A Study to Investigate the Efficacy, Safety and Tolerability of Four Different Doses of BI 409306 Compared to Placebo Given for 12 Weeks in Patients With Schizophrenia on Stable Antipsychotic Treatment.

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02281773
• Collaborator: (none)
• Enrollment: 518
• Locations: 43
• Arms: 5
• Actual Duration (Months): 19.1
• Patients Per Site: 12
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The objective of the study is to investigate the efficacy, safety and tolerability of four different doses of BI 409306 once daily compared to placebo given for 12 weeks in patients with schizophrenia on stable antipsychotic treatment.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: BI 409306 100 mg QD; Drug: BI 498306 50 mg QD; Drug: Placebo; Drug: BI 498306 25 mg QD; Drug: BI 409306 10 mg QD	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 518 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomised, Double-blinded, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Four Orally Administrated Doses of BI 409306 During a 12-week Treatment Period in Patients With Schizophrenia on Stable Antipsychotic Treatment
• Actual Study Start Date: Nov 10, 2014
• Actual Primary Completion Date: May 26, 2016
• Actual Study Completion Date: Jun 13, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: dose 1	Drug: BI 409306 10 mg QD
Experimental: dose 2	Drug: BI 498306 25 mg QD
Experimental: dose 3	Drug: BI 498306 50 mg QD
Experimental: dose 4	Drug: BI 409306 100 mg QD
Placebo Comparator: placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Composite Score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) After 12 Weeks of Treatment [Baseline and Week 12]

   MCCB comprises 10 tests, which assess 7 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning problem solving, and social cognition. The composite score was calculated by summing over the standardised score of each domain for analysis and it varies from -20 to 99 with higher score indicating better outcome. The trial was set up as "learn and confirm" model including 2 stages. Stage 1 analysis was conducted to identify the meaningful cognition endpoint(s) (CANTAB domain(s)) and the selected endpoint(s) were to be pre-specified as the primary endpoint(s) for Stage 2 analysis. Since none of the CANTAB outcome measures was selected in the Stage 1 analysis at planned time based on the pre-specified criteria, the MCCB composite score was chosen as the primary endpoint in the Stage 2 analysis, as pre-defined.

2. Occurrence of Serious Adverse Events (SAEs) (Including the Abnormalities of Physical Examination, Vital Signs, Electrocardiogram (ECG) Test and Laboratory Tests) [Up to 20 weeks]

   Occurrence of serious adverse events (SAEs) (including the abnormalities of physical examination, vital signs, electrocardiogram (ECG) test and laboratory tests).

3. Occurrence of Protocol-specified Adverse Events of Special Interest (AESI) [Up to 20 weeks]

   Occurrence of Protocol-specified adverse events of special interest (AESI).

4. Dramatic Worsening of Disease State as Assessed by Positive and Negative Syndrome Scale (PANSS) [Baseline, Week 6 and Week 12]

   Dramatic worsening of disease state as assessed by Positive and Negative Syndrome Scale (PANSS). It contains 30-items including seven positive symptom items, seven negative symptom items and 16 general psychopathology symptom items. Each item was scored on the same seven point severity scale. Fourteen of the PANSS items required input from an informant. Total score ranges from 30 to 210 (minimum is better). The descriptive statistics of change from baseline (CFB) in PANSS score at week 6 (W6) and week 12 (W12) are presented.

5. Suicidality as Assessed by Columbia Suicidal Severity Rating Scale (C-SSRS) [Up to 12 weeks]

   C-SSRS: Number (%) of subjects with an event of Suicidal Ideation (Wish to be dead, Non-specific active suicidal thoughts, Active suicidal ideation with any methods (not plan) without intent to act, Active suicidal ideation with some intent to act without specific plan, Active suicidal ideation with specific plan and intent) or Suicidal Behavior (Preparatory acts or behavior, Aborted attempt, Interrupted attempt, Non-fatal suicide attempt, Completed suicide) or Self-injurious behavior without suicidal intent is presented. C-SSRS used only to evaluate whether the patient developed suicidal ideation or behavior and no composite score will be used. Questions in the 1st section of suicidal ideation and suicidal behavior assessments in C-SSRS are "yes" and "no" type questions. If patient had suicidal ideation or behavior, 2nd section will be performed to evaluate the details with the scale from 0 to 5 or 0 to 2 and the larger number means the more severe condition.

Secondary Outcome Measures

1. Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Global Ratings After 12 Weeks of Treatment [Baseline and Week 12]

   Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) global ratings after 12 weeks of treatment. SCoRS is a 20-item interview-based assessment of cognitive deficits and the degree to which they affect day-to-day functions. Each item was rated on a 4-point scale. Higher ratings reflected a greater degree of impairment. The SCoRS global total scores is the sum of the 20 items and it varies from 20 to 80 with 20 being the best outcome and 80 being the worst. If any individual item was missing, it was imputed with the average of that patient's non missing responses. If >5 items were missing, the total score was missing.

2. Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Scale Score After 12 Weeks of Treatment [Baseline and Week 12]

   Change from baseline in Clinical Global Impressions-Severity (CGI-S) scale score after 12 weeks of treatment. The CGI-S is a one-item evaluation completed by the clinician on the patient's severity of psychopathology. The CGI-S was rated ordinally from one to 7. Higher scores indicate more severe symptoms.

3. Patient Global Impressions-Improvement (PGI-I) Scale Score Measured After 12 Weeks of Treatment [Up to 12 weeks]

   Patient Global Impressions-Improvement (PGI-I) scale score measured after 12 weeks of treatment. The PGI of improvement is a simple evaluation completed by the patient to assess the patient's overall evaluation of his/her status. The PGI of improvement was rated ordinally from one to 7. Higher scores indicate more severe symptoms.

4. Change From Baseline in PANSS Negative Symptom Factor Score After 12 Weeks of Treatment (for Subset of Patients Diagnosed With Negative Symptom) [Baseline and Week 12]

   Change from baseline in PANSS negative symptom factor score after 12 weeks of treatment (for subset of patients diagnosed with negative symptom). This outcome measure was not analysed due to low number of patients in the PANSS negative symptom subgroup. The PANSS negative symptom scale has 7 items. Each was rated from one to 7 points. The total factor score was the summation of the 7 points for each item, leading the total score ranging from 7 to 49.

5. Change in Psychopathology Symptoms as Assessed by Positive and Negative Syndrome Scale (PANSS) [Baseline, Week 6 and Week 12]

   Change in psychopathology symptoms as assessed by Positive and Negative Syndrome Scale (PANSS). It contains 30-items including seven positive symptom items, seven negative symptom items and 16 general psychopathology symptom items. Each item was scored on the same seven point severity scale. Fourteen of the PANSS items required input from an informant. Total score ranges from 30 to 210 (minimum is better). The descriptive statistics of change from baseline (CFB) in PANSS score at week 6 (W6) and week 12 (W12) are presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Patients with established diagnoses of schizophrenia (per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)) with the following clinical features:

1. Clinically stable and are in the residual (non-acute) phase of their illness for at least 8 weeks b) Current antipsychotic and concomitant psychotropic medications must meet the criteria below: b)-1 Maintained on current atypical (second generation) antipsychotic medications (in any approved dosage form) other than Clozapine and on current dose for at least 8 weeks prior to randomisation, and/or b)-2 Maintained on current typical (first generation) antipsychotic medications and on current dose for at least 6 months, optionally combined with anticholinergics if treated with a stable dose for at least 6 months prior to randomisation, and/or b)-3 Maintained on current concomitant psychotropic medications other than anticholinergics, antiepileptics and lithium, and on current dose for at least 8 weeks prior to randomisation. Antiepileptics and lithium are allowed if initiated at least 6 months prior to randomisation.

b)-4 Anticholinergics, antiepileptics and lithium have been washed out for at least 6 months prior to randomisation if the treatments that patients were using before entering the clinical trial are discontinued.

1. Have no more than a "moderate" severity rating on hallucinations and delusions (Positive and Negative Syndrome Scale (PANSS)-positive syndrome Hallucinatory Behavior item score < =4 and Delusions item score < = 4) d) Have no more than a "moderate" severity rating on positive formal thought disorder (PANSS-positive syndrome Conceptual Disorganization item score < = 4) e) Have a minimal level of extrapyramidal symptoms (Simpson-Angus Scale total score < 6) and depressive symptoms (PANSS-general psychopathology syndrome Depression item score < = 4)

1. Male or female patients age 18 to 55 years

2. Patients must exhibit reliability, physiologic capability, and an educational level sufficient to comply with all protocol procedures,in the investigator's opinion.

3. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and the local legislation. If the patient needs a legal representative, then this legal representative must give written informed consent as well.

4. Patients must have an identified informant who will be consistent throughout the study. The informant must interact with the subject at least 2 times a week.

Note: Informant ratings are needed for SCoRS global ratings at Randomisation Visit (Visit 2) and (early) End of Treatment Visit. In person informant ratings on the study visits are preferred whenever possible. However, if the informant is not available for in person ratings, telephone interview is acceptable. The informant must be available for a telephone interview at Visit 2 and (e)EOT Visit.

Exclusion criteria:

1. Patient treated with more than two antipsychotic medications (including more than two dosage forms)

2. Patient's cognitive impairment severity compromises the validity of the cognitive outcome measures, in the clinical judgment of the investigator

3. Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior)

4. Any suicidal ideation of type 4 or 5 in the Columbia Suicidal Severity Rating Scale (C-SSRS) in the past 3 months (i.e. active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent)

5. In the judgment of the investigator, any clinically significant finding of the medical examination (including BP, PR and ECG) or laboratory value deviating from normal or any evidence of a clinically significant concomitant disease or any other clinical condition that would jeopardize a patient's safety while participating in the clinical trial

6. History or diagnosis of symptomatic and unstable/uncontrolled gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, hematological or hormonal disorders

7. For female patients:

Pre-menopausal women (last menstruation < =1 year prior to informed consent) who:

• are nursing or pregnant or

• are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the trial until 28 days after the last treatment administration, and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, vasectomized partner, transdermal patch, intra uterine devices/systems (IUDs/IUSs), combined estrogen-progestin oral contraceptives as well as implantable or injectable hormonal contraceptives. Complete sexual abstinence (if acceptable by local health authorities) is allowed when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Double barrier methods are permissible (if acceptable by local health authorities, note that this is not an acceptable method in EU countries).

For male patients:

Men who are able to father a child, unwilling to be abstinent or use adequate contraception for the duration of study participation and for at least 28 days after treatment has ended.

1. Known history of HIV infection

2. Diseases of the central nervous system (including but not limited to any kind of seizures, stroke or any psychiatric disorders other than schizophrenia)

3. Any subject who on the Mini-international neuropsychiatric Interview (M.I.N.I.) has a categorical diagnosis of another current major psychiatric disorder.

4. History of malignancy within the last 5 years, except for basal cell carcinoma

5. Planned elective surgery requiring general anaesthesia, or hospitalisation for more than 1 day during the study period

6. Significant history of drug dependence or abuse (including alcohol, as defined in DSM-5-substance use disorder or in the opinion of the investigator) within the last two years prior to informed consent, or a positive urine drug screen for cocaine, opioid, PCP, amphetamine, heroin, or marijuana at screening

7. Patient needs to take long-acting hypnotics and anxiolytics (i.e. Diazepam)

8. Patients taking medications that are known to be strong or moderate CYP3A4 inhibitors

9. Participation in another trial with an investigational drug or procedure within 30 days or 6 half-lives (whichever is longer) or participation in another trial with any cognitive-enhancing therapy or procedure within 90 days prior to screening

10. Previous participation in any BI 409306 study

11. Not fluent in the language of the batteries/questionnaires which will be used in the country

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	K and S Professional Research Services, LLC	Little Rock	Arkansas	United States	72201
2	Comprehensive Clinical Development, Inc.	Cerritos	California	United States	90703
3	Collaborative Neuroscience Network	Garden Grove	California	United States	92845
4	Pacific Institute of Medical Research	Los Angeles	California	United States	90024
5	SRSD, Inc. dba Synergy San Diego	National City	California	United States	91950
6	NRC Research Institute	Orange	California	United States	92868
7	Artemis Institute for Clinical Research, LLC	San Diego	California	United States	92103
8	Collaborative Neuroscience Network	Torrance	California	United States	90502
9	Comprehensive Clinical Development	Washington, D.C.	District of Columbia	United States	20016
10	Innovative Clinical Research	Lauderhill	Florida	United States	33319
11	Florida Clinical Research Center	Maitland	Florida	United States	32751
12	Behavioral Clinical Research, Inc.	North Miami	Florida	United States	33161
13	Atlanta Center	Atlanta	Georgia	United States	30331
14	Northwestern University	Chicago	Illinois	United States	60611
15	Uptown Research Institute	Chicago	Illinois	United States	60640
16	Lake Charles Clinical Trials LLC	Lake Charles	Louisiana	United States	70629
17	Mid-America Clinical Research, LLC	Saint Louis	Missouri	United States	63109
18	St. Louis Clinical Trials	Saint Louis	Missouri	United States	63141
19	Neurobehavioral Research, Inc.	Cedarhurst	New York	United States	11516
20	Finger Lakes Research	Rochester	New York	United States	14618
21	University of Rochester Medical Center	Rochester	New York	United States	14623
22	Richmond Behavioral Associates	Staten Island	New York	United States	10312
23	Community Clinical Research, Inc.	Austin	Texas	United States	78754
24	InSite Clinical Research	DeSoto	Texas	United States	75115
25	Dr. Alexander McIntyre Inc.	Penticton	British Columbia	Canada	V2A 4M4
26	Depression, Mood Disorders and Schizophrenia Treatment Centr	Burlington	Ontario	Canada	L7R4E2
27	LVR-Klinikum Düsseldorf	Düsseldorf		Germany	40629
28	Uniklinikum Heidelberg	Heidelberg		Germany	69115
29	Universitätsklinikum Köln (AöR)	Köln		Germany	50937
30	Fujita Health University Hospital	Aichi, Toyoake		Japan	470-1192
31	Hokkaido University Hospital	Hokkaido, Sapporo		Japan	060-8648
32	Kobe University Hospital	Hyogo, Kobe		Japan	650-0017
33	Nara Medical University Hospital	Nara, Kashihara		Japan	634-8522
34	Kansai Med. Univ. Med. Ctr., Osaka, Neuropsychiatry	Osaka, Moriguchi-city		Japan	570-8507
35	Hizen Psychiatric Center, Saga, PSY	Saga, Kanzaki-gun		Japan	842-0192
36	Iwaki Clinic, Tokushima, Psychosomatic Medicine	Tokushima, Anan		Japan	774-0014
37	National Center Neurology and Psychiatry	Tokyo, Kodaira		Japan	187-8851
38	Showa University Karasuyama Hospital	Tokyo, Setagaya		Japan	157-8577
39	Showa University East Hospital	Tokyo, Shinagawa		Japan	142-0054
40	Chang-Hua Christian Hospital	Changhua		Taiwan	500
41	Kai-Syuan Psychiatric Hospital	Kaohsiung		Taiwan	802
42	NCKUH	Tainan		Taiwan	704
43	Taipei City Hospital	Taipei		Taiwan	110

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02281773
• Other Study ID Numbers: 1289.6; 2013-005015-28
• First Posted: Nov 4, 2014
• Last Update Posted: Oct 19, 2017
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Schizophrenia; BI 409306

Study Results

Participant Flow

Recruitment Details	A phase II multi-centre, multi-national, randomised, double-blind, placebo-controlled parallel group trial to evaluate the efficacy, safety and tolerability of four orally administrated doses of BI 409306 during a 12-week treatment period in patients with schizophrenia on stable antipsychotic treatment.
Pre-assignment Detail	Actually, 518 subjects were entered/randomised however 2 subjects were not treated and hence the number of subjects that started equals 516. One belongs to BI 409306 - 25 milligram and another to Placebo group.

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Period Title: Overall Study
STARTED	87	85	85	86	173
COMPLETED	76	70	67	65	143
NOT COMPLETED	11	15	18	21	30

Baseline Characteristics

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo	Total
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.	Total of all reporting groups
Overall Participants	87	85	85	86	173	516
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.1 (8.9)	43.2 (9.4)	41.4 (9.5)	42.3 (9.5)	41.5 (9.7)	42.3 (9.5)
Sex: Female, Male (Count of Participants)
Female	34 39.1%	29 34.1%	20 23.5%	28 32.6%	45 26%	156 30.2%
Male	53 60.9%	56 65.9%	65 76.5%	58 67.4%	128 74%	360 69.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Composite Score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) After 12 Weeks of Treatment
Description	MCCB comprises 10 tests, which assess 7 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning problem solving, and social cognition. The composite score was calculated by summing over the standardised score of each domain for analysis and it varies from -20 to 99 with higher score indicating better outcome. The trial was set up as "learn and confirm" model including 2 stages. Stage 1 analysis was conducted to identify the meaningful cognition endpoint(s) (CANTAB domain(s)) and the selected endpoint(s) were to be pre-specified as the primary endpoint(s) for Stage 2 analysis. Since none of the CANTAB outcome measures was selected in the Stage 1 analysis at planned time based on the pre-specified criteria, the MCCB composite score was chosen as the primary endpoint in the Stage 2 analysis, as pre-defined.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) was to consist of all randomisation patients who were treated with at least one dose of study drug and had a baseline and at least one post baseline on treatment primary endpoint MCCB composite score.

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	79	76	69	76	150
Least Squares Mean (Standard Error) [Unit on Scale]	1.2 (0.71)	2.7 (0.74)	2.8 (0.75)	1.8 (0.73)	2.5 (0.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 10 Milligram, Placebo
	Comments	The restricted maximum likelihood (REML) based mixed effects model with repeated measurements (MMRM) was used with baseline value as fixed covariate and planned treatment, analysis visit, first test done, geographic region grouping 1, planned treatment by analysis visit and baseline value by analysis visit as fixed effects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1256
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	Mixed Models Analysis
	Comments	Unstructured covariance structure has been used to fit the mixed model. Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -2.76 to 0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.79
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 10 mg minus Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 25 Milligram, Placebo
	Comments	The restricted maximum likelihood (REML) based mixed effects model with repeated measurements (MMRM) was used with baseline value as fixed covariate and planned treatment, analysis visit, first test done, geographic region grouping 1, planned treatment by analysis visit and baseline value by analysis visit as fixed effects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7337
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	Mixed Models Analysis
	Comments	Unstructured covariance structure has been used to fit the mixed model. Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -1.30 to 1.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.80
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 25 mg minus Placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 50 Milligram, Placebo
	Comments	The restricted maximum likelihood (REML) based mixed effects model with repeated measurements (MMRM) was used with baseline value as fixed covariate and planned treatment, analysis visit, first test done, geographic region grouping 1, planned treatment by analysis visit and baseline value by analysis visit as fixed effects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6994
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	Mixed Models Analysis
	Comments	Unstructured covariance structure has been used to fit the mixed model. Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -1.31 to 1.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.83
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 50 mg minus Placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 100 Milligram, Placebo
	Comments	The restricted maximum likelihood (REML) based mixed effects model with repeated measurements (MMRM) was used with baseline value as fixed covariate and planned treatment, analysis visit, first test done, geographic region grouping 1, planned treatment by analysis visit and baseline value by analysis visit as fixed effects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4270
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	Mixed Models Analysis
	Comments	Unstructured covariance structure has been used to fit the mixed model. Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -2.19 to 0.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.79
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 100 mg minus Placebo.

2. Primary Outcome

Title	Occurrence of Serious Adverse Events (SAEs) (Including the Abnormalities of Physical Examination, Vital Signs, Electrocardiogram (ECG) Test and Laboratory Tests)
Description	Occurrence of serious adverse events (SAEs) (including the abnormalities of physical examination, vital signs, electrocardiogram (ECG) test and laboratory tests).
Time Frame	Up to 20 weeks

Outcome Measure Data

Analysis Population Description

The treated set (TS) was to consist of all patients who were randomised and treated with at least one dose of study drug.

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	87	85	85	86	173
Number [Percentage of Participants]	0.0 0%	0.0 0%	0.0 0%	0.0 0%	5.8 3.4%

3. Primary Outcome

Title	Occurrence of Protocol-specified Adverse Events of Special Interest (AESI)
Description	Occurrence of Protocol-specified adverse events of special interest (AESI).
Time Frame	Up to 20 weeks

Outcome Measure Data

Analysis Population Description

The treated set (TS) was to consist of all patients who were randomised and treated with at least one dose of study drug.

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	87	85	85	86	173
Number [Percentage of Participants]	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%

4. Primary Outcome

Title	Dramatic Worsening of Disease State as Assessed by Positive and Negative Syndrome Scale (PANSS)
Description	Dramatic worsening of disease state as assessed by Positive and Negative Syndrome Scale (PANSS). It contains 30-items including seven positive symptom items, seven negative symptom items and 16 general psychopathology symptom items. Each item was scored on the same seven point severity scale. Fourteen of the PANSS items required input from an informant. Total score ranges from 30 to 210 (minimum is better). The descriptive statistics of change from baseline (CFB) in PANSS score at week 6 (W6) and week 12 (W12) are presented.
Time Frame	Baseline, Week 6 and Week 12

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	87	85	85	86	173
W6-Number of participants analyzed:79,74,67,71,154	-0.68 (6.022)	-0.28 (4.507)	-1.09 (5.415)	-1.20 (5.426)	-1.81 (5.895)
W12-Number of participant analyzed:83,78,76,81,157	-2.59 (5.342)	-0.97 (5.420)	-1.58 (6.990)	-0.94 (6.315)	-1.66 (6.942)

5. Primary Outcome

Title	Suicidality as Assessed by Columbia Suicidal Severity Rating Scale (C-SSRS)
Description	C-SSRS: Number (%) of subjects with an event of Suicidal Ideation (Wish to be dead, Non-specific active suicidal thoughts, Active suicidal ideation with any methods (not plan) without intent to act, Active suicidal ideation with some intent to act without specific plan, Active suicidal ideation with specific plan and intent) or Suicidal Behavior (Preparatory acts or behavior, Aborted attempt, Interrupted attempt, Non-fatal suicide attempt, Completed suicide) or Self-injurious behavior without suicidal intent is presented. C-SSRS used only to evaluate whether the patient developed suicidal ideation or behavior and no composite score will be used. Questions in the 1st section of suicidal ideation and suicidal behavior assessments in C-SSRS are "yes" and "no" type questions. If patient had suicidal ideation or behavior, 2nd section will be performed to evaluate the details with the scale from 0 to 5 or 0 to 2 and the larger number means the more severe condition.
Time Frame	Up to 12 weeks

Outcome Measure Data

Analysis Population Description

TS (Number of subjects with a post baseline C-SSRS)

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	84	84	79	85	166
Number [Percentage of Participants]	0.0 (3.677) 0%	1.2 (3.262) 1.4%	2.5 (3.759) 2.9%	1.2 (3.497) 1.4%	3.6 (3.954) 2.1%

6. Secondary Outcome

Title	Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Global Ratings After 12 Weeks of Treatment
Description	Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) global ratings after 12 weeks of treatment. SCoRS is a 20-item interview-based assessment of cognitive deficits and the degree to which they affect day-to-day functions. Each item was rated on a 4-point scale. Higher ratings reflected a greater degree of impairment. The SCoRS global total scores is the sum of the 20 items and it varies from 20 to 80 with 20 being the best outcome and 80 being the worst. If any individual item was missing, it was imputed with the average of that patient's non missing responses. If >5 items were missing, the total score was missing.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) was to consist of all randomisation patients who were treated with at least one dose of study drug and had a baseline and at least one post baseline on treatment primary endpoint MCCB composite score.

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	82	75	73	80	156
Least Squares Mean (Standard Error) [Unit on Scale]	-2.2 (0.53)	-3.1 (0.56)	-2.0 (0.56)	-2.3 (0.54)	-2.5 (0.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 10 Milligram, Placebo
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences (BI 409306 group minus placebo group) in the modelled changes from baseline to Week 12. The dependent variable was the change from the baseline score at Week 12 during the treatment period adjusted for fixed categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5972
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.9 to 1.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.66
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 10 mg minus Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 25 Milligram, Placebo
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences (BI 409306 group minus placebo group) in the modelled changes from baseline to Week 12. The dependent variable was the change from the baseline score at Week 12 during the treatment period adjusted for fixed categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3817
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -1.9 to 0.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.68
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 25 mg minus Placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 50 Milligram, Placebo
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences (BI 409306 group minus placebo group) in the modelled changes from baseline to Week 12. The dependent variable was the change from the baseline score at Week 12 during the treatment period adjusted for fixed categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4800
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -0.9 to 1.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.68
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 50 mg minus Placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 100 Milligram, Placebo
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences (BI 409306 group minus placebo group) in the modelled changes from baseline to Week 12. The dependent variable was the change from the baseline score at Week 12 during the treatment period adjusted for fixed categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7507
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -1.1 to 1.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.66
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 100 mg minus Placebo.

7. Secondary Outcome

Title	Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Scale Score After 12 Weeks of Treatment
Description	Change from baseline in Clinical Global Impressions-Severity (CGI-S) scale score after 12 weeks of treatment. The CGI-S is a one-item evaluation completed by the clinician on the patient's severity of psychopathology. The CGI-S was rated ordinally from one to 7. Higher scores indicate more severe symptoms.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) was to consist of all randomisation patients who were treated with at least one dose of study drug and had a baseline and at least one post baseline on treatment primary endpoint MCCB composite score.

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	82	77	73	81	157
Least Squares Mean (Standard Error) [Unit on Scale]	-0.1 (0.05)	-0.1 (0.05)	-0.1 (0.05)	-0.1 (0.05)	-0.1 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 10 Milligram, Placebo
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences (BI 409306 group minus placebo group) in the modelled changes from baseline to Week 12. The dependent variable was the change from the baseline score at Week 12 during the treatment period adjusted for fixed categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9399
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 10 mg minus Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 25 Milligram, Placebo
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences (BI 409306 group minus placebo group) in the modelled changes from baseline to Week 12. The dependent variable was the change from the baseline score at Week 12 during the treatment period adjusted for fixed categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9919
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 25 mg minus Placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 50 Milligram, Placebo
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences (BI 409306 group minus placebo group) in the modelled changes from baseline to Week 12. The dependent variable was the change from the baseline score at Week 12 during the treatment period adjusted for fixed categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3027
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 50 mg minus Placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 409306 - 100 Milligram, Placebo
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences (BI 409306 group minus placebo group) in the modelled changes from baseline to Week 12. The dependent variable was the change from the baseline score at Week 12 during the treatment period adjusted for fixed categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3901
	Comments	Due to the exploratory nature of this trial, no multiplicity adjustment was made. All statistical testing was performed using a two-sided, α=0.05 level of significance.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as BI 409306 100 mg minus Placebo.

8. Secondary Outcome

Title	Patient Global Impressions-Improvement (PGI-I) Scale Score Measured After 12 Weeks of Treatment
Description	Patient Global Impressions-Improvement (PGI-I) scale score measured after 12 weeks of treatment. The PGI of improvement is a simple evaluation completed by the patient to assess the patient's overall evaluation of his/her status. The PGI of improvement was rated ordinally from one to 7. Higher scores indicate more severe symptoms.
Time Frame	Up to 12 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	82	77	73	82	157
Mean (Standard Deviation) [Unit on Scale]	2.988 (1.117)	2.883 (1.124)	3.192 (1.101)	3.049 (1.342)	3.038 (1.109)

9. Secondary Outcome

Title	Change From Baseline in PANSS Negative Symptom Factor Score After 12 Weeks of Treatment (for Subset of Patients Diagnosed With Negative Symptom)
Description	Change from baseline in PANSS negative symptom factor score after 12 weeks of treatment (for subset of patients diagnosed with negative symptom). This outcome measure was not analysed due to low number of patients in the PANSS negative symptom subgroup. The PANSS negative symptom scale has 7 items. Each was rated from one to 7 points. The total factor score was the summation of the 7 points for each item, leading the total score ranging from 7 to 49.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

This endpoint was not analysed because as per internal Boehringer Ingelheim rules, descriptive statistics are not calculated if data is available for less than 2/3rds of participants.

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	0	0	0	0	0

10. Secondary Outcome

Title	Change in Psychopathology Symptoms as Assessed by Positive and Negative Syndrome Scale (PANSS)
Description	Change in psychopathology symptoms as assessed by Positive and Negative Syndrome Scale (PANSS). It contains 30-items including seven positive symptom items, seven negative symptom items and 16 general psychopathology symptom items. Each item was scored on the same seven point severity scale. Fourteen of the PANSS items required input from an informant. Total score ranges from 30 to 210 (minimum is better). The descriptive statistics of change from baseline (CFB) in PANSS score at week 6 (W6) and week 12 (W12) are presented.
Time Frame	Baseline, Week 6 and Week 12

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	BI 409306 - 10 Milligram	BI 409306 - 25 Milligram	BI 409306 - 50 Milligram	BI 409306 - 100 Milligram	Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.	Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.	Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.	Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
Measure Participants	87	85	85	86	173
W6-Number of participants analyzed:79,74,67,71,154	-0.39 (3.677)	-0.22 (3.262)	-0.31 (3.759)	-0.79 (3.497)	-0.99 (3.954)
W12-Number of participant analyzed:83,78,76,81,157	-1.36 (3.039)	-0.79 (3.277)	-0.68 (4.253)	-0.38 (3.587)	-0.76 (4.007)

Adverse Events

Time Frame	From first drug administration until 4 weeks after the last drug administration, up to 16 weeks
Arm/Group Title	BI 409306 - 10 Milligram		BI 409306 - 25 Milligram		BI 409306 - 50 Milligram		BI 409306 - 100 Milligram		Placebo
Arm/Group Description	Subject received single oral dose of 10 milligram (mg) BI 409306 (film-coated tablet) along with two placebo matching 25mg/50mg tablets once daily for 12 weeks.		Subject received single oral dose of 25 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.		Subject received single oral dose of 50 milligram (mg) BI 409306 (film-coated tablet) along with placebo matching 10mg and 25mg/50mg tablet once daily for 12 weeks.		Subject received single oral dose of 100 milligram (mg) BI 409306 (2 film-coated tablets of 50 mg) along with placebo matching 10mg tablet once daily for 12 weeks.		Subject received single oral dose of placebo matching tablets (one placebo matching 10mg tablet and two placebo matching 25mg/50mg tablets) once daily for 12 weeks.
All Cause Mortality
	BI 409306 - 10 Milligram		BI 409306 - 25 Milligram		BI 409306 - 50 Milligram		BI 409306 - 100 Milligram		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	BI 409306 - 10 Milligram		BI 409306 - 25 Milligram		BI 409306 - 50 Milligram		BI 409306 - 100 Milligram		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/87 (0%)		0/85 (0%)		0/85 (0%)		0/86 (0%)		10/173 (5.8%)
Cardiac disorders
Acute myocardial infarction	0/87 (0%)		0/85 (0%)		0/85 (0%)		0/86 (0%)		1/173 (0.6%)
Ischaemic cardiomyopathy	0/87 (0%)		0/85 (0%)		0/85 (0%)		0/86 (0%)		1/173 (0.6%)
Infections and infestations
Empyema	0/87 (0%)		0/85 (0%)		0/85 (0%)		0/86 (0%)		1/173 (0.6%)
Psychiatric disorders
Psychotic disorder	0/87 (0%)		0/85 (0%)		0/85 (0%)		0/86 (0%)		1/173 (0.6%)
Schizophrenia	0/87 (0%)		0/85 (0%)		0/85 (0%)		0/86 (0%)		5/173 (2.9%)
Suicidal ideation	0/87 (0%)		0/85 (0%)		0/85 (0%)		0/86 (0%)		3/173 (1.7%)
Vascular disorders
Hypertensive crisis	0/87 (0%)		0/85 (0%)		0/85 (0%)		0/86 (0%)		1/173 (0.6%)
Other (Not Including Serious) Adverse Events
	BI 409306 - 10 Milligram		BI 409306 - 25 Milligram		BI 409306 - 50 Milligram		BI 409306 - 100 Milligram		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/87 (5.7%)		9/85 (10.6%)		9/85 (10.6%)		12/86 (14%)		12/173 (6.9%)
Eye disorders
Photophobia	0/87 (0%)		2/85 (2.4%)		2/85 (2.4%)		6/86 (7%)		2/173 (1.2%)
Visual brightness	0/87 (0%)		2/85 (2.4%)		3/85 (3.5%)		6/86 (7%)		0/173 (0%)
Nervous system disorders
Headache	5/87 (5.7%)		5/85 (5.9%)		4/85 (4.7%)		1/86 (1.2%)		10/173 (5.8%)

Limitations/Caveats

"Change from baseline in PANSS negative symptom factor score after 12 weeks of treatment" was not analysed because as per internal BI rules, descriptive statistics are not calculated if data is available for less than 2/3rds of participants

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.