This Study Tests Whether BI 409306 Prevents Patients With Schizophrenia From Becoming Worse. This Study Looks at How Well Patients Tolerate BI 409306 and How Effective it is Over 6 Months

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03351244
• Collaborator: (none)
• Enrollment: 264
• Locations: 59
• Arms: 3
• Actual Duration (Months): 39.8
• Patients Per Site: 4.5
• 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 tolerability of BI 409306 once daily compared with placebo given for 28 weeks in patients with schizophrenia on antipsychotic treatment. The study is designed to show superiority of BI 409306 over placebo in preventing relapse of schizophrenia symptoms.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: BI 409306; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 264 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Orally Administered BI 409306 During a 28-week Treatment Period as Adjunctive Therapy to Antipsychotic Treatment for the Prevention of Relapse in Patients With Schizophrenia.
• Actual Study Start Date: Dec 7, 2017
• Actual Primary Completion Date: Mar 10, 2021
• Actual Study Completion Date: Mar 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 409306 50 mg 1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks.	Drug: BI 409306; 28 week treatment period
Experimental: BI 409306 25 mg 1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks.	Drug: BI 409306; 28 week treatment period
Placebo Comparator: Placebo 1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks.	Drug: Placebo; 28 week treatment period

Outcome Measures

Primary Outcome Measures

1. Incidence Rate of First Relapse After 28 Weeks of Treatment [28 weeks]

   The incidence rate of first relapse after 28 weeks of treatment is reported. For each treatment group, the incidence rate was calculated as the number of events / sum of the observational time (patient year) over all participants in this treatment group.

Secondary Outcome Measures

1. Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Symptoms Score After 28 Weeks of Treatment [At baseline and at Week 28.]

   Positive and Negative Syndrome Scale (PANSS): assesses the severity of psychotic symptoms and progression of disease. The PANSS positive symptoms score is the sum of scores from 7 Items where each item has a minimum score 1 (better outcome) and maximum score 7 (worse outcome). The PANSS positive symptoms score ranges from 7 (less severe the disease) to 49 (more severe the disease).

2. Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Scale Score After 28 Weeks of Treatment [At baseline and at Week 28]

   Clinical Global Impressions-Severity (CGI-S): One-item evaluation completed by the clinician to measure the severity of psychopathology. The CGI-S score ranges from 1 (normal) through to 7 (most severely ill). The higher the score, the worse the psychopathology.

3. Patient Global Impressions-Improvement (PGI-I) Scale Score After 28 Weeks of Treatment [At Week 28]

   Patient Global Impressions-Improvement (PGI-I): One-item evaluation completed by the patient to assess their overall evaluation of his/her status compared to how they felt at randomisation. The PGI-I score ranges from 1 (Very much better) through to 7 (Very much worse). The higher the score, the worse the improvement.

4. Incidence Rate of Suicidal Ideation and Behaviour (Assessed by Columbia Suicide Severity Rating Scale (C-SSRS)) After 28 Weeks of Treatment [28 weeks]

   Columbia Suicide Severity Rating Scale (C-SSRS): suicide risk assessment. At a minimum, the interview consists of 2 screening questions related to suicidal ideation and 4 related to suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free text entries are allowed. Suicidal behavior is collected in nominal scale as presence/absence of actual attempts, non-suicidal self-injurious behavior, interrupted attempts, aborted attempts, preparatory acts or behavior, and any suicidal behavior. Suicidal ideation is rated on a 6-point scale from 0 (No ideation present) to 5 (Active ideation with plan and intent). A score of 4 or 5 on this scale indicates serious suicidal ideation. For each treatment group, the incidence rate was calculated as the number of events / sum of the observational time (patient year) over all participants in this treatment group.

5. Change From Baseline in Personal and Social Performance Scale (PSP) Score After 28 Weeks of Treatment [At baseline and at Week 28]

   Personal and Social Performance scale (PSP): The PSP is a 100-point, single item, clinician rated scale to assess 4 domains of social functioning (Four domains over the past month: (1) socially useful activities, (2) personal and social relationships, (3) self-care and (4) disturbing and aggressive behaviors.) in patients with schizophrenia. The PSP score is a single score ranging from 1 to 100. Higher scores represent better personal and social functioning.

6. Incidence Rate of New Prescription or Increase in Dose of an Ongoing Antipsychotic Medication [28 weeks]

   The incidence rate of new prescription or increase in dose of an ongoing antipsychotic medication is reported. For each treatment group, the incidence rate was calculated as the number of events / sum of the observational time (patient year) over all participants in this treatment group.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) diagnosis of schizophrenia >= one year prior to randomisation.

• Outpatients in the stable phase of illness, as assessed by the investigator after review of medical records or documented discussion with treating clinician.

• Patients currently taking a stable dose of antipsychotic medication(s) for at least 12 weeks prior to randomisation.

• Detectable level of current antipsychotic medication(s) in plasma from blood drawn at Visit 1 (unless no assay is available for the antipsychotic(s) currently prescribed).

• Patients who have experienced at least 2 relapses within the past 5 years or at least 1 relapse if they were diagnosed less than 3 years ago. Relapse is defined as the patient having any of the following using the above number of relapses and time frames:

• Hospitalization for psychosis (involuntary or voluntary admission), intensive outpatient therapy or use of home treatment as an alternative to hospitalization (verified via medical record).

• Emergency Department visit for worsening schizophrenia symptoms (verified via medical record).

• Deliberate self-injury and/or violent behaviour resulting in significant injury to another person or property (verified by police record or treating mental health provider written record or documented phone conversation).

• Change in the patient's antipsychotic medication or increase in antipsychotic medication dosage due to worsening of schizophrenia symptoms (verified by pharmacy records or treating mental health provider written record or documented phone conversation).

• Clinical Global Impressions-Severity (CGI-S) score ≤4 at Visit 1 and 2.

• Positive and Negative Syndrome Scale (PANSS) total score <80 and a score of ≤ 4 on individual PANSS items conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content at Visit 1.

• Of full age (according to local legislation, usually ≥ 18 years) and ≤ 55 years at the time of informed consent.

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

• Patients who report living at the same address for the 3 months prior to randomisation.

• Male or female patients.

-- Female patients of childbearing potential must be ready and able to use highly effective methods of birth control per International Conference on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Patients must agree to use birth control throughout the trial and for at least 28 days after treatment has ended. Acceptable methods of birth control include combined estrogen-progestin oral, intravaginal or transdermal contraceptives, progestogen-only oral, injectable or implantable contraceptives, intrauterine devices (IUDs), intrauterine hormone releasing systems (IUSs), bilateral tubal occlusion, vasectomized sexual partner, and complete sexual abstinence (if acceptable by local health authorities) is allowed when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

• Male patients who are able to father a child must be ready and able to be abstinent or use adequate contraception for the duration of study participation and for at least 28 days after treatment has ended.

• Signed and dated written informed consent in accordance with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial. If the patient has a legal representative, then this legal representative must give written informed consent as well.

Exclusion criteria:

• Patients treated with more than two antipsychotic medications (including more than two dosage forms).

• Patients who are currently being treated with clozapine, or who have been treated with clozapine in the past 5 years.

• Patients with a categorical diagnosis of another current major psychiatric disorder per the Mini-international neuropsychiatric Interview (M.I.N.I.).

• Homicidal behaviour (in the investigator's judgement) in the past 2 years.

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

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

• In the judgment of the investigator, any clinically significant finding from the physical examination 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.

• Other known neurological diseases (including but not limited to any kind of seizures or stroke).

• Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix.

• Planned elective surgery requiring general anesthesia, or hospitalization for more than 1 day during the study period.

• Significant history of drug or alcohol dependence or abuse (Substance Use Disorder as defined in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) or ICD-10) within the last six months prior to informed consent. (Not including caffeine or nicotine).

• Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.

• Patients taking strong or moderate CYP1A2 inhibitors who are also a CYP2C19 Poor Metabolizer (PM). Patients taking medication known to be strong or moderate inhibitors of CYP1A2 must be prospectively genotyped to ensure they are not poor metabolizers of CYP2C19. (A list of CYP1A2 and CYP2C19 inhibitors can be found in the Investigator Site File (ISF)).

• Patients taking strong or moderate CYP1A2 inhibitors who are also taking concomitant strong or moderate CYP2C19 inhibitors. (A list of CYP1A2 and CYP2C19 inhibitors can be found in the ISF)

• Patients with a history of moderate to severe hepatic impairment (Child-Pugh B / C).

• Patients with a history of moderate to severe renal impairment (Stage 3 - 5).

• Women who are pregnant, nursing, or who plan to become pregnant while in the trial.

• In the judgment of the investigator, inability of the patient to comply with the clinical trial procedures.

• Currently enrolled in another investigational device or drug study, or less than 6 months from Visit 1 since ending another investigational device or drug study(s), or participation in > 2 investigational drug clinical trials in the past 2 years.

• Previous randomisation in any BI 409306 study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alea Research	Phoenix	Arizona	United States	85012
2	ATP Clinical Research, Inc.	Costa Mesa	California	United States	92626
3	Collaborative Neuroscience Network, LLC (CNS)	Garden Grove	California	United States	92845
4	Behavioral Research Specialists, LLC	Glendale	California	United States	91206
5	Synergy East	Lemon Grove	California	United States	91945
6	University of California Los Angeles	Los Angeles	California	United States	90095
7	Excell Research Inc.	Oceanside	California	United States	92056
8	Orange County Neuropsychiatric Research Center LLC	Orange	California	United States	92868
9	Collaborative Neuroscience Network, LLC (CNS)	Torrance	California	United States	90502
10	MD Clinical	Hallandale Beach	Florida	United States	33009
11	Reliable Clinical Research	Hialeah	Florida	United States	33012
12	Meridien Research	Maitland	Florida	United States	32751
13	Behavioral Clinical Research, Inc.	North Miami	Florida	United States	33161
14	Meridien Research	Orlando	Florida	United States	32810
15	Atlanta Center	Atlanta	Georgia	United States	30331
16	Alam Medical Research, Inc.	Chicago	Illinois	United States	60612
17	Lake Charles Clinical Trials LLC	Lake Charles	Louisiana	United States	70629
18	Clinical Trials of America, LLC	Monroe	Louisiana	United States	71201
19	Michigan Clinical Research Institute PC	Ann Arbor	Michigan	United States	48105
20	Precise Research Centers	Flowood	Mississippi	United States	39232
21	St. Charles Psychiatric Associates & Midwest Research Group	Saint Charles	Missouri	United States	63304
22	Arch Clinical Trials	Saint Louis	Missouri	United States	63125
23	PsychCare Consultants Research	Saint Louis	Missouri	United States	63128
24	Altea Research Institute	Las Vegas	Nevada	United States	89102
25	Hassman Research Institute	Berlin	New Jersey	United States	08009
26	Neurobehavioral Research, Inc.	Cedarhurst	New York	United States	11516
27	New York State Psychiatric Institute	New York	New York	United States	10032
28	Manhattan Behavioral Medicine PLLC	New York	New York	United States	10036
29	Community Clinical Research, Inc.	Austin	Texas	United States	78754
30	University Hills Clinical Research	Irving	Texas	United States	75062
31	Pillar Clinical Research, LLC	Richardson	Texas	United States	75080
32	@Health Texas	Richmond	Texas	United States	77407
33	University of Calgary	Calgary	Alberta	Canada	T2N 4Z6
34	Dr. Alexander McIntyre Inc.	Penticton	British Columbia	Canada	V2A 4M4
35	The Medical Arts Health Research Group	Vancouver	British Columbia	Canada	V7T 1C5
36	Chatham-Kent Clinical Trials Research Centre	Chatham	Ontario	Canada	N7L 1C1
37	Centre for Addiction and Mental Health (CAMH)	Toronto	Ontario	Canada	M6J 1H4
38	IUSMM Institut Universitaire en Sante Mentale de Montreal	Montreal	Quebec	Canada	H1N 3M5
39	HOP la Colombière	Montpellier		France	34295
40	GHU Paris Psychiatrie et Neurosciences	Paris		France	75674
41	HOP Guillaume Régnier	Rennes		France	35703
42	HOP Nord	Saint-Priest-en-Jarez		France	42270
43	HOP Sainte Musse	Toulon		France	83100
44	Okehazama Hospital Fujita Kokoro Care Center	Aichi, Toyoake		Japan	470-1168
45	Fujita Health University Hospital	Aichi, Toyoake		Japan	470-1192
46	National Center for Global Health and Medicine Kohnodai Hospital	Chiba, Ichikawa		Japan	272-8516
47	Fukuoka University Hospital	Fukuoka, Fukuoka		Japan	814-0180
48	Kuramitsu Hospital	Fukuoka, Fukuoka		Japan	819-0037
49	Soushu Hospital	Kanagawa, Atsugi		Japan	243-0201
50	Kishiro Mental Clinic	Kanagawa, Kawasaki		Japan	214-0014
51	Nara Medical University Hospital	Nara, Kashihara		Japan	634-8522
52	National Hospital Organization Hizen Psychiatric Medical Center	Saga, Kanzaki-gun		Japan	842-0192
53	National Center Neurology and Psychiatry	Tokyo, Kodaira		Japan	187-8851
54	Chonnam National University Hospital	Gwangju		Korea, Republic of	61453
55	Seoul National University Bundang Hospital	Seongnam		Korea, Republic of	13620
56	Seoul National University Hospital	Seoul		Korea, Republic of	03080
57	Hospital Universitario Marqués de Valdecilla	Santander		Spain	39008
58	NCKUH	Tainan		Taiwan	704
59	Taoyuan Psychiatric Center	Taoyuan		Taiwan	33058

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Nov 8, 2017
• Statistical Analysis Plan - Mar 17, 2021

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03351244
• Other Study ID Numbers: 1289-0049; 2017-002369-23
• First Posted: Nov 22, 2017
• Last Update Posted: May 12, 2022
• Last Verified: Apr 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Schizophrenia; BI 409306

Study Results

Participant Flow

Recruitment Details	This Phase II trial aimed to evaluate the impact of 28-week treatment with BI 409306 (added to standard antipsychotic medication) compared with placebo on preventing relapse in patients with schizophrenia.
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 409306 25 mg	BI 409306 50 mg	Placebo
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.
Period Title: Overall Study
STARTED	89	88	87
COMPLETED	62	48	53
NOT COMPLETED	27	40	34

Baseline Characteristics

Arm/Group Title	BI 409306 25 mg	BI 409306 50 mg	Placebo	Total
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.	Total of all reporting groups
Overall Participants	89	88	87	264
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	38.4 (9.8)	41.9 (9.6)	40.5 (9.8)	40.3 (9.8)
Sex: Female, Male (Count of Participants)
Female	29 32.6%	36 40.9%	32 36.8%	97 36.7%
Male	60 67.4%	52 59.1%	55 63.2%	167 63.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 11.2%	15 17%	15 17.2%	40 15.2%
Not Hispanic or Latino	75 84.3%	69 78.4%	68 78.2%	212 80.3%
Unknown or Not Reported	4 4.5%	4 4.5%	4 4.6%	12 4.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	23 25.8%	20 22.7%	20 23%	63 23.9%
Native Hawaiian or Other Pacific Islander	0 0%	2 2.3%	0 0%	2 0.8%
Black or African American	36 40.4%	37 42%	32 36.8%	105 39.8%
White	23 25.8%	24 27.3%	25 28.7%	72 27.3%
More than one race	1 1.1%	1 1.1%	2 2.3%	4 1.5%
Unknown or Not Reported	6 6.7%	4 4.5%	8 9.2%	18 6.8%

Outcome Measures

1. Primary Outcome

Title	Incidence Rate of First Relapse After 28 Weeks of Treatment
Description	The incidence rate of first relapse after 28 weeks of treatment is reported. For each treatment group, the incidence rate was calculated as the number of events / sum of the observational time (patient year) over all participants in this treatment group.
Time Frame	28 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type.

Arm/Group Title	BI 409306 25 mg	BI 409306 50 mg	BI 409306 Pooled	Placebo
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	This group included all participants who administered BI 409306 during the study.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.
Measure Participants	89	88	177	87
Number [Events per patient-years]	0.527	0.434	0.482	0.496

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7735
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.097
	Confidence Interval	(2-Sided) 95%; 0.585 to 2.056
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7809
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.910
	Confidence Interval	(2-Sided) 95%; 0.468 to 1.770
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 Pooled, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9862
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.005
	Confidence Interval	(2-Sided) 95%; 0.576 to 1.753
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Symptoms Score After 28 Weeks of Treatment
Description	Positive and Negative Syndrome Scale (PANSS): assesses the severity of psychotic symptoms and progression of disease. The PANSS positive symptoms score is the sum of scores from 7 Items where each item has a minimum score 1 (better outcome) and maximum score 7 (worse outcome). The PANSS positive symptoms score ranges from 7 (less severe the disease) to 49 (more severe the disease).
Time Frame	At baseline and at Week 28.

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type. Only participants with non-missing results were included in the analysis.

Arm/Group Title	BI 409306 25 mg	BI 409306 50 mg	BI 409306 Pooled	Placebo
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	This group included all participants who administered BI 409306 during the study.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.
Measure Participants	73	55	128	65
Mean (95% Confidence Interval) [Score on a scale]	-0.54	-0.71	-0.61	-0.92

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	A restricted maximum likelihood-based approach using a mixed model with repeated measurements was applied.
Statistical Test of Hypothesis	p-Value	0.5289
	Comments
	Method	Mixed model with repeated measurements
	Comments	The analysis included the fixed, categorical effects of treatment at each visit, and the fixed continuous effects of baseline at each visit.
Method of Estimation	Estimation Parameter	Placebo-corrected adjusted mean
	Estimated Value	0.38
	Confidence Interval	(2-Sided) 95%; -0.809 to 1.570
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	A restricted maximum likelihood-based approach using a mixed model with repeated measurements was applied.
Statistical Test of Hypothesis	p-Value	0.7440
	Comments
	Method	Mixed model with repeated measurements
	Comments	The analysis included the fixed, categorical effects of treatment at each visit, and the fixed continuous effects of baseline at each visit.
Method of Estimation	Estimation Parameter	Placebo-corrected adjusted mean
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; -1.055 to 1.475
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 Pooled, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	A restricted maximum likelihood-based approach using a mixed model with repeated measurements was applied.
Statistical Test of Hypothesis	p-Value	0.5659
	Comments
	Method	Mixed model with repeated measurements
	Comments	The analysis included the fixed, categorical effects of treatment at each visit, and the fixed continuous effects of baseline at each visit.
Method of Estimation	Estimation Parameter	Placebo-corrected adjusted mean
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; -0.745 to 1.358
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Scale Score After 28 Weeks of Treatment
Description	Clinical Global Impressions-Severity (CGI-S): One-item evaluation completed by the clinician to measure the severity of psychopathology. The CGI-S score ranges from 1 (normal) through to 7 (most severely ill). The higher the score, the worse the psychopathology.
Time Frame	At baseline and at Week 28

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type. Only participants with non-missing results were included in the analysis.

Arm/Group Title	BI 409306 25 mg	BI 409306 50 mg	BI 409306 Pooled	Placebo
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	This group included all participants who administered BI 409306 during the study.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.
Measure Participants	73	55	128	65
Mean (Standard Deviation) [Score on a scale]	-0.15 (0.758)	-0.22 (0.839)	-0.18 (0.791)	-0.22 (0.718)

4. Secondary Outcome

Title	Patient Global Impressions-Improvement (PGI-I) Scale Score After 28 Weeks of Treatment
Description	Patient Global Impressions-Improvement (PGI-I): One-item evaluation completed by the patient to assess their overall evaluation of his/her status compared to how they felt at randomisation. The PGI-I score ranges from 1 (Very much better) through to 7 (Very much worse). The higher the score, the worse the improvement.
Time Frame	At Week 28

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type. Only participants with non-missing results were included in the analysis.

Arm/Group Title	BI 409306 25 mg	BI 409306 50 mg	BI 409306 Pooled	Placebo
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	This group included all participants who administered BI 409306 during the study.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.
Measure Participants	72	54	126	63
Mean (Standard Deviation) [Score on a scale]	2.61 (1.328)	2.96 (1.197)	2.76 (1.280)	2.94 (1.190)

5. Secondary Outcome

Title	Incidence Rate of Suicidal Ideation and Behaviour (Assessed by Columbia Suicide Severity Rating Scale (C-SSRS)) After 28 Weeks of Treatment
Description	Columbia Suicide Severity Rating Scale (C-SSRS): suicide risk assessment. At a minimum, the interview consists of 2 screening questions related to suicidal ideation and 4 related to suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free text entries are allowed. Suicidal behavior is collected in nominal scale as presence/absence of actual attempts, non-suicidal self-injurious behavior, interrupted attempts, aborted attempts, preparatory acts or behavior, and any suicidal behavior. Suicidal ideation is rated on a 6-point scale from 0 (No ideation present) to 5 (Active ideation with plan and intent). A score of 4 or 5 on this scale indicates serious suicidal ideation. For each treatment group, the incidence rate was calculated as the number of events / sum of the observational time (patient year) over all participants in this treatment group.
Time Frame	28 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type.

Arm/Group Title	BI 409306 25 mg	BI 409306 50 mg	BI 409306 Pooled	Placebo
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	This group included all participants who administered BI 409306 during the study.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.
Measure Participants	89	88	177	87
Number [Events per patient-years]	0.070	0.077	0.073	0.071

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9938
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.006
	Confidence Interval	(2-Sided) 95%; 0.203 to 4.989
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8930
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.116
	Confidence Interval	(2-Sided) 95%; 0.225 to 5.531
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 Pooled, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9360
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.058
	Confidence Interval	(2-Sided) 95%; 0.265 to 4.233
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Personal and Social Performance Scale (PSP) Score After 28 Weeks of Treatment
Description	Personal and Social Performance scale (PSP): The PSP is a 100-point, single item, clinician rated scale to assess 4 domains of social functioning (Four domains over the past month: (1) socially useful activities, (2) personal and social relationships, (3) self-care and (4) disturbing and aggressive behaviors.) in patients with schizophrenia. The PSP score is a single score ranging from 1 to 100. Higher scores represent better personal and social functioning.
Time Frame	At baseline and at Week 28

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type. Only participants with non-missing results were included in the analysis.

Arm/Group Title	BI 409306 25 mg	BI 409306 50 mg	BI 409306 Pooled	Placebo
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	This group included all participants who administered BI 409306 during the study.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.
Measure Participants	72	54	126	65
Mean (Standard Deviation) [Score on a scale]	2.8 (8.8)	2.4 (9.4)	2.6 (9.1)	3.0 (10.2)

7. Secondary Outcome

Title	Incidence Rate of New Prescription or Increase in Dose of an Ongoing Antipsychotic Medication
Description	The incidence rate of new prescription or increase in dose of an ongoing antipsychotic medication is reported. For each treatment group, the incidence rate was calculated as the number of events / sum of the observational time (patient year) over all participants in this treatment group.
Time Frame	28 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): the FAS includes all patients in the treated set with at least 1 baseline and post-baseline measurement of any type.

Arm/Group Title	BI 409306 25 mg	BI 409306 50 mg	BI 409306 Pooled	Placebo
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.	This group included all participants who administered BI 409306 during the study.	1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.
Measure Participants	89	88	177	87
Number [Events per patient-years]	0.168	0.130	0.149	0.217

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6362
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.788
	Confidence Interval	(2-Sided) 95%; 0.293 to 2.118
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3782
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.612
	Confidence Interval	(2-Sided) 95%; 0.205 to 1.826
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 Pooled, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4253
	Comments
	Method	Regression, Cox
	Comments	The model included the treatment effect as the only covariate and was stratified by country.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.703
	Confidence Interval	(2-Sided) 95%; 0.296 to 1.671
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All-cause mortality: From first dose until withdraw or end of 1-week taper period + 3-week follow-up period, up to 32 weeks. Serious (non-serious) adverse events: From first dose until withdraw or end of 1-week taper period + 1-week residual effect period, up to 30 weeks.
Adverse Event Reporting Description	Treated set (TS): the TS includes all patients who were randomised and were documented to have taken at least 1 dose of trial drug.
Arm/Group Title	BI 409306 25 mg		BI 409306 50 mg		Placebo		Total
Arm/Group Description	1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 2 tablets of 10 mg BI 409306 and 2 tablets of placebo q.d. on Day 1 of the taper period; 2 tablets of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 2-3 of taper period; 1 tablet of 10 mg BI 409306 and 1 tablet of placebo q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.		1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Withdrawal period: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal period; 3 tablets of 10 mg placebo q.d. on Day2-3 of withdrawal period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal period. Taper period: 4 tablets of 10 mg BI 409306 q.d. on Day 1 of taper period; 3 tablets of 10 mg BI 409306 q.d. on Day 2-3 of taper period; 2 tablets of 10 mg BI 409306 q.d. on Day 4-5 of taper period; 1 tablet of 10 mg BI 409306 q.d. on Day 6-7 of taper period.		1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. Participants were randomized to either withdrawal or taper period in 1:1 ratio at the randomization of treatment groups. Both withdrawal and taper periods: 4 tablets of 10 mg placebo once daily (q.d.) on Day 1 of withdrawal/taper period; 3 tablets of 10 mg placebo q.d. on Day 2-3 of withdrawal/taper period; 2 tablets of 10mg placebo q.d. on Day 4-5 of withdrawal/taper period; 1 tablet of 10mg placebo q.d. on Day 6-7 of withdrawal/taper period.		All participants randomised in this study.
All Cause Mortality
	BI 409306 25 mg		BI 409306 50 mg		Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		1/88 (1.1%)		0/87 (0%)		1/264 (0.4%)
Serious Adverse Events
	BI 409306 25 mg		BI 409306 50 mg		Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/89 (10.1%)		7/88 (8%)		12/87 (13.8%)		28/264 (10.6%)
Cardiac disorders
Acute myocardial infarction	1/89 (1.1%)		0/88 (0%)		0/87 (0%)		1/264 (0.4%)
Cardiac arrest	0/89 (0%)		1/88 (1.1%)		0/87 (0%)		1/264 (0.4%)
Myocardial infarction	0/89 (0%)		1/88 (1.1%)		0/87 (0%)		1/264 (0.4%)
Pericarditis	1/89 (1.1%)		0/88 (0%)		0/87 (0%)		1/264 (0.4%)
Gastrointestinal disorders
Abdominal pain	1/89 (1.1%)		0/88 (0%)		0/87 (0%)		1/264 (0.4%)
Ileus	0/89 (0%)		0/88 (0%)		1/87 (1.1%)		1/264 (0.4%)
Infections and infestations
Complicated appendicitis	1/89 (1.1%)		0/88 (0%)		0/87 (0%)		1/264 (0.4%)
Pneumonia	0/89 (0%)		0/88 (0%)		3/87 (3.4%)		3/264 (1.1%)
Wound infection	0/89 (0%)		0/88 (0%)		1/87 (1.1%)		1/264 (0.4%)
Injury, poisoning and procedural complications
Skin abrasion	0/89 (0%)		0/88 (0%)		1/87 (1.1%)		1/264 (0.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/89 (0%)		1/88 (1.1%)		0/87 (0%)		1/264 (0.4%)
Psychiatric disorders
Acute psychosis	1/89 (1.1%)		0/88 (0%)		0/87 (0%)		1/264 (0.4%)
Agitation	0/89 (0%)		0/88 (0%)		1/87 (1.1%)		1/264 (0.4%)
Anxiety	0/89 (0%)		1/88 (1.1%)		0/87 (0%)		1/264 (0.4%)
Delusion	0/89 (0%)		0/88 (0%)		1/87 (1.1%)		1/264 (0.4%)
Depression suicidal	0/89 (0%)		0/88 (0%)		1/87 (1.1%)		1/264 (0.4%)
Hallucination, auditory	1/89 (1.1%)		0/88 (0%)		0/87 (0%)		1/264 (0.4%)
Psychotic disorder	1/89 (1.1%)		1/88 (1.1%)		0/87 (0%)		2/264 (0.8%)
Schizophrenia	2/89 (2.2%)		1/88 (1.1%)		4/87 (4.6%)		7/264 (2.7%)
Substance abuse	1/89 (1.1%)		0/88 (0%)		0/87 (0%)		1/264 (0.4%)
Suicidal behaviour	0/89 (0%)		1/88 (1.1%)		0/87 (0%)		1/264 (0.4%)
Suicidal ideation	3/89 (3.4%)		0/88 (0%)		2/87 (2.3%)		5/264 (1.9%)
Suicide attempt	0/89 (0%)		1/88 (1.1%)		0/87 (0%)		1/264 (0.4%)
Renal and urinary disorders
Nephrolithiasis	1/89 (1.1%)		0/88 (0%)		0/87 (0%)		1/264 (0.4%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/89 (0%)		0/88 (0%)		1/87 (1.1%)		1/264 (0.4%)
Other (Not Including Serious) Adverse Events
	BI 409306 25 mg		BI 409306 50 mg		Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/89 (33.7%)		25/88 (28.4%)		19/87 (21.8%)		74/264 (28%)
Eye disorders
Photophobia	3/89 (3.4%)		8/88 (9.1%)		1/87 (1.1%)		12/264 (4.5%)
Gastrointestinal disorders
Vomiting	1/89 (1.1%)		1/88 (1.1%)		5/87 (5.7%)		7/264 (2.7%)
Infections and infestations
Nasopharyngitis	7/89 (7.9%)		5/88 (5.7%)		7/87 (8%)		19/264 (7.2%)
Nervous system disorders
Headache	6/89 (6.7%)		7/88 (8%)		4/87 (4.6%)		17/264 (6.4%)
Somnolence	5/89 (5.6%)		3/88 (3.4%)		3/87 (3.4%)		11/264 (4.2%)
Psychiatric disorders
Insomnia	5/89 (5.6%)		6/88 (6.8%)		0/87 (0%)		11/264 (4.2%)
Schizophrenia	6/89 (6.7%)		4/88 (4.5%)		2/87 (2.3%)		12/264 (4.5%)

Limitations/Caveats

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

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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.