Clinical Trial of BI 425809 Effect on Cognition and Funct... | NCT02832037

ID	Type	Description	Link
2016-000285-28	EudraCT Number

Label	Type	Intervention Names
BI 425809 dose 1	Experimental	Drug: BI 425809 dose 1 Drug: Placebo
BI 425809 dose 2	Experimental	Drug: BI 425809 dose 2 Drug: Placebo
BI 425809 dose 3	Experimental	Drug: BI 425809 dose 3 Drug: Placebo
BI 425809 dose 4	Experimental	Drug: BI 425809 dose 4 Drug: Placebo
Placebo	Placebo Comparator	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
BI 425809 dose 1	Drug		BI 425809 dose 1
BI 425809 dose 2

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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	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.	Baseline, after 6 and 12 weeks of treatment

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Total Score 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.

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Collaborative Neuroscience Network, LLC (CNS)		Garden Grove	California	92845	United States
Synergy San Diego

PubMed Identifier	Type	Citation	Retractions
35953474	Derived	Schultheis C, Rosenbrock H, Mack SR, Vinisko R, Schuelert N, Plano A, Sussmuth SD. Quantitative electroencephalography parameters as neurophysiological biomarkers of schizophrenia-related deficits: A Phase II substudy of patients treated with iclepertin (BI 425809). Transl Psychiatry. 2022 Aug 11;12(1):329. doi: 10.1038/s41398-022-02096-5.
33610228

Label	URL
Related Info	View source

ID	Title	Description
FG000	BI 425809 2 mg Once a Day (q.d.)	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).
FG001

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Mar 28, 2019	Feb 5, 2021

Arm/Group Information

ID	Title	Description
BG000	BI 425809 2 mg Once a Day (q.d.)	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).
BG001	BI 425809 5 mg q.d.	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).
BG002	BI 425809 10 mg q.d.	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).
BG003	BI 425809 25 mg q.d.	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).
BG004	Placebo q.d.	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).
BG005	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

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.

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.

Posted

Least Squares Mean

Standard Error

scores on a scale

Baseline, after 6 and 12 weeks of treatment

ID	Title	Description
OG000	BI 425809 2 mg Once a Day (q.d.)	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).
OG001	BI 425809 5 mg q.d.	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).
OG002	BI 425809 10 mg q.d.	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).
OG003	BI 425809 25 mg q.d.	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).
OG004	Placebo q.d.	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).

Units	Counts
Participants	OG00079 OG00180 OG00282 OG003

Title

Denominators

Categories

Title	Measurements
	OG0001.784± 0.6805 OG0011.641± 0.6656 OG0023.486± 0.6410 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001 OG002 OG003 OG004	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).	MCP-Mod linear model fit		0.0145	Adjusted for multiplicity.													Other

Secondary

Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Total Score 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.

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline and after 12 weeks of treatment

ID	Title	Description
OG000	BI 425809 2 mg Once a Day (q.d.)	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).

Secondary

Percentage of Participants With Any Adverse Event

Percentage of participants with any Adverse Event.

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

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	BI 425809 2 mg Once a Day (q.d.)	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).
OG001	BI 425809 5 mg q.d.	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).
OG002	BI 425809 10 mg q.d.	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).

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	BI 425809 2 mg Once a Day (q.d.)	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).	85	2	85	22	85
EG001	BI 425809 5 mg q.d.	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).	84	4	84	23	84
EG002	BI 425809 10 mg q.d.	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).	85	2	85	14	85
EG003	BI 425809 25 mg q.d.	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).	85	4	85	13	85
EG004	Placebo q.d.	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).	170	4	170	31	170

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abscess limb	Infections and infestations	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0011 affected84 at risk EG0020 affected85 at risk EG0030 affected85 at risk EG0040 affected170 at risk
Infective myositis	Infections and infestations	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0010 affected84 at risk EG0021 affected85 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0010 affected84 at risk EG0020 affected85 at risk EG003
Lumbar vertebral fracture	Injury, poisoning and procedural complications	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0010 affected84 at risk EG0020 affected85 at risk EG003
Radius fracture	Injury, poisoning and procedural complications	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0010 affected84 at risk EG0020 affected85 at risk EG003
Blood creatine phosphokinase increased	Investigations	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0011 affected84 at risk EG0020 affected85 at risk EG003
Drug dependence	Psychiatric disorders	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0010 affected84 at risk EG0020 affected85 at risk EG003
Fear of disease	Psychiatric disorders	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0010 affected84 at risk EG0021 affected85 at risk EG003
Psychotic disorder	Psychiatric disorders	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0011 affected84 at risk EG0020 affected85 at risk EG003
Psychotic symptom	Psychiatric disorders	MedDRA 22.1	Systematic Assessment	EG0001 affected85 at risk EG0010 affected84 at risk EG0020 affected85 at risk EG003
Schizophrenia	Psychiatric disorders	MedDRA 22.1	Systematic Assessment	EG0001 affected85 at risk EG0011 affected84 at risk EG0020 affected85 at risk EG003
Suicidal behaviour	Psychiatric disorders	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0010 affected84 at risk EG0020 affected85 at risk EG003
Suicidal ideation	Psychiatric disorders	MedDRA 22.1	Systematic Assessment	EG0000 affected85 at risk EG0010 affected84 at risk EG0020 affected85 at risk EG003

ID	Term
D019967	Schizophrenia Spectrum and Other Psychotic Disorders
D001523	Mental Disorders

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nasopharyngitis	Infections and infestations	MedDRA 22.1	Systematic Assessment	EG0008 affected85 at risk EG0019 affected84 at risk EG0027 affected85 at risk EG0034 affected85 at risk EG00413 affected170 at risk
Dizziness	Nervous system disorders	MedDRA 22.1	Systematic Assessment	EG0005 affected85 at risk EG0014 affected84 at risk EG0022 affected85 at risk EG003
Headache	Nervous system disorders	MedDRA 22.1	Systematic Assessment	EG0008 affected85 at risk EG00110 affected84 at risk EG0027 affected85 at risk EG003
Somnolence	Nervous system disorders	MedDRA 22.1	Systematic Assessment	EG0002 affected85 at risk EG0015 affected84 at risk EG0025 affected85 at risk EG003