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Clinical Trial Results:
A Phase II, 6-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel group trial with a quetiapine arm to evaluate the efficacy, tolerability and safety of oral BI 1358894 in patients with Major Depressive Disorder with inadequate response to antidepressants

Summary
EudraCT number	2019-004264-21
Trial protocol	PL CZ SK DE HU BG
Global end of trial date	02 Feb 2024

Results information
Results version number	v2(current)
This version publication date	29 Mar 2025
First version publication date	15 Feb 2025
Other versions	v1
Version creation reason

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

1402-0011

ISRCTN number

US NCT number

NCT04521478

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

29 Feb 2024

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Jan 2024

Global end of trial reached?

Yes

Global end of trial date

02 Feb 2024

Was the trial ended prematurely?

Main objective of the trial

The main objectives of this trial are to provide proof of concept (PoC) and dose-ranging data of BI 1358894 compared to placebo in patients with MDD to support dose selection for pivotal studies.

Protection of trial subjects

Only subjects that met all the inclusion and none of the exclusion criteria were to be entered into 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.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Dec 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 51

Country: Number of subjects enrolled

Australia: 51

Country: Number of subjects enrolled

Bulgaria: 7

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

Czechia: 36

Country: Number of subjects enrolled

France: 36

Country: Number of subjects enrolled

Germany: 64

Country: Number of subjects enrolled

Hungary: 15

Country: Number of subjects enrolled

Japan: 95

Country: Number of subjects enrolled

Poland: 37

Country: Number of subjects enrolled

Russian Federation: 23

Country: Number of subjects enrolled

Slovakia: 31

Country: Number of subjects enrolled

Spain: 24

Country: Number of subjects enrolled

United States: 460

Worldwide total number of subjects

940

EEA total number of subjects

250

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)

932

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a Phase II, 6-week parallel-group multicenter, randomized, double blind, doubledummy, placebo-controlled trial with a Quetiapine arm in participants with MDD with inadequate response to ongoing treatment with a Selective Serotonin Reuptake Inhibitor or a Serotonin Norepinephrine Reuptake Inhibitor or bupropion.

Screening details

All patients were screened for eligibility prior to participation in the trial, to ensure that they met all inclusion and none of the exclusion criteria. One subject was randomized to the placebo arm but treated with 125 mg BI 1358894, and is shown here in the 125 mg arm. One subject was randomized to the Quetiapine arm, but not treated.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Data analyst, Subject

Blinding implementation details

Participants, investigators, central reviewers, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial remained blinded.

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants with an established diagnosis of Major Depressive Disorder (MDD) administered one dose of placebo matching BI 1358894 in the morning as film-coated tablets, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks. During the trial, participants also continued treatment with their Ongoing Antidepressants (OAD).

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

one daily dose of placebo matching quetiapine in the evening for 6 weeks

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

one daily dose of placebo matching BI 1358894 in the morning for 6 weeks

5 mg BI 1358894

Arm description

Participants with an established diagnosis of MDD administered one 5 milligram (mg) dose of BI 1358894 in the morning as film-coated tablet, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks. During the trial, participants also continued treatment with their OAD.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one daily dose of placebo matching quetiapine in the evening for 6 weeks

Investigational medicinal product name

BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

one daily 5 mg dose of BI 1358894 in the morning for 6 weeks

25 mg BI 1358894

Arm description

Participants with an established diagnosis of MDD administered one 25 mg dose of BI 1358894 in the morning as film-coated tablet, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks. During the trial, participants also continued treatment with their OAD.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one daily dose of placebo matching quetiapine in the evening for 6 weeks

Investigational medicinal product name

BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

one daily 25 mg dose of BI 1358894 in the morning for 6 weeks

75 mg BI 1358894

Arm description

Participants with an established diagnosis of MDD administered one 75 mg dose of BI 1358894 in the morning as film-coated tablets, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks. During the trial, participants also continued treatment with their OAD.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one daily dose of placebo matching quetiapine in the evening for 6 weeks

Investigational medicinal product name

BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

one daily 75 mg dose of BI 1358894 in the morning for 6 weeks

125 mg BI 1358894

Arm description

Participants with an established diagnosis of MDD administered one 125 mg dose of BI 1358894 in the morning as film-coated tablets, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks. During the trial, participants also continued treatment with their OAD.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one daily dose of placebo matching quetiapine in the evening for 6 weeks

Investigational medicinal product name

BI 1358894

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

one daily 125 mg dose of BI 1358894 in the morning for 6 weeks

Quetiapine

Arm description

Participants with an established diagnosis of MDD administered one dose of placebo matching BI 1358894 in the morning as film-coated tablets, and one 150 or 300 mg dose of quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks. The daily active dose at the start of therapy was 50 mg on Day 1, 100 mg at Day 2 and 150 mg on Day 3 and 4. Beginning with Day 5, the recommended daily dose of 300 mg was taken. If not tolerated by a participant, the dose was reduced to 150 mg in Week 1. Thereafter, this finally chosen dose had to be stable until end of treatment at Week 6. During the trial, participants also continued treatment with their OAD.

Arm type

Active comparator

Investigational medicinal product name

Quetiapine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one daily 150 or 300 mg dose of quetiapine in the evening for 6 weeks

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

one daily dose of placebo matching BI 1358894 in the morning for 6 weeks

Number of subjects in period 1 ^[1]	Placebo	5 mg BI 1358894	25 mg BI 1358894	75 mg BI 1358894	125 mg BI 1358894	Quetiapine
Started	128	36	39	39	75	71
Treated	128	36	39	39	75	71
Completed	115	31	33	34	68	59
Not completed	13	5	6	5	7	12
Adverse event, non-fatal	7	-	2	1	2	7
Technical Problems	-	-	-	1	-	-
Burden of Study Procedures	1	-	-	1	-	1
No Reason Available	-	2	-	-	1	-
Other than listed	3	3	3	2	3	3
Protocol deviation	2	-	1	-	-	-
Lack of efficacy	-	-	-	-	1	1

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: Out of the 940 enrolled subjects, only 388 were treated.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

5 mg BI 1358894

Reporting group description

Reporting group title

25 mg BI 1358894

Reporting group description

Reporting group title

75 mg BI 1358894

Reporting group description

Reporting group title

125 mg BI 1358894

Reporting group description

Reporting group title

Quetiapine

Reporting group description

Reporting group values	Placebo	5 mg BI 1358894	25 mg BI 1358894	75 mg BI 1358894	125 mg BI 1358894	Quetiapine	Total
Number of subjects	128	36	39	39	75	71	388
Age categorical
Treated Set (TS): all participants that have been randomized and that received at least one administration of study drug. Participants are analysed according to the actual received treatment.
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	125	36	39	39	73	71	383
From 65-84 years	3	0	0	0	2	0	5
85 years and over	0	0	0	0	0	0	0
Age Continuous
Treated Set (TS): all participants that have been randomized and that received at least one administration of study drug. Participants are analysed according to the actual received treatment.
Units: years
arithmetic mean (standard deviation)	42.9 ( 13.0 )	39.7 ( 13.8 )	44.7 ( 12.1 )	42.7 ( 12.2 )	47.7 ( 11.7 )	43.6 ( 12.4 )	-
Sex: Female, Male
Treated Set (TS): all participants that have been randomized and that received at least one administration of study drug. Participants are analysed according to the actual received treatment.
Units: Subjects
Female	82	27	28	26	51	49	263
Male	46	9	11	13	24	22	125
Race (NIH/OMB)
Treated Set (TS): all participants that have been randomized and that received at least one administration of study drug. Participants are analysed according to the actual received treatment.
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	24	5	6	6	15	12	68
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	6	2	3	1	7	6	25
White	98	29	30	32	53	53	295
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0
Ethnicity (NIH/OMB)
Treated Set (TS): all participants that have been randomized and that received at least one administration of study drug. Participants are analysed according to the actual received treatment.
Units: Subjects
Hispanic or Latino	19	5	2	5	8	12	51
Not Hispanic or Latino	109	31	37	34	67	59	337
Unknown or Not Reported	0	0	0	0	0	0	0
Montgomery-Åsberg Depression Rating Scale (MADRS) total score
The MADRS evaluates core symptoms of depression and consists of 10 items. Nine of them are based upon participant reports, and one is on the rater’s observation (apparent sadness) during the rating interview. MADRS items are rated on a 0–6 continuum (0=no abnormality, 6=severe). The possible total score could range from 0 (normal with absence of symptoms) to 60 (severe depression). Baseline MADRS total score is the last non-missing value recorded prior to first dose of trial medication. Treated Set (TS).
Units: Score on a scale
arithmetic mean (standard deviation)	32.0 ( 6.4 )	34.0 ( 4.8 )	34.1 ( 5.6 )	32.1 ( 6.4 )	33.1 ( 6.0 )	33.6 ( 5.6 )	-

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

5 mg BI 1358894

Reporting group description

Reporting group title

25 mg BI 1358894

Reporting group description

Reporting group title

75 mg BI 1358894

Reporting group description

Reporting group title

125 mg BI 1358894

Reporting group description

Reporting group title

Quetiapine

Reporting group description

Primary: Change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6

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End point title

Change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6 ^[1]

End point description

Change from baseline in MADRS total score at Week 6 is reported. Adjusted mean and standard error (SE) were estimated by Restricted Maximum Likelihood (REML)−based Mixed effects model for repeated measures (MMRM) including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline MADRS total score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors. Full analysis set (FAS): all participants in TS that have a baseline and at least one evaluable post-baseline measurement. As per protocol, data from participants assigned to the quetiapine arm were not included in the primary endpoint.

End point type

Primary

End point timeframe

MMRM included measurements from baseline (Week 0) and at Weeks 1, 2, 4 and 6 after first drug administration. MMRM estimates of change from baseline to Week 6 is reported.

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per protocol, the endpoint applies only to placebo and BI-treated arms.

End point values	Placebo	5 mg BI 1358894	25 mg BI 1358894	75 mg BI 1358894	125 mg BI 1358894
Number of subjects analysed	126	36	39	39	72
Units: Units on a scale
least squares mean (standard error)	-13.0 ( 1.0 )	-12.4 ( 2.0 )	-10.8 ( 1.9 )	-10.8 ( 1.9 )	-11.5 ( 1.4 )

Statistical analysis 1

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline MADRS total score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 5 mg BI 1358894

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

= 0.7636

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.7

Confidence interval

level

90%

sides

2-sided

lower limit

-3

upper limit

4.3

Variability estimate

Standard error of the mean

Dispersion value

2.2

Notes
[2] - Difference = (adjusted mean 5 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 2

Statistical analysis description

Comparison groups

Placebo v 25 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.304

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

2.3

Confidence interval

level

90%

sides

2-sided

lower limit

-1.4

upper limit

5.9

Variability estimate

Standard error of the mean

Dispersion value

2.2

Notes
[3] - Difference = (adjusted mean 25 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 3

Statistical analysis description

Comparison groups

Placebo v 75 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.309

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

2.2

Confidence interval

level

90%

sides

2-sided

lower limit

-1.4

upper limit

5.7

Variability estimate

Standard error of the mean

Dispersion value

2.2

Notes
[4] - Difference = (adjusted mean 75 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 4

Statistical analysis description

Comparison groups

Placebo v 125 mg BI 1358894

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.3694

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

1.5

Confidence interval

level

90%

sides

2-sided

lower limit

-1.3

upper limit

4.4

Variability estimate

Standard error of the mean

Dispersion value

1.7

Notes
[5] - Difference = (adjusted mean 125 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 5

Statistical analysis description

The Multiple Comparison Procedures and Modeling (MCPMod) procedure used the estimated values from an MMRM model as input and allowed for simultaneous evaluation of different potential dose response patterns (Linear, Exponential, Emax1, Emax2, Sigmoid Emax), while protecting the overall false positive rate (probability of Type I error) using a one-sided, nominal α level of 10 %.

Comparison groups

Placebo v 5 mg BI 1358894 v 25 mg BI 1358894 v 75 mg BI 1358894 v 125 mg BI 1358894

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.9158

Method

MCPMod Linear model

Confidence interval

Notes
[6] - MCPMod Linear model assumption: no parameter assumptions required. Corresponding dose response is linear

Statistical analysis 6

Statistical analysis description

Comparison groups

Placebo v 5 mg BI 1358894 v 25 mg BI 1358894 v 75 mg BI 1358894 v 125 mg BI 1358894

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.8676

Method

MCPMod Exponential model

Confidence interval

Notes
[7] - MCPMod Exponential model assumption: 5% of the maximum effect is achieved at 25 mg; corresponding to a drug effect achieved mainly at higher doses

Statistical analysis 7

Statistical analysis description

Comparison groups

Placebo v 5 mg BI 1358894 v 25 mg BI 1358894 v 75 mg BI 1358894 v 125 mg BI 1358894

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

other ^[8]

P-value

= 0.9552

Method

MCPMod Emax1 model

Confidence interval

Notes
[8] - MCPMod Emax1 model assumption: 50% of the maximum effect is achieved at 25 mg; corresponding to the assumed true median effective dose (ED50) = 25 mg

Statistical analysis 8

Statistical analysis description

Comparison groups

Placebo v 5 mg BI 1358894 v 25 mg BI 1358894 v 75 mg BI 1358894 v 125 mg BI 1358894

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

other ^[9]

P-value

= 0.9619

Method

MCPMod Emax2 model

Confidence interval

Notes
[9] - MCPMod Emax2 model assumption: 70% of the maximum effect is achieved at 5 mg; corresponding to a drug effect achieved mainly with low doses, ED50 = 2.14 mg

Statistical analysis 9

Statistical analysis description

Comparison groups

Placebo v 5 mg BI 1358894 v 25 mg BI 1358894 v 75 mg BI 1358894 v 125 mg BI 1358894

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.9507

Method

MCPMod Sigmoid Emax model

Confidence interval

Notes
[10] - MCPMod Sigmoid Emax model assumption: 50% of the maximum effect is achieved at 25 mg, 90% 75 mg; corresponding to a more flexible model of the assumed true ED50 = 25 mg

Secondary: Number of participants with response defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) reduction from baseline at Week 6

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End point title

Number of participants with response defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) reduction from baseline at Week 6 ^[11]

End point description

Number of participants with response defined as ≥ 50% MADRS reduction from baseline at Week 6 is reported. Percent reduction from baseline was calculated as follows: [(MADRS total score at baseline - MADRS total score at week 6)/ MADRS total score at baseline] *100. Full analysis set (FAS): all participants in TS that have a baseline and at least one evaluable post-baseline measurement. As per protocol, data from participants assigned to the quetiapine arm were not included in the secondary endpoints.

End point type

Secondary

End point timeframe

Prior to the first intake of the trial medication (week 0, baseline) and after 6 weeks of treatment.

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per protocol, the endpoint applies only to placebo and BI-treated arms.

End point values	Placebo	5 mg BI 1358894	25 mg BI 1358894	75 mg BI 1358894	125 mg BI 1358894
Number of subjects analysed	126	36	39	39	72
Units: Participants	40	10	9	12	23

Statistical analysis 10

Statistical analysis description

Logistic regression model, including the fixed categorical effects of treatment and baseline MDD severity.

Comparison groups

Placebo v 5 mg BI 1358894

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.8889

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.9427

Confidence interval

level

90%

sides

2-sided

lower limit

0.4709

upper limit

1.8873

Notes
[12] - Odds Ratio of 5 mg BI 1358894 vs Placebo

Statistical analysis 12

Statistical analysis description

Logistic regression model, including the fixed categorical effects of treatment and baseline MDD severity.

Comparison groups

Placebo v 75 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

= 0.8048

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.1026

Confidence interval

level

90%

sides

2-sided

lower limit

0.5757

upper limit

2.1114

Notes
[13] - Odds Ratio of 75 mg BI 1358894 vs Placebo

Statistical analysis 13

Statistical analysis description

Logistic regression model, including the fixed categorical effects of treatment and baseline MDD severity.

Comparison groups

Placebo v 125 mg BI 1358894

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.982

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.0072

Confidence interval

level

90%

sides

2-sided

lower limit

0.5968

upper limit

1.6999

Notes
[14] - Odds Ratio of 125 mg BI 1358894 vs Placebo

Statistical analysis 11

Statistical analysis description

Logistic regression model, including the fixed categorical effects of treatment and baseline MDD severity.

Comparison groups

Placebo v 25 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

= 0.3284

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.6581

Confidence interval

level

90%

sides

2-sided

lower limit

0.3255

upper limit

1.3307

Notes
[15] - Odds Ratio of 25 mg BI 1358894 vs Placebo

Secondary: Change from baseline in State-Trait Anxiety Inventory (STAI) State and Trait version scores at Week 6

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End point title

Change from baseline in State-Trait Anxiety Inventory (STAI) State and Trait version scores at Week 6 ^[16]

End point description

Change from baseline in STAI State and Trait version scores at Week 6 is reported. The STAI comprises separate self-report scales consisting of 20 statements for measuring state and trait anxiety. The S-Anxiety scale evaluates how respondents feel “right now, at this moment.” The T-Anxiety scale assesses how people generally feel. Each STAI item is given a score of 1 to 4. Scores for both scales can vary from 20 to 80. Higher scores indicate greater anxiety. Adjusted mean and SE were estimated by REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors. FAS. As per protocol, data from participants assigned to the quetiapine arm were not included in the secondary endpoints.

End point type

Secondary

End point timeframe

MMRM included measurements from baseline (Week 0) and at Weeks 1, 2, 4 and 6 after first drug administration. MMRM estimates of change from baseline to Week 6 is reported.

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per protocol, the endpoint applies only to placebo and BI-treated arms.

End point values	Placebo	5 mg BI 1358894	25 mg BI 1358894	75 mg BI 1358894	125 mg BI 1358894
Number of subjects analysed	126	36	39	39	72
Units: Units on a scale
least squares mean (standard error)
S-Anxiety	-11.3 ( 1.2 )	-7.0 ( 2.3 )	-8.9 ( 2.3 )	-12.3 ( 2.2 )	-8.6 ( 1.6 )
T-Anxiety	-11.0 ( 1.1 )	-6.9 ( 2.1 )	-10.2 ( 2.1 )	-9.9 ( 2.1 )	-7.2 ( 1.5 )

Statistical analysis 14

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score (S-Anxiety scale). Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 5 mg BI 1358894

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.1013

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.3

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

8.6

Variability estimate

Standard error of the mean

Dispersion value

2.6

Notes
[17] - Difference = (adjusted mean 5 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 15

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score (S-Anxiety scale). Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 25 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.3596

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

2.4

Confidence interval

level

90%

sides

2-sided

lower limit

-1.9

upper limit

6.6

Variability estimate

Standard error of the mean

Dispersion value

2.6

Notes
[18] - Difference = (adjusted mean 25 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 16

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score (S-Anxiety scale). Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 75 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

= 0.6745

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-1.1

Confidence interval

level

90%

sides

2-sided

lower limit

-5.2

upper limit

3.1

Variability estimate

Standard error of the mean

Dispersion value

2.5

Notes
[19] - Difference = (adjusted mean 75 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 17

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score (S-Anxiety scale). Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 125 mg BI 1358894

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

= 0.187

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

2.7

Confidence interval

level

90%

sides

2-sided

lower limit

-0.7

upper limit

Variability estimate

Standard error of the mean

Dispersion value

Notes
[20] - Difference = (adjusted mean 125 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 18

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score (T-Anxiety scale). Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 5 mg BI 1358894

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

= 0.0921

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.1

Confidence interval

level

90%

sides

2-sided

lower limit

0.1

upper limit

8.1

Variability estimate

Standard error of the mean

Dispersion value

2.4

Notes
[21] - Difference = (adjusted mean 5 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 19

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score (T-Anxiety scale). Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 25 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.7395

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.8

Confidence interval

level

90%

sides

2-sided

lower limit

-3.2

upper limit

4.8

Variability estimate

Standard error of the mean

Dispersion value

2.4

Notes
[22] - Difference = (adjusted mean 25 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 20

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score (T-Anxiety scale). Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 75 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.6296

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

1.1

Confidence interval

level

90%

sides

2-sided

lower limit

-2.7

upper limit

Variability estimate

Standard error of the mean

Dispersion value

2.4

Notes
[23] - Difference = (adjusted mean 75 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 21

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of baseline score (T-Anxiety scale). Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 125 mg BI 1358894

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

= 0.0429

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

3.8

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

6.9

Variability estimate

Standard error of the mean

Dispersion value

1.9

Notes
[24] - Difference = (adjusted mean 125 mg BI 1358894) - (adjusted mean Placebo)

Secondary: Change from baseline in Clinical Global Impression Severity Scale (CGI-S) score at Week 6

Top of page

End point title

Change from baseline in Clinical Global Impression Severity Scale (CGI-S) score at Week 6 ^[25]

End point description

Change from baseline in CGI-S score at Week 6 is reported. The CGI-S rating scale evaluates the severity of psychopathology on a scale of 1 to 7. Considering total clinical experience with the depression population, a participant is assessed on severity of illness at the time of rating according to: 1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill participants. Adjusted mean and SE were estimated by REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors. FAS. As per protocol, data from participants assigned to the quetiapine arm were not included in the secondary endpoints.

End point type

Secondary

End point timeframe

MMRM included measurements from baseline (Week 0) and at Weeks 1, 2, 4 and 6 after first drug administration. MMRM estimates of change from baseline to Week 6 is reported.

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per protocol, the endpoint applies only to placebo and BI-treated arms.

End point values	Placebo	5 mg BI 1358894	25 mg BI 1358894	75 mg BI 1358894	125 mg BI 1358894
Number of subjects analysed	126	36	39	39	72
Units: Units on a scale
least squares mean (standard error)	-1.3 ( 0.1 )	-1.2 ( 0.2 )	-1.2 ( 0.2 )	-1.1 ( 0.2 )	-1.1 ( 0.2 )

Statistical analysis 22

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 5 mg BI 1358894

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

other ^[26]

P-value

= 0.6211

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.1

Confidence interval

level

90%

sides

2-sided

lower limit

-0.3

upper limit

0.5

Variability estimate

Standard error of the mean

Dispersion value

0.3

Notes
[26] - Difference = (adjusted mean 5 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 23

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 25 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.5158

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.2

Confidence interval

level

90%

sides

2-sided

lower limit

-0.2

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.2

Notes
[27] - Difference = (adjusted mean 25 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 24

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 75 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[28]

P-value

= 0.4518

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.2

Confidence interval

level

90%

sides

2-sided

lower limit

-0.2

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.2

Notes
[28] - Difference = (adjusted mean 75 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 25

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 125 mg BI 1358894

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

= 0.2347

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.2

Confidence interval

level

90%

sides

2-sided

lower limit

-0.1

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.2

Notes
[29] - Difference = (adjusted mean 125 mg BI 1358894) - (adjusted mean Placebo)

Secondary: Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) total score at Week 6

Top of page

End point title

Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) total score at Week 6 ^[30]

End point description

Change from baseline in SMDDS total score at Week 6 is reported. The SMDDS is a 16-item, patient-reported outcome measure developed to capture the core symptoms of MDD. The SMDDS uses a recall of “over the past 7 days” and participants respond to each question using a rating scale between 0 ("Not at all" or "Never") to 4 ("Extremely" or "Always"). The total score ranges from 0 to 60 with a higher score indicating more severe depressive symptomatology. Adjusted mean and SE were estimated by REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors. FAS. As per protocol, data from participants assigned to the quetiapine arm were not included in the secondary endpoints.

End point type

Secondary

End point timeframe

MMRM included measurements from baseline (Week 0) and at Weeks 1, 2, 4 and 6 after first drug administration. MMRM estimates of change from baseline to Week 6 is reported.

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per protocol, the endpoint applies only to placebo and BI-treated arms.

End point values	Placebo	5 mg BI 1358894	25 mg BI 1358894	75 mg BI 1358894	125 mg BI 1358894
Number of subjects analysed	126	36	39	39	72
Units: Units on a scale
least squares mean (standard error)	-13.3 ( 1.2 )	-9.9 ( 2.2 )	-8.9 ( 2.2 )	-12.3 ( 2.1 )	-10.5 ( 1.6 )

Statistical analysis 26

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 5 mg BI 1358894

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

= 0.1723

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

3.4

Confidence interval

level

90%

sides

2-sided

lower limit

-0.7

upper limit

7.6

Variability estimate

Standard error of the mean

Dispersion value

2.5

Notes
[31] - Difference = (adjusted mean 5 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 28

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 75 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

= 0.6864

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-3

upper limit

Variability estimate

Standard error of the mean

Dispersion value

2.4

Notes
[32] - Difference = (adjusted mean 75 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 29

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 125 mg BI 1358894

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

= 0.1585

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

2.8

Confidence interval

level

90%

sides

2-sided

lower limit

-0.5

upper limit

Variability estimate

Standard error of the mean

Dispersion value

1.9

Notes
[33] - Difference = (adjusted mean 125 mg BI 1358894) - (adjusted mean Placebo)

Statistical analysis 27

Statistical analysis description

Adjusted means and confidence intervals were estimated using REML−based MMRM including the fixed categorical effects of treatment, concomitant psychotherapy use (yes vs. no), and the fixed continuous effect of the baseline score. Visit was treated as a repeated measure with an unstructured covariance matrix. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors.

Comparison groups

Placebo v 25 mg BI 1358894

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

other ^[34]

P-value

= 0.0757

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.4

Confidence interval

level

90%

sides

2-sided

lower limit

0.3

upper limit

8.5

Variability estimate

Standard error of the mean

Dispersion value

2.5

Notes
[34] - Difference = (adjusted mean 25 mg BI 1358894) - (adjusted mean Placebo)

Adverse events

Top of page

Timeframe for reporting adverse events

From first treatment administration until last treatment administration + 28 days, up to approximately 11 weeks.

Adverse event reporting additional description

Treated Set (TS): all participants that have been randomized and that received at least one administration of study drug. Participants are analysed according to the actual received treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Placebo

Reporting group description

Reporting group title

5 mg BI 1358894

Reporting group description

Reporting group title

Quetiapine

Reporting group description

Reporting group title

75 mg BI 1358894

Reporting group description

Reporting group title

125 mg BI 1358894

Reporting group description

Reporting group title

25 mg BI 1358894

Reporting group description

Serious adverse events	Placebo	5 mg BI 1358894	Quetiapine	75 mg BI 1358894	125 mg BI 1358894	25 mg BI 1358894
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 128 (5.47%)	0 / 36 (0.00%)	1 / 71 (1.41%)	2 / 39 (5.13%)	1 / 75 (1.33%)	2 / 39 (5.13%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Investigations
Blood creatinine increased
subjects affected / exposed	1 / 128 (0.78%)	0 / 36 (0.00%)	0 / 71 (0.00%)	0 / 39 (0.00%)	0 / 75 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myeloproliferative neoplasm
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	0 / 39 (0.00%)	1 / 75 (1.33%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary fibrosis
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	0 / 39 (0.00%)	0 / 75 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Emotional distress
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	0 / 39 (0.00%)	0 / 75 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	6 / 128 (4.69%)	0 / 36 (0.00%)	1 / 71 (1.41%)	2 / 39 (5.13%)	0 / 75 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Genital herpes
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	1 / 39 (2.56%)	0 / 75 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0

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

Non-serious adverse events	Placebo	5 mg BI 1358894	Quetiapine	75 mg BI 1358894	125 mg BI 1358894	25 mg BI 1358894
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 128 (25.00%)	16 / 36 (44.44%)	43 / 71 (60.56%)	24 / 39 (61.54%)	34 / 75 (45.33%)	22 / 39 (56.41%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	0 / 39 (0.00%)	0 / 75 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	2
Nervous system disorders
Disturbance in attention
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	1 / 39 (2.56%)	0 / 75 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	1	0	5
Dizziness
subjects affected / exposed	3 / 128 (2.34%)	2 / 36 (5.56%)	6 / 71 (8.45%)	2 / 39 (5.13%)	4 / 75 (5.33%)	6 / 39 (15.38%)
occurrences all number	3	2	6	2	5	11
Somnolence
subjects affected / exposed	4 / 128 (3.13%)	1 / 36 (2.78%)	24 / 71 (33.80%)	7 / 39 (17.95%)	5 / 75 (6.67%)	1 / 39 (2.56%)
occurrences all number	6	1	28	7	6	1
Sedation
subjects affected / exposed	1 / 128 (0.78%)	0 / 36 (0.00%)	6 / 71 (8.45%)	2 / 39 (5.13%)	2 / 75 (2.67%)	1 / 39 (2.56%)
occurrences all number	1	0	6	2	2	1
Headache
subjects affected / exposed	13 / 128 (10.16%)	9 / 36 (25.00%)	2 / 71 (2.82%)	4 / 39 (10.26%)	13 / 75 (17.33%)	4 / 39 (10.26%)
occurrences all number	13	12	3	5	15	5
General disorders and administration site conditions
Fatigue
subjects affected / exposed	4 / 128 (3.13%)	5 / 36 (13.89%)	7 / 71 (9.86%)	2 / 39 (5.13%)	4 / 75 (5.33%)	3 / 39 (7.69%)
occurrences all number	6	5	9	2	4	6
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 128 (0.78%)	0 / 36 (0.00%)	1 / 71 (1.41%)	0 / 39 (0.00%)	3 / 75 (4.00%)	2 / 39 (5.13%)
occurrences all number	1	0	1	0	4	2
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	1 / 71 (1.41%)	2 / 39 (5.13%)	0 / 75 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	0	1	2	0	0
Abdominal pain
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	1 / 71 (1.41%)	0 / 39 (0.00%)	0 / 75 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	1	0	0	2
Dry mouth
subjects affected / exposed	4 / 128 (3.13%)	0 / 36 (0.00%)	4 / 71 (5.63%)	1 / 39 (2.56%)	1 / 75 (1.33%)	2 / 39 (5.13%)
occurrences all number	5	0	4	1	1	2
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	0 / 39 (0.00%)	0 / 75 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	1 / 39 (2.56%)	1 / 75 (1.33%)	2 / 39 (5.13%)
occurrences all number	0	0	0	1	1	2
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 128 (0.00%)	1 / 36 (2.78%)	1 / 71 (1.41%)	2 / 39 (5.13%)	1 / 75 (1.33%)	1 / 39 (2.56%)
occurrences all number	0	1	1	3	1	1
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 128 (0.78%)	2 / 36 (5.56%)	1 / 71 (1.41%)	0 / 39 (0.00%)	2 / 75 (2.67%)	0 / 39 (0.00%)
occurrences all number	2	2	1	0	3	0
Aggression
subjects affected / exposed	0 / 128 (0.00%)	2 / 36 (5.56%)	0 / 71 (0.00%)	0 / 39 (0.00%)	0 / 75 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	2	0	0	0	0
Sleep disorder
subjects affected / exposed	2 / 128 (1.56%)	0 / 36 (0.00%)	0 / 71 (0.00%)	0 / 39 (0.00%)	1 / 75 (1.33%)	2 / 39 (5.13%)
occurrences all number	2	0	0	0	1	2
Insomnia
subjects affected / exposed	1 / 128 (0.78%)	0 / 36 (0.00%)	6 / 71 (8.45%)	1 / 39 (2.56%)	2 / 75 (2.67%)	2 / 39 (5.13%)
occurrences all number	1	0	6	1	2	2
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 128 (0.00%)	0 / 36 (0.00%)	0 / 71 (0.00%)	0 / 39 (0.00%)	1 / 75 (1.33%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	1	2
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	2 / 128 (1.56%)	1 / 36 (2.78%)	2 / 71 (2.82%)	2 / 39 (5.13%)	3 / 75 (4.00%)	2 / 39 (5.13%)
occurrences all number	2	1	2	2	3	3
Respiratory tract infection
subjects affected / exposed	0 / 128 (0.00%)	2 / 36 (5.56%)	3 / 71 (4.23%)	0 / 39 (0.00%)	0 / 75 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	2	3	0	0	0
Nasopharyngitis
subjects affected / exposed	2 / 128 (1.56%)	0 / 36 (0.00%)	3 / 71 (4.23%)	2 / 39 (5.13%)	2 / 75 (2.67%)	2 / 39 (5.13%)
occurrences all number	2	0	3	3	2	2
COVID-19
subjects affected / exposed	5 / 128 (3.91%)	1 / 36 (2.78%)	0 / 71 (0.00%)	3 / 39 (7.69%)	1 / 75 (1.33%)	1 / 39 (2.56%)
occurrences all number	5	1	0	3	1	1

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Were there any global substantial amendments to the protocol? Yes

07 Jul 2020

Global amendment 2 was issued on 7-Jul-2020 and included the following changes: addition of backup procedures to cover for potential impact of coronavirus disease (COVID-19) during trial conduct; removal of restriction for “combined cytochrome P450 (CYP) 3A4 and Uridine diphosphate (UDP)-Glucuronosyltransferase (UGT) inhibitors” as co-meds; addition of speech recording collection; change of inclusionary MADRS entry score from ≥22 to ≥26; addition of exclusion criteria #24 and #25; addition of a description of the role of the external vendor responsible for confirmation of eligibility; addition of Erythrocyte Sedimentation Rate (ESR) test to Haematology; addition of information and rational that drug screen results will be included in the clinical database.

07 Sep 2020

Global amendment 3 was issued on 7-Sep-2020 and included the following changes: addition of the specification on how to split the screening visit on separate days, if needed; restrictions of strong or moderate CYP3A inhibitors according to the Summary of Product Characteristics (SmPC) of quetiapine; addition of an additional manufacturer of the placebos; definition of Patient Reported Outcomes (PROs) data as source documents; clarification that the investigator must adhere to the global Clinical Trial Protocol (CTP) and referring local amendments, where applicable; definition of minimum required laboratory parameters in case a local laboratory is needed due to restrictions due to COVID-19.

03 Mar 2021

Global amendment 4 was issued on 3-Mar-2021 and included the following changes: addition of Verification of duplicate participants (VCT); inclusion of optional participant’s feedback questionnaire at End of Treatment (EOT); revision of Urinalysis test to align with Central lab testing standards; addition of Norfluoxetine to Fluoxetine.

28 Jun 2021

Global Amendment 5 was issued on 28-Jun-2021 and included the following changes: woman of childbearing potential (WOCBP) who were sexually abstinent were considered to fulfil the requirements of safe contraception; an option to extend the screening period by 7 days (i.e. to 28 days) was added, to allow for administrative issues such as late reporting of Selective Serotonin Reuptake Inhibitor (SSRI) / Serotonin Norepinephrine Reuptake Inhibitor (SNRI) blood levels.

28 Sep 2021

Global Amendment 6 was issued on 28-Sep-2021 and included the following changes: the duration of the current depressive episode was extended from 12 months to 18 months; the MADRS score required for entry was changed from ≥ 26 to ≥ 24; the minimum required duration of ongoing SSRI/SNRI monotherapy at screening was reduced from 8 weeks to 6 weeks; confirmation of SSRI/SNRI levels in urine at screening was added to analysis in serum; background SSRI/SNRI could optionally be stopped at EOT, and not only after the end of the trial; other antidepressants were permitted (excluding bupropion) if less than the lowest dose indicated for MDD, e.g., for treatment of anxiety or sleep disorder.

27 Apr 2022

Global Amendment 7 was issued on 27-Apr-2022 and included the following changes: counseling about the need of contraception at Visit 1 during Informed Consent (IC); reiteration of adherence to contraception at all visits; removal of onsite ESR; confirmation of SSRI/SNRI exposure can be done either in urine or serum under conditions as described; new data added from preclinical trials showing teratogenicity potential in animals; renaming of Visits; update of the Seroquel Summary of Product Characteritics reference.

26 Sep 2022

Global Amendment 8 was issued on 26-Sep-2022 and included the following changes: investigators were required to ensure that participants understood the contraception requirements, and were to confirm that participants were willing to abide by these; counselling on contraception was to be provided at all visits.

26 Oct 2022

Global Amendment 9 was issued on 26-Oct-2022 and included the following changes: the duration of the current depressive episode was extended from 18 months to 24 months; Bupropion (Selective Norepinephrine Dopamine Reuptake Inhibitor) was added as an acceptable antidepressant background treatment; the restriction on sensitive CYP2B6 concomitant medications was lifted; the minimal needed duration of ongoing monotherapy with an SSRI/SNRI/bupropion was reduced from 6 to 4 weeks; lifetime usage of transcranial magnetic stimulation (TMS) was changed to only exclude TMS if used during the current depressive episode, or within 12 months prior to screening;´ the customized Antidepressant Treatment Response Questionnaire (ATRQ) defining the minimal required duration for stable antidepressant therapy at screening was changed from 6 to 4 weeks; it was recommended to use different raters for the Columbia Suicide Severity Rating Scale (C-SSRS) scale and adverse events.

Were there any global interruptions to the trial? No

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6

Primary: Change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6

Secondary: Number of participants with response defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) reduction from baseline at Week 6

Secondary: Number of participants with response defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) reduction from baseline at Week 6

Secondary: Change from baseline in State-Trait Anxiety Inventory (STAI) State and Trait version scores at Week 6

Secondary: Change from baseline in State-Trait Anxiety Inventory (STAI) State and Trait version scores at Week 6

Secondary: Change from baseline in Clinical Global Impression Severity Scale (CGI-S) score at Week 6

Secondary: Change from baseline in Clinical Global Impression Severity Scale (CGI-S) score at Week 6

Secondary: Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) total score at Week 6

Secondary: Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) total score at Week 6

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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