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Clinical Trial Results:
A phase II randomised, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of orally administered BI 409306 during a 28-week treatment period as adjunctive therapy to antipsychotic treatment for the prevention of relapse in patients with schizophrenia

Summary
EudraCT number	2017-002369-23
Trial protocol	ES
Global end of trial date	31 Mar 2021

Results information
Results version number	v2(current)
This version publication date	21 May 2022
First version publication date	25 Mar 2022
Other versions	v1
Version creation reason

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

1289-0049

ISRCTN number

US NCT number

NCT03351244

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 Call Center, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 18002430127, clintriage.rdg@boehringer-ingelheim.com

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

28 Apr 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Mar 2021

Global end of trial reached?

Yes

Global end of trial date

31 Mar 2021

Was the trial ended prematurely?

Yes

Main objective of the trial

The objective of the trial was to investigate the efficacy, safety, and tolerability of BI 409306 25 mg and 50 mg once daily compared with placebo given for 28 weeks in patients with schizophrenia on antipsychotic treatment. The trial was designed to show superiority of BI 409306 over placebo in preventing relapse of schizophrenia symptoms.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Dec 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 353

Country: Number of subjects enrolled

Japan: 66

Country: Number of subjects enrolled

Canada: 25

Country: Number of subjects enrolled

France: 18

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Taiwan: 2

Country: Number of subjects enrolled

Spain: 1

Worldwide total number of subjects

470

EEA total number of subjects

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)

470

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This Phase II trial aimed to evaluate the impact of 28-week treatment with BI 409306 (added to standard antipsychotic medication) compared with placebo on preventing relapse in patients with schizophrenia.

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

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

Are arms mutually exclusive

Yes

BI 409306 25 mg

Arm description

1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.

Arm type

Experimental

Investigational medicinal product name

BI 409306

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

BI 409306 50 mg

Arm description

1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.

Arm type

Experimental

Investigational medicinal product name

BI 409306

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo

Arm description

1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.

Arm type

Placebo

Investigational medicinal product name

Placebo

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]	BI 409306 25 mg	BI 409306 50 mg	Placebo
Started	89	88	87
Completed	62	48	53
Not completed	27	40	34
COVID-19 restrictions	3	-	1
Consent withdrawn by subject	11	16	13
Investigator's decision	-	-	2
System error	-	-	2
Adverse event, non-fatal	7	11	12
Non-compliance	2	5	-
Lost to follow-up	2	6	4
Protocol deviation	2	2	-

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: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

Baseline characteristics

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Reporting group title

BI 409306 25 mg

Reporting group description

Reporting group title

BI 409306 50 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	BI 409306 25 mg	BI 409306 50 mg	Placebo	Total
Number of subjects	89	88	87	264
Age categorical
Treated set (TS): the TS includes all patients who were randomised and were documented to have taken at least 1 dose of trial drug.
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	89	88	87	264
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age Continuous
Treated set (TS): the TS includes all patients who were randomised and were documented to have taken at least 1 dose of trial drug.
Units: years
arithmetic mean (standard deviation)	38.4 ( 9.8 )	41.9 ( 9.6 )	40.5 ( 9.8 )	-
Sex: Female, Male
Treated set (TS): the TS includes all patients who were randomised and were documented to have taken at least 1 dose of trial drug.
Units: Participants
Female	29	36	32	97
Male	60	52	55	167
Race (NIH/OMB)
Treated set (TS): the TS includes all patients who were randomised and were documented to have taken at least 1 dose of trial drug.
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	23	20	20	63
Native Hawaiian or Other Pacific Islander	0	2	0	2
Black or African American	36	37	32	105
White	23	24	25	72
More than one race	1	1	2	4
Unknown or Not Reported	6	4	8	18
Ethnicity (NIH/OMB)
Treated set (TS): the TS includes all patients who were randomised and were documented to have taken at least 1 dose of trial drug.
Units: Subjects
Hispanic or Latino	10	15	15	40
Not Hispanic or Latino	75	69	68	212
Unknown or Not Reported	4	4	4	12

End points

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Reporting group title

BI 409306 25 mg

Reporting group description

Reporting group title

BI 409306 50 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Subject analysis set title

BI 409306 pooled

Subject analysis set type

Full analysis

Subject analysis set description

This group included all participants who administered BI 409306 during the study.

Primary: Incidence rate of first relapse after 28 weeks of treatment

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End point title

Incidence rate of first relapse after 28 weeks of treatment

End point description

The incidence rate of first relapse after 28 weeks of treatment is reported. For each treatment group, the incidence rate was calculated as the number of events / sum of the observational time (patient year) over all participants in this treatment group. Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type.

End point type

Primary

End point timeframe

28 weeks

End point values	BI 409306 25 mg	BI 409306 50 mg	Placebo	BI 409306 pooled
Number of subjects analysed	89	88	87	177
Units: Events per patient-years
number (not applicable)	0.527	0.434	0.496	0.482

Statistical analysis 1

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

BI 409306 25 mg v Placebo

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7735

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.097

Confidence interval

level

95%

sides

2-sided

lower limit

0.585

upper limit

2.056

Statistical analysis 2

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

BI 409306 50 mg v Placebo

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7809

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.468

upper limit

1.77

Statistical analysis 3

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

Placebo v BI 409306 pooled

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9862

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.005

Confidence interval

level

95%

sides

2-sided

lower limit

0.576

upper limit

1.753

Secondary: Change from baseline in Positive and Negative Syndrome Scale (PANSS) positive symptoms score after 28 weeks of treatment

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End point title

Change from baseline in Positive and Negative Syndrome Scale (PANSS) positive symptoms score after 28 weeks of treatment

End point description

Positive and Negative Syndrome Scale (PANSS): assesses the severity of psychotic symptoms and progression of disease. The PANSS positive symptoms score is the sum of scores from 7 Items where each item has a minimum score 1 (better outcome) and maximum score 7 (worse outcome). The PANSS postive symptoms score ranges from 7 (less severe the disease) to 49 (more severe the disease). Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type. Only participants with non-missing results were included in the analysis.

End point type

Secondary

End point timeframe

At baseline and at Week 28.

End point values	BI 409306 25 mg	BI 409306 50 mg	Placebo	BI 409306 pooled
Number of subjects analysed	73	55	65	128
Units: Score on a scale
arithmetic mean (confidence interval 95%)	-0.54 (-1.370 to 0.294)	-0.71 (-1.641 to 0.224)	-0.92 (-1.769 to -0.070)	-0.61 (-1.231 to 0.005)

Statistical analysis 4

Statistical analysis description

A restricted maximum likelihood-based approach using a mixed model with repeated measurements was applied. The analysis included the fixed, categorical effects of treatment at each visit, and the fixed continuous effects of baseline at each visit.

Comparison groups

BI 409306 25 mg v Placebo

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5289

Method

Mixed model with repeated measurements

Parameter type

Placebo-corrected adjusted mean

Point estimate

0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-0.809

upper limit

1.57

Statistical analysis 5

Statistical analysis description

Comparison groups

BI 409306 50 mg v Placebo

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.744

Method

Mixed model with repeated measurements

Parameter type

Placebo-corrected adjusted mean

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-1.055

upper limit

1.475

Statistical analysis 6

Statistical analysis description

Comparison groups

Placebo v BI 409306 pooled

Number of subjects included in analysis

193

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5659

Method

Mixed model with repeated measurements

Parameter type

Placebo-corrected adjusted mean

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.745

upper limit

1.358

Secondary: Change from baseline in Clinical Global Impressions–Severity (CGI-S) scale score after 28 weeks of treatment

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End point title

Change from baseline in Clinical Global Impressions–Severity (CGI-S) scale score after 28 weeks of treatment

End point description

Clinical Global Impressions-Severity (CGI-S): One-item evaluation completed by the clinician to measure the severity of psychopathology. The CGI-S score ranges from 1 (normal) through to 7 (most severely ill). The higher the score, the worse the psychopathology. Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type. Only participants with non-missing results were included in the analysis.

End point type

Secondary

End point timeframe

At baseline and at Week 28

End point values	BI 409306 25 mg	BI 409306 50 mg	Placebo	BI 409306 pooled
Number of subjects analysed	73	55	65	128
Units: Score on a scale
arithmetic mean (standard deviation)	-0.15 ( 0.758 )	-0.22 ( 0.839 )	-0.22 ( 0.718 )	-0.18 ( 0.791 )

No statistical analyses for this end point

Secondary: Patient Global Impressions-Improvement (PGI-I) scale score after 28 weeks of treatment

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End point title

Patient Global Impressions-Improvement (PGI-I) scale score after 28 weeks of treatment

End point description

Patient Global Impressions-Improvement (PGI-I): One-item evaluation completed by the patient to assess their overall evaluation of his/her status compared to how they felt at randomisation. The PGI-I score ranges from 1 (Very much better) through to 7 (Very much worse). The higher the score, the worse the improvement. Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type. Only participants with non-missing results were included in the analysis.

End point type

Secondary

End point timeframe

At Week 28

End point values	BI 409306 25 mg	BI 409306 50 mg	Placebo	BI 409306 pooled
Number of subjects analysed	72	54	63	126
Units: Score on a scale
arithmetic mean (standard deviation)	2.61 ( 1.328 )	2.96 ( 1.197 )	2.94 ( 1.190 )	2.76 ( 1.280 )

No statistical analyses for this end point

Secondary: Incidence rate of suicidal ideation and behaviour (assessed by Columbia Suicide Severity Rating Scale (C-SSRS)) after 28 weeks of treatment

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End point title

Incidence rate of suicidal ideation and behaviour (assessed by Columbia Suicide Severity Rating Scale (C-SSRS)) after 28 weeks of treatment

End point description

C-SSRS: suicide risk assessment. 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. Suicidal behavior is collected in nominal scale as presence/absence of actual attempts, non-suicidal self-injurious behavior, interrupted attempts, aborted attempts, preparatory acts or behavior, and any suicidal behavior. Suicidal ideation is rated on a 6-point scale from 0 (No ideation present) to 5 (Active ideation with plan and intent). A score of 4 or 5 on this scale indicates serious suicidal ideation. For each treatment group, the incidence rate was calculated as the number of events / sum of the observational time (patient year) over all participants in this treatment group. Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type.

End point type

Secondary

End point timeframe

28 weeks

End point values	BI 409306 25 mg	BI 409306 50 mg	Placebo	BI 409306 pooled
Number of subjects analysed	89	88	87	177
Units: Events per patient-years
number (not applicable)	0.070	0.077	0.071	0.073

Statistical analysis 7

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

BI 409306 25 mg v Placebo

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9938

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.006

Confidence interval

level

95%

sides

2-sided

lower limit

0.203

upper limit

4.989

Statistical analysis 9

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

Placebo v BI 409306 pooled

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

P-value

= 0.936

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.058

Confidence interval

level

95%

sides

2-sided

lower limit

0.265

upper limit

4.233

Statistical analysis 8

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

BI 409306 50 mg v Placebo

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.893

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.116

Confidence interval

level

95%

sides

2-sided

lower limit

0.225

upper limit

5.531

Secondary: Change from baseline in Personal and Social Performance scale (PSP) score after 28 weeks of treatment

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End point title

Change from baseline in Personal and Social Performance scale (PSP) score after 28 weeks of treatment

End point description

Personal and Social Performance scale (PSP): The PSP is a 100-point, single item, clinician rated scale to assess 4 domains of social functioning (Four domains over the past month: (1) socially useful activities, (2) personal and social relationships, (3) self-care and (4) disturbing and aggressive behaviors.) in patients with schizophrenia. The PSP score is a single score ranging from 1 to 100. Higher scores represent better personal and social functioning. Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type. Only participants with non-missing results were included in the analysis.

End point type

Secondary

End point timeframe

At baseline and at Week 28

End point values	BI 409306 25 mg	BI 409306 50 mg	Placebo	BI 409306 pooled
Number of subjects analysed	72	54	65	126
Units: Score on a scale
arithmetic mean (standard deviation)	2.8 ( 8.8 )	2.4 ( 9.4 )	3.0 ( 10.2 )	2.6 ( 9.1 )

No statistical analyses for this end point

Secondary: Incidence rate of new prescription or increase in dose of an ongoing antipsychotic medication

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End point title

Incidence rate of new prescription or increase in dose of an ongoing antipsychotic medication

End point description

The incidence rate of new prescription or increase in dose of an ongoing antipsychotic medication is reported. Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type.

End point type

Secondary

End point timeframe

28 weeks

End point values	BI 409306 25 mg	BI 409306 50 mg	Placebo	BI 409306 pooled
Number of subjects analysed	89	88	87	177
Units: Events per patient-years
number (not applicable)	0.168	0.130	0.217	0.149

Statistical analysis 10

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

BI 409306 25 mg v Placebo

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6362

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.788

Confidence interval

level

95%

sides

2-sided

lower limit

0.293

upper limit

2.118

Statistical analysis 11

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

BI 409306 50 mg v Placebo

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3782

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.612

Confidence interval

level

95%

sides

2-sided

lower limit

0.205

upper limit

1.826

Statistical analysis 12

Statistical analysis description

The model included the treatment effect as the only covariate and was stratified by country.

Comparison groups

Placebo v BI 409306 pooled

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4253

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.703

Confidence interval

level

95%

sides

2-sided

lower limit

0.296

upper limit

1.671

Adverse events

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Timeframe for reporting adverse events

All-cause mortality: From 1st dose until withdraw or end of 1-week (1W) taper period + 3W follow-up, up to 32W. Serious (non-serious) adverse events: From 1st dose until withdraw or end of 1W taper period + 1W residual effect period, up to 30W.

Adverse event reporting additional description

Treated set (TS): the TS includes all patients who were randomised and were documented to have taken at least 1 dose of trial drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

BI 409306 50mg

Reporting group description

Reporting group title

Placebo

Reporting group description

1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a followup period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.

Reporting group title

BI 409306 25mg

Reporting group description

Serious adverse events	BI 409306 50mg	Placebo	BI 409306 25mg
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 88 (7.95%)	12 / 87 (13.79%)	9 / 89 (10.11%)
number of deaths (all causes)	1	0	0
number of deaths resulting from adverse events	1	0	0
Injury, poisoning and procedural complications
Skin abrasion
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 88 (1.14%)	0 / 87 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 88 (1.14%)	0 / 87 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Acute psychosis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Agitation
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	1 / 88 (1.14%)	0 / 87 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Delusion
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression suicidal
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hallucination, auditory
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	1 / 88 (1.14%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Schizophrenia
subjects affected / exposed	1 / 88 (1.14%)	4 / 87 (4.60%)	2 / 89 (2.25%)
occurrences causally related to treatment / all	0 / 2	1 / 4	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Substance abuse
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicidal behaviour
subjects affected / exposed	1 / 88 (1.14%)	0 / 87 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 88 (0.00%)	2 / 87 (2.30%)	3 / 89 (3.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 88 (1.14%)	0 / 87 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 88 (1.14%)	0 / 87 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Complicated appendicitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 88 (0.00%)	3 / 87 (3.45%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	BI 409306 50mg	Placebo	BI 409306 25mg
Total subjects affected by non serious adverse events
subjects affected / exposed	25 / 88 (28.41%)	19 / 87 (21.84%)	30 / 89 (33.71%)
Nervous system disorders
Headache
subjects affected / exposed	7 / 88 (7.95%)	4 / 87 (4.60%)	6 / 89 (6.74%)
occurrences all number	13	4	6
Somnolence
subjects affected / exposed	3 / 88 (3.41%)	3 / 87 (3.45%)	5 / 89 (5.62%)
occurrences all number	3	3	5
Eye disorders
Photophobia
subjects affected / exposed	8 / 88 (9.09%)	1 / 87 (1.15%)	3 / 89 (3.37%)
occurrences all number	8	1	3
Gastrointestinal disorders
Vomiting
subjects affected / exposed	1 / 88 (1.14%)	5 / 87 (5.75%)	1 / 89 (1.12%)
occurrences all number	1	6	1
Psychiatric disorders
Insomnia
subjects affected / exposed	6 / 88 (6.82%)	0 / 87 (0.00%)	5 / 89 (5.62%)
occurrences all number	6	0	5
Schizophrenia
subjects affected / exposed	4 / 88 (4.55%)	2 / 87 (2.30%)	6 / 89 (6.74%)
occurrences all number	4	2	6
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 88 (5.68%)	7 / 87 (8.05%)	7 / 89 (7.87%)
occurrences all number	5	10	7

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Were there any global substantial amendments to the protocol? Yes

08 Nov 2017

- The key secondary endpoint, change from baseline in Positive and Negative Syndrome Scale (PANSS) positive symptoms score after 28 weeks of treatment, was added (it was a further endpoint prior to the revision). The key secondary endpoint was added to the hypothesis testing hierarchy. - To ensure clinical stability of patients entering the trial, 2 inclusion criteria were modified: Criterion 3: patients were required to take a stable dose of antipsychotic medication(s) for at least 12 weeks (instead of 8) prior to randomisation; Criterion 6: patients were required to have Clinical Global Impressions-Severity (CGI-S) score ≤4 at both Visits 1 and 2 (instead of only at Visit 1). - Inclusion criteria 4 and 7 were slightly modified. - A Japan-specific requirement for Informed consent form (ICF) signature was added.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
13 Mar 2020	Due to the current COVID-19 pandemic, the recruitment of new subjects was temporarily discontinued. Ongoing, randomised patients were managed per Trial Protocol.	28 Apr 2020

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

The study was terminated due to sponsor decision. The planned number of participants to be recruited was not reached.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence rate of first relapse after 28 weeks of treatment

Primary: Incidence rate of first relapse after 28 weeks of treatment

Secondary: Change from baseline in Positive and Negative Syndrome Scale (PANSS) positive symptoms score after 28 weeks of treatment

Secondary: Change from baseline in Positive and Negative Syndrome Scale (PANSS) positive symptoms score after 28 weeks of treatment

Secondary: Change from baseline in Clinical Global Impressions–Severity (CGI-S) scale score after 28 weeks of treatment

Secondary: Change from baseline in Clinical Global Impressions–Severity (CGI-S) scale score after 28 weeks of treatment

Secondary: Patient Global Impressions-Improvement (PGI-I) scale score after 28 weeks of treatment

Secondary: Patient Global Impressions-Improvement (PGI-I) scale score after 28 weeks of treatment

Secondary: Incidence rate of suicidal ideation and behaviour (assessed by Columbia Suicide Severity Rating Scale (C-SSRS)) after 28 weeks of treatment

Secondary: Incidence rate of suicidal ideation and behaviour (assessed by Columbia Suicide Severity Rating Scale (C-SSRS)) after 28 weeks of treatment

Secondary: Change from baseline in Personal and Social Performance scale (PSP) score after 28 weeks of treatment

Secondary: Change from baseline in Personal and Social Performance scale (PSP) score after 28 weeks of treatment

Secondary: Incidence rate of new prescription or increase in dose of an ongoing antipsychotic medication

Secondary: Incidence rate of new prescription or increase in dose of an ongoing antipsychotic medication

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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