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Clinical Trial Results:
A phase II randomized, double-blinded, placebo-controlled, parallel group trial to examine the efficacy and safety of 4 oral doses of BI 1358894 once daily over 12-week treatment period in patients with borderline personality disorder

Summary
EudraCT number	2020-000078-12
Trial protocol	SE FR PL DE BG DK CZ BE IT RO
Global end of trial date	25 Jan 2023

Results information
Results version number	v1(current)
This version publication date	07 Feb 2024
First version publication date	07 Feb 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1402-0012

ISRCTN number

US NCT number

NCT04566601

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim, Boehringer Ingelheim, Call Center, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.co

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

10 Mar 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Dec 2022

Global end of trial reached?

Yes

Global end of trial date

25 Jan 2023

Was the trial ended prematurely?

Main objective of the trial

The main objectives of this trial were to provide proof of concept (PoC) and dose-ranging data of BI 1358894 compared to placebo in patients with borderline personality disorder (BPD) to support dose selection for pivotal studies.

Protection of trial subjects

A log of all patients enrolled into the trial (i.e. who had signed informed consent) was maintained in the Investigator site file (ISF) irrespective of whether they have been treated with investigational medication or not. If a patient was enrolled in error (did not meet all inclusion criteria or met one or more exclusion criteria on the day of enrolment), the sponsor was to be contacted immediately. After premature trial medication discontinuation, patients were to be asked to further attend scheduled trial visits unless they withdrew consent to participate in the trial. If it was not possible to attend all visits, at least phone contacts were to occur at the scheduled visit time points. It was vital to explain to patients the importance of continuing trial participation and the value of collecting data for all randomised patients. This text was added in Global Amendment 1 of the clinical trial protocol (CTP). If new efficacy or safety information became available, Boehringer Ingelheim was to review the benefit-risk-assessment and, if needed, pause or discontinue the trial medication for all patients or take any other appropriate action to guarantee the safety of the trial patients. Even if the trial medication was discontinued, the patients were asked to remain in the trial and, given their agreement, underwent the procedures for early treatment discontinuation and follow-up as outlined in the CTP.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Nov 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 82

Country: Number of subjects enrolled

Australia: 31

Country: Number of subjects enrolled

Belgium: 9

Country: Number of subjects enrolled

Bulgaria: 17

Country: Number of subjects enrolled

Czechia: 27

Country: Number of subjects enrolled

Denmark: 6

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 64

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Japan: 19

Country: Number of subjects enrolled

Mexico: 64

Country: Number of subjects enrolled

Poland: 24

Country: Number of subjects enrolled

Spain: 7

Country: Number of subjects enrolled

Sweden: 15

Country: Number of subjects enrolled

United States: 283

Worldwide total number of subjects

655

EEA total number of subjects

176

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

654

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Eligible patients with BPD were randomised to receive either BI 1358894 or placebo in a 2.5:1:1:1:2 ratio (placebo or BI 1358894 5 milligram (mg), 25 mg, 75 mg, or 125 mg), for 12 weeks. This trial included a screening period, a 12-week randomised treatment period, and a 4-week follow-up period.

Screening details

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Carer, Data analyst, Assessor, Subject

Blinding implementation details

Study medications were administered double-blinded. In order to maintain blinding in regard to each treatment, each dose contained 4 tablets in a double-dummy design. Double-dummy design was required since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes. Placebo tablets were identical in size and appearance to the corresponding active tablet and were combined with active tablets as needed in each dose group to maintain the blinding.

Are arms mutually exclusive

Yes

Placebo

Arm description

In order to maintain blinding in regard to each treatment group since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes, patients were administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 5 milligram (mg), one film-coated tablet of placebo matching BI 1358894 25 mg and two film-coated tablets of placebo matching BI 1358894 50 mg.

Arm type

Placebo

Investigational medicinal product name

Placebo matching BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Patients were administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 5 milligram (mg), one film-coated tablet of placebo matching BI 1358894 25 mg and two film-coated tablets of placebo matching BI 1358894 50 mg.

BI 1358894 5mg

Arm description

Patients were administered for 12 weeks once daily, orally one film-coated tablet of 5 milligram (mg) of BI 1358894. In order to maintain blinding in regard to each treatment group since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes, patients were also administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 25 mg and two film-coated tablets of placebo matching BI 1358894 50 mg.

Arm type

Experimental

Investigational medicinal product name

Placebo matching BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

In order to maintain blinding in regard to each treatment group since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes, patients were also administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 25 mg and two film-coated tablets of placebo matching BI 1358894 50 mg.

Investigational medicinal product name

BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Patients were administered for 12 weeks once daily, orally one film-coated tablet of 5 milligram (mg) of BI 1358894.

BI 1358894 25mg

Arm description

Patients were administered for 12 weeks once daily, orally one film-coated tablet of 25 milligram (mg) of BI 1358894. In order to maintain blinding in regard to each treatment group since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes, patients were also administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 5 mg and two film-coated tablets of placebo matching BI 1358894 50 mg.

Arm type

Experimental

Investigational medicinal product name

Placebo matching BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

In order to maintain blinding in regard to each treatment group since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes, patients were also administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 5 mg and two film-coated tablets of placebo matching BI 1358894 50 mg.

Investigational medicinal product name

BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Patients were administered for 12 weeks once daily, orally one film-coated tablet of 25 milligram (mg) of BI 1358894.

BI 1358894 75mg

Arm description

Patients were administered for 12 weeks once daily, orally one film-coated tablet of 25 milligram (mg) of BI 1358894 and one film-coated tablet of 50 milligram (mg) of BI 1358894 (total BI 1358894 dose=75 mg). In order to maintain blinding in regard to each treatment group since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes, patients were also administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 5 mg and one film-coated tablet of placebo matching BI 1358894 50 mg.

Arm type

Experimental

Investigational medicinal product name

Placebo matching BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

In order to maintain blinding in regard to each treatment group since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes, patients were also administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 5 mg and one film-coated tablet of placebo matching BI 1358894 50 mg.

Investigational medicinal product name

BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

BI 1358894 125mg

Arm description

Patients were administered for 12 weeks once daily, orally one film-coated tablet of 25 milligram (mg) of BI 1358894 and two film-coated tablets of 50 milligram (mg) of BI 1358894 (total BI 1358894 dose=125 mg). In order to maintain blinding in regard to each treatment group since BI 1358894 tablets (5 mg, 25 mg, 50 mg) are different sizes, patients were also administered for 12 weeks once daily, orally one film-coated tablet of placebo matching BI 1358894 5 mg.

Arm type

Experimental

Investigational medicinal product name

Placebo matching BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg
Started	128	52	53	53	104
Completed	95	40	35	40	77
Not completed	33	12	18	13	27
Adverse event, non-fatal	7	4	6	5	12
Technical problems	-	-	1	-	-
Perceived lack of efficacy	2	-	1	1	2
Protocol deviation	3	-	1	1	1
No reason available	3	2	7	1	5
Burden of study procedures	3	-	-	3	1
Change of residence	2	2	-	1	2
Other than listed	13	4	2	1	4

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of 655 enrolled subjects only 390 were randomized.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

BI 1358894 5mg

Reporting group description

Reporting group title

BI 1358894 25mg

Reporting group description

Reporting group title

BI 1358894 75mg

Reporting group description

Reporting group title

BI 1358894 125mg

Reporting group description

Reporting group values	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg	Total
Number of subjects	128	52	53	53	104	390
Age categorical
Treated Set (TS).
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	128	52	53	53	103	389
From 65-84 years	0	0	0	0	1	1
85 years and over	0	0	0	0	0	0
Age Continuous
Treated Set (TS).
Units: years
arithmetic mean (standard deviation)	30.4 ± 9.9	29.2 ± 9.6	31.0 ± 11.1	30.6 ± 9.7	29.9 ± 11.2	-
Sex: Female, Male
Treated Set (TS).
Units: Participants
Female	107	50	48	48	83	336
Male	21	2	5	5	21	54
Race (NIH/OMB)
Treated Set (TS).
Units: Subjects
American Indian or Alaska Native	5	2	1	1	6	15
Asian	2	3	2	4	7	18
Native Hawaiian or Other Pacific Islander	1	0	0	0	0	1
Black or African American	8	3	3	1	4	19
White	112	44	46	46	85	333
More than one race	0	0	1	1	2	4
Unknown or Not Reported	0	0	0	0	0	0
Ethnicity (NIH/OMB)
Treated Set (TS).
Units: Subjects
Hispanic or Latino	50	17	25	20	34	146
Not Hispanic or Latino	78	35	28	33	70	244
Unknown or Not Reported	0	0	0	0	0	0
ZAN−BPD total score at Baseline
The ZANarini rating scale for Borderline Personality Disorder (ZAN-BPD) reflects the nine DSM-5 (Diagnostic and Statistical Manual of Mental Disorders) criteria and the scale has 4 domain scores that reveal core areas of BPD (i.e., affective, cognitive, impulsive and interpersonal symptoms). The ZAN-BPD scale includes a 5-point rating scale (i.e., 0 = no symptoms to 4 = severe symptoms) for each criterion. The total ZAN-BPD score is the sum of the 4 domain scores and ranges from 0 to 36 where higher scores mean severe symptoms. Treated Set (TS).
Units: score on a scale
arithmetic mean (standard deviation)	16.6 ± 5.0	15.7 ± 5.4	15.8 ± 4.8	16.1 ± 4.6	16.4 ± 5.2	-

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

BI 1358894 5mg

Reporting group description

Reporting group title

BI 1358894 25mg

Reporting group description

Reporting group title

BI 1358894 75mg

Reporting group description

Reporting group title

BI 1358894 125mg

Reporting group description

Subject analysis set title

Full analysis set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

FAS consisted of all patients in TS who had a baseline and at least 1 evaluable post-baseline measurement for the primary endpoint. This was the main analysis set for the evaluation of efficacy data.

Subject analysis set title

Treated set (TS)

Subject analysis set type

Per protocol

Subject analysis set description

TS) consisted of all patients who were randomised and that received at least 1 administration of trial medication. The TS was the main analysis set for the evaluation of safety. Patients were analysed according to the actual received treatment.

Primary: Change from baseline in Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD) total score at Week 10

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End point title

Change from baseline in Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD) total score at Week 10

End point description

The ZAN-BPD scale reflects the nine DSM-5 criteria and the scale has 4 domain scores that reflect core areas of BPD (i.e., affective, cognitive, impulsive and interpersonal symptoms). The ZAN-BPD scale includes a 5-point rating scale (i.e., 0 = no symptoms to 4 = severe symptoms) for each criterion. The total ZAN-BPD score is the sum of the 4 domain scores and ranges from 0 to 36 where higher scores mean severe symptoms. Least squares means and 95% confidence intervals were estimated by restricted maximum likelihood-based mixed effects mixed repeated measures (REML-based MMRM). LS mean (standard error) for Week 10 are reported. Since the MMRM included the measurements from baseline, Week 1, Week 2, Week 4, Week 6, Week 8 and Week 10, number of participants analyzed for the primary endpoint for each arm are the participants who had a ZAN-BPD score value at baseline and one ZAN-BPD score value at one of the post-baseline timepoints up to Week 10.

End point type

Primary

End point timeframe

The change from baseline at Week 10 in the total ZAN-BPD score was calculated using the MMRM model which is a longitudinal analyses and it incorporates ZAN-BPD measurements from baseline, Weeks 1, 2, 4, 6, 8 and Week 10.

End point values	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg
Number of subjects analysed	124 ^[1]	52 ^[2]	52 ^[3]	52 ^[4]	102 ^[5]
Units: units on a scale
least squares mean (standard error)	-8.7 ± 0.5	-8.0 ± 0.9	-9.2 ± 0.9	-8.9 ± 0.8	-9.0 ± 0.6

Notes
[1] - Full analysis set (FAS).
[2] - Full analysis set (FAS).
[3] - Full analysis set (FAS).
[4] - Full analysis set (FAS).
[5] - Full analysis set (FAS).

MMMRM "Placebo" vs. "BI 1358894 5mg"

Statistical analysis description

Least Squares (LS) mean difference and 95 % confidence interval were estimated by REML−based MMRM including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the baseline ZAN−BPD total score strata indicator (<=18 vs. >=19), the continuous fixed covariate of baseline ZAN−BPD total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. LS means differences (95 % confidence intervals) for Week 10 are reported.

Comparison groups

BI 1358894 5mg v Placebo

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.4994 ^[7]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.31

upper limit

2.69

Notes
[6] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 5mg" - Least Squares Mean of "Placebo".
[7] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 75mg"

Statistical analysis description

Comparison groups

Placebo v BI 1358894 75mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[8]

P-value

= 0.8166 ^[9]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.17

upper limit

1.72

Notes
[8] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 75mg" - Least Squares Mean of "Placebo".
[9] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 125mg"

Statistical analysis description

Comparison groups

Placebo v BI 1358894 125mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.6588 ^[11]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.96

upper limit

1.24

Notes
[10] - No formal hypotheses were tested. Mean Difference (Net)=Least Squares Mean of "BI 1358894 125mg" - Least Squares Mean of "Placebo".
[11] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 25mg"

Statistical analysis description

Comparison groups

Placebo v BI 1358894 25mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.6014 ^[13]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.6

upper limit

1.51

Notes
[12] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 25mg" - Least Squares Mean of "Placebo".
[13] - P-value is considered nominal.

MCP-Mod sigmoid Emax model fit

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 1358894 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.100).

Comparison groups

Placebo v BI 1358894 5mg v BI 1358894 25mg v BI 1358894 75mg v BI 1358894 125mg

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.3914

Method

MCP-Mod sigmoid Emax model fit

Confidence interval

Notes
[14] - MMRM estimates were used as input for the MCP-Mod. MMRM included the fixed categorical covariates of treatment, visit (baseline, Week 1, 2, 4, 6, 8, 10) and the baseline ZAN−BPD total score strata indicator (<=18 vs. >=19), the continuous fixed covariate of baseline ZAN−BPD total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Sigmoid Emax model assumption: 50% of the maximum effect is achieved at 25 mg, and 90% of the maximum effect is achieved at 75 mg.

MCP-Mod Emax1 model fit

Statistical analysis description

Comparison groups

Placebo v BI 1358894 5mg v BI 1358894 25mg v BI 1358894 75mg v BI 1358894 125mg

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

= 0.4104

Method

MCP-Mod Emax1 model fit

Confidence interval

Notes
[15] - MMRM estimates were used as input for the MCP-Mod. MMRM included the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10 and 12) and the baseline ZAN−BPD total score strata indicator (<=18 vs. >=19), the continuous fixed covariate of baseline ZAN−BPD total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Emax1 model assumption: 50% of the maximum effect is achieved at 25 mg.

MCP-Mod linear model fit

Statistical analysis description

Comparison groups

Placebo v BI 1358894 5mg v BI 1358894 25mg v BI 1358894 75mg v BI 1358894 125mg

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

= 0.456

Method

MCP-Mod linear model fit

Confidence interval

Notes
[16] - MMRM estimates were used as input for the MCP-Mod. MMRM included the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the baseline ZAN−BPD total score strata indicator (<=18 vs. >=19), the continuous fixed covariate of baseline ZAN−BPD total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Linear model assumption: No parameter assumptions required.

MCP-Mod exponential model fit

Statistical analysis description

Comparison groups

Placebo v BI 1358894 5mg v BI 1358894 25mg v BI 1358894 75mg v BI 1358894 125mg

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.4908

Method

MCP-Mod exponential model fit

Confidence interval

Notes
[17] - MMRM estimates were used as input for the MCP-Mod. MMRM included the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the baseline ZAN−BPD total score strata indicator (<=18 vs. >=19), the continuous fixed covariate of baseline ZAN−BPD total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Exponential model assumption: 5% of the maximum effect is achieved at 25 mg.

MCP-Mod Emax2 model fit

Statistical analysis description

Comparison groups

Placebo v BI 1358894 5mg v BI 1358894 25mg v BI 1358894 75mg v BI 1358894 125mg

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.4974

Method

MCP-Mod Emax2 model fit

Confidence interval

Notes
[18] - MMRM estimates were used as input for the MCP-Mod. MMRM included the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the baseline ZAN−BPD total score strata indicator (<=18 vs. >=19), the continuous fixed covariate of baseline ZAN−BPD total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Emax2 model assumption: 70% of the maximum effect is achieved at 5 mg.

Secondary: Zanarini rating scale for borderline personality disorder (ZAN-BPD) response: defined as ≥30% ZAN-BPD reduction from baseline at Week 10

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End point title

Zanarini rating scale for borderline personality disorder (ZAN-BPD) response: defined as ≥30% ZAN-BPD reduction from baseline at Week 10

End point description

Number of participants with ZAN-BPD response is reported. ZAN-BPD response was defined as ≥30% ZAN-BPD reduction from baseline at Week 10. The ZAN-BPD scale reflects the nine DSM-5 criteria and the scale has 4 domain scores that reflect core areas of BPD (i.e., affective, cognitive, impulsive and interpersonal symptoms). The ZAN-BPD scale includes a 5-point rating scale (i.e., 0 = no symptoms to 4 = severe symptoms) for each criterion. The total ZAN-BPD score is the sum of the 4 domain scores and ranges from 0 to 36 where higher scores mean severe symptoms.

End point type

Secondary

End point timeframe

Baseline and at Week 10

End point values	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg
Number of subjects analysed	92 ^[19]	37 ^[20]	33 ^[21]	41 ^[22]	74 ^[23]
Units: Participants	68	22	28	34	59

Notes
[19] - FAS. Only participants with ZAN BPD total score data at Week 10 are reported.
[20] - FAS. Only participants with ZAN BPD total score data at Week 10 are reported.
[21] - FAS. Only participants with ZAN BPD total score data at Week 10 are reported.
[22] - FAS. Only participants with ZAN BPD total score data at Week 10 are reported.
[23] - FAS. Only participants with ZAN BPD total score data at Week 10 are reported.

Logistic regression "Placebo" vs "BI 1358894 5mg"

Statistical analysis description

Logistic regression included treatment, baseline ZAN−BPD score and baseline ZAN−BPD strata indicator as covariates.

Comparison groups

Placebo v BI 1358894 5mg

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

other ^[24]

Method

Parameter type

Odds ratio (OR)

Point estimate

0.486

Confidence interval

level

95%

sides

2-sided

lower limit

0.207

upper limit

1.14

Notes
[24] - Odds Ratio was calculated as: BI 1358894 5mg/Placebo.

Logistic regression "Placebo" vs "BI1358894 125mg"

Statistical analysis description

Logistic regression included treatment, baseline ZAN−BPD score and baseline ZAN−BPD strata indicator as covariates.

Comparison groups

Placebo v BI 1358894 125mg

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

other ^[25]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.352

Confidence interval

level

95%

sides

2-sided

lower limit

0.642

upper limit

2.913

Notes
[25] - Odds Ratio was calculated as: BI 1358894 125mg/Placebo.

Logistic regression "Placebo" vs "BI 1358894 75mg"

Statistical analysis description

Logistic regression included treatment, baseline ZAN−BPD score and baseline ZAN−BPD strata indicator as covariates.

Comparison groups

Placebo v BI 1358894 75mg

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

other ^[26]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.753

Confidence interval

level

95%

sides

2-sided

lower limit

0.698

upper limit

4.861

Notes
[26] - Odds Ratio was calculated as: BI 1358894 75mg/Placebo.

Logistic regression "Placebo" vs "BI 1358894 25mg"

Statistical analysis description

Logistic regression included treatment, baseline ZAN−BPD score and baseline ZAN−BPD strata indicator as covariates.

Comparison groups

Placebo v BI 1358894 25mg

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other ^[27]

Method

Parameter type

Odds ratio (OR)

Point estimate

2.294

Confidence interval

level

95%

sides

2-sided

lower limit

0.829

upper limit

7.48

Notes
[27] - Odds Ratio was calculated as: BI 1358894 25mg/Placebo.

Secondary: Change from baseline in Difficulties in Emotion Regulation Scale (DERS-16) total score at Week 10

Top of page

End point title

Change from baseline in Difficulties in Emotion Regulation Scale (DERS-16) total score at Week 10

End point description

The DERS is a self-report measure of emotion regulation difficulties. It consists of 16 items that assess non-acceptance of negative emotions, inability to engage in goal-directed behaviors when distressed, difficulties controlling impulsive behaviors when distressed, limited access to emotion regulation strategies perceived as effective, and lack of emotional clarity. Each item is scored from 1 (almost never (0-10%)) to 5 (almost always (91-100%)). Total DERS-16 can range from 16 to 80, with higher scores reflecting greater levels of emotion dysregulation. Least squares means and 95% confidence intervals were estimated by restricted maximum likelihood-based mixed effects mixed repeated measures (REML-based MMRM). LS mean (standard error) for Week 10 are reported. For this endpoint were analyzed participants who had a DERS-16 total score value at baseline and a DERS-16 total score value at one of the post-baseline timepoints up to Week 10.

End point type

Secondary

End point timeframe

Change from baseline in DERS-16 total score at Week 10 was calculated using the MMRM model which is a longitudinal analyses and it incorporates DERS-16 measurements from baseline, Weeks 1, 2, 4, 6, 8 and Week 10.

End point values	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg
Number of subjects analysed	124 ^[28]	52 ^[29]	52 ^[30]	52 ^[31]	102 ^[32]
Units: units on a scale
least squares mean (standard error)	-9.77 ± 1.4	-9.87 ± 2.1	-9.76 ± 2.2	-10.56 ± 2.1	-8.60 ± 1.5

Notes
[28] - Full analysis set (FAS).
[29] - Full analysis set (FAS).
[30] - Full analysis set (FAS).
[31] - Full analysis set (FAS).
[32] - Full analysis set (FAS).

MMRM "Placebo" vs. "BI 1358894 5mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by REML−based MMRM including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline DERS−16 total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 5mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

= 0.9675 ^[34]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.11

upper limit

4.9

Notes
[33] - No formal hypotheses were tested. Mean Difference (Net): Least Squares Mean of "BI 1358894 5mg" - Least Squares Mean of "Placebo".
[34] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 25mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by REML−based MMRM including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline DERS−16 total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 25mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.9969 ^[36]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-5.08

upper limit

5.1

Notes
[35] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 25mg" - Least Squares Mean of "Placebo".
[36] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 75mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by REML−based MMRM including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline DERS−16 total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 75mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

= 0.7542 ^[38]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.79

Confidence interval

level

95%

sides

2-sided

lower limit

-5.73

upper limit

4.15

Notes
[37] - No formal hypotheses were tested. No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 75mg" - Least Squares Mean of "Placebo".
[38] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 125mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by REML−based MMRM including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline DERS−16 total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 125mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.5683 ^[40]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

-2.86

upper limit

5.19

Notes
[39] - No formal hypotheses were tested. No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 125mg" - Least Squares Mean of "Placebo".
[40] - P-value is considered nominal.

Secondary: Change from baseline in State-Trait Anxiety Inventory (STAI-S) total score at Week 10

Top of page

End point title

Change from baseline in State-Trait Anxiety Inventory (STAI-S) total score at Week 10

End point description

The STAI-S consists of 20 item state anxiety questions that evaluate how respondents feel “right now, at this moment”. All items are rated on a weighted score of 1 to 4 scale (e.g. from ‘Almost Never to ‘Almost Always’). STAI-S score ranges from 20 to 80 where higher scores indicate greater anxiety. Least squares means and 95% confidence intervals were estimated by restricted maximum likelihood-based mixed effects mixed repeated measures (REML-based MMRM). LS mean (standard error) for Week 10 are reported. Since the MMRM included the measurements from baseline, Week 1, Week 2, Week 4, Week 6, Week 8 and Week 10, number of participants analyzed for the primary endpoint for each arm are the participants who had a STAI-S total score value at baseline and a STAI-S total score value at one of the post-baseline timepoints up to Week 10.

End point type

Secondary

End point timeframe

Change from baseline in STAI-S total score at Week 10 was calculated using the MMRM model which is a longitudinal analyses and it incorporates STAI-S measurements from baseline, Weeks 1, 2, 4, 6, 8 and Week 10.

End point values	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg
Number of subjects analysed	124 ^[41]	52 ^[42]	52 ^[43]	52 ^[44]	102 ^[45]
Units: units on a scale
least squares mean (standard error)	-6.64 ± 1.2	-8.71 ± 1.9	-5.43 ± 2.0	-7.00 ± 1.8	-5.49 ± 1.3

Notes
[41] - Full analysis set (FAS).
[42] - Full analysis set (FAS).
[43] - Full analysis set (FAS).
[44] - Full analysis set (FAS).
[45] - Full analysis set (FAS).

MMRM "Placebo" vs. "BI 1358894 25mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline STAI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 25mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[46]

P-value

= 0.6009 ^[47]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

-3.33

upper limit

5.75

Notes
[46] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 25mg" - Least Squares Mean of "Placebo".
[47] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 5mg"

Statistical analysis description

Comparison groups

Placebo v BI 1358894 5mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[48]

P-value

= 0.3568 ^[49]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.07

Confidence interval

level

95%

sides

2-sided

lower limit

-6.49

upper limit

2.35

Notes
[48] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 5mg" - Least Squares Mean of "Placebo".
[49] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 125mg"

Statistical analysis description

Comparison groups

Placebo v BI 1358894 125mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

other ^[50]

P-value

= 0.5262 ^[51]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

-2.41

upper limit

4.71

Notes
[50] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 125mg" - Least Squares Mean of "Placebo".
[51] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 75mg"

Statistical analysis description

Comparison groups

Placebo v BI 1358894 75mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[52]

P-value

= 0.8705 ^[53]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-4.7

upper limit

3.98

Notes
[52] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 75mg" - Least Squares Mean of "Placebo".
[53] - P-value is considered nominal.

Secondary: Change from baseline in Patient Health Questionnaire (PHQ-9) total score at Week 10

Top of page

End point title

Change from baseline in Patient Health Questionnaire (PHQ-9) total score at Week 10

End point description

The PHQ-9 is a 9-item brief self-reported tool used for screening and assessing the severity of depression. PHQ-9 has a maximum total score of 27. Depression Severity is assessed as: none (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), or severe (20-27). Least squares means and 95% confidence intervals were estimated by restricted maximum likelihood-based mixed effects mixed repeated measures (REML-based MMRM). LS mean (standard error) for Week 10 are reported. Since the MMRM included the measurements from baseline, Week 1, Week 2, Week 4, Week 6, Week 8 and Week 10, number of participants analyzed for the primary endpoint for each arm are the participants who had a PHQ-9 total score value at baseline and a PHQ-9 total score value at one of the post-baseline timepoints up to Week 10.

End point type

Secondary

End point timeframe

Change from baseline in PHQ-9 total score at Week 10 was calculated using the MMRM model which is a longitudinal analyses and it incorporates PHQ-9 measurements from baseline, Weeks 1, 2, 4, 6, 8 and Week 10.

End point values	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg
Number of subjects analysed	124 ^[54]	52 ^[55]	52 ^[56]	52 ^[57]	102 ^[58]
Units: units on a scale
least squares mean (standard error)	-1.30 ± 0.6	-3.13 ± 0.9	-1.07 ± 0.9	-1.57 ± 0.9	-1.43 ± 0.6

Notes
[54] - Full analysis set (FAS).
[55] - Full analysis set (FAS).
[56] - Full analysis set (FAS).
[57] - Full analysis set (FAS).
[58] - Full analysis set (FAS).

MMRM "Placebo" vs. "BI 1358894 5mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline PHQ−9 total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 5mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[59]

P-value

= 0.0782 ^[60]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-1.83

Confidence interval

level

95%

sides

2-sided

lower limit

-3.87

upper limit

0.21

Notes
[59] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 5mg" - Least Squares Mean of "Placebo".
[60] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 125mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline PHQ−9 total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 125mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

other ^[61]

P-value

= 0.8743 ^[62]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-1.77

upper limit

1.51

Notes
[61] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 125mg" - Least Squares Mean of "Placebo".
[62] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 75mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline PHQ−9 total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 75mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[63]

P-value

= 0.791 ^[64]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-2.28

upper limit

1.74

Notes
[63] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 75mg" - Least Squares Mean of "Placebo".
[64] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 25mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline PHQ−9 total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 25mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[65]

P-value

= 0.8266 ^[66]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-1.86

upper limit

2.32

Notes
[65] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 25mg" - Least Squares Mean of "Placebo".
[66] - P-value is considered nominal.

Secondary: Change from baseline in Clinical Global Impression Severity scale (CGI-S) at Week 10

Top of page

End point title

Change from baseline in Clinical Global Impression Severity scale (CGI-S) at Week 10

End point description

The CGI-S rating scale measures the clinician's impression of the severity of illness exhibited by a participant. The CGI-S only question states “Considering your total clinical experience with this particular population, please choose the response below that best describes how mentally ill the patient was over the past week?”, and is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. Least squares means and 95% confidence intervals were estimated by restricted maximum likelihood-based mixed effects mixed repeated measures (REML-based MMRM). LS mean (standard error) for Week 10 are reported. For this endpoint were analyzed participants who had a CGI-S scale value at baseline and a CGI-S scale value at one of the post-baseline timepoints up to Week 10.

End point type

Secondary

End point timeframe

Change from baseline in CGI-S scale at Week 10 was calculated using the MMRM model which is a longitudinal analyses and it incorporates CGI-S measurements from baseline, Weeks 1, 2, 4, 6, 8 and Week 10.

End point values	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg
Number of subjects analysed	124 ^[67]	52 ^[68]	51 ^[69]	51 ^[70]	102 ^[71]
Units: units on a scale
least squares mean (standard error)	-1.23 ± 0.1	-1.29 ± 0.2	-1.47 ± 0.2	-1.24 ± 0.2	-1.42 ± 0.1

Notes
[67] - Full analysis set (FAS).
[68] - Full analysis set (FAS).
[69] - Full analysis set (FAS).
[70] - Full analysis set (FAS).
[71] - Full analysis set (FAS).

MMRM "Placebo" vs. "BI 1358894 5mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline CGI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 5mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[72]

P-value

= 0.8016 ^[73]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

0.37

Notes
[72] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 5mg" - Least Squares Mean of "Placebo".
[73] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 25mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline CGI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 25mg

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

other ^[74]

P-value

= 0.2929 ^[75]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

0.2

Notes
[74] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 25mg" - Least Squares Mean of "Placebo".
[75] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 75mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline CGI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 75mg

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

other ^[76]

P-value

= 0.9666 ^[77]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

0.4

Notes
[76] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 75mg" - Least Squares Mean of "Placebo".
[77] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 125mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline CGI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 125mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

other ^[78]

P-value

= 0.2833 ^[79]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

0.15

Notes
[78] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 125mg" - Least Squares Mean of "Placebo".
[79] - P-value is considered nominal.

Secondary: Change from baseline in Patient Global Impression Severity scale (PGI-S) at Week 10

Top of page

End point title

Change from baseline in Patient Global Impression Severity scale (PGI-S) at Week 10

End point description

The PGI-S measures the patient’s impression of the severity of their illness. It is a single item 5-point scale that asks patients to rate the severity of their illness. The PGI-S question states “Please choose the response below that best describes the overall severity of your symptoms of Borderline Personality Disorder at this time. (Select one response)”: 1=No symptoms; 2=Mild; 3=Moderate; 4=Severe; 5=Very severe. Least squares means and 95% confidence intervals were estimated by restricted maximum likelihood-based mixed effects mixed repeated measures (REML-based MMRM). LS means (standard error) for Week 10 are reported. Since the MMRM included the measurements from baseline, Week 1, Week 2, Week 4, Week 6, Week 8 and Week 10, number of participants analyzed for the primary endpoint for each arm are the participants who had a PGI-S scale value at baseline and a PGI-S scale value at one of the post-baseline timepoints up to Week 10.

End point type

Secondary

End point timeframe

Change from baseline in PGI-S scale at Week 10 was calculated using the MMRM model which is a longitudinal analyses and it incorporates PGI-S measurements from baseline, Weeks 1, 2, 4, 6, 8 and Week 10.

End point values	Placebo	BI 1358894 5mg	BI 1358894 25mg	BI 1358894 75mg	BI 1358894 125mg
Number of subjects analysed	124 ^[80]	52 ^[81]	50 ^[82]	52 ^[83]	102 ^[84]
Units: units on a scale
least squares mean (standard error)	-0.61 ± 0.1	-0.73 ± 0.1	-0.73 ± 0.2	-0.64 ± 0.1	-0.69 ± 0.1

Notes
[80] - Full analysis set (FAS).
[81] - Full analysis set (FAS).
[82] - Full analysis set (FAS).
[83] - Full analysis set (FAS).
[84] - Full analysis set (FAS).

MMRM "Placebo" vs. "BI 1358894 5mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline PGI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 5mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[85]

P-value

= 0.4552 ^[86]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

0.2

Notes
[85] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 5mg" - Least Squares Mean of "Placebo".
[86] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 125mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline PGI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 125mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

other ^[87]

P-value

= 0.554 ^[88]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

0.19

Notes
[87] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 125mg" - Least Squares Mean of "Placebo".
[88] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 75mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline PGI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 75mg

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other ^[89]

P-value

= 0.8388 ^[90]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.29

Notes
[89] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 75mg" - Least Squares Mean of "Placebo".
[90] - P-value is considered nominal.

MMRM "Placebo" vs. "BI 1358894 25mg"

Statistical analysis description

Least Squares (LS) mean difference and 95% confidence interval were estimated by restricted maximum likelihood-based mixed effects model repeated measures (REML−based MMRM) including the fixed categorical covariates of treatment, visit (baseline and Week 1, 2, 4, 6, 8, 10) and the continuous fixed covariate of baseline PGI−S total score, and treatment−by−visit interaction, as well as baseline−by−visit interaction. Patient was considered as random. Unstructured covariance matrix was used.

Comparison groups

Placebo v BI 1358894 25mg

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

other ^[91]

P-value

= 0.4734 ^[92]

Method

Mixed effects model repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

0.22

Notes
[91] - No formal hypotheses were tested. Mean Difference (Net) = Least Squares Mean of "BI 1358894 25mg" - Least Squares Mean of "Placebo".
[92] - P-value is considered nominal.

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug administration until the last dose of study drug administration + 4 weeks of residual effect period, up to 17 weeks.

Adverse event reporting additional description

Treated set (TS) consisted of all patients who were randomised and that received at least 1 administration of trial medication. Patients were analysed according to the actual received treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Placebo

Reporting group description

Reporting group title

BI 1358894 5mg

Reporting group description

Reporting group title

BI 1358894 125mg

Reporting group description

Reporting group title

BI 1358894 75mg

Reporting group description

Reporting group title

BI 1358894 25mg

Reporting group description

Serious adverse events	Placebo	BI 1358894 5mg	BI 1358894 125mg	BI 1358894 75mg	BI 1358894 25mg
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 128 (8.59%)	4 / 52 (7.69%)	16 / 104 (15.38%)	4 / 53 (7.55%)	3 / 53 (5.66%)
number of deaths (all causes)	0	0	2	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 128 (0.00%)	1 / 52 (1.92%)	0 / 104 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Aggression
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug abuse
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Panic attack
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal behaviour
subjects affected / exposed	0 / 128 (0.00%)	1 / 52 (1.92%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post-traumatic stress disorder
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	8 / 128 (6.25%)	3 / 52 (5.77%)	6 / 104 (5.77%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	2 / 9	0 / 9	0 / 6	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Comminuted fracture
subjects affected / exposed	1 / 128 (0.78%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Forearm fracture
subjects affected / exposed	1 / 128 (0.78%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Cannabinoid hyperemesis syndrome
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	1 / 104 (0.96%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	1 / 128 (0.78%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis A
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound abscess
subjects affected / exposed	1 / 128 (0.78%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 128 (0.00%)	0 / 52 (0.00%)	0 / 104 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	BI 1358894 5mg	BI 1358894 125mg	BI 1358894 75mg	BI 1358894 25mg
Total subjects affected by non serious adverse events
subjects affected / exposed	75 / 128 (58.59%)	32 / 52 (61.54%)	61 / 104 (58.65%)	34 / 53 (64.15%)	40 / 53 (75.47%)
Investigations
Weight increased
subjects affected / exposed	0 / 128 (0.00%)	1 / 52 (1.92%)	5 / 104 (4.81%)	3 / 53 (5.66%)	1 / 53 (1.89%)
occurrences all number	0	1	6	3	1
Nervous system disorders
Somnolence
subjects affected / exposed	4 / 128 (3.13%)	3 / 52 (5.77%)	4 / 104 (3.85%)	6 / 53 (11.32%)	5 / 53 (9.43%)
occurrences all number	4	5	5	7	6
Headache
subjects affected / exposed	32 / 128 (25.00%)	18 / 52 (34.62%)	33 / 104 (31.73%)	15 / 53 (28.30%)	23 / 53 (43.40%)
occurrences all number	86	27	94	38	32
Dizziness
subjects affected / exposed	9 / 128 (7.03%)	6 / 52 (11.54%)	8 / 104 (7.69%)	7 / 53 (13.21%)	5 / 53 (9.43%)
occurrences all number	10	7	11	11	5
Disturbance in attention
subjects affected / exposed	5 / 128 (3.91%)	3 / 52 (5.77%)	0 / 104 (0.00%)	4 / 53 (7.55%)	2 / 53 (3.77%)
occurrences all number	5	3	0	4	2
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 128 (1.56%)	4 / 52 (7.69%)	1 / 104 (0.96%)	2 / 53 (3.77%)	3 / 53 (5.66%)
occurrences all number	3	6	1	2	4
Fatigue
subjects affected / exposed	11 / 128 (8.59%)	6 / 52 (11.54%)	9 / 104 (8.65%)	6 / 53 (11.32%)	1 / 53 (1.89%)
occurrences all number	13	8	14	6	4
Gastrointestinal disorders
Constipation
subjects affected / exposed	2 / 128 (1.56%)	2 / 52 (3.85%)	1 / 104 (0.96%)	1 / 53 (1.89%)	5 / 53 (9.43%)
occurrences all number	3	2	1	1	5
Diarrhoea
subjects affected / exposed	10 / 128 (7.81%)	4 / 52 (7.69%)	4 / 104 (3.85%)	3 / 53 (5.66%)	3 / 53 (5.66%)
occurrences all number	11	5	4	3	3
Nausea
subjects affected / exposed	17 / 128 (13.28%)	5 / 52 (9.62%)	7 / 104 (6.73%)	2 / 53 (3.77%)	5 / 53 (9.43%)
occurrences all number	28	7	11	3	6
Dyspepsia
subjects affected / exposed	1 / 128 (0.78%)	2 / 52 (3.85%)	0 / 104 (0.00%)	3 / 53 (5.66%)	1 / 53 (1.89%)
occurrences all number	1	2	0	3	1
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	3 / 128 (2.34%)	0 / 52 (0.00%)	4 / 104 (3.85%)	5 / 53 (9.43%)	1 / 53 (1.89%)
occurrences all number	3	0	5	9	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 128 (5.47%)	0 / 52 (0.00%)	2 / 104 (1.92%)	2 / 53 (3.77%)	1 / 53 (1.89%)
occurrences all number	7	0	2	2	1
Oropharyngeal pain
subjects affected / exposed	9 / 128 (7.03%)	3 / 52 (5.77%)	4 / 104 (3.85%)	2 / 53 (3.77%)	0 / 53 (0.00%)
occurrences all number	10	3	6	2	0
Psychiatric disorders
Anxiety
subjects affected / exposed	9 / 128 (7.03%)	6 / 52 (11.54%)	3 / 104 (2.88%)	3 / 53 (5.66%)	3 / 53 (5.66%)
occurrences all number	12	8	3	5	3
Intentional self-injury
subjects affected / exposed	7 / 128 (5.47%)	2 / 52 (3.85%)	3 / 104 (2.88%)	2 / 53 (3.77%)	1 / 53 (1.89%)
occurrences all number	10	2	4	3	1
Insomnia
subjects affected / exposed	10 / 128 (7.81%)	5 / 52 (9.62%)	6 / 104 (5.77%)	4 / 53 (7.55%)	5 / 53 (9.43%)
occurrences all number	15	6	7	4	5
Initial insomnia
subjects affected / exposed	5 / 128 (3.91%)	1 / 52 (1.92%)	0 / 104 (0.00%)	3 / 53 (5.66%)	0 / 53 (0.00%)
occurrences all number	6	1	0	3	0
Infections and infestations
Pharyngitis
subjects affected / exposed	2 / 128 (1.56%)	3 / 52 (5.77%)	0 / 104 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)
occurrences all number	2	3	0	0	0
COVID-19
subjects affected / exposed	16 / 128 (12.50%)	3 / 52 (5.77%)	7 / 104 (6.73%)	6 / 53 (11.32%)	1 / 53 (1.89%)
occurrences all number	17	3	10	6	1
Influenza
subjects affected / exposed	8 / 128 (6.25%)	3 / 52 (5.77%)	7 / 104 (6.73%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	8	3	7	1	1
Nasopharyngitis
subjects affected / exposed	10 / 128 (7.81%)	3 / 52 (5.77%)	9 / 104 (8.65%)	7 / 53 (13.21%)	3 / 53 (5.66%)
occurrences all number	11	4	12	10	3
Metabolism and nutrition disorders
Hyperinsulinaemia
subjects affected / exposed	1 / 128 (0.78%)	0 / 52 (0.00%)	0 / 104 (0.00%)	3 / 53 (5.66%)	1 / 53 (1.89%)
occurrences all number	1	0	0	3	1
Increased appetite
subjects affected / exposed	4 / 128 (3.13%)	1 / 52 (1.92%)	8 / 104 (7.69%)	1 / 53 (1.89%)	1 / 53 (1.89%)
occurrences all number	5	2	13	1	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

08 Dec 2020

Global Amendment 1 - Update of the term ‘End of Treatment (EoT) Visit’ to ‘Visit 9 or End of Treatment (EoT) Visit’ to distinguish patients who discontinue trial medication prematurely and continue with trial visits when they reach Week 12 (Visit 9) and patients completing the 12-week treatment (EoT). Addition of “the patient shows disease progression/worsening that precludes further participation in the trial per investigator’s clinical judgement” as another reason for individual patient treatment discontinuation. Addition of “an unexpected and unusual high dropout rate” as a reason for discontinuation of the trial by the sponsor. Addition of erythrocyte sedimentation rate (ESR) in the haematology tests. Correction to urinalysis specifications to align with laboratory terminology. Addition of alternate trial procedures in case of COVID-19 restriction. Removing inhibitors of uridine glucuronyl transferases (UGT) enzymes from restricted medications. Patient Eligibility Review.

28 Jun 2021

Global Amendment 2 - The following main changes were implemented: Addition of telemedicine visits and the use of local laboratory in case of COVID-19-related kit shortage. Addition of patient global impressions of impact (PGI-I) assessment. Correction of “Initiation or change in any type or frequency of psychotherapy for BPD within the last 3 months prior to randomisation” to “(…) prior to screening”. Clarification of the 7-day recall period for clinical global impression severity scale (CGI-S). Addition of participant check for multiple trial participation.

27 Apr 2022

Global Amendment 3 - The following main changes were implemented: Addition of new safety information on embryo-foetal development toxicity data, which suggests that a risk for teratogenicity in humans cannot be excluded. Addition of sexual abstinence as a non-allowed method of contraception for women of child bearing potential (WOCBP) who are heterosexually active. Addition of pregnancy test at Visits 3, 4, 6, and 8, and follow-up (FUP) Visit 1. Addition of contraception counselling for WOCBP.

23 Sep 2022

Global Amendment 4: The following main changes were implemented: Addition of confirmation by the investigator and the patient about the use of contraception. Removal of sensitive substrates of CYP2B6 from restricted medications based on the information from a clinical drug-drug interaction (DDI) study with bupropion. Addition of the possibility to perform ESR analysis locally at sites with an ongoing inability to obtain ESR result from the central laboratory.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A phase II randomized, double-blinded, placebo-controlled, parallel group trial to examine the efficacy and safety of 4 oral doses of BI 1358894 once daily over 12-week treatment period in patients with borderline personality disorder

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD) total score at Week 10

Primary: Change from baseline in Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD) total score at Week 10

Secondary: Zanarini rating scale for borderline personality disorder (ZAN-BPD) response: defined as ≥30% ZAN-BPD reduction from baseline at Week 10

Secondary: Zanarini rating scale for borderline personality disorder (ZAN-BPD) response: defined as ≥30% ZAN-BPD reduction from baseline at Week 10

Secondary: Change from baseline in Difficulties in Emotion Regulation Scale (DERS-16) total score at Week 10

Secondary: Change from baseline in Difficulties in Emotion Regulation Scale (DERS-16) total score at Week 10

Secondary: Change from baseline in State-Trait Anxiety Inventory (STAI-S) total score at Week 10

Secondary: Change from baseline in State-Trait Anxiety Inventory (STAI-S) total score at Week 10

Secondary: Change from baseline in Patient Health Questionnaire (PHQ-9) total score at Week 10

Secondary: Change from baseline in Patient Health Questionnaire (PHQ-9) total score at Week 10

Secondary: Change from baseline in Clinical Global Impression Severity scale (CGI-S) at Week 10

Secondary: Change from baseline in Clinical Global Impression Severity scale (CGI-S) at Week 10

Secondary: Change from baseline in Patient Global Impression Severity scale (PGI-S) at Week 10

Secondary: Change from baseline in Patient Global Impression Severity scale (PGI-S) at Week 10

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
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Cyprus
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Denmark
Estonia
Finland
France
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Greece
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Italy
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Outside EU/EEA

Clinical trials

Clinical Trial Results: A phase II randomized, double-blinded, placebo-controlled, parallel group trial to examine the efficacy and safety of 4 oral doses of BI 1358894 once daily over 12-week treatment period in patients with borderline personality disorder

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD) total score at Week 10

Primary: Change from baseline in Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD) total score at Week 10

Secondary: Zanarini rating scale for borderline personality disorder (ZAN-BPD) response: defined as ≥30% ZAN-BPD reduction from baseline at Week 10

Secondary: Zanarini rating scale for borderline personality disorder (ZAN-BPD) response: defined as ≥30% ZAN-BPD reduction from baseline at Week 10

Secondary: Change from baseline in Difficulties in Emotion Regulation Scale (DERS-16) total score at Week 10

Secondary: Change from baseline in Difficulties in Emotion Regulation Scale (DERS-16) total score at Week 10

Secondary: Change from baseline in State-Trait Anxiety Inventory (STAI-S) total score at Week 10

Secondary: Change from baseline in State-Trait Anxiety Inventory (STAI-S) total score at Week 10

Secondary: Change from baseline in Patient Health Questionnaire (PHQ-9) total score at Week 10

Secondary: Change from baseline in Patient Health Questionnaire (PHQ-9) total score at Week 10

Secondary: Change from baseline in Clinical Global Impression Severity scale (CGI-S) at Week 10

Secondary: Change from baseline in Clinical Global Impression Severity scale (CGI-S) at Week 10

Secondary: Change from baseline in Patient Global Impression Severity scale (PGI-S) at Week 10

Secondary: Change from baseline in Patient Global Impression Severity scale (PGI-S) at Week 10

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase II randomized, double-blinded, placebo-controlled, parallel group trial to examine the efficacy and safety of 4 oral doses of BI 1358894 once daily over 12-week treatment period in patients with borderline personality disorder