Clinical Trial of BI 425809 Effect on Cognition and Functional Capacity in Schizophrenia

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02832037
• Collaborator: (none)
• Enrollment: 509
• Locations: 81
• Arms: 5
• Actual Duration (Months): 42.2
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The objective of the study is to investigate the efficacy, safety and pharmacokinetics of four different doses of BI 425809 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 425809 dose 1; Drug: BI 425809 dose 2; Drug: BI 425809 dose 3; Drug: BI 425809 dose 4; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 509 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase II Randomised, Double-blinded, Placebo-controlled Parallel Group Trial to Examine the Efficacy and Safety of 4 Oral Doses of BI 425809 Once Daily Over 12 Week Treatment Period in Patients With Schizophrenia
• Actual Study Start Date: Jul 25, 2016
• Actual Primary Completion Date: Dec 27, 2019
• Actual Study Completion Date: Jan 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 425809 dose 1	Drug: BI 425809 dose 1; Drug: Placebo
Experimental: BI 425809 dose 2	Drug: BI 425809 dose 2; Drug: Placebo
Experimental: BI 425809 dose 3	Drug: BI 425809 dose 3; Drug: Placebo
Experimental: BI 425809 dose 4	Drug: BI 425809 dose 4; Drug: Placebo
Placebo Comparator: Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Cognitive Function as Measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Overall Composite T-score After 12 Weeks of Treatment [Baseline, after 6 and 12 weeks of treatment]

   MCCB overall composite T-score was derived from scores of 7 cognitive domains (Speed of Processing, Verbal Learning, Working Memory, Reasoning and Problem Solving, Visual Learning, Social Cognition, Attention) obtained from a total of 10 tests (Trail Making, Brief Assessment of Cognition in Schizophrenia, Hopkins Verbal Learning, Wechsler Memory Scale, Letter-Number Span, Neuropsychological Assessment Battery, Brief Visuospatial Memory, Category Fluency, Mayer-Salovey-Caruso Emotional Intelligence, Continuous Performance) and ranges typically between -20 and +99, a larger T-score indicates better cognition. Change from baseline in MCCB overall composite T-score after 12 weeks of treatment was modeled using a MMRM with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (week 6 and week 12 of treatment) as repeated measures, subject as random effect, adjusted mean (standard error) after 12 weeks of treatment is reported.

Secondary Outcome Measures

1. Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Total Score After 12 Weeks of Treatment [Baseline and after 12 weeks of treatment]

   SCoRS total score was derived as the sum of non-missing responses from 20 interview-based items rated by an interviewer on a 4-point scale. A response of "not available" to an item was treated as missing. If six or more of the 20 items were missing for a participant at a visit, then the corresponding SCoRS total score was missing for that participant at the visit. If five or less of the 20 items were missing for a participant at a visit, then the item(s) with missing value(s) were imputed first with the average of the non-missing item values, then the SCoRS total score for the participant at the visit was derived as the sum of non-missing item values and the imputed item values. SCoRS total score is between 20 and 80 where higher score values represent greater degree of impairment in day-to-day functions due to cognitive deficits. Analysis of covariance model was fitted to calculate adjusted mean and standard error, model details in the Statistical Analysis section.

2. Percentage of Participants With Any Adverse Event [On-treatment period, that is, from first intake of any trial drug until the last intake of any trial drug (planned: 84 days) + residual effect period (11 days), up to 103 days]

   Percentage of participants with any Adverse Event.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Men or women who are 18-50 years (inclusive) of age at time of consent

• Established schizophrenia with the following clinical features:

• Outpatient, with no hospitalization for worsening of schizophrenia within 3 months prior to randomisation

• Medically stable over the prior 4 weeks and psychiatrically stable without symptom exacerbation within 3 months prior to randomisation

• patients who have no more than a moderate severe rating on the Positive and Negative Symptom Scale (PANSS) positive items P1, P3-P7 and no more than a moderate rating on the PANSS positive item P2

• Current antipsychotic and concomitant psychotropic medications as assessed at Visit 1 must meet the criteria below:

• patients may have up to 2 antipsychotics (typical and/or atypical)

• patients must be maintained on current typical and/or atypical antipsychotics other than Clozapine and on current dose for at least 4 weeks prior to randomisation and/or maintained on current long acting injectable antipsychotics and current dose for at least 3 months prior to randomization

• patients must be maintained on current concomitant psychotropic medications, anticholinergics, antiepileptics and/or lithium for at least 3 months prior to randomisation and on current dose for at least 4 weeks prior to randomisation

• Women of child-bearing potential must be ready and able to use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly.

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

• Patients must have an identified informant who will be consistent throughout the study.

• Further inclusion criteria apply

Exclusion criteria:

• Patients who have a categorical diagnosis of another current major psychiatric disorder

• Diseases of the central nervous system that may impact cognitive test performance

• Movement disorder not currently controlled

• Patients receiving another investigational drug or procedure within 30 days or 6 half-lives (whichever is longer) or recent participation in another trial with any cognitive enhancing therapy

• Recent participation in formal cognitive remediation program

• Recent electroconvulsive therapy

• Patients who have been on BI 409306, encenicline or other investigational drug testing effects on cognition in schizophrenia within the last 6 months prior to randomisation or who have previously been on bitopertin

• Participation in a clinical trial with repeated Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) assessments within the last 6 months

• Patients who required change in ongoing stable benzodiazepine or sleep medication regimen within the last 4 weeks prior to randomisation

• Treatment with Clozapine within 6 months prior to randomisation

• Treatment with medical devices (e.g. Transcranial Magnetic Stimulation (TMS), neurofeedback) for any psychiatric condition within the last 3 months prior to randomisation

• Patients taking strong or moderate Cytochrome P450 (CYPA4) inhibitors or inducers within the last 30 days prior to randomization

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

• 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) prior to randomisation

• Known history of Human Immunodeficiency Virus (HIV) infection and/or a positive result for ongoing Hepatitis B or C infection on the Visit 1 central lab report

• Hemoglobin less than 120 g/L (12g/dL) in men or 115 g/L (11.5 g/dL) in women

• History of hemoglobinopathy such as thalassemia major or sickle-cell anemia

• Women who are pregnant, nursing, or who plan to become pregnant while in the trial or men who are able to father a child, unwilling to be abstinent or use adequate contraception for the duration of the study participation and for at least 28 days after treatment has ended

• Significant history of drug abuse disorder (including alcohol) within the last 6 months prior to informed consent or a positive urine drug screen at screening (except for Benzodiazepines taken according to prescription and as an ongoing, stable regimen)

• Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Collaborative Neuroscience Network, LLC (CNS)	Garden Grove	California	United States	92845
2	Synergy San Diego	Lemon Grove	California	United States	91945
3	NRC Research Institute	Orange	California	United States	92868
4	Alliance for Wellness	Panorama City	California	United States	91402
5	CNRI - Los Angeles	Pico Rivera	California	United States	90660
6	CNRI-San Diego, LLC	San Diego	California	United States	92102
7	Premier Clinical Research Institute	Miami	Florida	United States	33122
8	Synexus	Atlanta	Georgia	United States	30328
9	Atlanta Center	Atlanta	Georgia	United States	30331
10	Uptown Research Institute	Chicago	Illinois	United States	60640
11	Lake Charles Clinical Trials LLC	Lake Charles	Louisiana	United States	70629
12	Michigan Clinical Research Institute PC	Ann Arbor	Michigan	United States	48105
13	Mid-America Clinical Research, LLC	Saint Louis	Missouri	United States	63109
14	University at Buffalo, The State University of New York	Buffalo	New York	United States	14215
15	Neurobehavioral Research, Inc.	Cedarhurst	New York	United States	11516
16	Finger Lakes Clinical Research	Rochester	New York	United States	14618
17	North Carolina Psychiatric Research Center	Raleigh	North Carolina	United States	27610
18	Midwest Clinical Research	Dayton	Ohio	United States	45417
19	InSite Clinical Research	DeSoto	Texas	United States	75115
20	Psychiatric and Behavioral Solutions, LLC	Salt Lake City	Utah	United States	84105
21	Northwest Clinical Research Center	Bellevue	Washington	United States	98007
22	Medical University of Innsbruck	Innsbruck		Austria	6020
23	AKH - Medical University of Vienna	Vienna		Austria	1090
24	Dr. Alexander McIntyre Inc.	Penticton	British Columbia	Canada	V2A 4M4
25	The Medical Arts Health Research Group	Vancouver	British Columbia	Canada	V7T 1C5
26	Chatham-Kent Clinical Trials Research Centre	Chatham	Ontario	Canada	N7L 1C1
27	Centre for Addiction and Mental Health (CAMH)	Toronto	Ontario	Canada	M5T 1R8
28	IUSMM Institut Universitaire en Sante Mentale de Montreal	Montreal	Quebec	Canada	H1N 3M5
29	Zentrum für klinische Forschung Dr. med. Irma Schöll & Kollegen	Bad Homburg		Germany	61348
30	Praxis Dr. Volker Schumann	Berlin		Germany	10245
31	Berufsausübungsgemeinschaft, Dr. sc. med. Alexander Schulze und Prof. Dr. med. Hagen Kunte	Berlin		Germany	13156
32	Praxis Dr. Hahn, Berlin	Berlin		Germany	13187
33	PANAKEIA Arzneimittelforschung Leipzig GmbH	Leipzig		Germany	04275
34	Zentralinstitut für seelische Gesundheit	Mannheim		Germany	68159
35	Neurologie und Psychiatrie / Psychotherapie	Westerstede		Germany	26655
36	ASST degli Spedali Civili di Brescia	Concesio (BS)		Italy	25062
37	Asst Santi Paolo E Carlo	Milano		Italy	20142
38	Azienda Sanitaria Ospedale S. Luigi Gonzaga	Orbassano (TO)		Italy	10043
39	Fujita Health University Hospital	Aichi, Toyoake		Japan	470-1192
40	Chiba University Hospital	Chiba, Chiba		Japan	260-8677
41	National Center for Global Health and Medicine Kohnodai Hospital	Chiba, Ichikawa		Japan	272-8516
42	Hospital of the University of Occupational and Environmental Health	Fukuoka, Kitakyushu		Japan	807-8556
43	Hokkaido University Hospital	Hokkaido, Sapporo		Japan	060-8648
44	Kobe University Hospital	Hyogo, Kobe		Japan	650-0017
45	Kagawa University Hospital	Kagawa, Kita-gun		Japan	761-0793
46	Kishiro Mental Clinic	Kanagawa, Kawasaki		Japan	214-0014
47	Nara Medical University Hospital	Nara, Kashihara		Japan	634-8522
48	Kansai Medical University Medical Center	Osaka, Moriguchi		Japan	570-8507
49	Iwaki Clinic, Tokushima, Psychosomatic Medicine	Tokushima, Anan		Japan	774-0014
50	National Center Neurology and Psychiatry	Tokyo, Kodaira		Japan	187-8851
51	Showa University Karasuyama Hospital	Tokyo, Setagaya		Japan	157-8577
52	Tokyo Women's Medical University Hospital	Tokyo, Shinjuku-ku		Japan	162-8666
53	Chonnam National University Hospital	Gwangju		Korea, Republic of	61453
54	Gachon University Gil Medical Center	Incheon		Korea, Republic of	21565
55	Seoul National University Bundang Hospital	Seongnam		Korea, Republic of	13620
56	Seoul National University Hospital	Seoul		Korea, Republic of	03080
57	Severance Hospital	Seoul		Korea, Republic of	03722
58	National Center for Mental Health	Seoul		Korea, Republic of	04933
59	Asan Medical Center	Seoul		Korea, Republic of	05505
60	Wlokiennicza Med,Spec.Med.Prac,MD Tomasz Markowski,Bialystok	Bialystok		Poland	15 464
61	Podlassian Center of Psychogeriatry, Bialystok	Bialystok		Poland	15-756
62	Osrodek Badan Klinicznych CLINSANTE S.C.	Bydgoszcz		Poland	85794
63	Non-public Health Care Psychiatric Institution MENTIS,Leszno	Leszno		Poland	64100
64	EUROMEDIS Sp. z o.o., Szczecin	Szczecin		Poland	70-111
65	Clin.Research Centre Clinsante SC Ewa Galczak-Nowak,Torun	Torun		Poland	87-100
66	Therapy Centre DIALOG Sp.z o.o. S.j.	Warszawa		Poland	02-791
67	Hospital del Mar	Barcelona		Spain	08003
68	Centro de Salud Mental de Fuencarral	Madrid		Spain	28029
69	Fundación Jiménez Díaz	Madrid		Spain	28040
70	Hospital Puerta de Hierro	Majadahonda (Madrid)		Spain	28222
71	Centro de Salud de San Juan	Salamanca		Spain	37005
72	Hospital Universitario Marqués de Valdecilla	Santander		Spain	39008
73	NCKUH	Tainan		Taiwan	704
74	National Taiwan University Hospital	Taipei		Taiwan	10016
75	Taipei City Hospital	Taipei		Taiwan	110
76	Taipei Veterans General Hospital	Taipei		Taiwan	11217
77	Bushey Fields Hospital	Dudley		United Kingdom	DY1 2LZ
78	Royal Edinburgh Hospital	Edinburgh		United Kingdom	EH10 5HF
79	Queen Elizabeth University Hospital	Glasgow		United Kingdom	G51 4TF
80	King's College Hospital	London		United Kingdom	SE5 8AF
81	Royal Cornwall Hospital	Truro		United Kingdom	TR1 3HD

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Mar 28, 2019
• Statistical Analysis Plan - Feb 17, 2020

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02832037
• Other Study ID Numbers: 1346.9; 2016-000285-28
• First Posted: Jul 13, 2016
• Last Update Posted: Feb 24, 2021
• Last Verified: Feb 1, 2021

• Additional relevant MeSH terms: Schizophrenia; BI 425809

Study Results

Participant Flow

Recruitment Details	This was a phase II randomized, double-blind, double-dummy, placebo-controlled, multi-center, multi-national, 12-week parallel-group trial in participants with schizophrenia. Abbreviation: MMRM=Mixed-effects Model Repeated Measures
Pre-assignment Detail	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.

Arm/Group Title	BI 425809 2 mg Once a Day (q.d.)	BI 425809 5 mg q.d.	BI 425809 10 mg q.d.	BI 425809 25 mg q.d.	Placebo q.d.
Arm/Group Description	2 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 1 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	5 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 5 mg BI 425809, 1 placebo tablet matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	10 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 5 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food in the morning, once daily. Continuous daily dosing for 12 weeks (planned treatment duration).	25 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 25 mg BI 425809, 2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	Placebo administered orally (2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).
Period Title: Overall Study
STARTED	85	84	85	85	170
COMPLETED	66	72	77	78	151
NOT COMPLETED	19	12	8	7	19

Baseline Characteristics

Arm/Group Title	BI 425809 2 mg Once a Day (q.d.)	BI 425809 5 mg q.d.	BI 425809 10 mg q.d.	BI 425809 25 mg q.d.	Placebo q.d.	Total
Arm/Group Description	2 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 1 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	5 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 5 mg BI 425809, 1 placebo tablet matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	10 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 5 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food in the morning, once daily. Continuous daily dosing for 12 weeks (planned treatment duration).	25 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 25 mg BI 425809, 2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	Placebo administered orally (2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	Total of all reporting groups
Overall Participants	85	84	85	85	170	509
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.5 (8.5)	37.5 (7.9)	37.9 (6.8)	36.2 (7.8)	37.2 (7.7)	37.1 (7.7)
Sex: Female, Male (Count of Participants)
Female	34 40%	27 32.1%	24 28.2%	35 41.2%	60 35.3%	180 35.4%
Male	51 60%	57 67.9%	61 71.8%	50 58.8%	110 64.7%	329 64.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 7.1%	8 9.5%	7 8.2%	5 5.9%	15 8.8%	41 8.1%
Not Hispanic or Latino	79 92.9%	76 90.5%	78 91.8%	80 94.1%	155 91.2%	468 91.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.2%	0 0%	0 0%	0 0%	1 0.2%
Asian	24 28.2%	18 21.4%	25 29.4%	22 25.9%	56 32.9%	145 28.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	1 1.2%	0 0%	1 0.2%
Black or African American	15 17.6%	20 23.8%	21 24.7%	22 25.9%	41 24.1%	119 23.4%
White	44 51.8%	44 52.4%	39 45.9%	38 44.7%	72 42.4%	237 46.6%
More than one race	2 2.4%	1 1.2%	0 0%	2 2.4%	1 0.6%	6 1.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score (Score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on a scale]	30.0 (13.8)	32.8 (12.0)	31.8 (12.8)	30.2 (13.2)	32.3 (13.6)	31.5 (13.2)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Cognitive Function as Measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Overall Composite T-score After 12 Weeks of Treatment
Description	MCCB overall composite T-score was derived from scores of 7 cognitive domains (Speed of Processing, Verbal Learning, Working Memory, Reasoning and Problem Solving, Visual Learning, Social Cognition, Attention) obtained from a total of 10 tests (Trail Making, Brief Assessment of Cognition in Schizophrenia, Hopkins Verbal Learning, Wechsler Memory Scale, Letter-Number Span, Neuropsychological Assessment Battery, Brief Visuospatial Memory, Category Fluency, Mayer-Salovey-Caruso Emotional Intelligence, Continuous Performance) and ranges typically between -20 and +99, a larger T-score indicates better cognition. Change from baseline in MCCB overall composite T-score after 12 weeks of treatment was modeled using a MMRM with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (week 6 and week 12 of treatment) as repeated measures, subject as random effect, adjusted mean (standard error) after 12 weeks of treatment is reported.
Time Frame	Baseline, after 6 and 12 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included all participants who were randomized and were treated with at least 1 dose of trial medication and who had a non-missing baseline measurement and at least 1 non-missing post-baseline and on-treatment measurement for the primary or secondary efficacy endpoint.

Arm/Group Title	BI 425809 2 mg Once a Day (q.d.)	BI 425809 5 mg q.d.	BI 425809 10 mg q.d.	BI 425809 25 mg q.d.	Placebo q.d.
Arm/Group Description	2 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 1 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	5 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 5 mg BI 425809, 1 placebo tablet matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	10 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 5 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food in the morning, once daily. Continuous daily dosing for 12 weeks (planned treatment duration).	25 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 25 mg BI 425809, 2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	Placebo administered orally (2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).
Measure Participants	79	80	82	83	163
Least Squares Mean (Standard Error) [scores on a scale]	1.784 (0.6805)	1.641 (0.6656)	3.486 (0.6410)	3.234 (0.6410)	1.504 (0.4579)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.0145
	Comments	Adjusted for multiplicity.
	Method	MCP-Mod linear model fit
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.0148
	Comments	Adjusted for multiplicity.
	Method	MCP-Mod linear in log model fit
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.0089
	Comments	Adjusted for multiplicity.
	Method	MCP-Mod Emax model fit
	Comments	Model assumption: 20% of the maximum effect is achieved at 2 mg of BI 425809 .

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.0038
	Comments	Adjusted for multiplicity.
	Method	MCP-Mod Sigmoid Emax model fit
	Comments	Model assumption: 25% of the maximum effect is achieved at 5 mg and 75% of the maximum effect is achieved at 10 mg of BI 425809.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.0085
	Comments	Adjusted for multiplicity.
	Method	MCP-Mod logistic model fit
	Comments	Model assumption: 10% of the maximum effect is achieved at 5 mg and 50% of the maximum effect is achieved at 10 mg of BI 425809.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.2280
	Comments	Adjusted for multiplicity.
	Method	MCP-Mod beta model fit
	Comments	Assumption:75% of maximum (max) effect at 2mg, 87.5% of max effect at 5mg,25% of max effect at 25mg,max effect at 10mg BI 425809, scalar parameter=26.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), Placebo q.d.
	Comments	Secondary analysis. No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments	Mixed Model Repeated Measures included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.7330
	Comments	P-value is considered nominal.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	0.280
	Confidence Interval	(2-Sided) 95%; -1.332 to 1.892
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.8205
	Estimation Comments	Difference was calculated as BI 425809 - placebo.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	BI 425809 5 mg q.d., Placebo q.d.
	Comments	Secondary analysis. No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments	Mixed Model Repeated Measures included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.8655
	Comments	P-value is considered nominal.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	0.137
	Confidence Interval	(2-Sided) 95%; -1.450 to 1.724
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.8074
	Estimation Comments	Difference was calculated as BI 425809 - placebo.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	BI 425809 10 mg q.d., Placebo q.d.
	Comments	Secondary analysis. No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments	Mixed Model Repeated Measures included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.0122
	Comments	P-value is considered nominal.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	1.982
	Confidence Interval	(2-Sided) 95%; 0.434 to 3.530
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7875
	Estimation Comments	Difference was calculated as BI 425809 - placebo.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	BI 425809 25 mg q.d., Placebo q.d.
	Comments	Secondary analysis. No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments	Mixed Model Repeated Measures included fixed, categorical factors of treatment, analysis visit as repeated measures per subject, and treatment by analysis visit interaction, continuous fixed covariate of baseline value and baseline value by analysis visit interaction, subject as random effect, covariance structure= Unstructured.
Statistical Test of Hypothesis	p-Value	0.0287
	Comments	P-value is considered nominal.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger was used to estimate denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	1.730
	Confidence Interval	(2-Sided) 95%; 0.181 to 3.280
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7884
	Estimation Comments	Difference was calculated as BI 425809 - placebo.

2. Secondary Outcome

Title	Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Total Score After 12 Weeks of Treatment
Description	SCoRS total score was derived as the sum of non-missing responses from 20 interview-based items rated by an interviewer on a 4-point scale. A response of "not available" to an item was treated as missing. If six or more of the 20 items were missing for a participant at a visit, then the corresponding SCoRS total score was missing for that participant at the visit. If five or less of the 20 items were missing for a participant at a visit, then the item(s) with missing value(s) were imputed first with the average of the non-missing item values, then the SCoRS total score for the participant at the visit was derived as the sum of non-missing item values and the imputed item values. SCoRS total score is between 20 and 80 where higher score values represent greater degree of impairment in day-to-day functions due to cognitive deficits. Analysis of covariance model was fitted to calculate adjusted mean and standard error, model details in the Statistical Analysis section.
Time Frame	Baseline and after 12 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included all participants who were randomized and were treated with at least 1 dose of trial medication and who had a non-missing baseline measurement and at least 1 non-missing post-baseline and on-treatment measurement for the primary or secondary efficacy endpoint.

Arm/Group Title	BI 425809 2 mg Once a Day (q.d.)	BI 425809 5 mg q.d.	BI 425809 10 mg q.d.	BI 425809 25 mg q.d.	Placebo q.d.
Arm/Group Description	2 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 1 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	5 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 5 mg BI 425809, 1 placebo tablet matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	10 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 5 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food in the morning, once daily. Continuous daily dosing for 12 weeks (planned treatment duration).	25 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 25 mg BI 425809, 2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	Placebo administered orally (2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).
Measure Participants	77	80	82	83	158
Least Squares Mean (Standard Error) [units on a scale]	-1.637 (0.5992)	-3.652 (0.5890)	-3.078 (0.5803)	-3.887 (0.5770)	-2.815 (0.4181)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Analysis of covariance (ANCOVA) model estimates were used as input for the MCP-Mod. ANCOVA included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Statistical Test of Hypothesis	p-Value	0.0660
	Comments	P-value is considered nominal.
	Method	MCP-Mod linear model fit
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Analysis of covariance (ANCOVA) model estimates were used as input for the MCP-Mod. ANCOVA included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Statistical Test of Hypothesis	p-Value	0.1619
	Comments	P-value is considered nominal.
	Method	MCP-Mod linear in log model fit
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Analysis of covariance (ANCOVA) model estimates were used as input for the MCP-Mod. ANCOVA included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Statistical Test of Hypothesis	p-Value	0.0832
	Comments	P-value is considered nominal.
	Method	MCP-Mod Emax model fit
	Comments	Model assumption: 20% of the maximum effect is achieved at 2 mg of BI 425809.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Analysis of covariance (ANCOVA) model estimates were used as input for the MCP-Mod. ANCOVA included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Statistical Test of Hypothesis	p-Value	0.0625
	Comments	P-value is considered nominal.
	Method	MCP-Mod Sigmoid Emax model fit
	Comments	Model assumption: 25% of the maximum effect is achieved at 5 mg and 75% of the maximum effect is achieved at 10 mg of BI 425809.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Analysis of covariance (ANCOVA) model estimates were used as input for the MCP-Mod. ANCOVA included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Statistical Test of Hypothesis	p-Value	0.0768
	Comments	P-value is considered nominal.
	Method	MCP-Mod logistic model fit
	Comments	Model assumption: 10% of the maximum effect is achieved at 5 mg and 50% of the maximum effect is achieved at 10 mg of BI 425809.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), BI 425809 5 mg q.d., BI 425809 10 mg q.d., BI 425809 25 mg q.d., Placebo q.d.
	Comments	A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, linear in log, Emax, Sigmoid Emax, logistic, and beta) while protecting the overall probability of type I error (one-sided alpha of 0.05).
	Type of Statistical Test	Other
	Comments	Analysis of covariance (ANCOVA) model estimates were used as input for the MCP-Mod. ANCOVA included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Statistical Test of Hypothesis	p-Value	0.7479
	Comments	P-value is considered nominal.
	Method	MCP-Mod beta model fit
	Comments	Assumption:75% of maximum (max) effect at 2mg, 87.5% of max effect at 5mg,25% of max effect at 25mg,max effect at 10mg BI 425809, scalar parameter=26.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	BI 425809 2 mg Once a Day (q.d.), Placebo q.d.
	Comments	Secondary analysis. No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments	P-value is considered nominal.
	Method	ANCOVA
	Comments	Analysis of covariance (ANCOVA) model included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	1.178
	Confidence Interval	(2-Sided) 95%; -0.258 to 2.613
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7306
	Estimation Comments	Difference was calculated as BI 425809 - placebo.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	BI 425809 5 mg q.d., Placebo q.d.
	Comments	Secondary analysis. No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments	P-value is considered nominal.
	Method	ANCOVA
	Comments	Analysis of covariance (ANCOVA) model included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	-0.837
	Confidence Interval	(2-Sided) 95%; -2.257 to 0.582
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7224
	Estimation Comments	Difference was calculated as BI 425809 - placebo.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	BI 425809 10 mg q.d., Placebo q.d.
	Comments	Secondary analysis. No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments	P-value is considered nominal.
	Method	ANCOVA
	Comments	Analysis of covariance (ANCOVA) model included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	-0.263
	Confidence Interval	(2-Sided) 95%; -1.669 to 1.142
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7152
	Estimation Comments	Difference was calculated as BI 425809 - placebo.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	BI 425809 25 mg q.d., Placebo q.d.
	Comments	Secondary analysis. No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments	P-value is considered nominal.
	Method	ANCOVA
	Comments	Analysis of covariance (ANCOVA) model included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	-1.072
	Confidence Interval	(2-Sided) 95%; -2.473 to 0.328
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7125
	Estimation Comments	Difference was calculated as BI 425809 - placebo.

3. Secondary Outcome

Title	Percentage of Participants With Any Adverse Event
Description	Percentage of participants with any Adverse Event.
Time Frame	On-treatment period, that is, from first intake of any trial drug until the last intake of any trial drug (planned: 84 days) + residual effect period (11 days), up to 103 days

Outcome Measure Data

Analysis Population Description

The Treated Set included all participants who were randomized and were treated with at least 1 dose of trial medication.

Arm/Group Title	BI 425809 2 mg Once a Day (q.d.)	BI 425809 5 mg q.d.	BI 425809 10 mg q.d.	BI 425809 25 mg q.d.	Placebo q.d.
Arm/Group Description	2 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 1 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	5 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 5 mg BI 425809, 1 placebo tablet matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	10 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 5 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food in the morning, once daily. Continuous daily dosing for 12 weeks (planned treatment duration).	25 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 25 mg BI 425809, 2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).	Placebo administered orally (2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).
Measure Participants	85	84	85	85	170
Number [Percentage of participants]	58.8 69.2%	52.4 62.4%	41.2 48.5%	42.4 49.9%	43.5 25.6%

Adverse Events

Time Frame	For Serious and Other Adverse Events: On-treatment period, that is, from first intake of any trial drug until the last intake of any trial drug (planned: 84 days) + residual effect period (11 days), up to 103 days. For All-Cause Mortality: On-treatment period + Follow-up period (planned: 28±7 days), up to 127 days.
Adverse Event Reporting Description	The Treated Set included all participants who were randomized and were treated with at least 1 dose of trial medication.
Arm/Group Title	BI 425809 2 mg Once a Day (q.d.)		BI 425809 5 mg q.d.		BI 425809 10 mg q.d.		BI 425809 25 mg q.d.		Placebo q.d.
Arm/Group Description	2 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 1 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).		5 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 5 mg BI 425809, 1 placebo tablet matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).		10 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 5 mg BI 425809, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food in the morning, once daily. Continuous daily dosing for 12 weeks (planned treatment duration).		25 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 25 mg BI 425809, 2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).		Placebo administered orally (2 placebo tablets matching 1 mg and 5 mg BI 425809 tablets, 1 placebo tablet matching 25 mg BI 425809 tablets) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).
All Cause Mortality
	BI 425809 2 mg Once a Day (q.d.)		BI 425809 5 mg q.d.		BI 425809 10 mg q.d.		BI 425809 25 mg q.d.		Placebo q.d.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/85 (0%)		0/84 (0%)		0/85 (0%)		0/85 (0%)		0/170 (0%)
Serious Adverse Events
	BI 425809 2 mg Once a Day (q.d.)		BI 425809 5 mg q.d.		BI 425809 10 mg q.d.		BI 425809 25 mg q.d.		Placebo q.d.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/85 (2.4%)		4/84 (4.8%)		2/85 (2.4%)		4/85 (4.7%)		4/170 (2.4%)
Infections and infestations
Abscess limb	0/85 (0%)		1/84 (1.2%)		0/85 (0%)		0/85 (0%)		0/170 (0%)
Infective myositis	0/85 (0%)		0/84 (0%)		1/85 (1.2%)		0/85 (0%)		0/170 (0%)
Injury, poisoning and procedural complications
Fall	0/85 (0%)		0/84 (0%)		0/85 (0%)		0/85 (0%)		1/170 (0.6%)
Lumbar vertebral fracture	0/85 (0%)		0/84 (0%)		0/85 (0%)		0/85 (0%)		1/170 (0.6%)
Radius fracture	0/85 (0%)		0/84 (0%)		0/85 (0%)		1/85 (1.2%)		0/170 (0%)
Investigations
Blood creatine phosphokinase increased	0/85 (0%)		1/84 (1.2%)		0/85 (0%)		0/85 (0%)		0/170 (0%)
Psychiatric disorders
Drug dependence	0/85 (0%)		0/84 (0%)		0/85 (0%)		1/85 (1.2%)		0/170 (0%)
Fear of disease	0/85 (0%)		0/84 (0%)		1/85 (1.2%)		0/85 (0%)		0/170 (0%)
Psychotic disorder	0/85 (0%)		1/84 (1.2%)		0/85 (0%)		0/85 (0%)		0/170 (0%)
Psychotic symptom	1/85 (1.2%)		0/84 (0%)		0/85 (0%)		0/85 (0%)		0/170 (0%)
Schizophrenia	1/85 (1.2%)		1/84 (1.2%)		0/85 (0%)		0/85 (0%)		1/170 (0.6%)
Suicidal behaviour	0/85 (0%)		0/84 (0%)		0/85 (0%)		1/85 (1.2%)		1/170 (0.6%)
Suicidal ideation	0/85 (0%)		0/84 (0%)		0/85 (0%)		1/85 (1.2%)		3/170 (1.8%)
Other (Not Including Serious) Adverse Events
	BI 425809 2 mg Once a Day (q.d.)		BI 425809 5 mg q.d.		BI 425809 10 mg q.d.		BI 425809 25 mg q.d.		Placebo q.d.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/85 (25.9%)		23/84 (27.4%)		14/85 (16.5%)		13/85 (15.3%)		31/170 (18.2%)
Infections and infestations
Nasopharyngitis	8/85 (9.4%)		9/84 (10.7%)		7/85 (8.2%)		4/85 (4.7%)		13/170 (7.6%)
Nervous system disorders
Dizziness	5/85 (5.9%)		4/84 (4.8%)		2/85 (2.4%)		3/85 (3.5%)		6/170 (3.5%)
Headache	8/85 (9.4%)		10/84 (11.9%)		7/85 (8.2%)		8/85 (9.4%)		9/170 (5.3%)
Somnolence	2/85 (2.4%)		5/84 (6%)		5/85 (5.9%)		2/85 (2.4%)		4/170 (2.4%)

Limitations/Caveats

After identifying a new major metabolite (BI 761036), the sponsor communicated a voluntary hold of Phase II to relevant competent authorities on 16-Sep-2016. This was formalized to a full clinical hold of the development program by the Food and Drug Administration (FDA) on 26-Oct-2016. Before start of the hold, 1 patient was screened, but not randomized. Clinical hold was removed by FDA on 21-Nov-2017, the trial was re-initiated with version 3 of the clinical trial protocol, dated 13-Dec-2017.

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.