyl-D-aspartate receptor
PAL
Paired Associates Learning
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PDE9
Phosphodiesterase-9
P-gp
P-glycoprotein
PM
Poor metaboliser


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PR
Pulse rate
qd
Quaque die, once daily
qPCR
Quantitative polymerase chain reaction
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
Rmax
Maximum rate of urinary excretion
RVP
Rapid Visual Information Processing
SAE
SaO2
Serious adverse event
Oxygen saturation
SCR
Screening
SD
Standard deviation
SFST
Standardized Field Sobriety Test
SOA
Stimulus onset asynchrony
SOP
Standard operating procedure
SPL
Sound pressure level
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected unexpected serious adverse reaction
SWM
Spatial Working Memory
T
Test product or treatment
TMF
Trial master file
 
 
TSAP
Trial statistical analysis plan
WHO
World Health Organization
XTC
Ecstasy 


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1.
INTRODUCTION
BI 409306 is a 
that is being developed for relapse 
prevention in patients 
), and for the prevention of 
) in subjects with 
.
BI 425809 is a 
 under development for treatment of 
 in adult patients 
 also referred to as 
 
1.1
MEDICAL BACKGROUND
 is a chronic, severe, and disabling brain disorder affecting both men and
women. For the majority of patients, the 
 and
 symptoms of 
 preceded
by many months and years. In the course of the 
, most patients experience 
multiple relapses, which are characterized by 
 has been 
shown to be a major determinant of poor functional outcome [R14-3766]. The c
 
i
 seen in 
tend to be severe, leading to functional disability for life, 
and there is no pharmacological treatment of 
. Existing treatment options for 
) are primarily efficacious in 
treating 
 and have limited, if any, efficacy for the prevention o
 
No pharmacologic therapies have been approved to delay or 
prevent a first
, and none are indicated for the symptomatic treatment of 
the 
 seen in patients 
is characterized by abnormalitie
[R13-4521]. These abnormalities are hypothesized to lead to
activation triggers a cascade 
of intracellular, 
 through elevation of 
 
 and 
 
 and manifestation of
 
 
 [R10-5092], [R10-5102].
with the highest affinity of 
 and is highly 
. Therefore, it is likely to be a significant determinant of
intracellular 
. In addition, increasing evidence
suggests that 
 may play a key role in 
 individuals with 
 [R15-3327], [R15-1457].
 may be a proximal cause of
 seen in those who 
presumably via 
 [R15-1457].
Consequently, 
 should restore 
 and thus 
 and translate into 
 via strengthening of 
. Moreover, based on mode-of-action and on preclinical 


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data in a 
 model, 
 also represents a rational
approach for improvement and potentially normalization of those 
leading to the 
 even 
[c01694347][n00270327].
 properties of BI 409306 have been demonstrated in 
 
 and signal of clinical 
 
Treatment with BI 409306 is expected to
 
in subjects 
 and to reduce the 
.
 aims at improving 
 in patients with 
 
thereby leading to improvement of
 
Results from preclinical studies with BI 425809 demonstrated 
. Currently in Phase 
, treatment with BI 425809 resulted in 
in patients 
1.2
DRUG PROFILE


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1.2.3
Lamotrigine
Lamotrigine is approved for epilepsy and bipolar disorders [R19-0416] and was first brought
into clinical practice in Europe in 1990 [R19-0502]. The exact mechanism by which 
lamotrigine exerts its anticonvulsant action as well as its therapeutic action in bipolar 
disorders have not been elucidated yet.
One proposed mechanism of its anticonvulsant action involves a use- and voltage-dependent 
blockade of neuronal sodium channels. In vitro pharmacological studies suggest that 
lamotrigine inhibits these sodium channels, thereby stabilizing neuronal membranes and 


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consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., 
glutamate and aspartate). However, its relevance to humans remains to be established 
[R20-0058].
For lamotrigine’s psychotropic effects in bipolar disorders, anti-glutamatergic and 
neuroprotective actions are considered to be important candidate mechanisms [R19-0413].
To increase tolerability lamotrigine is up-titrated up to the usual therapeutic dose of 300 –
500 mg/day [R19-0414].
1.2.3.1
Clinical pharmacokinetics
After oral administration lamotrigine is rapidly and completely absorbed with negligible first-
pass metabolism (absolute bioavailability is 98%, no food effect). Peak plasma 
concentrations occur within 1.4 to 4.8 hours following drug administration. Lamotrigine is 
marketed in different formulations, namely as a chewable/dispersible and as a compressed 
tablet. However, in terms of rate and extent of absorption the lamotrigine 
chewable/dispersible tablets were found to be equivalent, whether they were administered 
dispersed in water, chewed and swallowed, or swallowed as whole, and they were also
equivalent to the lamotrigine compressed tablets [R19-0416]. Lamotrigine exhibits linear 
kinetics in healthy volunteers over a dose range of 50 – 400 mg. In vitro data show that 
lamotrigine is not highly bound to plasma proteins (approx. 55% bound in human plasma). 
Clinically significant interactions with other drugs through competition for protein binding 
sites are unlikely. In accordance with this, no change in protein binding was observed for 
combinations of lamotrigine and phenytoin, phenobarbital, valproate or carbamazepine 
[R19-0416].
Lamotrigine is metabolized predominantly by glucuronic acid conjugation via Uridine 5´-
diphospho-glucuronyl transferases (UGT). Its major metabolite is an inactive 2-N-
glucuronide conjugate. Drugs that induce or inhibit glucuronidation may therefore affect the 
apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 
(CYP3A4) enzyme, which are also known to induce UGT may also enhance the metabolism 
of lamotrigine. For example, rifampicin, phenytoin, and phenobarbital reduce lamotrigine 
concentration by approx. 40% due to induction of lamotrigine glucuronidation. After oral 
administration of 14C-lamotrigine to healthy volunteers, 94% (10% unchanged) was 
recovered in the urine and 2% was recovered in the faeces. 
In healthy volunteers, following single doses of lamotrigine from 50 to 400 mg, elimination 
half-life (t1/2) averages 33 hours. The t1/2 decreased by an average of 26% (mean steady state 
t1/2 of 26.4 hours) following repeated dosing in healthy volunteers. In patients taking further 
anti-epileptic drugs (AED) half-life varied depending on concomitant AEDs. [R19-4225]
Some estrogen-containing oral contraceptives (e.g. levonorgestrel, ethinylestradiol) have
been shown to decrease serum concentrations of lamotrigine. The effect of lamotrigine on 
these oral contraceptives had no clinical significance.


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Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 
(OCT2) proteins which may result in increased plasma levels of certain drugs that are 
substantially excreted via this route. Co-administration of lamotrigine with OCT2 substrates 
with a narrow therapeutic index (e.g., dofetilide) is therefore not recommended.
1.2.3.2
Clinical experience in humans
Clinical experience of 300 mg lamotrigine in healthy volunteers
Single doses of 300 mg lamotrigine have previously been administered to healthy volunteers 
without any reported safety concern.

180 healthy male and female volunteers aged 18 - 55 years received a single dose of 300 
mg lamotrigine XR (single 300 mg XR tablet or 100 mg XR + 200 mg XR tablet) in an 
open-label, randomized bioequivalence and food effect study [R19-0420], [R19-0415]. 
All doses of lamotrigine XR were well tolerated in the fasted and fed states and there 
were no clinically significant safety findings. The most frequent AE were headache 
(~13%) fatigue, nasopharyngitis, flatulence, nausea, dizziness, erythema and sleep 
disorder. There was one serious adverse event (SAE) of multiple injuries, which was 
unrelated to study drug [R19-0420].

In another study LAM105377, 60 healthy male and female subjects, aged 18 - 55 years 
were exposed to 4 single doses of 300 mg lamotrigine to investigate the bioavailability of 
three, prototype, 300 mg enteric coated, modified release tablet formulations of 
lamotrigine compared to a reference formulation. Reported AEs were headache (most 
frequent), nausea and hot flush (only in one formulation). Further, petechiae and 
erythematous rash were each reported by one subject, but both of these AEs were of a 
mild intensity and neither was considered by the investigator to be related to study drug. 
There were no SAEs, deaths, or withdrawals due to AEs in study LAM105377 
[R19-0415].

SCA104648 was a placebo-controlled repeat-dose/multi-dose study to evaluate the effect 
of lamotrigine at doses up to 400 mg/day on QT/QTc interval. Adverse events in this 
study were consistent with those seen in earlier clinical pharmacology studies with 
lamotrigine (headache, dizziness, nausea) [R19-0415].

In a ketamine challenge trial done by Anand at al, healthy subjects were exposed to a 
single dose of 300 mg lamotrigine/placebo followed by an infusion of low-dose ketamine 
or placebo. In this trial, no rash has been observed after lamotrigine administration. One 
subject dropped out due to the AE nausea; however, it is not reported if this was 
considered related to lamotrigine or ketamine [R19-0417].

In two MRI trials investigating the effect of lamotrigine on ketamine induced MRI 
responses 37 subjects in total were exposed to a single dose of 300 mg lamotrigine. 
[R19-1361], [R19-1360]
Safety profile in patients


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In clinical trials in patients suffering from epilepsy the most common adverse reactions 
(incidence ≥ 5%) in adults were dizziness, headache, ataxia, coordination abnormalities, 
accidental injury, tremor, dyspepsia, nausea, vomiting, anxiety, insomnia, nystagmus, 
diplopia, blurred vision, somnolence, lymphadenopathy, sinusitis, rhinitis, pharyngitis, 
infection, pain, weight decrease, asthenia, chest pain, dysmenorrhea, pruritus and rash.
Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related.
Approximately 10% of the adult patients diagnosed with epilepsy and treated with 
lamotrigine as monotherapy in premarketing clinical trials discontinued treatment because of 
an adverse reaction. The adverse reactions most commonly associated with discontinuation 
were rash (4.5%), headache (3.1%), and asthenia (2.4%). The overall adverse reaction profile 
for lamotrigine was similar between female and male patients and was independent of age.
In clinical trials with adult patients (18 - 82 years) diagnosed with bipolar disorder the most 
common adverse reactions (incidence ≥ 5%) seen in association with the use of lamotrigine 
as monotherapy (100 to 400 mg/day) over 18 months were nausea, constipation, vomiting, 
abdominal pain, insomnia, somnolence, xerostomia, back pain, fatigue, rash, rhinitis, 
pharyngitis, exacerbation of cough, and xerostomia.
Adverse reactions that occurred with a frequency of <5% and >1% of patients treated with 
lamotrigine were nervous system disorders (amnesia, depression, agitation, emotional 
lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia) as well as fever, 
neck pain, migraine, flatulence, weight gain, oedema, arthralgia, myalgia and urinary 
frequency.
In addition, looking at all patients (n = 6694) treated with lamotrigine in clinical trials 
confusion, paraesthesia, and amblyopia were frequently (occurring in at least 1/100 patients) 
reported. All other adverse drug reactions occurred infrequently (occurring in 1/100 to 
1/1,000 patients) or rarely (occurring in less than 1/1,000 patients).
Lamotrigine is contraindicated in patients who have demonstrated hypersensitivity (e.g. rash, 
angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its 
ingredients.
The following serious adverse reactions are described for lamotrigine [R19-0414], 
[R20-0058].

Serious Skin Rashes
In clinical trials, serious rash (e.g. Stevens-Johnson syndrome, toxic epidermal 
necrolysis, and angioedema) associated with hospitalization and discontinuation of 
lamotrigine treatment occurred in 0.08% - 0.3% of adult patients. There were no rash-
related deaths reported in adult clinical trials, however, in worldwide post marketing 
experience, rare cases of toxic epidermal necrolysis and/or rash-related death have 
been reported. However, their numbers are too few to permit a precise estimate of the 
rate.


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Apart from age (higher risk in paediatric population) there are no further risk factors 
identified to predict the risk of occurrence or the severity of rash caused by 
lamotrigine. There are suggestions that the risk of rash may also be increased by
(1) co-administration of lamotrigine with valproate,
(2) exceeding the recommended initial dose of lamotrigine, or
(3) exceeding the recommended dose escalation for lamotrigine.
However, cases have occurred in the absence of these factors.
Nearly all cases of life-threatening rashes caused by lamotrigine have occurred within 
2 to 8 weeks of treatment initiation; but isolated cases have also occurred after 
prolonged treatment (e.g. 6 months).
Lamotrigine can also cause benign rashes but as it is not possible to predict which 
rashes will turn out to be serious or life threatening, lamotrigine has to be stopped at 
the first sign of rash (refer to Section 3.3.4.1).

Hemophagocytic Lymphohistiocytosis (HLH)
HLH is a life-threatening syndrome of pathologic immune activation characterized by 
clinical signs and symptoms of extreme systemic inflammation, e.g. fever, 
hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high 
serum ferritin, and liver function and coagulation abnormalities. It is associated with
high mortality rates if not recognized early and treated. In cases of HLH associated 
with lamotrigine, symptoms have been reported to occur within 8 to 24 days after 
initiation of treatment. Therefore, subjects that develop early manifestations of 
pathologic immune activation should be evaluated immediately, considering a 
diagnosis of HLH. These subjects must not be exposed to lamotrigine again (see 
stopping rules).

Multiorgan Hypersensitivity Reactions and Organ Failure (= drug reaction with 
eosinophilia and systemic symptoms (DRESS))
DRESS typically presents with fever, rash, and/or lymphadenopathy in association 
with other organ system involvement, such as hepatitis, nephritis, hematologic 
abnormalities, myocarditis, or myositis, sometimes resembling an acute viral 
infection. Eosinophilia is often present. This disorder is variable in its expression, and 
other organ systems not noted here may be involved. Isolated liver failure without 
rash or involvement of other organs has also been reported
In clinical trials, fatalities associated with acute multiorgan failure and various 
degrees of hepatic failure have been reported in 2 of 3,796 adult patients suffering 
from epilepsy who received lamotrigine. Rare fatalities from multiorgan failure 
have also been reported in post marketing use.
It is important to note that early manifestations of hypersensitivity (e.g., fever, 
lymphadenopathy) may be present even though a rash is not evident. If such signs or 
symptoms are present, the patient should be evaluated immediately and not be 
reexposed to lamotrigine (refer to Section 3.3.4.1).


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
Blood Dyscrasias
Cases of blood dyscrasias, including neutropenia, leukopenia, anemia, pancytopenia, 
thrombocytopenia, and, rarely, aplastic anemia and pure red cell aplasia have been 
reported, that may or may not be associated with DRESS.

Suicidal Behavior and Ideation
It is known that AEDs, including lamotrigine, increase the risk of suicidal thoughts or 
behavior in patients taking these drugs for any indication. The increased risk of 
suicidal thoughts or behavior with AEDs was observed as early as 1 week after 
starting treatment with AEDs and persisted for the duration of treatment assessed (up 
to 24 weeks).

Aseptic Meningitis
Postmarketing experience showed an increased risk of developing aseptic meningitis 
in patients treated with lamotrigine. The onset of symptoms varied from 1 day up to 
1.5 months after start of treatment and mostly resolved after discontinuation of 
lamotrigine. However, in case of re-exposure symptoms returned quickly (within 30 
min – 1 day after re-start of treatment) and often were more severe.
Some patients also presented with signs and symptoms of involvement of other organs 
(predominantly hepatic and renal involvement), which may suggest that in these cases 
the aseptic meningitis observed was part of a hypersensitivity reaction.

Withdrawal Seizures, Status Epilepticus, Sudden Unexplained Death in Epilepsy
Overdoses up to 15 g of lamotrigine have been reported, some of which have been 
fatal. Subjects presented with ataxia, nystagmus, seizures (including tonic-clonic 
seizures), decreased level of consciousness, coma, and intraventricular conduction 
delay. For treatment of overdose, refer to Section 4.2.
For a more detailed description of lamotrigine profile, including a list of infrequent and rare 
adverse reactions, refer to the Lamotrigine (
) Drug Label Information 
[R20-0058].
1.2.4
Ketamine
Ketamine acts as an non-competitive NMDA-receptor (NMDAR) antagonist. It is a 
phencyclidine (PCP) derivative that binds to the allosteric PCP binding site within the pore of 
the NMDAR ion channel [R19-0419]. Since 1970, Ketamine (ketamine hydrochloride) has
been in clinical use as rapid acting iv-anaesthetic and has FDA approval

As the sole anaesthetic agent for diagnostic and surgical procedures that do not require 
skeletal muscle relaxation,

For the induction of anaesthesia prior to the administration of other general anaesthetic 
agents and


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
To supplement low-potency agents such as nitrous oxide [R19-0414], [R19-0419].
The onset of its anaesthetic action is rapid; an intravenous dose of 2 mg/kg of body weight 
usually produces surgical anaesthesia within 30 seconds after injection, with the anaesthetic 
effect lasting five to ten minutes [R19-0414]. Average steady state plasma concentrations of 
2200 ng/ml are needed to induce anaesthesia and awakening from ketamine-induced 
anaesthesia occurs at plasma concentrations ranging from 640 to 1100 ng/ml [R19-0419].
Apart from its well-known anaesthetic effect, ketamine also possesses analgesic, anti-
inflammatory and antidepressant effects. Intravenous ketamine is used in sub-anaesthetic
doses, as low as 
, as an analgesic, e.g. to reduce chronic and acute 
postoperative pain or after acute trauma. When administered intravenously, ketamine’s 
analgesic effects are associated with plasma concentrations ranging between 70 and 160 
ng/ml, i.e. below anaesthetic concentrations [R19-0419].
In addition, sub-anaesthetic doses of ketamine have an antidepressant action as shown in 
clinical trials with patients suffering from treatment-refractory major depression, or bipolar 
depression [R19-0418], [P19-01142]. The most commonly used sub-anaesthetic
antidepressant dose of ketamine (0.5 mg/kg; 40-minute infusion) results in a maximal plasma 
concentration (Cmax) of 185 ng/ml [R19-0419].
1.2.4.1
Use of ketamine as a challenge agent
Of special interest for this trial is the observation, that single sub-anaesthetic doses of 
ketamine produce schizophrenia-like symptoms, including memory deficits, in healthy 
volunteers [R97-3753], [R19-1363]. This observation is in accordance with the hypothesis of 
an underlying dysfunction in NMDAR-mediated glutamatergic neurotransmission in the 
pathology of schizophrenia [R19-0484]. NMDAR inhibitors are used in animal and human 
models of schizophrenia [R13-0697], [R19-0485].
The Ketamine model of schizophrenia in healthy volunteers was first fully verified by Krystal 
et al [R13-0697], [R97-3753].
Focussing on the effects of the ketamine model on cognition, cognitive dysfunction 
associated with the activity of frontal and temporo-hippocampal parts of the brain is impaired 
in healthy volunteers. This ketamine-induced cognitive dysfunction is similar to findings in 
schizophrenia, and includes worsening of verbal fluency tests, interpretation of proverbs, 
working and semantic memory, Stroop test and Wisconsin Card Sorting Test [R13-0697]. In 
the trial done by Krystal et al, vigilance, verbal fluency, and delayed recall were impaired 
during/immediately following a 40-minute i.v. infusion of 0.5 mg/kg ketamine (resulting in 
plasma Cmax estimated to be 100–250 ng/ml) and recovered shortly after termination of the 
infusion [R19-0419]. NMDAR are necessary for long-term potentiation (LTP) and thereby
for learning and memory. Their dysfunction in schizophrenic or Alzheimer patients as well as 
their inhibition in the ketamine model in healthy volunteers are in accordance with the 
observed learning and memory deficits in these subjects.


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There is significant heterogeneity how “sub-anaesthetic” is translated into an infusion 
dose/regimen in trials using ketamine as challenge as well as in ketamine trials investigating 
its antidepressant and/or analgesic effect [P19-11590]. For example, in one clinical trial 
evaluating intravenous ketamine for cancer-related pain, a low-dose, 24-hour infusion of 1 
mg/kg was used; in another pain trial, a low-dose ketamine infusion of 0.6 mg/kg over 4 
hours was administered [P19-11590].
In this trial, the ketamine infusion will be performed as an initial 0.26 mg/kg bolus over 1
min followed by a 89 min continuous infusion of 0.65 mg/kg (or 0.0073 mg/kg/min) as it 
demonstrated to achieve the systemic exposure at which cognitive effects were observed. In 
turn, these effects were attenuated by a single dose of 300 mg of lamotrigine administered 2 
hours prior to ketamine infusion [R19-0417]. After a bolus ketamine infusion, the 
maintenance dose will be reduced by 10% (or 0.00073 mg/kg/min) every 15 min to hold 
concentrations constant [R19-4226], [R15-3321].
Perry et al reviewed the mental/psychiatric safety and tolerability of the ketamine challenge 
in healthy volunteers [R19-1358]. Safety data of fifteen ketamine challenge studies with 
healthy volunteers, plus one study with abstinent alcohol-abusing subjects were analysed, 
accounting to a total of 450 subjects receiving at least 1 ketamine infusion and 833 ketamine 
infusions being administered. The frequency of mental/psychiatric adverse events was low (< 
2% of subjects) and AEs resolved spontaneously. Further, during long-term follow up (1wk –
6 months after last ketamine infusion) no evidence of ketamine abuse by subjects following 
study participation and no evidence of subsequent psychiatric problems related to ketamine 
exposure was found [R19-1358].
Published data on adverse events related to sub-anaesthetic doses of ketamine in a ketamine 
challenge is limited; but more data are available about the use of sub-anaesthetic ketamine in 
depression or pain treatment.
In a systematic review of safety and tolerability of ketamine used for treatment of depression, 
the most common side effects were headache, dizziness, dissociation, elevated blood 
pressure, and blurred vision. The most common psychiatric side-effects was anxiety. Most 
adverse effects occurred immediately/during intravenous ketamine infusion and resolved 
shortly after the administration [R19-0673]. In clinical trials with sub-anaesthetic ketamine 
for chronic pain no serious adverse reactions observed are and most of the adverse events 
were transient and could be treated by lowering the rate of infusion or stopping it [consensus 
paper ketamine in chronic pain]. However, it was also pointed out, that ketamine is associated 
with significant adverse events; mainly neuropsychiatric (incl. sedation, vivid dreams or 
nightmares, hallucinations, out-of-body experiences, headache, dizziness, fatigue, changes in 
mood, altered vision and hearing, light-headedness, paresthesia, changes in taste, dysarthria, 
euphoria, and inebriation), gastrointestinal, cardiovascular (incl. tachycardia, arrhythmias, 
and hypertension), and respiratory (incl. hypoventilation or hyperventilation, oxygen 
desaturation, and hypoxia). These adverse effects vary depending on the dose and subject.


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1.2.4.2
Clinical pharmacokinetics
Ketamine is a racemic mixture consisting of (S)- and (R)-ketamine. As an anaesthetic for 
humans, (S)-ketamine is reported to be twice as potent as the racemic mixture and 
approximately three times more potent than (R)-ketamine. The pure S-ketamine stereoisomer 
is also marketed (e.g. Ketanest). In this trial, the racemic form will be used as it appears to 
cause more pronounced cognitive impairment as equianalgesic doses of the stereo-isomere 
[R19-1359].
Ketamine is administered to humans via multiple routes, including i.v., i.m., oral, intranasal, 
epidural and intrarectal. However, the most common route of administration is via i.v. 
infusion. Following i.v. administration, the ketamine concentration has an initial alpha phase 
lasting about 45 minutes (half-life of 10 to 15 minutes) that corresponds clinically to the 
anaesthetic effect of the drug. The anaesthetic action is terminated by a combination of 
redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic 
biotransformation to its less active metabolite norketamine. The later half-life of ketamine 
(beta phase) is 2.5 hours [R19-0414]. Oral administration is less preferable as due to its 
extensive first-pass hepatic metabolism the oral bioavailability of ketamine (16%–29%, with 
peak concentration levels of the drug occurring within 20–120 minutes) is limited 
[R19-0419]. Ketamine undergoes extensive metabolism starting with demethylation to 
norketamine primarily by CYP2B6 and CYP3A4. CYP3A4 demethylates the (S)-ketamine 
enantiomer more rapidly than the (R)-ketamine enantiomer, whereas CYP2B6 demethylates 
both enantiomers of ketamine with near equal efficiency. Norketamine is further metabolized 
to the hydroxynorketamines (HNKs) and dehydronorketamine (DHNK). In addition to this 
major metabolic pathway further minor pathways exist [R19-0419].
Following an i.v. sub-anaesthetic (antidepressant) dose of ketamine (0.5 mg/kg administered 
over a 40-minute infusion) plasma levels of ketamine were below detectable levels within 1 
day; however, circulating levels of DHNK and HNK were observed for up to 3 days 
[R19-0419]. In adult humans, racemic ketamine has a high volume of distribution (Vd = 3-5 
l/kg), a fast systemic clearance (26.3 +/- 3.5 ml/kg) and a short elimination half-life (2–4 h). 
Compared to the racemic mixture, the elimination half-life of (S)-ketamine is slightly longer 
(5 h) and its systemic clearance is faster (14.8 +/- 1.7 ml/kg). A possible explanation for this 
observation may be an inhibition of (S)-ketamine’s clearance by the (R)-ketamine.
Elimination of ketamine is primarily via the kidneys, with low levels excreted as ketamine 
(2%), norketamine (2%), and DHNK (16%) whereas the majority of the drug (~80%) is 
excreted as hydroxyketamine (HK) and HNK.
1.2.4.3
Clinical safety
Ketamine is known to affect the cardiovascular and respiratory system. Commonly (≥1/100 
to <1/10) an increase in blood pressure, heart rate and respiratory rate is observed. However, 
although to a lesser rate (uncommon (≥1/1,000 to <1/100) an apparently opposite effect, 
namely bradycardia, arrhythmias and hypotension, as well as respiratory depression and 
laryngospasm and in rare cases (≥1/10,000 to <1/1,000) obstructive airway disorders and 
apnoea can occur.


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Central nervous system and psychiatric disorders are also reported, ranging from common 
(hallucination, abnormal dreams, nightmare, confusion, agitation, abnormal behavior, 
nystagmus, hypertonia, tonic clonic movements), over uncommon (anxiety) to rare ones 
(delirium, flashback, dysphoria, insomnia, disorientation). If Ketamine is used as a general 
anaesthetic, an emergence delirium may occur (often consisting of dissociative or floating 
sensations) that some patients experience as unpleasant [R20-2543].
In addition, common adverse reactions are skin disorders (erythema, rash morbilliform), 
nausea and vomiting, and diplopia.
Anorexia, injection site pain and injection site rash are classified as uncommon and 
anaphylactic reactions, salivary hypersecretion, cystitis and haemorrhagic cystitis are rarely 
observed. After prolonged use (> 3 days or chronic use) abnormal liver function tests and 
Drug-induced liver injury has been reported, but the frequency cannot be estimated from the 
available data. In addition, single cases of increased intraocular pressure are known.
Ketamine has a wide safety margin; reported overdoses of Ketamine (up to 10 times that 
usually required) have been followed by prolonged but complete recovery [R20-2543].
For a more detailed description of ketamine profile, refer to the Ketamine hydrochloride 
(
) Drug Label Information [R20-2543].
1.2.5
Residual Effect Period
The Residual Effect Period (REP) of 
, for 
lamotrigine 10 days, and for ketamine 24 hours. This is the period after the last dose with 
measurable drug levels and/or pharmacodynamic effects is still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
This exploratory trial is designed to investigate if there is a
 effect of BI 409306
and BI 425809 in an 
. In this pharmacological model in 
healthy volunteers (as described in Section 1.2.3.1), infusion of the
 
 
[R13-0697], [P19-01512].
 affects various 
 and 
 
 specific disruption 
 
[R19-4239], [R19-4224]. In preclinical models, an effect on 
was also seen.
Moreover, effects of 
on 
 was observed in human subjects 
[R20-0059], [R20-0060]. Similarly, 
 induces effects in 
 
R19-3170], [R19-3171]. Pre-treatment with drugs that 
reduce or counteract the effects of
 should therefore result in a measurable 
improvement in the mentioned 
 and thereby in the respective 
 


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BI 409306 is a 
 in clinical development. As 
 its 
should restore
 due to 
 
to physiological levels and give rise 
 
manifestation of
 
[R10-5110], [P10-10289], [R10-5097].
BI 425809 is a 
 in clinical development that is targeting 
 
with 
 Inhibition of
 leads to 
 of 
 a physiological 
 
showing efficacy in 
 are available as well as indirect evidence of BI 425809’s 
pharmacodynamic efficiency in humans (
 
 treatment with BI 425809 resulted in 
improved 
in patients with 
Considering the mode of action of BI 409306 and BI 425809 as well as ketamine, BI 409306 
and BI 425809 are expected to
 
 
Lamotrigine, a drug with a known positive effect on
 
-0417].
1.4
BENEFIT - RISK ASSESSMENT
For details on the specific benefit/risk assessment of participation of healthy subjects in this 
clinical study in context of the COVID-19 pandemic, refer to Appendix 10.7.
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance to investigate the effect of BI 409306
and BI 425809 on 
 Subjects are exposed to risks of 
study procedures and risks related to the exposure to the trial medication and ketamine.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
Risks related to BI 409306 administration
Based on the results from completed trials in healthy volunteers, main adverse events are 
 


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see Section 1.2.1). 
 
 
 
 (also refer to Section 1.2).
Thus, for this trial the assumed therapeutic dose of 
(single dose) was selected that was
shown to be safe and well tolerated in healthy volunteers.
Risks related to BI 425809 administration
Based on the results from completed Phase I/II trials, the main dose-limiting AEs observed so 
far, were
 
 
 
 
 
 
 
Risks related to lamotrigine administration 
The selected dose of 300 mg of lamotrigine is a dose commonly used in the setting of such a 
ketamine challenge trial (Section 1.2.2) with no published safety concerns, including rash, so 
far. However, for patients treated with lamotrigine further serious adverse reactions, 
including serious rashes, have been reported, therefore specific safety measures will be 
implemented (see further below).
Risks related to ketamine administration
Ketamine is a broadly used drug and has a long history of clinical use. The dose administered 
in this trial is sub-anaesthetic and has been used safely as a challenge agent for cognitive 
effects before, alone as well as in combination with lamotrigine [R19-1361], [R19-1360], 
[R19-0417]. BI 409603 and ketamine, as well as BI 425809 and ketamine, have not been
administered together so far. However, considering their modes of action, ketamine causing 


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NMDA-receptor hypofunction and BI 409306 and BI 425809 attenuating NMDA receptor 
hypofunction you would rather expect an attenuation of ketamine induced psychotomimetic 
effects.
To minimize the risk for subjects the following safety measures will apply:

Careful selection of eligible subjects (ref Section 3.3.2 and 3.3.3)

Investigators will pay special attention to
o
The skin of subjects to detect any early sign of rash and check for 
lymphadenopathy (targeted physical examination as indicated in the 
Flow Chart)
o
Any signs of mood change in the subjects
o
Any symptoms of pathologic immune activation, e.g. fever, lymphadenopathy. 
In this case, the subject should be evaluated immediately, considering a 
diagnosis of HLH or DRESS
o
Any signs of meningitis (e.g. stiff-back)

Subjects will be instructed prior to lamotrigine treatment
o
To observe their own skin carefully and report any changes
o
That a rash or other signs or symptoms of hypersensitivity (e.g., fever, 
lymphadenopathy) may herald a serious medical event and that, the subject 
should report any such occurrence to a trial staff immediately.

Any new rash will be evaluated by a licensed medical practitioner qualified to 
evaluate dermatological abnormalities. If the rash is then deemed of clinical 
significance or of indeterminate significance, the subject will be referred to a 
dermatologist

In case a subject develops rash/signs of pathologic immune activation after drug 
administration he will not be dosed again (ref Section 3.3.4.1)

Resuscitative equipment should be ready for use

The subject will be informed before the first ketamine infusion that he may 
experience psychotomimetic symptoms and that he can request to stop the infusion at 
any time

The initial intravenous ketamine bolus has to be administered over a period of 60 
seconds as more rapid administration may result in respiratory depression or apnoea 
and enhanced pressor response

Close monitoring of blood pressure, pulse rate and oxygen saturation during and after 
ketamine infusion


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
Continuous ECG monitoring during and after ketamine infusion until confirmation of 
recovery from ketamine

Recovery from the ketamine administration will be followed up for at least 60 min 
after stop of infusion, until confirmation of recovery from ketamine as per criteria of 
recovery from ketamine, and must be documented. (see Section 5.2.5.6).
 

Visual acuity test will be performed at the Screening Examination and the End of 
Trial Examination, and also in case visual disturbances develop. Subjects with 
ophthalmologic disorders will be excluded from the study.

Regular safety laboratory examinations, including haematology to monitor for blood 
dyscrasias

Only healthy subjects with no co-medication will be enrolled.

In case AEs occur that require treatment, anti-epileptic drugs (AEDs) are not allowed

Prior to discharge the subjects will be assessed by an investigator for their fitness, 
including a DSST, MOAA/S, CADSS and a SFST, and suicidality including C-SSRS. 
Their in-house refinement can be extended anytime if deemed necessary by the 
medical judgment of the investigator

Subjects will be informed that driving an automobile, operating hazardous machinery 
or engaging in hazardous activities should not be undertaken for 24 hours or more
after ketamine infusion
Drug-induced liver disease
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 5.2.6.1.4, adverse events of special interest.
Summary
Considering the good safety profile of BI 409306 and BI 425809 observed so far, the 
published tolerability data of the ketamine challenge model with and without lamotrigine and 
the implemented safety measures, the overall potential risk for participating subjects is 
considered to be low. Successful investigation of a pro-cognitive effects of BI 409306 and 
425809 would provide further evidence of their potential for clinical development.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate if and to what extent BI 409306, BI 425809
and lamotrigine attenuate 
2.1.2
Primary endpoint
The primary endpoint of the study is

PAL Total Errors Adjusted (PALTEA28) on ketamine
2.1.3
Secondary endpoints
The secondary endpoints of the study are

SWM Between Errors (SWMBE468) on ketamine

RVP A’ Prime (RVPA) on ketamine


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2.2.2.3
Safety and tolerability
Safety and tolerability of BI 409306, BI 425809, lamotrigine and ketamine will be assessed 
based on:

Adverse events (including clinically relevant findings from the physical examination
incl. targeted examination, visual acuity test, vital signs; as well as clinically relevant 
abnormal results in C-SSRS and safety tests (DSST, MOAA/S, CADSS and SFST))

Safety laboratory tests (only abnormal findings will be reported as AEs)

12-lead ECG and continuous ECG monitoring (only abnormal findings will be 
reported as AEs)

Vital signs (BP, PR, SaO2)

Suicidality assessment (C-SSRS)


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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 randomized, placebo controlled, double-blind, double-
dummy, three-way cross over trial in healthy male subjects in order to investigate if and to 
what extent BI 409306, BI 425809 and lamotrigine attenuate ketamine 
 
In total, 36 healthy male subjects are planned to participate in this study. The subjects will be 
randomly allocated to one of the 18 3-period sequences including placebo in one of the 
periods and 2 out of the 3 active treatments in the remaining periods, namely T1–T2–R,    
T1–R–T2, T1–T3–R, T1–R–T3, T2–T1–R, T2–R–T1, T2–T3–R, T2–R–T3, T3–R–T1,     
T3–T1–R, T3–T2–R, T3–R–T2, R–T1–T2, R–T2–T1, R–T1–T3, R–T3–T1, R–T2–T3,       
R–T3–T2. For details, see below and refer to Section 4.1.
The treatments will be:

Lamotrigine Treatment (T1): one single dose of 300 mg of lamotrigine and one single 
dose of placebo to BI 409306 (2h prior to ketamine infusion), and one single dose of 
placebo to BI 425809 (5h prior to ketamine infusion), administered to subjects orally 
after a light snack/ breakfast, followed by intravenous ketamine infusion (a bolus of 0.26 
mg/kg over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 89 
minutes (reduced by 10% every 15 min))

BI 409306 
 
 (T2): one single dose of 
 of BI 409306 and one 
single dose of placebo to lamotrigine (2h prior to ketamine infusion), and one single dose 
of placebo to BI 425809 (5h prior to ketamine infusion), administered to subjects orally 
after a light snack/ breakfast, followed by intravenous ketamine infusion (a bolus of 0.26 
mg/kg over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 89 
minutes (reduced by 10% every 15 min))

BI 425809 
 
(T3): one single dose of placebo to BI 409306 and one 
single dose of placebo to lamotrigine (2h prior to ketamine infusion), and one single dose 
of 
 of BI 425809 (5h prior to ketamine infusion), administered to subjects orally 
after a light snack/ breakfast followed by intravenous ketamine infusion (a bolus of 0.26 
mg/kg over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 89 
minutes (reduced by 10% every 15 min))

Placebo Treatment (R): one single dose of placebo to lamotrigine and one single dose 
of placebo to BI 409306 and one single dose of placebo to BI 425809 administered to 
subjects orally after a light snack/ breakfast, followed by intravenous ketamine infusion 
(a bolus of 0.26 mg/kg over 1 min, followed by continuous infusion of 0.0073 mg/kg/min
over 89 minutes (reduced by 10% every 15 min))
There will be a washout period of at least 11 days between the treatments.
As part of the screening procedure, subjects will be challenged with intravenous ketamine 
infusion (a bolus of 0.26 mg/kg over 1 min, followed by continuous infusion of 0.0073


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mg/kg/min over 89 minutes (reduced by 10% every 15 min)). The subjects who achieved < 
10 errors change on CANTAB PALTEA28 on ketamine vs. pre-ketamine infusion will not be 
included in the study.
Prior to ketamine challenge at screening, all subjects will be genotyped for CYP2C19 status
(if CYP2C19 status isn’t known at screening). Only CYP2C19 non-poor metabolizers will be 
eligible for the ketamine challenge at screening. For details, refer to Section 5.6.1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For this trial, the crossover design is preferred because of its efficiency: since each subject 
serves as his own control, the comparison between treatments is based on an intra-subject 
comparison, thus removing inter-subject variability from the comparison between treatments
[R94-1529]. However, more than 3 periods are deemed not feasible due to the burden for the 
subjects. In addition, an increased dropout rate has to be expected with an increased duration 
of the study period. For these reasons, a 3-period incomplete block crossover design will be 
applied maintaining most of the benefits of the complete crossover design as each subject still 
serves as his own control with regard to the comparison to placebo while limiting subjects’ 
burden and duration of study period.
The anticipated effects on CANTAB tests on ketamine of the lamotrigine treatment (T1) will 
serve as a benchmark to conclude about effects on CANTAB tests on ketamine of the BI 
409306 treatment (T2) and the BI 425809 treatment (T3). The use of placebo treatment (R)
will allow estimating the impact of individual factors on the cognitive effects of the ketamine
challenge.
Double-blind, double dummy conditions will be maintained throughout the study. The trial 
medication will be dispensed by unblinded pharmacists from the bulk bottles to the individual 
subjects’ dispensing bottles (see Section 4.1.4).Because lamotrigine and placebo could be 
distinguished due to an imprint on lamotrigine tablets (see Section 4.1.1), the study drug will 
be administered by unblinded nurses. The subjects will be kept blinded regarding lamotrigine 
or placebo treatment via using a blinding eye mask in each treatment period during the study 
drug administration (see Section 4.1.4).
3.3
SELECTION OF TRIAL POPULATION
It is planned that 36 healthy male subjects will enter the study. They will be recruited from 
the trial site’s participant database and other means, such as advertisement pre-approved by 
the Institutional Review Board.
Only CYP2C19 non-poor metabolisers will be included in the trial in order to minimize 
potential impact on the study endpoints due to the known higher exposure of BI 409306 in 
CYP2C19 poor metabolisers, and minimize the safety risks related to this as well (see 
Section 1.2.1.4 and the current version of the IB [c01694347]). CYP2C19 status must be


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known prior to the ketamine challenge at screening in order to avoid exposure of non-eligible
subjects to ketamine.
 subjects performing within the normative range on CANTAB 
PALTEA28 at screening will be put forward for evaluation of ketamine response. Subjects 
will identify as normative if they perform within 2 SD of an age matched normative sample at 
Visit 1 and Visit 2 prior to ketamine infusion. The CANTAB software will use detailed 
normative data and compare each recruited participant against it. At the end of each screening 
session, a report will be available for download that will indicate whether the subject is 
eligible to proceed to ketamine challenge.
Only subjects who demonstrated response to ketamine at the selected dose/regimen at the 
screening ketamine challenge (Visit 2) will be included in the trial in order to increase study 
sensitivity. Response to ketamine is defined as a change of ≥ 10 errors on CANTAB 
PALTEA28 from baseline (pre-ketamine) to ketamine challenge (on ketamine). A change of 
10 or more errors on PALTEA28 is equivalent to a 1 (between subjects) SD change in 
performance. This threshold for change will allow sufficient variability for evaluating 
attenuation of ketamine-induced cognitive deficits between the study treatment arms.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests
2. Age of 18 to 55 years (inclusive)
3. BMI of 18.5 to 32 kg/m2 (inclusive)
4. Signed and dated written informed consent prior to admission to the study, in 
accordance with GCP and local legislation
5. Male subjects who meet any of the following criteria from at least 30 days before the
first administration of trial medication until 30 days after trial completion:
-
Use of adequate contraception, e.g. use of condom (male subjects) plus any of 
the following methods (female partners): intrauterine device, hormonal 
contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) 
that started at least 2 months prior to first drug administration, or barrier method 
(e.g. diaphragm with spermicide)
-
Sexually abstinent
-
Vasectomised (vasectomy at least 1 year prior to enrolment)


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-
Surgically sterilised female partner (including hysterectomy, bilateral tubal 
occlusion or bilateral oophorectomy)
-
Postmenopausal female partner, defined as at least 1 year of spontaneous 
amenorrhea
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 ECG) deviating from normal and 
assessed 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 50 to 90 bpm evaluated as clinically significant by Investigators
3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair)
7. History of 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, the challenge agent or its excipients)
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation 
in another clinical trial in which investigational drug is administered
13. Current smoker or ex-smoker who quit smoking less than 30 days prior to screening
14. Inability to refrain from smoking
15. Alcohol abuse (consumption of more than 24 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial


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19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance,
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study
The following trial-specific exclusion criteria apply:
23. CYP2C19 poor metabolizers (CYP2C19 status must be known prior to the ketamine 
challenge at screening (Visit 2))
24. At the screening examination (Visit 1) or the screening ketamine challenge (Visit 2) 
prior to ketamine infusion, demonstrated results outside of the normative range (± 2
SD or percentile equivalent) per age group on CANTAB PALTEA28
25. At the ketamine challenge at screening (Visit 2), demonstrated no response to 
ketamine, defined as a change of < 10 errors on CANTAB PALTEA28 from baseline 
(pre-ketamine) to ketamine challenge (on ketamine)
27. Subjects with any condition that would preclude administration of lamotrigine and 
ketamine (i.e. contraindicated as per [R20-0058] and [R20-2543])
28. Any lifetime history of suicidal behavior (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behavior)
29. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with 
intent but without specific plan, or active suicidal thought with plan and intent)
30. Subjects with ophthalmological disorders, which may result in photophobia, 
chromatopsia, visual brightness or other visual disturbances, with exception of 
myopia and hyperopia
In addition, the following SARS-CoV-2/ COVID-19-specific exclusion criteria apply:
31. A positive PCR test for SARS-CoV-2 and/ or any clinical symptom suggestive for 
COVID-19 at screening examination (Visit 1) and each time within 72 h prior to 
admission to trial site at screening ketamine challenge (Visit 2) and treatment period 1 
(Visit 3)
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.


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If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication (BI 425809 or BI 409306 or lamotrigine or placebo) or ketamine, the data of 
this subject will not be entered in the case report form (CRF) and will not be reported in the 
clinical trial report (CTR). If a subject is removed from or withdraws from the trial after the 
first administration of trial medication, this will be documented and the reason for 
discontinuation must be recorded in the CRF; in addition, the data will be included in the 
CRF 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 CRF. 
If the discontinuation occurs before the end of the REP (see Section 1.2.4), the discontinued 
subject should if possible be questioned for AEs and concomitant therapies at or after the end 
of the REP in order to ensure collection of AEs and concomitant therapies throughout the 
REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the 
decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of 
total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be 
followed up according to the DILI checklist provided in the ISF
6. The subject has rash or other signs or symptoms of hypersensitivity or pathologic 
immune activation (e.g., fever, lymphadenopathy)
7. The subject exhibits hypoxemia (i.e. SaO2 <90%) during and up to 30 min after the 
ketamine infusion 
8. During the ketamine infusion, the subjects experiences psychotomimetic symptoms 
which are intolerable, and requests to stop the infusion
9. The subject exhibits serious suicidality, in the clinical judgment of the investigator or 
according to the following criteria:
- any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted 
attempt, or preparatory acts or behavior)
- any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought
with intent but without specific plan, or active suicidal thought with plan and 
intent)
10. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 


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sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP 
>180/100 mmHg) or of clinically relevant changes in ECG requiring intervention as 
well as unexplained liver enzyme elevations at any time during the trial
11. The subject experiences a serious adverse reaction which is considered at least 
possibly related to the IMP administration
12. The subject experiences COVID-19 virus infection as confirmed by PCR test for 
SARS-CoV-2 and/or other applicable criteria (e.g. CT of lungs)
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3. If treatment is discontinued due to SARS-CoV-
2/ COVID-19, refer to Appendix 10.7.3.2 for details of other related measures.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
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. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information
invalidating the earlier positive benefit-risk-assessment. More specifically, the trial 
will be terminated if more than 50% of the subjects have drug-related and clinically 
relevant adverse events of moderate or severe intensity, or if at least 1 drug-related 
serious adverse event is reported
3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the Clinical Trial Lead together with the Trial 
Statistician are to decide, if and how many subjects will be replaced. A replacement subject 
will be assigned a unique trial subject number, and will be assigned to the same treatment as 
the subject he replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products BI 409306 and matching placebo, BI 425809 and matching 
placebo, and placebo to lamotrigine have been manufactured by BI Pharma GmbH & Co. 
KG. Placebo to lamotrigine was originally produced as placebo matching BI 425809, but 
because of comparable tablets’ characteristics will be used to match lamotrigine in this 
clinical study.
Lamotrigine tablets, USP 100mg produced by 
 
& Ketamine HCl Injection, USP 500 mg/10 mL produced by 
 
will be sourced from a local pharmacy.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
Lamotrigine
Pharmaceutical formulation: tablet*
Source:
Unit strength:
100 mg
Posology:
3-0-0 on Day 1 of Treatment T1, 2h prior to ketamine infusion
Route of administration:
oral
Duration of use:
Single dose in Treatment T1
Substance:
BI 409306
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
1-0-0 on Day 1 of Treatment T2, 2h prior to ketamine infusion
Route of administration:
oral
Duration of use:
Single dose in Treatment T2
Substance:
BI 425809
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Route of administration:
oral
Posology:
1-0-0 on Day 1 of Treatment T3, 5h prior to ketamine infusion
Route of administration:
oral
Duration of use:
Single dose in Treatment T3


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The characteristics of the reference product are given below:
Substance:
Placebo to lamotrigine
Pharmaceutical formulation: film-coated tablet*
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
3-0-0 on Day 1 of Treatment T2, 2h prior to ketamine infusion
3-0-0 on Day 1 of Treatment T3, 2h prior to ketamine infusion
3-0-0 on Day 1 of Treatment R, 2h prior to ketamine infusion
Route of administration:
oral
Duration of use:
Single dose in treatments T2, T3 & R
Substance:
Placebo to 
 BI 409306 tablet
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 on Day 1 of Treatment T1, 2h prior to ketamine infusion
1-0-0 on Day 1 of Treatment T3, 2h prior to ketamine infusion
1-0-0 on Day 1 of Treatment R, 2h prior to ketamine infusion
Route of administration:
oral
Duration of use:
Single dose in Treatments T1, T3 & R
Substance:
Placebo to 
 BI 425809 tablet
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 on Day 1 of Treatment T1, 5h prior to ketamine infusion
1-0-0 on Day 1 of Treatment T2, 5h prior to ketamine infusion
1-0-0 on Day 1 of Treatment R, 5h prior to ketamine infusion
Route of administration:
oral
Duration of use:
Single dose in Treatments T1, T2 & R
The characteristics of the challenge agent are given below:
Substance:
Ketamine hydrochloride
Pharmaceutical formulation: injection solution
Source:
, 
(or equivalent)


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Unit strength:
500 mg/10 mL (administered as a bolus of 0.26 mg/kg over 1 
min, followed by continuous infusion of 0.0073 mg/kg/min over 
89 min (reduced by 10% (or 0.00073 mg/kg/min) every 15 min)
Posology:
X**-0-0 at SCR Visit 2
X**-0-0 on Day 1 of Treatment T1
X**-0-0 on Day 1 of Treatment T2
X**-0-0 on Day 1 of Treatment T3
X**-0-0 on Day 1 of Treatment R
Route of administration:
i.v.
Duration of use:
90 min infusion***, consisting of a bolus over 1 minute, 
followed by continuous infusion over 89 minutes at SCR KET, 
and in treatments T1, T2, T3 & R
* tablets of lamotrigine have imprint “ZC 80” on one side whereas matching placebo do not 
have it. To ensure double-blind conditions, an eye blinding mask will be used by subjects 
each time during the study drug administration, and unblinded staff will be involved in 
dispensing and administration of the study drug.
** ketamine to be administered intravenously 5h after administration of BI 425809 or 
placebo and 2h after administration of BI 409306 or lamotrigine or placebo.
*** infusion can be prolonged for a maximum of 15 min, i.e. to 105 min in total, in case of 
delays from the planned time of the assessments on ketamine, or terminated earlier if the 
planned assessments on ketamine are completed or any test drops out.
4.1.2
Selection of doses in the trial and dose modifications
BI 409306:
The dose of 
 was selected in order to measure the effect of the anticipated therapeutic
dose of BI 409306. It is the highest dose tested in the ongoing Phase 2 study. So far, single 
doses of BI 409306 up to 
 were administered to healthy volunteers in multiple studies 
with no safety concern (see Section 1.2.1.3).
BI 425809:
The dose of 
 was selected because it provides comparable plasma concentrations after a 
single dose, i.e. 
 to the steady state exposures at multiple doses of 10 mg of 
BI 425809 (the assumed therapeutic dose), i.e. 
. So far, single doses of BI 
425809 up to 
 were administered to healthy volunteers in Phase I studies without 
safety concerns (see Section 1.2.2.3).
Lamotrigine:
The dose of 300 mg of lamotrigine selected for this trial is one of the standard clinical doses.
In case of multiple doses administration, up-titration is recommended to increase tolerability. 
[R19-0414]. In this study, a single dose of 300 mg of lamotrigine will be administered as it 
has demonstrated to attenuate ketamine induced cognitive deficits with no safety concern 


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[R19-0417]. So far, single doses of 300 mg lamotrigine have previously been administered to 
healthy volunteers in multiple studies without any reported safety concern (see 
Section 1.2.2.2).
Ketamine:
A single sub-anaesthetic dose of ketamine produces schizophrenia-like symptoms, including 
memory deficits, in healthy volunteers [R97-3753], [R19-1363]. In this trial, ketamine 
infusion will be performed intravenously as an initial 0.26 mg/kg bolus over 1 min followed 
by a 89 min continuous infusion of 0.65 mg/kg (or 0.0073 mg/kg/min) as per Anand et al. 
This demonstrated to be sufficient to achieve the systemic exposure at which ketamine 
induced cognitive deficits, and which in turn were attenuated by a single dose of 300 mg of 
lamotrigine [R19-0417].
The total duration of ketamine infusion will be 90 min based on the planned duration of the 
required evaluations on ketamine as per the Flow Chart. Previous research has demonstrated 
that ketamine blood levels slowly increase during a constant ketamine infusion [R19-4226]. 
Thus, after an initial bolus infusion of ketamine, maintenance dose will be reduced by 10% 
(or 0.00073 mg/kg/min) every 15 minutes to keep ketamine levels fairly constant as per 
Umbricht et al [R15-3321]. Ketamine infusion can be prolonged for a maximum of 15 min, 
i.e. to 105 min in total, in case delays from the planned time occur for CANTAB tests, 
 
 Ketamine infusion is to be terminated earlier, if the above
assessments on ketamine are completed (or any test drops out) 
 
If ketamine infusion is interrupted for a technical reason (e.g. occlusion of i.v. catheter), the 
reason to be eliminated as soon as possible, before start of a new test. If an interruption 
occurred during the ongoing test, the reason should be eliminated after the test has been 
completed (if it can distract the subject and thereby influence the outcome). An interruption 
of maximum of 15 min for technical reasons is allowed.
If ketamine infusion is interrupted due to safety reasons (e.g. the subject exhibits hypoxemia 
or experiences psychotomimetic symptoms, which are intolerable, and requests to stop the 
infusion), the subject will discontinue trial treatment (see Section 3.3.4.1).
BI 425809 or placebo will be administered 5 hours prior to ketamine infusion
 
 
BI 409306 or lamotrigine or placebo will be administered 2 hours prior to ketamine infusion 
based on the anticipated tmax of lamotrigine in plasma and BI 409306 in CSF. BI 409306 
 
 
 
). 
There is no data about tmax of lamotrigine in CSF in human, the design of Anand et al using 
mean tmax in plasma will be followed.


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4.1.3
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 3). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by the method ‘first come first served’. Subjects are then 
assigned to a treatment sequence according to the randomisation list. Access to the 
randomisation lists are restricted to unblinded pharmacists and pharmacy staff members at the 
investigators’ sites.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.4.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a 3-way crossover study with 4 treatment arms (see Table 4.1.4: 1).
At screening, all subjects will undergo a ketamine challenge receiving ketamine infusion as a 
bolus of 0.26 mg/kg over 1 min, followed by continuous infusion of 0.0073 mg/kg/min over 
89 min (reduced by 10% every 15 min). Only those subjects who demonstrated response to 
ketamine, as well as confirmed their eligibility in accordance to the other inclusion and 
exclusion criteria indicated in Sections 3.3.2 and 3.3.3, will be included in the study, and will
receive 3 treatments: each subject will be randomly allocated to one of the 18 3-period 
sequences including placebo in one of the periods and 2 out of the 3 active treatments (T1, T2 
and T3) in the remaining periods.
Administration of BI 425809 or placebo will be performed 5 h prior to ketamine infusion,
after subjects had a light breakfast (e.g. a muffin with a glass of juice), which will be served 
30 min before the drug administration.
Administration of lamotrigine or BI 409306 or placebo will be performed 2 h prior to 
ketamine infusion, after subjects had a light snack (clear liquid) (e.g. one or two cups of 
gelatin or a popsicle), which will be served approximately 5 min before the drug 
administration.
Before administration, the study drug will be dispensed into the individual subjects’ 
dispensing bottles by the unblinded pharmacists. The unblinded nurses will administer the 
trial medication as oral doses each time together with about 240 mL of water to subjects who 
are in a sitting position. During administration of lamotrigine or BI 409306 or placebo in 
each treatment period, subjects will wear an eye blinding mask. For drug administration, the 
so-called four-eye principle (two-person rule) should be applied. For this, one unblinded 
authorised employee of the trial site should witness the administration of trial medication, and 
its dispensing.


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Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength Dosage
Total dose
T1 (Test 1)
Lamotrigine
Tablet
100 mg
3 tablets once 2h prior to 
ketamine infusion
300 mg
Lamotrigine 
Treatment
Placebo to 
 BI 
409306
Tablet
N/A
1 tablet once 2h prior to 
ketamine infusion
N/A
Placebo to 
 BI 
425809
Tablet
N/A
1 tablet once 5h prior to 
ketamine infusion
N/A
Ketamine
Solution for 
intravenous 
injection
500 mg/10 
ml
bolus of 0.26 mg/kg over 1 min, 
followed by continuous infusion of 
0.0073 mg/kg/min over 89 min 
(reduced by 10% every 15 min)
T2 (Test 2)
BI 409306 
Treatment
Placebo to 
 BI 
425809 (= placebo 
to lamotrigine)
Tablet
N/A
3 tablets once 2h prior to 
ketamine infusion
N/A
BI 409306
Tablet
1 tablet once 2h prior to 
ketamine infusion
Placebo to 
 BI 
425809
Tablet
N/A
1 tablet once 5h prior to 
ketamine infusion
N/A
Ketamine
Solution for 
intravenous 
injection
500 mg/10 
ml
bolus of 0.26 mg/kg over 1 min, 
followed by continuous infusion of 
0.0073 mg/kg/min over 89 min 
(reduced by 10% every 15 min)
T3 (Test 3)
BI 425809
Treatment
Placebo to 
 BI 
425809 (= placebo 
to lamotrigine)
Tablet
N/A
3 tablets once 2h prior to 
ketamine infusion
N/A
Placebo to 
 BI 
409306
Tablet
N/A
1 tablet once 2h prior to 
ketamine infusion
N/A
BI 425809
Tablet
1 tablet once 5h prior to 
ketamine infusion
Ketamine
Solution for 
intravenous 
injection
500 mg/10 
ml
bolus of 0.26 mg/kg over 1 min, 
followed by continuous infusion of 
0.0073 mg/kg/min over 89 min 
(reduced by 10% every 15 min)
R (Reference) 
Placebo 
Treatment
Placebo to 
 BI 
425809 (= placebo 
to lamotrigine)
Tablet
N/A
3 tablets once 2h prior to 
ketamine infusion
N/A
Placebo to 
 BI 
409306
Tablet
N/A
1 tablet once 2h prior to 
ketamine infusion
N/A
Placebo to 
 BI 
425809
Tablet
N/A
1 tablet once 5h prior to 
ketamine infusion
N/A
Ketamine
Solution for 
intravenous 
injection
500 mg/10 
ml
bolus of 0.26 mg/kg over 1 min, 
followed by continuous infusion of 
0.0073 mg/kg/min over 89 min 
(reduced by 10% every 15 min)


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5 h after administration of BI 425809 or placebo and 2 hours after administration of 
lamotrigine or BI 409306 or placebo, ketamine infusion will start. Ketamine will be provided 
in vials containing 500 mg of ketamine hydrochloride in 10 ml solution for intravenous 
injection. Immediately prior to use, 10 ml of the solution from the vial will be aseptically 
transferred to 240 mL of Sodium Chloride (0.9%) Injection, USP (Normal Saline) and mixed
well. The resultant solution will contain 2 mg of ketamine per ml. Ketamine infusion will be 
performed as a bolus of 0.26 mg/kg over 1 min, followed by continuous infusion of 0.0073
mg/kg/min over 89 min (reduced by 10% every 15 min). Infusion systems, e.g. B.Braun Vista 
Basic Infusion Pump or comparable, should be used for the i.v. administration of ketamine.
After ketamine infusion, recovery must be confirmed via criteria of recovery from ketamine 
as compared to pre-ketamine infusion. Recovery follow up can be terminated after a 
minimum of 60 minutes when all applicable criteria are met (see Section 5.2.5.6).
Subjects will be kept under close medical surveillance until 24 h after the last study drug 
administration (i.e. lamotrigine or BI 409306 or placebo) in each treatment period, and 
overnight after ketamine infusion at screening. During ketamine infusion, vital signs 
including oxygen saturation will be measured frequently as per the Flow Chart.
The treatments will be separated by a wash-out phase of at least 11 days.
4.1.5
Blinding and procedures for unblinding
The trial is designed double-blind. Neither subject nor investigator will be aware of the trial 
treatments. The investigator will be supplied with a set of sealed envelopes containing the 
medication codes. The envelopes will be kept unopened at the study site until the end of data 
collection or, in an emergency requiring the investigator to know a subject’s treatment 
allocation, opened with appropriate documentation. At the trial close-out visit, all envelopes 
will be collected.
At the investigators’ sites, access to the randomisation schedule is restricted to unblinded 
pharmacists and pharmacy staff members for drug dispensing. Access to the randomisation 
codes will be controlled and documented by a signed confidentiality statement, which will be 
stored in the TMF.
Persons directly involved in the conduct of the trial will be blinded to trial treatments. 
Because lamotrigine and placebo could be distinguished due to an imprint on lamotrigine 
tablets (see Section 4.1.1), the study drug will be administered by the unblinded nurses. In 
case of occasional unblinding of investigators, the risk of an observer bias regarding the study 
endpoints is considered minimal. The subjects’ blinding status will be ensured via wearing a 
blinding eye mask during drug administration (see Section 4.1.4).
 
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the
trial functions of the sponsor are unblinded (including clinical trial lead, data manager, 


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statistician, pharmacovigilance, bioanalyst, pharmacokineticist, pharmacokinetic analyst as 
well as dedicated CRO personnel). The objective of the trial is not expected to be affected.
4.1.6
Packaging, labelling, and re-supply
4.1.6.1
BI 409306, BI 425809, placebo to BI 409306, placebo to 425809, placebo to 
Lamotrigine
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice.
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form.
No re-supply is planned.
4.1.6.2
Lamotrigine, Ketamine
The marketed products will be used for the study. Transport and storage are under the 
responsibility of the investigators and must comply with the pertinent information[R20-
2543], [R20-0058].
Documentation on the commercial drug products, containing at least the following
information, must be available on-site in the ISF:

Clinical trial number

Investigator name

Trade name of drug product

Substance International non-proprietary name (INN)

Holder of marketing authorization

Dosage form

Quantity

Unit strength

Batch/lot number

Use-by date

Point of purchase

Date of receipt

Recipient (name and function)
In addition, documentation of drug purchase, including identification of drug products and
quantity, must be available at the clinical site and filed in the ISF.
No re-supply is planned.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor 
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol

Availability of FDA Form 1572
Only authorised personnel 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.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
No specific rescue medication is foreseen for BI 409306 and BI 425809, and there are no
special emergency procedures to be followed. No additional treatment is planned. However, 


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if adverse events require treatment, the investigator can authorise symptomatic therapy. In 
those cases, subjects will be treated as necessary and, if required, kept under supervision at 
the trial site or transferred to a hospital until all results of medical evaluations are acceptable.
In case of ketamine overdose, respiratory depression can occur requiring supportive 
ventilation. Each time after start of ketamine infusion until confirmation of recovery from 
ketamine, oxygen saturation (SaO2) will be monitored continuously, and if SaO2 is <90%, a 
prompt medical evaluation is to be done. Mechanical support of respiration that will maintain 
adequate blood oxygen saturation and carbon dioxide elimination is preferred to 
administration of analeptics.

In case of clinically significant changes in blood pressure and pulse rate during the 
ketamine infusion, the infusion has to be stopped immediately. Treatment, e.g. with 
α2-agonists (e.g. Clonidine) or β-blockers may be initiated in case of sustained and 
severe hypertension and tachycardia [P19-11590].

If the subject experiences distressing psychomimetic symptoms, the ketamine infusion 
has to be stopped and further treatment with benzodiazepines, such as midazolam or 
diazepam may be indicated [P19-11590].

If the subject experiences distressing psychomimetic symptoms, the ketamine infusion 
has to be stopped and further treatment with benzodiazepines, such as midazolam or 
diazepam may be indicated [P19-11590].

In the rare event of ketamine-induced seizures, treatment should be started with 
benzodiazepines followed by barbiturates or propofol if persistent [P19-11590].
Following a suspected lamotrigine overdose, hospitalization and general supportive care is 
indicated, including frequent monitoring of vital signs and close observation of the patient. 
Induction of emesis should be considered. It is uncertain whether haemodialysis is an 
effective means of removing lamotrigine from the blood.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.

Paracetamol and diclofenac must be avoided as symptomatic therapy of AEs due to its 
potential liver toxicity. Ibuprofen may be used if needed.

Anti-epileptic drugs (AEDs) are not allowed due to their potential impact on the PK 
characteristics of lamotrigine.


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
Carbamazepine, extracts from Gingko, artemisinin, enzalutamide, efavirenz, 
lopinavir, ritonavir, tipranavir, rifampicin are not allowed due to CYP2C19 induction 
potential.

Allicin, indomethacin, fluvoxamine, fluoxetine, ticlopidine, moclobemide, etravirine, 
ketoconazole (non-topical), voriconazole (non-topical), fluconazole (non-topical), 
esomeprazole, lansoprazole, pantoprazole, or omeprazole are not allowed due
CYP2C19 inhibition potential.

Ciprofloxacin, enoxacin, cinafloxacin, zafirlukast, oltipraz, mexiletine, 
phenylpropanolamine, methoxalen, hormonal oral contraceptives and hormonal 
replacement therapy are not allowed due to potential for CYP1A2 inhibition.

The use of moderate and strong CYP3A4 inhibitors and inducers is not permitted.

CYP3A4 sensitive drugs with narrow therapeutic range are not permitted during the 
trial period.

Use of N-methyl-D-aspartate (NMDA)-antagonists (except ketamine administration 
as indicated in the Flow Chart) such as amantadine, or dextromethorphan
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No other food is allowed during the stationary stay.
On all treatment days (Day 1 of Visit 3, 4 and 5), the trial medication will be administered 
after a light breakfast at least 5 h prior to ketamine infusion (BI 425809 or placebo) and a 
light snack at least 2 h prior to ketamine infusion (lamotrigine or BI 409306 or placebo) (see 
Flow Chart). Meals will be served in order to avoid prolonged fasting and related to it 
inconveniences and common AEs (e.g. headache, fatigue). After stop of ketamine infusion, 
food intake is allowed after confirmation of recovery from ketamine, after a minimum of 60 
minutes of recovery follow up. From 1 h before intake of BI 425809 or placebo until
confirmation of recovery from ketamine, fluid intake is restricted to 240 mL of water with 
each study drug administration and an additional 240 mL of water at confirmation of 
recovery from ketamine (mandatory for all subjects).
At the screening ketamine challenge (Day -21 to -2 of Visit 2), subjects are supposed to 
adhere to same restrictions and follow same schedule of trial procedures as on all treatments 
days, so that response to ketamine at screening could be demonstrated in same conditions, 
that would be applied on treatment days. Thus, subjects will be instructed to admit to the trial 
site after an overnight fast of at least 10 h (mandatory for all subjects). A light breakfast and a 
light snack will be served at least 5 h and 2 h prior to ketamine infusion accordingly. Fluids 
will be limited to 240 mL of water at 5 h and 2 h before ketamine infusion and at 
confirmation of recovery from ketamine (mandatory for all subjects).


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Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until 
 
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed starting from 30 days prior to screening until end-of-trial 
examination.
Excessive physical activity (such as competitive or high performance sport) should be 
avoided from 7 days before the first administration of trial medication until the end of trial 
examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the unblinded site staff. The measured plasma concentrations of trial 
medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination, incl. targeted examination
At the screening examination (Visit 1), the medical examination will include demographics, 
height and body weight, smoking and alcohol history, relevant medical history and 
concomitant therapy, visual acuity test, C-SSRS assessment, safety testing (DSST, MOAA/S, 
CADSS and SFST), review of vital signs (BP and PR incl. orthostatic testing, SaO2), 12-lead 
ECG, 
 laboratory tests, and a physical examination.
At the screening ketamine challenge (Visit 2) and during the treatment periods (Visits 3, 4 
and 5), vital signs (BP, PR, SaO2), 12-lead ECG, continuous ECG monitoring, laboratory 
tests, and a physical examination with a targeted examination (skin inspection for signs of 
rash, check for lymphadenopathy and neurological examination (mental status, motor 
examination, reflexes, sensory, gait and cranial nerves)) will be performed at the time points 
indicated in the Flow Chart. Each time at discharge from trial site, the subjects will be 
assessed by an investigator for their fitness including C-SSRS assessment, safety testing 
(DSST, MOAA/S, CADSS and SFST), review of vital signs (BP, PR, SaO2), 12-lead ECG, 
laboratory tests, a physical examination with a targeted examination as described above.
At the end of trial examination (Visit 6), the medical examination will include review of vital 
signs (BP, PR, SaO2), 12-lead ECG, laboratory tests, C-SSRS assessment, visual acuity test, a 
physical examination with a targeted examination as described above and determination of 
weight.
In context of pandemic, evaluation of subjects for COVID-19 will be performed at each visit, 
including temperature assessment, questionnaire and medical assessment, and PCR test for 
SARS-CoV-2. For details, refer to Appendix 10.7.
Results of the physical examinations incl. targeted examinations and evaluation of subjects 
for COVID-19 will be kept in source data only, but not collected in the CRF. Only clinically 
relevant abnormal findings will be reported as AEs.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (e.g. Dinamap Pro 100, 
or 
comparable) at the times indicated in the Flow Chart, after subjects have rested for at least 5 
min in a supine position when possible.
Pulse oximetry is a non-invasive method for monitoring O2 saturation (SaO2). A blood-
oxygen monitor displays the percentage of blood that is loaded with oxygen and used to 


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detect abnormalities in ventilation. SaO2 will be measured by a pulse oximeter (e.g. 
 
 TruSat, 
or comparable).
All recordings should be made using the same type of blood pressure and oxygen saturation 
recording instrument on the same arm, if possible.
At the screening examination (Visit 1), orthostatic tests will be performed. Subjects should 
have spent at least 5 min in the supine position before blood pressure and pulse rate will be 
measured the first time. Further 2 measurements will be performed immediately after 
standing up and after 3 min in a standing position.
At the screening ketamine challenge (Visit 2) and on treatment days (Visits 3, 4 and 5):
- Before ketamine infusion and after confirmation of recovery from ketamine, vital signs (BP, 
PR, SaO2) to be measured at the time points indicated in the Flow Chart C and Flow Chart D. 
Vital signs 5 min prior to start of ketamine infusion (incl. recording of respiratory rate and 
effort this time) will serve as baseline for confirmation of recovery from ketamine.
- During ketamine infusion, vital signs (BP, PR, SaO2) to be measured and recorded in the 
breaks between the tests at the time points indicated in the Flow Chart C and Flow Chart D. 
Oxygen saturation (SaO2) will be monitored continuously from start of ketamine infusion 
until confirmation of recovery from ketamine (see below). If SaO2 is <90%, a prompt medical 
evaluation is to be done.
- After stop of the ketamine infusion, vital signs to be measured every 15 minutes for at least 
60 min until confirmation of recovery from ketamine. Recovery must be confirmed via 
criteria of recovery from ketamine as compared to pre-ketamine infusion. Vital signs 5 min 
prior to start of ketamine infusion (incl. recording of respiratory rate and effort this time) will 
serve as baseline. Recovery follow up can be terminated after a minimum of 60 minutes when 
all applicable recovery criteria are met (see Section 5.2.5.6).
Blood pressure and pulse rate values will be collected in the CRF. Oxygen saturation, 
respiratory rate and effort assessments will be kept in source data only, but not collected in 
the CRF. Only clinically relevant abnormal findings will be reported as AEs.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
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.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
The safety laboratory tests’ results will not be entered in the CRF/database and will not be 
reported in the CTR. Only clinically relevant abnormal findings will be reported as AEs.


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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.
The eGFR based on the CDK-EPI creatinine equation [R13-3447] will be calculated at
screening:
eGFR (males) = 141 x min(SCr/0.9, 1)-0.411 x max(SCr /0.9, 1)-1.209 x 0.993Age x 1.159 [if Black]
With
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2
SCr (standardized serum creatinine) = mg/dL
min = indicates the minimum of SCr/κ or 1
max = indicates the maximum of SCr/κ or 1
age = years
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 
Reticulocytes, absol.
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
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.
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
Free T3 - Triiodothyronine 
Free T4 – Thyroxine
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
Substrates
Glucose (Plasma)
Hemoglobin A1C
Creatinine 
eGFR
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
--
X
--
X
X
X
X
X
X
--
--
X
--
X
--
X
X
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
X
X
X
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
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 at Visit 3, 4 and 5; on Day 1, prior to drug administration
C: parameters to be determined at Visit 3, 4 and 5; on Day 2, prior to discharge
D: parameters to be determined at Visit 6 (end of trial examination)
The tests listed in Table 5.2.3:2 are exclusionary laboratory tests that may be repeated as 
required. It is planned to perform tobacco screening and infectious serology at screening 
examination (V1) only. Drug screening will be performed at screening examination and each 
time at admission to trial site. COVID-19 screening will be performed at screening 
examination and each time shortly (within 72 hours) prior to admission to trial site (see 
Flow Chart).


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Tobacco screening (urine)
Cotinine
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies and RNA (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
COVID-191
SARS CoV-2 PCR test from a nasal swab sample
1 evaluation will be performed at screening examination (V1) and shortly (within 72 hours) prior to each 
admission to trial site (V2, V3, V4 and V5).
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410,
or comparable) will be performed at screening and prior to each 
treatment period, and may be repeated at any time during the study at the discretion of an 
investigator or designee. The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at the local 
laboratory of the trial sites (see Section 8.7), with the exception of drug screening tests. These 
tests will be performed at the trial site using e.g.
 
respectively, or comparable test systems.
5.2.4
Electrocardiography
5.2.4.1
12-lead ECG
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g. CardioSoft EKG System,
or comparable) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position when possible. ECG assessment will always precede all other study 
procedures scheduled for the same time to avoid compromising ECG quality. 


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All ECGs will be stored electronically. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists).
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG
recording using e.g. CARESCAPE Monitor B450 (
) or comparable 
from start of ketamine infusion until confirmation of recovery from ketamine. 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 ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial
database. Abnormal findings during continuous ECG recording will be recorded as AEs if
judged clinically relevant by the Investigator.
5.2.5
Other safety parameters
 
5.2.5.2
Suicidality monitoring
Based on the FDA guidance on prospective assessment of suicidality [R12-4395] suicidal
ideation and behavior should be assessed as part of the evaluation of any drug being 
developed for a psychiatric condition.
Suicidality assessment to further evaluate the psychological status of the subject will be
performed at the times indicated in the Flow Chart using the Columbia Suicidal Severity 
Rating scale (C-SSRS). The C-SSRS is a brief measure which is designed to assess severity 
and change of suicidality by integrating both, behavior and ideation. The C-SSRS was 
designed to address the need for a summary measure to track change in the severity of 
suicidality across both clinical settings and treatment trials.
The original English version is shown in Appendix 10.2.


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5.2.5.4
Visual acuity test (near visual acuity)
Near vision cards (e.g. Jaeger Eye Chart) will be used to measure visual acuity at the 
screening examination and the end-of-trial examination, and also in case visual disturbances 
develop during the course of study. The smallest line that a subject can read at a distance of 
35 cm will be recorded. If the subject uses glasses or contact lenses, then the test should be 
performed using them. Tests results will be reviewed by investigator or his/her designee for 
correctness and deteriorations. Any deterioration occurring during the study will be 
documented as an AE and an additional ophthalmologic examination should be considered.
5.2.5.5
Safety tests (DSST, MOAA/S, CADSS and SFST)
At the screening examination and each time prior to discharge from trial site, the subjects will 
be assessed by an investigator for their fitness, including a DSST, MOAA/S, CADSS and 
SFST. Based on the outcome of these tests and the medical judgment of the investigator, their 
in-house refinement can be extended anytime if deemed necessary.
Results of the safety tests will be kept in source data only, but not collected in the CRF. Only 
clinically relevant abnormal results will be reported as AEs.
Digit Symbol Substitution Test (DSST)
The DSST [R20-0105] is a psychometric test assessing the integrity of several 
 
 domains, including executive function, processing speed, attention, spatial 
perception, and visual scanning. It has been shown to be a valid and sensitive instrument to 
evaluate 
 and changes in 
[R20-0054]. The DSST is a 
paper-and-pen timed (2-minutes) test where the subject is required to copy into spaces below 
rows of numbers the symbols that are matched to each number according to a key located on 
the top of the page. The DSST is scored based on both the number of correct answers and the 
speed at which they were determined. The DSST is arguably the most commonly used 
 due to its brevity, high discriminant validity, and 
sensitivity to change [R20-0055]. The DSST is being administered in this trial to ensure the 
subject has the 
before being discharged from the unit.
The original English version is shown in Appendix 10.3.
Modified Observer's Assessment of Alertness/Sedation (MOAA/S)
The MOAA/S [R20-0053] will be used in the current study to measure treatment-emergent 
sedation. The MOAA/S is a widely used clinician-administered measure of alertness/sedation 
for clinical trials. The MOAA/S measures the alertness/sedation spectrum on a 6-point scale 
(0 to 5) based on verbal cues using a here-and-now timeframe [R20-0057].
The original English version is shown in Appendix 10.4.
Clinician Administered Dissociative States Scale (CADSS)
The CADSS [R20-0052] is a 28-item clinician-administered measure of perceptual, 
behavioral, and attentional alterations occurring during active dissociative experiences 


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composed of 23 subjective self-reported and 5 objective observer-reported ratings, each 
scored from 0 (not at all) to 4 (extremely). The CADSS provides a validated assessment of 
dissociative states sensitive to change over time and amenable to repeated measures 
[R20-0052]. The CADSS is a clinician-administered instrument which for the purposes of the 
current study has a here-and-now (current) lookback timeframe.
The original English version is shown in Appendix 10.5.
Standardized Field Sobriety Test (SFST)
The Standardized Field Sobriety Test (SFST) is a battery of three tests administered and 
evaluated in a standardized manner to obtain validated indicators of impairment, e.g. in 
persons who have used narcotics [R19-1364], [R19-1365]. These tests were developed based 
on research sponsored by the National Highway Traffic Safety Administration (NHTSA).
The description of SFST is provided in Appendix 10.6.
5.2.5.6
Criteria of recovery from ketamine
Each time after ketamine infusion, recovery must be confirmed via criteria of recovery from
ketamine (see below) as compared to pre-ketamine infusion. Vital signs at 5 min prior to start
of ketamine infusion (incl. recording of respiratory rate and effort this time) will serve as a
baseline for confirmation of recovery. Recovery follow up can be terminated after a
minimum of 60 min. The physician responsible for the administration of ketamine or another
qualified care provider must remain available until all applicable recovery criteria are met.
Criteria of recovery from ketamine:
a) Patient is able to freely move their extremities
b) Respiratory rate and effort are at baseline
c) Blood pressure is within 20% of baseline
d) Patient is fully awake
e) Oxygen saturation is greater than 94% on room air
f) Patient has minimal or no nausea and no emesis for at least 20 minutes
5.2.6
Assessment of adverse events
5.2.6.1
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):


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
Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
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 trial medication and must be reported 
as described in Section 5.2.6.2, 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.


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Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

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


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
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:

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 trial drug treatment continues or remains 
unchanged
Suicidality assessment 
Suicidality assessment to further evaluate the psychological status of the subject will be
performed at the time points indicated in the Flow Chart using the Columbia Suicidal 
Severity Rating scale (C-SSRS).
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does
not give a global score, but provides some categorical and some severity information
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a
typical duration of five minutes, and causes only a low burden on subjects. At a minimum,
the interview consists of 2 screening questions related to suicidal ideation and 4 related to
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free
text entries are allowed for; the investigator has to directly evaluate the scale and write a
report.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be
administered at the screening visit (using the ‘screening/baseline’ version) with the aim to
exclude subjects with active moderate or severe symptomatology within a specified time


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prior to the screening or baseline visit. The life time history of suicidal ideation and behavior
will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at each clinic or
phone visit (‘since last visit’ version). The investigator is to review positive and negative
reports for plausibility and clinical relevance. Doubtful reports may be repeated or reports
may be validated by a consulting psychiatrist. If there is a confirmed positive report of
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist. If 
the positive report is confirmed, appropriate actions for the subject’s safety have to be
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must
be reported as separate SAEs by the investigator. For ‘Self-injurious behavior, no suicidal
intent’ (Type 11) standard AE / SAE reporting rules are to be applied.
For each negative report (suicidal ideation type 1, 2 or 3) after start of the trial, the
investigator is to decide based on clinical judgment whether it represents an adverse event
(AE) as defined in the protocol, and if it is considered an AE then it must be reported
accordingly.
5.2.6.2
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
time, 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, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs in 
Phase I trials in healthy volunteers, when subjects discontinue from the trial due 
to screening failures prior to administration of any trial medication or ketamine. 


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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 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 the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process 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 send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
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 sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.


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5.4
ASSESSMENT OF BIOMARKERS
5.4.1
Cambridge Neuropsychological Test Automated Battery (CANTAB)
Attenuation of 
will be evaluated on the CANTAB test 
battery. The 
assessed in this battery include: Paired Associates
Learning task (PAL; visuospatial episodic memory), Spatial Working Memory (SWM; 
working memory), and Rapid Visual Information Processing (RVP; sustained attention).
The CANTAB tests will be performed in the same order, i.e. RVP, SWM, PAL, with a 4 min 
break between tests, pre-ketamine and during ketamine infusion, following administration of 
BI 409306 (T2) or BI 425809 (T3) or lamotrigine (T1, positive control) or placebo (R). The 
anticipated effects on the CANTAB tests on ketamine of the lamotrigine treatment (T1) will 
serve as a benchmark to conclude about effects on the CANTAB tests on ketamine of the BI 
409306 (T2) or BI 425809 (T3) treatment. The use of placebo treatment (R) will allow 
estimating the impact of individual factors on the cognitive effects of the ketamine challenge.
The full list of outcome measures to be analysed from the CANTAB test battery is included 
in Table 5.4.1: 1 below.
The CANTAB tests (RVP, SWM, PAL) can be completed in approx. 35 minutes.


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Table 5.4.1: 1 
CANTAB tests, domains and outcome measures
CANTAB test
Domain
Outcome measurements
Paired Associates 
Learning (PAL)
Episodic memory & new 
learning
KEY: Total Errors Adjusted (PALTEA28)
Spatial Working Memory 
(SWM)
Executive function & 
working memory
KEY: Between Errors (SWMBE468)
Rapid Visual Information 
Processing (RVP)
Sustained 
attention/vigilance
KEY: A Prime (RVPA)
5.4.1.1
Paired Associates Learning (PAL)
PAL assesses visual memory and new learning.
Description: Boxes are displayed on the screen and open in turn to reveal a number of 
patterns. Participants are instructed to try to remember the location in which each pattern was 
shown. After all the boxes have been opened, each pattern is then shown in the center of the 
screen in a randomised order, and the participant touches the box in which the pattern was 
located. If an error is made, all the patterns are re-presented to remind the participant of their 
locations. As the test progresses so the stages become more difficult as the number of patterns 
to be remembered increases. For participants who fail to complete all levels, an adjusted total 
is calculated that allows for errors predicted in the stages that were not attempted.
Key Outcome Measure: Total Errors Adjusted (PALTEA28). The number of errors 
committed by the subject plus an adjustment for the estimated number of errors they would 
have made on any stages that were not reached. Calculated across all assessed two, four, six 
and eight box trials.
5.4.1.2
Spatial Working Memory (SWM)
SWM assesses the ability of the participant to retain spatial information and manipulate it in 
working memory. It is a self-ordered task that also gives a measure of strategy (an aspect of 
executive function).
Description: A number of coloured boxes are presented on the screen, and the computer 
hides a token in these boxes one at a time. The participant is instructed to touch the boxes in 
turn to search for the token that has been hidden. When a token is found it should be placed in 
a home area on the right side of the screen. The participant then searches for more tokens 


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until the same number of tokens as the number of coloured boxes has been found. The key 
task instruction is that the computer will never hide a token in the same coloured box twice in 
the same problem. As the test progresses, so it becomes more difficult.
Key Outcome Measure: Between Errors (SWMBE468). The number of times the subject 
incorrectly revisits a box in which a token has previously been found. Calculated across all 
assessed four, six and eight token trials.
5.4.1.3
Rapid Visual Information Processing (RVP)
RVP is a sensitive measure of sustained attention, outputting measures of response accuracy, 
target sensitivity and reaction times.
Description: During the RVP task, single digits appear in a pseudo-random order at a rate of 
100 digits per minute in a box in the centre of the screen. Subjects must detect a series of 3-
digit target sequences (e.g. 3-5-7; 2-4-6; 4-6-8) and respond by touching the button at the 
bottom of the screen when they see the final number of the sequence. Nine target sequences 
appear every minute.
Key Outcome Measure: A’ Prime (RVPA). The signal detection measure of a subject's 
sensitivity to the target sequence (string of three numbers), regardless of response tendency 
(the expected range is 0.00 to 1.00; bad to good). In essence, this metric is a measure of how 
good the subject is at detecting target sequences.


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5.5
BIOBANKING
Not applicable.


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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, C-SSRS, safety tests, 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 
and intravenously administered drugs, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure. The biomarkers and pharmacodynamic parameters and 
measurements outlined in Sections 5.4 and 5.6 are of exploratory nature only. The C-SSRS is 
a validated tool to monitor for suicidality and recommended by the FDA [R12-4395]. The
visual acuity test is commonly used to screen for visual disturbances and can be extended to a 
full ophthalmologic examination if needed. DSST, MOAA/S, CADSS and SFST are 
commonly used for assessment and confirmation of subjects’ fitness after administration of 
ketamine before discharge from the clinic. Recovery from ketamine will be evaluated as per 
criteria common in clinical practice.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements will be documented. The acceptable time windows for 
screening and the end of trial examination are provided in the Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ planned time 0:00 on Day -
21 to -2 of Visit 2 are to be performed and completed within a 2 h period prior to planned 
time 0:00.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 of Visit 3, 4 and 5 are to be performed and completed within a 2 h
period prior to the trial drug administration.
The acceptable deviation from the scheduled time for C-SSRS assessments, targeted 
physical examination, safety tests (DSST, MOAA/S, CADSS and SFST) and laboratory 
tests will be ± 2 h for all days.
On treatment days (Day 1 of Visit 3, 4 and 5) and at the Screening Ketamine Challenge (Day 
-21 to -2 of Visit 2), the planned times for CANTAB tests, E
 
as per the Flow Chart should be adhered as closely as possible before ketamine 
infusion, whereas during ketamine infusion time intervals between these tests should be 
minimized, i.e. if any test is completed earlier or dropped out, the next test should start 
straight away. Overall, deviations ± 15 min from the planned times for these tests are 
acceptable.
CANTAB tests, 
 at the Screening Ketamine Challenge 
(Visit 2) have to occur time-matched to these assessments in each treatment period (Visit 3, 4 
and 5). Therefore, planned time 0:00 on Day -21 to -2, the Screening Ketamine Challenge, 
should equal planned time 0:00 relative to drug administration on Day 1 of Period 1, 2 and 3.
Before start of ketamine infusion and after confirmation of recovery from ketamine, the 
acceptable deviation from the scheduled time for vital signs, ECG and Questioning for AEs 
and concomitant therapy will be ± 15 min. During ketamine infusion until confirmation of 
recovery from ketamine, the planned times for vital signs, ECG assessments and Questioning 
for AEs and concomitant therapy as per the Flow Chart C and Flow Chart D should be 
adhered as closely as possible.
Ketamine infusion can be prolonged for a maximum of 15 min, i.e. to 105 min in total, in 
case delays from the planned time occur for CANTAB tests, 
 
 Ketamine infusion is to be terminated earlier, if the above assessments on ketamine 
are completed (or any test drops out) 
 Evaluation as per 
criteria of recovery from ketamine must be not earlier than 60 min after stop of ketamine 
infusion.
If several actions are indicated in the Flow Chart at the same time point, the intake of meals 
will be the last action, and 12-lead ECG recordings have to be done first. Furthermore, if 


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several measurements including venepuncture are scheduled for the same time, venepuncture 
should be the last of the measurements due to its inconvenience to the subject and possible 
influence on physiological parameters.
 
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
The screening period consists of the Screening Examination (Visit 1) and (if applicable) the 
Screening Ketamine Challenge (Visit 2). Only subjects who have already passed all 
eligibility criteria, incl. confirmation on CYP2C19 status, except not yet determined response 
to ketamine, will be invited to the Screening Ketamine Challenge, that has to be scheduled on
a different day after the screening examination.
At the Screening Examination, genotyping for CYP2C19 will be performed in those 
volunteers whose genotypes have not been previously determined (for details, see 
Section 3.3.3 and 5.6.1).
At the Screening Examination, subjects who are not able to tolerate procedures of 
 
or demonstrate abnormal results will be excluded from further screening activities (see 
Section 5.2.5.3).
At the Screening Examination (Visit 1) and the Screening Ketamine Challenge (Visit 2) prior 
to ketamine infusion, subjects will be tested on CANTAB RVP, SWM and PAL. Each 
subject will be compared to an age matched sample of normative individuals from Cambridge 
Cognition’s CANTAB normative database (to be made for PALTEA28 only). Subjects will 
be excluded if they perform at any visit outside of the normative range (± 2 SD or percentile 
equivalent) for their age level on the PAL outcome measure PAL Total Errors Adjusted 
(PALTEA28). An indication of whether the subject should be excluded from further 
screening procedures due to absence of normative performance will be provide through the 
CANTAB software as a downloadable report and will be available after completion of the 
CANTAB assessments.
For the Screening Ketamine Challenge eligible subjects will come to the clinic in the morning 
of the test day, where they will participate in two assessment-sessions:

Screening Baseline (= SCR BL)
CANTAB tests, 
 will be done without any 
treatment, i.e. with no ketamine infusion


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
Screening Ketamine (= SCR KET)
CANTAB tests, 
 will be done during ketamine 
infusion
SCR BL will be done first followed by SCR KET, as indicated in the Flow Chart. Only
subjects that show 
will be allowed to enter the trial.
 
. A 
change of 10 or more errors on PALTEA28 is equivalent to a 1 SD (between subjects) change 
in performance. This will allow ample variability to evaluate attenuation of k
 
 between treatment arms. An indication of whether a participant should be 
screened out due to absence of 
 will be provided through 
the CANTAB software as a downloadable report and will be available following completion 
of the CANTAB assessments.
The assessments of SCR KET will also be used as baseline for the assessments performed on 
the test days of the treatment periods, i.e. under treatments T1, T2, T3 and R. Therefore, it is 
of upmost importance that SCR KET assessments will be performed time-matched, i.e. 
exactly at the same time of the day, to the later assessments under treatments T1, T2, T3 and 
R.
Recovery from ketamine must be confirmed via criteria of recovery from ketamine. Recovery 
follow up can be terminated after a minimum of 60 minutes when all applicable recovery 
criteria are met (see Section 5.2.5.6).
During and after assessments subjects are kept under close medical surveillance for at least 5
h after stop of the ketamine infusion. The subjects will then be allowed to leave the trial site 
after successful completion of the discharge assessments (incl. C-SSRS; DSST, MOAA/S, 
CADSS, SFST), formal assessment and confirmation of their fitness. Discharge will be 
postponed if subjects fail to pass C-SSRS, DSST, MOAA/S, CADSS and/or SFST or any 
time if deemed necessary by the investigator (for details refer to Sections 5.2.5.2 and 5.2.5.5).
For information regarding laboratory tests (including drug and virus screening), ECG, 
 C-SSRS, vital signs, safety tests (DSST, MOAA/S, CADSS, SFST), visual 
acuity test and physical examination incl. targeted examination, refer to Section 5.2.
For details on the trial procedures related to SARS-CoV-2/ COVID-19 in context of
pandemic during screening period, refer to Appendix 10.7.3.1.
6.2.2
Treatment periods
Each subject is expected to participate in 3 treatment periods (Days 1, 2, 4, 6 and 8 in each 
period). At least 11 days will separate drug administrations in all treatment periods.
In the evening of 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 study drug 
administration. The subjects will then be allowed to leave the trial site after successful 
completion of the discharge assessments (incl. C-SSRS; DSST, MOAA/S, CADSS, SFST) 
and formal assessment and confirmation of their fitness. These in-house period can be 


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extended any time in case considered necessary by the investigator or if the subject failed to 
pass the discharge assessments (for details refer to Section 5.2.5.2 and 5.2.5.5). On Days 4, 6
and 8 subjects will be contacted via phone and questioned about their well-being.
 
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 times of 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.
For details on the trial procedures related to SARS-CoV-2/ COVID-19 in context of
pandemic during treatment periods, refer to Appendix 10.7.3.2.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, visual acuity tests, C-
SSRS and physical examination incl. targeted examination during the follow-up period, see
Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This is a randomised, placebo-controlled, double-blind, double-dummy, three-way cross-over 
trial applying an incomplete block design, including a washout of at least 11 days between 
the treatments (Section 3.1).
The main objective of this trial is to investigate the pharmacodynamic effects of single doses
of BI 409306 (T2) and BI 425809 (T3) on 
 
compared to placebo (R) on the basis of the pharmacodynamic endpoints listed in 
Section 2.1.2. The trial is designed to allow intra-subject comparisons and will be evaluated 
statistically by use of linear mixed effects models.
The primary and secondary PD endpoints will be compared between BI 409306 and placebo
as well as BI 425809 and placebo. The Lamotrigene (T1) treatment period acts as a positive 
control group. It is not planned to compare PD effects between Lamotrigine, BI 425809 and 
BI 409306. The primary and secondary PD endpoints will be compared between Lamotrigine
and placebo to investigate the sensitivity of the design.
7.1
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory testing is performed and hence no null and alternative hypotheses are 
defined. A justification of the sample size is provided in Section 7.5.
7.2
PLANNED ANALYSES
7.2.1
General considerations
Statistical analyses will be based on the following analysis sets:

Treated set (TS):
The treated set includes all subjects who were randomized and treated with at least 
one dose of study drug or ketamine. The treated set will be used for safety analyses.

Pharmacodynamic set (PDS):
PD analyses will be based on the PDS which is defined as all randomised patients 
who performed the post ketamine tests in at least one period. More details on the 
definition of the PDS and any potential updates will be provided in the TSAP.
All individual data will be listed.
Adherence to the protocol will be assessed by the trial team. Important protocol deviations 
(IPD) categories will be suggested in the IQRMP and specified in more detail in the TSAP, 
IPDs will be identified no later than in the Report Planning Meeting, and the IPD categories 
will be updated as needed.


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7.2.2
Primary endpoint analyses
A linear mixed effects model will be used for the analysis of the primary endpoint. This 
model will include effects for sequence, subject within sequence, period, baseline values
(obtained at screening visit 2 prior to and on ketamine) and treatment. The effect 'subject 
within sequence' will be considered as random, whereas the other effects will be considered 
as fixed. All three periods (if available) will be included in the analysis.
7.2.3
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be assessed statistically using the same 
methods as described for the primary endpoint.
7.2.5
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 11 days after the last 
dose of randomised trial medication, will be assigned to the on-treatment period for 
evaluation.
The safety analysis will be done by ‘treatment at onset’.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
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.
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.


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7.2.6
Interim analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
It is not planned to impute missing values.
7.4
RANDOMISATION
Subjects will be randomised in blocks to one of the 18 treatment sequences in a 1:1:…:1:1
ratio. Approximately equal numbers of subjects will be randomised to each sequence. The 
block size will be documented in the CTR.
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 that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
7.5
DETERMINATION OF SAMPLE SIZE
This is an exploratory trial and the sample size is not based on any formal sample size 
estimation. Based on available literature, a sample size of 36 subjects, i.e. 24 within subject
comparisons, is considered sufficient to detect relevant effects (BI 409306 versus placebo, BI 
425809 versus placebo and Lamotrigine versus placebo).
The figures in the subsequent table are based on the following assumptions:
-
Normative data in healthy subjects show a SD of about 12
-
high retest reliability of the test results in small within patient differences (with low 
variability) in case the drug is not working. The table below shows as examples SDs 
of 3, 6 and 8.
-
with increasing effect size variability of within patient differences is in increasing


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Table 7.5: 1
Probabilities to observe certain differences between periods for given 
drug effects and standard deviations for a sample size of 24 within 
subject comparison. 
Δ is the underlying true treatment difference and Δ the observed 
treatment difference.
∆
(Plc – BI)
SD(∆)
Prob(Δ<=0)
Prob(Δ>=1)
Prob(Δ>=2)
Prob(Δ>=3)
0
3
50%
5%
<0.1%
0
6
50%
21%
5%
<1%
0
8
50%
27%
11%
3%
4
6
<0.1%
99%
95%
79%
4
8
0.7%
97%
89%
73%
4
12
5%
89%
80%
66%
6
8
<0.1%
>99%
99%
97%
Based on this considerations it is unlikely to observe a difference to placebo of 2 or more 
errors with 24 within subject comparisons in case of no effect. The probability to observe a 
difference of 2 or more errors assuming a standard deviation of 3 is less than 0.1% and with 
an assumed SD of 8 about 11%. On the other hand, it is unlikely to observe a difference of 
less than 2 errors in case about 30%-50% of the 
 are 
restored resulting in a difference of presumably 4 to 6 errors or even more. In case of a true 
difference of 4 errors and an assumed SD of 12 the probability to observe a difference of at 
least 2 errors is still 80%.So, even if the variability is higher and multiple testing is 
considered the sample size of 36 subjects should suffice to detect a difference of about 30%-
50% of the ketamine induced deficit.
So far no experience exist with the trial design in this setting and sequence or period effects 
cannot be excluded a priori. Therefore the sample size of 36 subjects, i.e. 2 per sequence and 
at least 8 per period is deemed the minimum to investigate whether such effects potentially 
exist.


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


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history


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
AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 


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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) 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.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).


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The trial will be conducted at 
 
., under the supervision of the Principal Investigators. Relevant documentation 
on the participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the 
ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of local clinical trial managers (CTM), 
Clinical Research Associates, and investigators of participating trial sites
BI 409306 and matching placebo, BI 425809 and matching placebo, and matching placebo to 
lamotrigine will be provided by the 
 
. Lamotrigine and ketamine will be supplied by the pharmacies at the 
above mentioned investigators’ sites.
Safety laboratory tests will be performed by the local laboratories of the trial sites.
 
at
.
The genotyping of CYP2C19 will be performed at a contract analytical laboratory (details 
will be available prior to start of screening in the study).
 
 
.
 
.
 
 
.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES


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10.
APPENDICES


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10.2
COLUMBIA-SUICIDE SEVERITY RATING SCALE


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10.3
DIGIT SYMBOL SUBSTITUTION TEST (DSST)


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10.4
MODIFIED OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION 
(MOAA/S)


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10.5
CLINICIAN ADMINISTERED DISSOCIATIVE STATES SCALE 
(CADSS)


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10.6
STANDARDIZED FIELD SOBRIETY TEST (SFST)
The Standardized Field Sobriety Test (SFST) is a battery of three tests administered and 
evaluated in a standardized manner to obtain validated indicators of impairment, e.g. in 
persons who have used narcotics [R19-1364], [R19-1365]. These tests were developed based 
on research sponsored by the National Highway Traffic Safety Administration (NHTSA).
The three tests of the SFST are:
1. Horizontal gaze nystagmus (HGN):
Hereby the investigator asks the subject to follow a torch light, moved horizontally 
about 25-30 cm in front of the subject`s eyes, only with his eyes, i.e. without moving 
the head. Occurrence of a nystagmus is considered an abnormal finding.
2. Walk-and-turn (WAT):
In this test, the subject is directed to take nine steps, heel-to-toe, along a straight line, 
then turn on one foot and return in the same manner in the opposite.
The following signs are considered abnormal: the subject

cannot keep balance while listening to the instructions

begins before the instructions are finished

stops while walking to regain balance

does not touch heel-to-toe

steps off the line

uses arms to balance

makes an improper turn

takes an incorrect number of steps
3. One-leg stand (OLS):
The subject is instructed to stand with one foot approx. 10 cm off the ground and count 
aloud by thousands (one thousand-one, one thousand-two, etc.) until told to put the foot 
down (after 30 seconds).
Abnormal findings are:

swaying while balancing

using arms to balance

hopping to maintain balance

putting the foot down


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The SFST findings are assessed using the following table:
If the subject’s score is within the shaded area the subject may not be discharged until the 
result of control test lies within the white area.


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10.7
SARS-COV-2/ COVID-19 RELATED BENEFIT-RISK ASSESSMENT 
AND RISK MITIGATION MEASURES
10.7.1
Introduction
Due to the COVID-19 pandemic early 2020, it was assessed (based on current knowledge) if 
treatment with BI 409306 and BI 425809, as well as lamotrigine and ketamine, may pose a 
higher risk associated with SARS-CoV-2 infection. The general risk of SARS-CoV-2/ 
COVID-19 in context of the trial population’s underlying disease and common co-
morbidities was assessed as well. In addition, risk mitigation measures were implemented to 
protect study participants and personal involved in clinical trials. This document summarizes 
the benefit-risk assessment and the measures in context of COVID-19 pandemic. 
10.7.2
Benefit-Risk Assessment in Context of COVID-19 Pandemic
Risks in context of the trial medication
No additional risks related to administration of BI 409306 and BI 425809 have been 
identified. For details, refer to Benefit-Risk Assessments in context of COVID-19 pandemic 
for patients participating in clinical trials investigating BI 409306 [c32968037] and BI 
425809 [c32354247].
The exact mechanism of action of lamotrigine have not been elucidated yet. Presumably, 
lamotrigine inhibits neuronal sodium channels, thereby stabilizing neuronal membranes and 
consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., 
glutamate and aspartate). Ketamine is a non-competitive NMDA-receptor (NMDAR) 
antagonist. These effects are not expected to increase the risk of acquiring or progression of 
SARS-CoV-2/ COVID-19. So far, there is no evidence in the literature of increased risk of 
infection or severe illness upon treatment with lamotrigine or ketamine.
Considerations around drug-drug-interactions are not included in this benefit-risk assessment 
– for those it should be referred to the Investigator’s Brochures of BI 409306 and BI 425809, 
Drug Label Information of lamotrigine (
) and ketamine (
 
), and the most recent label of the respective medication(s) used for treatment of 
COVID-19.
Risks in context of the trial population:
The study is planned in male healthy volunteers 18 to 55 years of age (inclusive). This 
population does not have co-morbid medical conditions that predispose to a higher risk of 
severe COVID-19. While it is understood that in general, older age is associated with more 
severe disease, mortality was highest amongst the oldest individuals (i.e. age ≥ 65) 
[R20-1319], who are not represented in this study population.
Procedure-related risks:
During COVID-19 pandemic, participation in this clinical study will increase the risk of 
SARS-CoV-2/ COVID-19 virus infection due to traveling to the trial site, overnight stays at 
the trial site and completing the protocol-defined procedures at the trial site during 


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ambulatory visits and overnight stays. Therefore, this study will only be conducted after the 
COVID-19 situation has been managed and in accordance with the local public health 
precautions.
The risk mitigation plan has been set up at both trial sites that detail specific precautionary 
measures (e.g. hygiene rules, wearing of face masks and physical distance), screening for 
SARS-CoV-2, and discontinuation of trial treatment of subjects with confirmed SARS-CoV-
2/ COVID-19 virus infection.
Summary:
The overall benefit-risk assessment of participation in this clinical study for healthy subjects 
remains unchanged, i.e. low as indicated in Section 1.4, after consideration of COVID-19 
risks and implementation of mitigation strategies. Thus, this trial can be conducted after the 
COVID-19 situation has been managed and in accordance with the local public health 
precautions.
The investigators will take the totality of information related to each single subject and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each subject’s (continued) participation in the planned trial. BI as the sponsor, where 
required, will support the investigator in their decision finding. It is acknowledged that the 
investigator may decide to implement protocol deviations where this protects the safety, 
wellbeing and/or is in the best interest of the subject.
10.7.3
Risk Mitigation Measures in Context of COVID-19 Pandemic
10.7.3.1
Screening Period
Subjects with positive PCR test from nasal swab for SARS-CoV-2 and/ or any clinical 
symptom suggestive for COVID-19 virus infection at screening examination (V1) and each 
time within 72 hours prior to admission to trial site at screening ketamine challenge (V2) and 
treatment period 1 (V3, if subjects leave the site premises after V2) will be not eligible for
this study.
The following measures will be performed:
(1)
Study participants will be informed about, and asked to agree to SARS-CoV-2/ 
COVID-19 specific requirements with their diagnostic, therapeutic, and legal 
implications
(2)
Evaluation of subjects for SARS-CoV-2/ COVID-19 will be performed at screening 
examination (V1) and each time not later than 72 hours prior to admission to trial site at
screening ketamine challenge (V2) and treatment period 1 (V3), including

Temperature assessment

Questionnaire and medical assessment

PCR test for SARS-CoV-2 from a nasal swab sample


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10.7.3.2
Treatment Periods
Evaluation of subjects will be performed each time not later than 72 h prior to admission to 
trial site in treatment periods 2 and 3 (V4 and V5), incl. temperature assessment, 
questionnaire and medical assessment, and PCR test for SARS-CoV-2 from a nasal swab 
sample.
In case COVID-19 is suspected in a subject during trial participation, a SARS-CoV-2
PCR test and other applicable diagnostic measures (if required, e.g. CT of lungs) will be 
initiated without delay.

If COVID-19 virus infection is confirmed, the measures will include isolation,
sponsor/ authority notification, contact tracing and other as appropriate. Subjects who 
discontinue treatment should undergo the EoTrial Visit, but only after recovery from 
COVID-19 is confirmed incl. negative SARS-CoV-2 viral testing in accordance to the 
local public health precautions.

If COVID-19 virus infection is not confirmed by SARS CoV-2 PCR test and other 
applicable criteria, the treatment may be not discontinued, but the next treatment (if 
applicable) will be conservatively postponed for at least 10 days have passed since 
symptoms first appeared and at least 72 hours have passed since last fever without the 
use of fever-reducing medications and symptoms (e.g., cough, shortness of breath)
have resolved. Ultimately, clinical judgement and suspicion of SARS-CoV-2 
infection determine whether to discontinue the subject for trial treatment.
The Risk Mitigation and Response Plans fully describing the site-specific measures related to 
SARS-CoV-2/ COVID-19 (e.g. hygiene rules, wearing of face masks and physical distance) 
will be filed in the ISF.
10.7.4
Assessment of Adverse Events related to COVID-19
For any AE related to SARS-CoV-2/ COVID-19, please note the BI standard processes 
should be followed, meaning:
(1) If a SARS-CoV-2/ COVID-19 virus infection is associated with clinical symptoms (AEs):

Report as a non-serious AE, if the serious criteria are not met

Report as a SAE, if serious criteria are met – e.g., hospitalization, serious for medical 
reasons, or AE term describing the clinical symptoms is on the “always serious list”. 
The mere fact that someone is infected with the SARS-CoV-2/ COVID-19 should not 
lead to a judgement of seriousness
(2) If a SARS-CoV-2/ COVID-19 virus infection is not associated with clinical symptoms, 
meaning there is just a positive SARS-CoV-2 PCR test:

Report as a (non-serious) AE, as a positive test means a subject has an infection


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
11.1
GLOBAL AMENDMENT 1
Date of amendment
25 Aug 2020
EudraCT number
EU number
n.a.
BI Trial number
1289-0057
BI Investigational Medicinal 
Products
BI 409306, BI 425809
Title of protocol
A study in healthy men to test whether BI 409306, 
BI 425809 or lamotrigine can reverse the memory 
problems caused by ketamine
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
Title Page
Clinical Trial Protocol Synopsis
Flow Charts A-D
Sections 1-9
Appendices 10.1, 10.3-10.7
Description of change
1. BI 425809 (T3) treatment arm has been added.
Drug profile and B/R assessment related to BI 
425809 have been described.
2. The number of total entered subjects has been 
increased to 36.
3. Randomisation of subjects will be conducted 
applying incomplete block design: each subject will 
receive R treatment and 2 of 3 randomly allocated 
T1 or T2 or T3.
4. Washout period between treatments has been 
increased to 11 days 
.
5. Flow Charts B, C and D detailing procedures at 
screening examination, screening ketamine 
challenge and treatment days have been added;
Flow Chart A (Summary) has been updated.
6. 
 will be implemented 
during the breaks between the CANTAB tests (pre-
ketamine and during ketamine infusion) and in the 
start of ketamine infusion.


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8. Light breakfast and light snack (clear liquid) will 
be served not later than 5h and 2h accordingly 
before the start of ketamine infusion.
9. SARS-CoV-2 virus PCR tests are being 
implemented at screening examination and shortly 
before each admission to the study site.
10. Exclusion and Discontinuation of trial treatment 
criteria specific to SARS-CoV-2/ COVID-19 have 
been added.
11. B/R assessment and risk mitigation measures in 
context of COVID-19 pandemic have been 
summarized in Appendix 10.7.
Rationale for change
1-5. Due to progress in clinical development, BI 
425809 has been included as additional treatment 
(T3) in the study, which required further update of 
the study design.
 
.
8. Because of increased total duration of procedures 
at screening ketamine challenge and treatment days, 
meals will be served in order to avoid prolonged 
fasting and related to it common AEs.
9-11. Due to the COVID-19 pandemic, and given 
infected individuals may be clinically 
asymptomatic, the study design has been adapted to 
safeguard the subject’s safety, and exclude infected 
volunteers from study participation.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
12 Nov 2021
EudraCT number
EU number
n.a.
BI Trial number
1289-0057
BI Investigational Medicinal 
Products
BI 409306, BI 425809
Title of protocol
A study in healthy men to test whether BI 409306, 
BI 425809 or lamotrigine can reverse the memory 
problems caused by ketamine
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Clinical Trial Protocol Synopsis
2. Flow Charts C-D
3. Section 3.3.3
4. Section 5.6.1.1
Description of change
1. Number of subjects in each treatment has been 
clarified. Criteria of normative performance on 
CANTAB PAL test have been clarified.
2. In Screening V2, admission of subjects is 
allowed in the evening before the screening 
ketamine challenge.
In V2-V5, admission in the morning of ketamine 
challenge is also possible at discretion of the 
Investigator or designee.
3. Exclusion criteria have been clarified.
4. Methods of pharmacogenomics sample collection
have been adapted to include requirements of the 
sites’ local laboratories, as well as the central lab
Rationale for change
Changes are based on the need to facilitate and 
operationally adapt the procedures of Screening 
Visit 2 by including an overnight stay prior to 
screening ketamine challenge. With this amendment 
minor inconsistencies in the study protocol have 
been corrected and other protocol clarifications 
have been provided.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26985010
3.0
clinical-trial-protocol-version-03
A randomized, placebo controlled, double-blind, double-dummy three-way cross
over trial to investigate the effect of BI 409306, BI 425809 and lamotrigine on
ketamine-induced cognitive deficits in healthy male subjects
Author-Clinical Trial Leader
16 Nov 2021 12:46 CET
Verification-Paper Signature
Completion
18 Nov 2021 09:32 CET
Approval-Team Member Medicine
18 Nov 2021 20:27 CET
Approval-Biostatistics
19 Nov 2021 13:00 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26985010
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
                     c40434427-01
BI Trial No.:
1289-0057
Title:
A randomized, placebo controlled, double-blind, double-dummy 
three-way cross over trial to investigate the effect of BI 409306, 
BI 425809 and lamotrigine on ketamine-induced cognitive 
deficits in healthy male subjects
Including Protocol Amendment 1 [c26985010-02]
Including Protocol Amendment 2 [c26985010-03]
Investigational
Product:
BI 409306, BI 425809
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
14-Oct-2022 SIGNED
Version:
1
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reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINTS...................................................................................10
5.2
SECONDARY ENDPOINT ...............................................................................10
5.2.1
Key secondary endpoints....................................................................................10
5.2.2
Secondary endpoint.............................................................................................10
5.3.1
Safety parameters ...............................................................................................10
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 .................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................20
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................20
7.
PLANNED ANALYSIS......................................................................................25
7.1
DISPOSITION, DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS........................................................................................26
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................26
7.3
TREATMENT COMPLIANCE........................................................................26
7.4
PRIMARY ENDPOINTS...................................................................................26
7.4.1
Primary analysis of the primary endpoint........................................................26
7.5
SECONDARY ENDPOINTS.............................................................................28
7.5.1
Key secondary endpoints....................................................................................28
7.5.2
Secondary endpoints...........................................................................................28
7.5.2.1
Secondary endpoint analysis.................................................................................28


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7.6.1
Safety parameters ...............................................................................................29
7.7
EXTENT OF EXPOSURE.................................................................................31
7.8
SAFETY ANALYSIS..........................................................................................31
7.8.1
Adverse Events ....................................................................................................31
7.8.2
Laboratory data ..................................................................................................33
7.8.3
Vital signs.............................................................................................................33
7.8.4
ECG......................................................................................................................33
7.8.5
Others...................................................................................................................33
7.8.5.1
Physical examination ............................................................................................33
7.8.5.2
Body weight ..........................................................................................................34
7.8.5.3
Suicidality assessment...........................................................................................34
7.8.5.5
Visual acuity test...................................................................................................34
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............35
11.
HISTORY TABLE..............................................................................................38


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs and actual treatment for 
analysis of vital signs .......................................................................................15
Table 6.3: 1
Subject sets analysed........................................................................................19
Table 11: 1
History table .....................................................................................................38


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
 
BI 
Boehringer Ingelheim
BP
Blood pressure
CADSS
Clinician Administered Dissociative States Scale
CANTAB
Cambridge Neuropsychological Test Automated Battery
 
COVID
Coronavirus disease
C-SSRS
Columbia Suicidal Severity Rating scale
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DSST
Digit Symbol Substitution Test
ECG
Electrocardiogram
FU
Follow-up
gCV
Geometric coefficient of variation


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Term
Definition / description
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
IQRMP
Integrated Quality and Risk Management Plan
MedDRA
Medical Dictionary For Regulatory Activities
MOAA/S
Modified Observer's Assessment of Alertness/Sedation
PAL
Paired Associates Learning
PK
Pharmacokinetic(s)
PD
Pharmacodynamic(s)
PDS
Pharmacodynamic set
PR
Pulse rate
RAGe
Report appendix generator
REP
Residual effect period
RPM
Report Planning Meeting
RVP
Rapid Visual Information Processing
SAE
Serious adverse event
SaO2
Oxygen saturation
SD
Standard Deviation
SFST
Standardized Field Sobriety Test
SOC
System Organ Class


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Term
Definition / description
SWM
Spatial Working Memory
 
 
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range
VA
Visual acuity
WHO
World Health Organization


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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 revised CTP, and to 
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its 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 revised CTP 
for more background information on the study, e.g., on study objectives, study design and 
population, treatments, definition of measurements and variables, planning of sample size, 
randomisation.
Study data as collected in the eCRF will be stored in a trial database within the RAVE EDC 
system. All study data also including external data will then be uploaded to the CDR data 
warehouse.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
In addition to the CTP-described analysis summary statistics as well as profile plots will be 
provided for the primary and secondary endpoint. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All other analyses described in this TSAP are in accordance with the statistical methods 
described in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary endpoint of BI 409306, BI 425809, lamotrigine and placebo is as named in 
Section 2.1.2 and defined in Section 5.4.1.1 of the CTP:

PAL Total Errors Adjusted (PALTEA28) on ketamine
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoint
The secondary endpoints of BI 409306, BI 425809, lamotrigine and placebo are as named in 
Section 2.1.3 and defined in Sections 5.4.1.2 and 5.4.1.3 of the CTP:

SWM Between Errors (SWMBE468) on ketamine

RVP A’ Prime (RVPA) on ketamine
5.3.1
Safety parameters
Safety and tolerability of BI 409306, BI 425809, lamotrigine, placebo and ketamine will be 
assessed based on further safety parameters named in Section 2.2.2.3 and defined in 
Section 5.2 of the CTP:

Adverse events (including clinically relevant findings from the physical examination
incl. targeted examination, visual acuity test, vital signs; as well as clinically relevant 
abnormal results in C-SSRS and safety tests (DSST, MOAA/S, CADSS and SFST))

Safety laboratory tests (only abnormal findings will be reported as AEs)1

12-lead ECG and continuous ECG monitoring (only abnormal findings will be 
reported as AEs)

Vital signs (BP, PR, SaO2)2

Suicidality assessment (C-SSRS)
1 According to the CTP Section 5.2.3 safety laboratory test results will only be kept in the 
source data but not collected in the CRF. Clinically relevant abnormal findings will be 
reported as AEs.


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2 According to the CTP Section 5.2.2 SaO2 will only be kept in the source data but not 
collected in the CRF. Clinically relevant abnormal findings will be reported as AEs.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment 
groups, and selection of doses, cf. Section 4 of the CTP.
Each subject is planned to be treated in three subsequent treatment periods with one single 
dose at Day 1 in each treatment period:

Test treatment 1 (T1):
300 mg of Lamotrigine as tablet

Test treatment 2 (T2):
of BI 409306 as film-coated tablet

Test treatment 3 (T3):
of BI 425809 as film-coated tablet

Reference treatment (R):
Placebo as film-coated tablet
Each subject is planned to be randomly allocated to one of 18 3-period sequences including 
placebo in one of the periods and 2 out of 3 active treatments in the remaining periods: 
T1–T2–R, T1–R–T2, T1–T3–R, T1–R–T3, T2–T1–R, T2–R–T1, T2–T3–R, T2–R–T3, T3–
R–T1, T3–T1–R, T3–T2–R, T3–R–T2, R–T1–T2, R–T2–T1, R–T1–T3, R–T3–T1, R–T2–
T3, R–T3–T2. 
Each treatment period is separated by a washout period of at least 11 days.
: The Residual Effect Period (REP) 
 
, for lamotrigine 10 days, and for ketamine 24 hours. This is the period 
after the last dose with measurable drug levels and/or pharmacodynamic effects is still likely 
to be present.
For statistical analyses of AEs and vital signs, the following separate analysis phases will be 
defined for each subject:


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Table 6.1: 1
Analysis phases for statistical analysis of AEs and actual treatment for 
analysis of vital signs
Study 
analysis 
phase
Label of analysing 
treatment
Label of actual treatment
Start
End
Screening
Screening
Screening
Date of informed consent
Start date/time of screening 
ketamine infusion
Screening+Ketamine
Start date/time of screening 
ketamine infusion
End date/time of screening 
ketamine infusion + 24 h 
Screening
End date/time of screening 
ketamine infusion + 24 h 
Start date/time of first 
administration of study treatment 
(Planned time: 00:00h) in the 
respective treatment period
On 
treatment
1, 2, 3
Placebo,
 BI 409306,
BI 425809 or
300mg Lamotrigine,
respectively
Placebo,
 BI 409306,
 BI 425809 or
300mg Lamotrigine,
respectively
Start date/time of 
administration of the first 
study treatment (Planned 
time: 00:00h) in the 
respective treatment period
Start date/time of on-treatment 
ketamine infusion
or
12:00 a.m. on day after subject's 
trial completion date,
whatever comes first
Placebo+Ketamine,
 BI 
409306+Ketamine,
 BI 
425809+Ketamine or
300mg 
Lamotrigine+Ketamine,
respectively
Start date/time of on-
treatment ketamine infusion
End date/time of on-treatment 
ketamine infusion + 24 h
or
12:00 a.m. on day after subject's 
trial completion date,
whatever comes first 
Placebo,
BI 409306,
BI 425809 or
300mg Lamotrigine,
respectively
End date/time of on-
treatment ketamine infusion 
+ 24 h 
Start date/time of administration of 
the second study treatment 
(Planned time: 03:00h) in the 
respective treatment period + 11 
days * 24 h/day (for BI 409306, BI 
425809, lamotrigine and placebo)
or
Date/time of administration of 
study drug in the next treatment 
period
or
12:00 a.m. on day after subject's 
trial completion date,
whatever comes first
Follow-up
F/U Placebo,
F/U 
 BI 
409306,
F/U 
 BI 425809 
or
F/U 300mg 
Lamotrigine,
respectively
F/U Placebo,
F/U 
 BI 409306,
F/U 
 BI 425809 or
F/U 300mg 
Lamotrigine,
respectively
Start date/time of 
administration of the second
study treatment (Planned 
time: 03:00h) in the 
respective treatment period 
+ 11 days * 24 h/day (for BI 
409306, BI 425809, 
lamotrigine and placebo)
Date/time of administration of the 
respective treatment in the next 
treatment period, if applicable,
or
12:00 a.m. on day after subject's 
trial completion date,
whatever comes first.
1 See Section 6.7 for definition of baseline, which will be used in the statistical analyses of 
vital signs.
2 A REP of 11 days will be used for all study treatments (BI 409306, BI 425809, lamotrigine
and placebo) to avoid any bias which might occur due to different observation times. This 
may lead to an overestimation of AEs in the treatment periods in which subjects received a 
study treatment with considerably lower REP.


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3 The on-treatment phase extends from Day 1 00:00h (planned time) to Day 11 03:00h 
(planned time) to include AEs which occur after the start of the first study drug (or 
corresponding placebo) administration (which is not necessarily the analysing treatment of 
the respective treatment period) as well as AEs which occur within the REP of the second 
study drug (or corresponding placebo).
Analysis phases for statistical analysis of AEs are defined for each subject as described in 
Table 6.1: 1.
AE summary tables will present results for the on-treatment phase only. All AEs will be 
listed.
In AE tables in CTR Section 15.3 (but not in displays for ClinicalTrials.gov) the following 
total will be provided in addition:

"Total on-trt", defined as the total over all on-treatment phases
Listings of AEs presented in Section 15.4 will display results for the screening, on-treatment 
and follow-up phases (labelled with the name of the study treatment (short label)).
AE tables and listings will be displayed by analysing treatment. Beyond that, listings will 
include an additional column for the actual treatment (defined in Table 6.1: 1).
Vital signs, ECG, CANTAB, 
will be analysed based on the respective 
treatment (Placebo, BI 409306, BI 425809 or Lamotrigine) with clear differentiation between 
baseline (cf. Section 6.7) and post-baseline measurements. Measurements will be considered 
on-treatment, if they were taken within the on-treatment phases as defined in Table 6.1: 1. 
ECG measurements are considered to be on-treatment if they were measured between the 
first administration of the respective treatment and the corresponding residual effect period 
after the last administration of the respective treatment.
Vital signs listings will include an additional column for the actual treatment (defined in 
Table 6.1: 1).
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting. At this meeting, it will be 
decided whether a discrepant data value can be used in analyses, must be corrected in the 
clinical database or constitutes a PD. 
Each protocol deviation must be assessed to determine whether it is an important PD (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).


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If any IPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be IPDs in this trial are defined in the 
DV domain template. If the data show other IPDs, the definition in the DV domain template
will be supplemented accordingly by the time of the Report Planning Meeting.
CTP Section 7.2.1: Important protocol deviations (IPD) categories will be suggested in the 
IQRMP and specified in more detail in the TSAP, IPDs will be identified no later than in the 
Report Planning Meeting, and the IPD categories will be updated as needed.
IPDs will be summarized and listed. Which kind of IPDs could potentially lead to exclusion 
from which analysis set is specified in the DV domain template. The decision on exclusion of 
subjects from analysis sets will be made at the latest at the Report Planning Meeting, after 
discussion of exceptional cases and implications for analyses. If the data show other IPDs, 
this table will be supplemented accordingly by the time of the Report Planning Meeting.
Non-important COVID-19 related PDs will only be listed.
6.3
SUBJECT SETS ANALYSED
Subject sets will be used as defined in Section 7.2.1 of the CTP:

Treated set (TS):
The treated set includes all subjects who were randomized and treated with at least 
one dose of study drug or ketamine. The treated set will be used for safety analyses.

Pharmacodynamic set (PDS):
PD analyses will be based on the PDS which is defined as all randomised patients 
who performed the post ketamine tests in at least one period.
The following additional subject sets will be used:

Screened set (SCS):
This set includes all subjects who signed the informed consent form.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
SCS
TS
PDS
Disposition
X
iPDs
X
Primary endpoint –
PALTEA28
X
Secondary endpoint –
SWMBE468 
X
Secondary endpoint –
RVPA
X
X
X
X
X
X
X
Safety parameters 
X
Demographic/baseline 
characteristics
X
Treatment exposure
X
 
6.5
POOLING OF CENTRES
Data from both centers involved in this trial will be pooled.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
CTP Section 3.3.4: “If a subject is removed from or withdraws from the trial prior to the first 
administration of trial medication (BI 425809 or BI 409306 or lamotrigine or placebo) or 
ketamine, the data of this subject will not be entered in the case report form (CRF) and will 
not be reported in the clinical trial report (CTR). If a subject is removed from or withdraws 
from the trial after the first administration of trial medication, this will be documented and 
the reason for discontinuation must be recorded in the CRF; in addition, the data will be 
included in the CRF and will be reported in the CTR.“
CTP Section 7.3: “It is not planned to impute missing values.”
One exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Due to the different analysing approaches with regard to the consideration of ketamine,
baselines for pharmacodynamic and safety endpoints are defined separately.
On-ketamine analysis of CANTAB,
 parameters (according to Section 
2.2.2.2 of the CTP):
CTP Section 6.2.1: “For the Screening Ketamine Challenge eligible subjects will come to the 
clinic in the morning of the test day, where they will participate in two assessment-sessions:

Screening Baseline (= SCR BL)
CANTAB tests, 
 will be done without any treatment, 
i.e. with no ketamine infusion

Screening Ketamine (= SCR KET)
CANTAB tests, 
 will be done during ketamine 
infusion
[…]
The assessments of SCR KET will also be used as baseline for the assessments performed on 
the test days of the treatment periods, i.e. under treatments T1, T2, T3 and R.”
For the analysis of the pharmacodynamic endpoints (CANTAB tests, 
 
 two baselines exist. The pre-ketamine baseline is defined as the last non-
missing value prior to start of ketamine infusion at screening. The during-ketamine baseline 
is defined as the first non-missing value during ketamine infusion at screening.


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Safety analyses:
For safety analyses the baseline is defined as the last available value prior to administration 
of the respective treatment.
For ECG as well as vital signs a separate baseline can be defined for each treatment period as 
a pre-dose assessment on Day 1 (at Visit 3/4/5) is available.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the Report Planning Meeting.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment or 
sequence group, subject number and visit (if visit is applicable in the respective listing). AE 
listings will be sorted by assigned treatment (see Section 7.8.1 below for details). The listings 
will be contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DISPOSITION, DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. Whereas disposition will 
be based on the SCS, demographics and other baseline characteristics will be presented based 
on the TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
Only descriptive statistics based on the TS are planned for this section of the CTR.
CTP Section 4.2.2.1: “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.”
A medication will be considered concomitant to a treatment period, if it

is ongoing at the time of study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
Concomitant medications as well as their time relative to the previous and subsequent study 
drug administration will be listed.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoint
The analysis of the primary endpoint will be based on the PDS.
CTP Section 7.2.2: “A linear mixed effects model will be used for the analysis of the primary 
endpoint. This model will include effects for sequence, subject within sequence, period, 
baseline values (obtained at screening visit 2 prior to and on ketamine) and treatment. The 


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effect 'subject within sequence' will be considered as random, whereas the other effects will 
be considered as fixed. All three periods (if available) will be included in the analysis.”
The corresponding baseline values are described in Section 6.7 of this TSAP (see baseline 
definition for ‘On-ketamine analysis of CANTAB, 
 parameters 
(according to Section 2.2.2.2 of the CTP)’).
The model is described by the following equation:
yijklmp = µ + i + sim + j + k + p + l + eijklmp, where
yijklmp = response measured on subject m in sequence i receiving treatment k in period j with 
pre-ketamine baseline p and during-ketamine baseline l
µ = 
the overall mean,
i = 
the ith sequence effect, i = 1, 2, …, 18
sim = 
the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni
j = 
the jth period effect, j = 1, 2, 3
k = 
the kth treatment effect, k = 1, 2, 3, 4
p =    the pth pre-ketamine baseline effect, p = 1, …, 40
l =    the lth during-ketamine baseline effect, l = 1, …, 40
eijklmp = the random error associated with subject m in sequence i who received treatment k in 
period j with pre-ketamine baseline p and during-ketamine baseline l
where sim ~ N(0,σ2) i.i.d., eijklmp ~ N(0,σ2) i.i.d. and sim, eijklmp are independent random
variables.
CTP Section 7: The primary and secondary PD endpoints will be compared between BI 
409306 and placebo as well as BI 425809 and placebo. The Lamotrigine (T1) treatment 
period acts as a positive control group. It is not planned to compare PD effects between 
Lamotrigine, BI 425809 and BI 409306. The primary and secondary PD endpoints will be 
compared between Lamotrigine and placebo to investigate the sensitivity of the design.
In addition the primary endpoint will be analysed descriptively for each study treatment.
N, mean, SD, median, minimum and maximum will be provided for absolute values as well 
as for the change from baseline. Additionally placebo-corrected values will be presented as 
difference between the value of the respective study treatment and the value of placebo. 


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Profile plots will be provided to display absolute pre- and during-ketamine values at baseline 
as well as for each treatment period.
 
 
 
 
 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The analysis of the secondary endpoints will be based on the PDS.
 
 
7.5.2.1
Secondary endpoint analysis
According to the CTP Section 7.2.3 the secondary endpoints will be assessed statistically 
using the same methods as described for the primary endpoint (see also Section 7.4.1 of this 
TSAP).
 
 
 


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7.6.1
Safety parameters
Safety and tolerability endpoints will be analysed as described in Section 7.8 of this TSAP.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses for BI 409306, BI 425809, lamotrigine and ketamine will be performed on 
the TS.
CTP Section 7.2.5: “The safety analysis will be done by ‘treatment at onset’.”
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
All AEs will be assigned to the screening, on-treatment or follow-up phase as defined in 
Section 6.1. AEs will be analysed based on treatments as actually received, defined in Table 
6.1: 1.


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CTP Section 7.2.5: “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’.”
The longest REP, i.e. 11 days will be taken for all study treatments (Placebo, BI 409306, BI 
425809 and Lamotrigine) to avoid any bias which might occur due to different observation 
times. This may lead to an overestimation of AEs in the treatment periods in which subjects 
received a study treatment with considerably lower REP.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of AESIs.
CTP Section 5.2.6.1.4: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
○
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 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted).
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs will also be summarized by maximum intensity. AEs which were 
considered by the investigator to be drug related will be presented separately. Separate tables 
will also be provided for subjects with SAEs, related SAEs and subjects with AESIs.
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.
All AEs occurring in screening, on-treatment and follow-up phase will be listed.
7.8.2
Laboratory data
No analyses are planned as safety laboratory test results will only be kept in the source data
but not collected in the CRF (according to the CTP Section 5.2.3). Clinically relevant 
abnormal findings will be reported as AEs.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Unscheduled measurements of vital signs will be assumed to be repeat measurements of the 
most recent scheduled measurement (e.g. for follow-up or confirmation of a particular value). 
Therefore, unscheduled measurements will be assigned to the planned time point of the 
previous scheduled measurement. However, for vital signs, descriptive statistics will be 
calculated by planned time point based on the last value of the subject at that planned time 
point (or assigned to that planned time point). If the time of measurement is missing for a 
scheduled post-baseline measurement, the scheduled measurement will be used in calculation 
of descriptive statistics (as time difference between scheduled and unscheduled cannot be 
assessed).
If the time of measurement is missing for an unscheduled measurement, this measurement 
will be listed but will be ignored for the calculation of descriptive statistics.
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study
treatment) if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Abnormal findings in ECG will be reported as baseline conditions (at screening) or as AEs 
(during the trial) if judged clinically relevant by the investigator, and will be analyzed as 
such. No separate listing or analysis of ECG data will be prepared.
7.8.5
Others
7.8.5.1
Physical examination
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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7.8.5.2
Body weight 
Body weight will only be listed.
7.8.5.3
Suicidality assessment
Suicidality monitoring will be performed as described in Section 5.2.5.2 of the CTP, results 
will be listed. Additionally, the frequency of subjects categorized by any question answered 
with ‘Yes’ (or all answered with ‘No’ or missing) will be presented. Results for subjects who 
answered any question with ‘Yes’ will additionally be listed. Findings will also be reported as 
AEs.
 
 
7.8.5.5
Visual acuity test
The visual acuity test will be performed as described in Section 5.2.5.4 of the CTP.
Any deterioration occurring during the study will be documented as an AE.
 
 
 
 
 
 


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


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Boehringer Ingelheim
TSAP for BI Trial No: 1289-0057
c40434427-01
Page 38 of 38
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
14-Oct-2022
None
First final TSAP version