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Clinical Trial Results:
A phase II randomized, 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

Summary
EudraCT number	2016-000285-28
Trial protocol	DE AT ES IT
Global end of trial date	29 Jan 2020

Results information
Results version number	v2(current)
This version publication date	15 Sep 2022
First version publication date	12 Feb 2021
Other versions	v1
Version creation reason	Correction of full data set Correction of previously submitted information.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1346.9

ISRCTN number

US NCT number

NCT02832037

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

27 Feb 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Dec 2019

Global end of trial reached?

Yes

Global end of trial date

29 Jan 2020

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this trial were to provide proof of clinical concept (PoCC) and dose finding data in patients with schizophrenia on stable antipsychotic treatment who were treated with oral once daily administration of BI 425809 or placebo.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

Germany: 40

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Japan: 80

Country: Number of subjects enrolled

Poland: 75

Country: Number of subjects enrolled

Korea, Republic of: 57

Country: Number of subjects enrolled

Spain: 33

Country: Number of subjects enrolled

Taiwan: 29

Country: Number of subjects enrolled

United Kingdom: 17

Country: Number of subjects enrolled

United States: 320

Worldwide total number of subjects

684

EEA total number of subjects

170

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

684

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A phase II randomized, double-blind, double-dummy, placebo-controlled, multi-center, multi-national, parallel-group trial. Abbreviation: FAS=All subjects randomized, treated with at least 1 dose of trial drug, a non-missing baseline measurement (mt) and at least 1 non-missing post-baseline and on-treatment mt for the primary or secondary endpoint.

Screening details

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. The number of subjects reported to start in the baseline period are actually the randomized subjects.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

BI 425809 2 mg once a day (q.d.)

Arm 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).

Arm type

Experimental

Investigational medicinal product name

BI 425809 2 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 1 mg BI 425809) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).

BI 425809 5 mg q.d.

Arm description

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).

Arm type

Experimental

Investigational medicinal product name

BI 425809 5 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

5 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 5 mg BI 425809) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).

BI 425809 10 mg q.d.

Arm description

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 type

Experimental

Investigational medicinal product name

BI 425809 10 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 milligram (mg) of BI 425809 administered orally (2 tablets with tablet strength 5 mg BI 425809) with water, with or without food in the morning, once daily. Continuous daily dosing for 12 weeks (planned treatment duration).

BI 425809 25 mg q.d.

Arm description

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).

Arm type

Experimental

Investigational medicinal product name

BI 425809 25 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 milligram (mg) of BI 425809 administered orally (1 tablet with tablet strength 25 mg BI 425809) with water, with or without food, once daily in the morning. Continuous daily dosing for 12 weeks (planned treatment duration).

Placebo q.d.

Arm description

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).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	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.
Started	85	84	85	85	170
Completed	66	72	77	78	151
Not completed	19	12	8	7	19
Consent withdrawn by subject	9	8	-	4	8
Adverse event, non-fatal	5	4	-	2	4
Administrative reasons	-	-	1	-	-
Lost to follow-up	2	-	3	-	5
Protocol deviation	3	-	4	1	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The number of subjects reported to start in the baseline period are actually the randomized subjects.

Baseline characteristics

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Reporting group title

BI 425809 2 mg once a day (q.d.)

Reporting group description

Reporting group title

BI 425809 5 mg q.d.

Reporting group description

Reporting group title

BI 425809 10 mg q.d.

Reporting group description

Reporting group title

BI 425809 25 mg q.d.

Reporting group description

Reporting group title

Placebo q.d.

Reporting group description

Reporting group values	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
Number of subjects	85	84	85	85	170	509
Age categorical
The Treated Set included all subjects who were randomized and were treated with at least 1 dose of trial medication.
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	85	84	85	85	170	509
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Age Continuous
The Treated Set included all participants who were randomized and were treated with at least 1 dose of trial medication.
Units: years
arithmetic mean (standard deviation)	36.5 ( 8.5 )	37.5 ( 7.9 )	37.9 ( 6.8 )	36.2 ( 7.8 )	37.2 ( 7.7 )	-
Sex: Female, Male
The Treated Set included all subjects who were randomized and were treated with at least 1 dose of trial medication.
Units: Participants
Female	34	27	24	35	60	180
Male	51	57	61	50	110	329
Ethnicity (NIH/OMB)
The Treated Set included all subjects who were randomized and were treated with at least 1 dose of trial medication.
Units: Subjects
Hispanic or Latino	6	8	7	5	15	41
Not Hispanic or Latino	79	76	78	80	155	468
Unknown or Not Reported	0	0	0	0	0	0
Race (NIH/OMB)
The Treated Set included all subjects who were randomized and were treated with at least 1 dose of trial medication.
Units: Subjects
American Indian or Alaska Native	0	1	0	0	0	1
Asian	24	18	25	22	56	145
Native Hawaiian or Other Pacific Islander	0	0	0	1	0	1
Black or African American	15	20	21	22	41	119
White	44	44	39	38	72	237
More than one race	2	1	0	2	1	6
Unknown or Not Reported	0	0	0	0	0	0
MATRICS Consensus Cognitive Battery (MCCB) overall composite t-score
Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) overall composite t-score was derived from scores of seven cognitive domains (Speed of Processing, Verbal Learning, Working Memory, Reasoning and Problem Solving, Visual Learning, Social Cognition, Attention/Vigilance) obtained from a total of ten tests. MCCB overall composite t-score ranges typically between –20 and +99 where a larger MCCB overall composite t-score indicates better cognition. Treated Set: All subjects randomized and treated with at least 1 dose of trial drug.
Units: Score on a scale
arithmetic mean (standard deviation)	30.0 ( 13.8 )	32.8 ( 12.0 )	31.8 ( 12.8 )	30.2 ( 13.2 )	32.3 ( 13.6 )	-

End points

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Reporting group title

BI 425809 2 mg once a day (q.d.)

Reporting group description

Reporting group title

BI 425809 5 mg q.d.

Reporting group description

Reporting group title

BI 425809 10 mg q.d.

Reporting group description

Reporting group title

BI 425809 25 mg q.d.

Reporting group description

Reporting group title

Placebo q.d.

Reporting group description

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

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End point 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

End point description

MCCB overall composite t-score was derived from scores of seven cognitive domains (Speed of Processing, Verbal Learning, Working Memory, Reasoning and Problem Solving, Visual Learning, Social Cognition, Attention/Vigilance) obtained from a total of ten tests (Trail Making Test, Brief Assessment of Cognition in Schizophrenia: symbol coding subtest, Hopkins Verbal Learning Test, Wechsler Memory Scale test: Spatial Span subtest, Letter-Number Span test, Neuropsychological Assessment Battery: mazes subtest, Brief Visuospatial Memory Test, Category Fluency test: animal naming, Mayer-Salovey-Caruso Emotional Intelligence Test: managing emotions branch, Continuous Performance Test). MCCB overall composite t-score ranges typically between –20 and +99, where a larger MCCB overall composite t-score indicates better cognition. Mixed-effects Model Repeated Measures (MMRM) was fitted to calculate adjusted mean, standard error, MMRM details in Statistical Analysis section.

End point type

Primary

End point timeframe

Baseline, after 6 and 12 weeks of treatment

End point values	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.
Number of subjects analysed	79 ^[1]	80 ^[2]	82 ^[3]	83 ^[4]	163 ^[5]
Units: units on a scale
least squares mean (standard error)	1.784 ( 0.6805 )	1.641 ( 0.6656 )	3.486 ( 0.6410 )	3.234 ( 0.6410 )	1.504 ( 0.4579 )

Notes
[1] - FAS
[2] - FAS
[3] - FAS
[4] - FAS
[5] - FAS

Statistical Analysis 1

Statistical analysis description

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).

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

^[6]

P-value

≤ 0.0145 ^[7]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[6] - 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.
[7] - Adjusted for multiplicity.

Statistical Analysis 2

Statistical analysis description

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

^[8]

P-value

≤ 0.0148 ^[9]

Method

MCP-Mod linear in log model fit

Confidence interval

Notes
[8] - 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.
[9] - Adjusted for multiplicity.

Statistical Analysis 3

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns while protecting the overall probability of type I error (one-sided alpha of 0.05). Emax model assumption: 20% of the maximum effect is achieved at 2 mg of BI 425809.

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

^[10]

P-value

≤ 0.0089 ^[11]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[10] - 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.
[11] - Adjusted for multiplicity.

Statistical Analysis 4

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns while protecting the overall probability of type I error (one-sided alpha of 0.05). Sigmoid Emax 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.

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

^[12]

P-value

≤ 0.0038 ^[13]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[12] - 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.
[13] - Adjusted for multiplicity.

Statistical Analysis 5

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns while protecting the overall probability of type I error (one-sided alpha of 0.05). Logistic 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.

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

^[14]

P-value

≤ 0.0085 ^[15]

Method

MCP-Mod logistic model fit

Confidence interval

Notes
[14] - 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.
[15] - Adjusted for multiplicity.

Statistical Analysis 6

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns while protecting the overall probability of type I error (one-sided alpha of 0.05). Beta model assumption: 75% of maximum (max) effect at 2 mg, 87.5% of max effect at 5 mg, 25% of max effect at 25 mg, max effect at 10 mg BI 425809, scalar parameter=26.

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

^[16]

P-value

≤ 0.228 ^[17]

Method

MCP-Mod beta model fit

Confidence interval

Notes
[16] - 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.
[17] - Adjusted for multiplicity.

Statistical Analysis 7

Statistical analysis description

Secondary analysis. No formal hypotheses were tested. Mixed Model Repeated Measures (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.

Comparison groups

BI 425809 2 mg once a day (q.d.) v Placebo q.d.

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

≤ 0.733 ^[19]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-1.332

upper limit

1.892

Variability estimate

Standard error of the mean

Dispersion value

0.8205

Notes
[18] - Kenward-Roger was used to estimate denominator degrees of freedom. Difference of adjusted means based on MMRM was calculated as BI 425809 - placebo.
[19] - P-value is considered nominal.

Statistical Analysis 8

Statistical analysis description

Comparison groups

BI 425809 5 mg q.d. v Placebo q.d.

Number of subjects included in analysis

243

Analysis specification

Pre-specified

Analysis type

^[20]

P-value

≤ 0.8655 ^[21]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

0.137

Confidence interval

level

95%

sides

2-sided

lower limit

-1.45

upper limit

1.724

Variability estimate

Standard error of the mean

Dispersion value

0.8074

Notes
[20] - Kenward-Roger was used to estimate denominator degrees of freedom. Difference of adjusted means based on MMRM was calculated as BI 425809 - placebo.
[21] - P-value is considered nominal.

Statistical Analysis 9

Statistical analysis description

Comparison groups

BI 425809 10 mg q.d. v Placebo q.d.

Number of subjects included in analysis

245

Analysis specification

Pre-specified

Analysis type

^[22]

P-value

≤ 0.0122 ^[23]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

1.982

Confidence interval

level

95%

sides

2-sided

lower limit

0.434

upper limit

3.53

Variability estimate

Standard error of the mean

Dispersion value

0.7875

Notes
[22] - Kenward-Roger was used to estimate denominator degrees of freedom. Difference of adjusted means based on MMRM was calculated as BI 425809 - placebo.
[23] - P-value is considered nominal.

Statistical Analysis 10

Statistical analysis description

Comparison groups

BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

^[24]

P-value

≤ 0.0287 ^[25]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

1.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.181

upper limit

3.28

Variability estimate

Standard error of the mean

Dispersion value

0.7884

Notes
[24] - Kenward-Roger was used to estimate denominator degrees of freedom. Difference of adjusted means based on MMRM was calculated as BI 425809 - placebo.
[25] - P-value is considered nominal.

Secondary: Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) total score after 12 weeks of treatment

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End point title

Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) total score after 12 weeks of treatment

End point 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.

End point type

Secondary

End point timeframe

Baseline and after 12 weeks of treatment

End point values	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.
Number of subjects analysed	77 ^[26]	80 ^[27]	82 ^[28]	83 ^[29]	158 ^[30]
Units: units on a scale
least squares mean (standard error)	-1.637 ( 0.5992 )	-3.652 ( 0.5890 )	-3.078 ( 0.5803 )	-3.887 ( 0.5770 )	-2.815 ( 0.4181 )

Notes
[26] - FAS
[27] - FAS
[28] - FAS
[29] - FAS
[30] - FAS

Statistical Analysis 11

Statistical analysis description

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

^[31]

P-value

≤ 0.066 ^[32]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[31] - 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.
[32] - P-value is considered nominal.

Statistical Analysis 12

Statistical analysis description

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

^[33]

P-value

≤ 0.1619 ^[34]

Method

MCP-Mod linear in log model fit

Confidence interval

Notes
[33] - 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.
[34] - P-value is considered nominal.

Statistical Analysis 13

Statistical analysis description

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

^[35]

P-value

≤ 0.0832 ^[36]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[35] - 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.
[36] - P-value is considered nominal.

Statistical Analysis 14

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns while protecting the overall probability of type I error (one-sided alpha of 0.05). Sigmoid Emax 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.

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

^[37]

P-value

≤ 0.0625 ^[38]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[37] - 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.
[38] - P-value is considered nominal.

Statistical Analysis 16

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns while protecting the overall probability of type I error (one-sided alpha of 0.05). Beta model assumption: 75% of maximum (max) effect at 2 mg, 87.5% of max effect at 5 mg, 25% of max effect at 25 mg, max effect at 10 mg BI 425809, scalar parameter=26.

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

^[39]

P-value

≤ 0.7479 ^[40]

Method

MCP-Mod beta model fit

Confidence interval

Notes
[39] - 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.
[40] - P-value is considered nominal.

Statistical Analysis 15

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 425809 and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns while protecting the overall probability of type I error (one-sided alpha of 0.05). Logistic 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.

Comparison groups

BI 425809 2 mg once a day (q.d.) v BI 425809 5 mg q.d. v BI 425809 10 mg q.d. v BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

^[41]

P-value

≤ 0.0768 ^[42]

Method

MCP-Mod logistic model fit

Confidence interval

Notes
[41] - 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.
[42] - P-value is considered nominal.

Statistical Analysis 17

Statistical analysis description

Secondary analysis. No formal hypotheses were tested. Analysis of covariance (ANCOVA) model included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.

Comparison groups

BI 425809 2 mg once a day (q.d.) v Placebo q.d.

Number of subjects included in analysis

235

Analysis specification

Pre-specified

Analysis type

^[43]

P-value

≤ 0.11 ^[44]

Method

ANCOVA

Parameter type

Difference of adjusted means

Point estimate

1.178

Confidence interval

level

95%

sides

2-sided

lower limit

-0.258

upper limit

2.613

Variability estimate

Standard error of the mean

Dispersion value

0.7306

Notes
[43] - Difference of adjusted means based on ANCOVA was calculated as BI 425809 - placebo.
[44] - P-value is considered nominal.

Statistical Analysis 18

Statistical analysis description

Secondary analysis. No formal hypotheses were tested. Analysis of covariance (ANCOVA) model included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.

Comparison groups

BI 425809 5 mg q.d. v Placebo q.d.

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

^[45]

P-value

≤ 0.25 ^[46]

Method

ANCOVA

Parameter type

Difference of adjusted means

Point estimate

-0.837

Confidence interval

level

95%

sides

2-sided

lower limit

-2.257

upper limit

0.582

Variability estimate

Standard error of the mean

Dispersion value

0.7224

Notes
[45] - Difference of adjusted means based on ANCOVA was calculated as BI 425809 - placebo.
[46] - P-value is considered nominal.

Statistical Analysis 19

Statistical analysis description

Secondary analysis. No formal hypotheses were tested. Analysis of covariance (ANCOVA) model included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.

Comparison groups

BI 425809 10 mg q.d. v Placebo q.d.

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

^[47]

P-value

≤ 0.71 ^[48]

Method

ANCOVA

Parameter type

Difference of adjusted means

Point estimate

-0.263

Confidence interval

level

95%

sides

2-sided

lower limit

-1.669

upper limit

1.142

Variability estimate

Standard error of the mean

Dispersion value

0.7152

Notes
[47] - Difference of adjusted means based on ANCOVA was calculated as BI 425809 - placebo.
[48] - P-value is considered nominal.

Statistical Analysis 20

Statistical analysis description

Secondary analysis. No formal hypotheses were tested. Analysis of covariance (ANCOVA) model included treatment as fixed categorical factor, and baseline score as continuous fixed covariate.

Comparison groups

BI 425809 25 mg q.d. v Placebo q.d.

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

^[49]

P-value

≤ 0.13 ^[50]

Method

ANCOVA

Parameter type

Difference of adjusted means

Point estimate

-1.072

Confidence interval

level

95%

sides

2-sided

lower limit

-2.473

upper limit

0.328

Variability estimate

Standard error of the mean

Dispersion value

0.7125

Notes
[49] - Difference of adjusted means based on ANCOVA was calculated as BI 425809 - placebo.
[50] - P-value is considered nominal.

Secondary: Percentage of participants with Adverse Events

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End point title

Percentage of participants with Adverse Events

End point description

Percentage of participants with Adverse Events. The Treated Set (TS) included all subjects who were randomized and were treated with at least 1 dose of trial medication.

End point type

Secondary

End point timeframe

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

End point values	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.
Number of subjects analysed	85 ^[51]	84 ^[52]	85 ^[53]	85 ^[54]	170 ^[55]
Units: Percentage of participants
number (not applicable)	58.8	52.4	41.2	42.4	43.5

Notes
[51] - TS
[52] - TS
[53] - TS
[54] - TS
[55] - TS

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

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.

Adverse event reporting additional description

Timeframe for "Deaths (all causes)": On-treatment period + Follow-up period (planned: 28±7 days), up to 127 days. The Treated Set included all subjects who were randomized and were treated with at least 1 dose of trial medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

BI 425809 2mg QD

Reporting group description

Reporting group title

BI 425809 5mg QD

Reporting group description

Reporting group title

BI 425809 10mg QD

Reporting group description

Reporting group title

BI 425809 25mg QD

Reporting group description

Reporting group title

Placebo QD

Reporting group description

Serious adverse events	BI 425809 2mg QD	BI 425809 5mg QD	BI 425809 10mg QD	BI 425809 25mg QD	Placebo QD
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 85 (2.35%)	4 / 84 (4.76%)	2 / 85 (2.35%)	4 / 85 (4.71%)	4 / 170 (2.35%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 85 (0.00%)	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 85 (0.00%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 85 (0.00%)	0 / 85 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 85 (0.00%)	0 / 85 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 85 (1.18%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Drug dependence
subjects affected / exposed	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 85 (1.18%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fear of disease
subjects affected / exposed	0 / 85 (0.00%)	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 85 (0.00%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 85 (0.00%)	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 85 (0.00%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychotic symptom
subjects affected / exposed	1 / 85 (1.18%)	0 / 84 (0.00%)	0 / 85 (0.00%)	0 / 85 (0.00%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Schizophrenia
subjects affected / exposed	1 / 85 (1.18%)	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 85 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal behaviour
subjects affected / exposed	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 85 (1.18%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 85 (1.18%)	3 / 170 (1.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 85 (0.00%)	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 85 (0.00%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective myositis
subjects affected / exposed	0 / 85 (0.00%)	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 85 (0.00%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	BI 425809 2mg QD	BI 425809 5mg QD	BI 425809 10mg QD	BI 425809 25mg QD	Placebo QD
Total subjects affected by non serious adverse events
subjects affected / exposed	22 / 85 (25.88%)	23 / 84 (27.38%)	14 / 85 (16.47%)	13 / 85 (15.29%)	31 / 170 (18.24%)
Nervous system disorders
Dizziness
subjects affected / exposed	5 / 85 (5.88%)	4 / 84 (4.76%)	2 / 85 (2.35%)	3 / 85 (3.53%)	6 / 170 (3.53%)
occurrences all number	5	4	2	3	6
Headache
subjects affected / exposed	8 / 85 (9.41%)	10 / 84 (11.90%)	7 / 85 (8.24%)	8 / 85 (9.41%)	9 / 170 (5.29%)
occurrences all number	10	11	10	8	10
Somnolence
subjects affected / exposed	2 / 85 (2.35%)	5 / 84 (5.95%)	5 / 85 (5.88%)	2 / 85 (2.35%)	4 / 170 (2.35%)
occurrences all number	2	6	5	2	4
Infections and infestations
Nasopharyngitis
subjects affected / exposed	8 / 85 (9.41%)	9 / 84 (10.71%)	7 / 85 (8.24%)	4 / 85 (4.71%)	13 / 170 (7.65%)
occurrences all number	8	10	8	4	14

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Apr 2016

A new exclusion criterion and restrictions on herbal medications were added. In addition, information on a planned substudy with ophthalmologic safety assessments was added.

13 Dec 2017

To capture additional data on quality of life and social functioning further endpoints were added. Wording in exclusion criteria was updated and clarified.

28 Mar 2019

The investigator-rated Columbia Suicide Severity Rating Scale (C-SSRS) assessment was added to allow psychiatrists to repeat or validate the telephone assessment in case doubtful reports from the telephone assessment were obtained.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
16 Sep 2016	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.	13 Dec 2017

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

None reported

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Clinical trials

Clinical Trial Results:
A phase II randomized, 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Secondary: Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) total score after 12 weeks of treatment

Secondary: Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) total score after 12 weeks of treatment

Secondary: Percentage of participants with Adverse Events

Secondary: Percentage of participants with Adverse Events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Outside EU/EEA

Clinical trials

Clinical Trial Results: A phase II randomized, 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Secondary: Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) total score after 12 weeks of treatment

Secondary: Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) total score after 12 weeks of treatment

Secondary: Percentage of participants with Adverse Events

Secondary: Percentage of participants with Adverse Events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase II randomized, 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