Depressive Disorder, Major
Conditions
Brief summary
This study is open to adults with depression (major depressive disorder) for whom standard treatment with antidepressants alone does not work sufficiently. The purpose of the trial is to find out whether a medicine called BI 1358894 helps to improve symptoms of depression. Four different doses of BI 1358894 are tested in the study. Participants continue their standard antidepressant therapy throughout the study. Participants are put into 6 groups by chance. Participants in 4 of the 6 groups take different doses of BI 1358894, and placebo. Participants in the fifth group take quetiapine, a medicine already used to treat depression, and placebo. Participants in the sixth group take placebo only. Participants take BI 1358894, quetiapine, or placebo as tablets. Placebo tablets look like BI 1358894 or quetiapine tablets but do not contain any medicine. Each participant takes tablets twice a day. Participants are in the study for about 3 months. During this time, they visit the study site about 8 times and get about 2 phone calls. At the visits, doctors ask participants about their symptoms. The results between the BI 1358894 groups, the quetiapine group, and the placebo group are then compared. The doctors also regularly check the general health of the participants.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
--Established diagnosis of Major Depressive Disorder (MDD), single episode or recurrent, as confirmed at the time of screening by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 5th version (DSM-5) (SCID-5), with a duration of current depressive episode ≥ 8 weeks and ≤ 24 months at the time of screening visit * Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 24 at screening, as confirmed by a trained site based rater AND interactive, computer administered MADRS. The difference in the rater and computer administered MADRS must not exceed more than 7 points (for details refer to section 6.2). In addition, trial participants must have a score of ≥ 3 on the Reported Sadness Item on both MADRS scales (computer administered and rater-administered MADRS) * A documented ongoing monotherapy treatment of ≥ 4 weeks at the screening visit, with bupropion or a protocol specified Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin Norepinephrine Reuptake Inhibitor (SNRI) (refer to the ISF) at adequate dose (at least minimum effective dose as per prescribing information and as confirmed per detectable drug levels in the screening blood or urine sampling) * Male and female participants, 18 to 65 years of age, both inclusively at the time of consent * Women who are of child-bearing potential (WOCBP)1 must be able and willing, as confirmed by the investigator, to use two methods of contraception which include one highly effective method of birth control per ICH M3 (R2) that result in a low failure rate of less than 1%, plus one additional barrier * Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial * Able to communicate well, and to understand and comply with trial requirements
Exclusion criteria
* Per DSM-5, had ever met diagnostic criteria for schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar disorder, delusional disorder or MDD with psychotic features as assessed by the Structured Clinical Interview for DSM-5 Clinical Trials (SCID-5) at the time of screening * Diagnosis of any other mental disorder (in addition to those as described in Exclusion Criterion #1) that was the primary focus of treatment within 6 months prior to screening or at baseline (as per clinical discretion of the investigator) * Diagnosis with antisocial, paranoid, schizoid or schizotypal personality disorder as per DSM-5 criteria, at the time of screening visit. Any other personality disorder at screening visit that significantly affects current psychiatric status and likely to impact trial participation, as per the judgement of investigator * Diagnosis of a substance related disorder within 3 months prior to screening visit (with exception of caffeine and tobacco) * History of seizure disorders, stroke, brain tumor or any other major neurological illness that can impact participation in the trial * History of more than 2 unsuccessful monotherapy treatments (at adequate dosage and duration, per local prescribing information of the product) with an approved antidepressant medication for the current ongoing major depressive episode. These include ongoing monotherapy treatment with bupropion or a protocol specified SSRI or SNRI as described in Inclusion Criterion #3 * Any suicidal behavior in the past 12 months prior to screening (per investigator judgement including an actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behaviour) * Any suicidal ideation of type 4 or 5 in the Columbia Suicide Severity Rating Scale (CSSRS) in the past 3 months prior to screening or at screening or baseline visit (i.e. active suicidal thought with method and intent but without specific plan, or active suicidal thought with method, intent and plan)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6 | 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. | Change from baseline in MADRS total score at Week 6 is reported. 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). Least squares mean and adjusted standard error 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response Defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) Reduction From Baseline at Week 6 | Prior to the first intake of the trial medication (week 0, baseline) and after 6 weeks of treatment. | 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. |
| Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | 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. | Change from baseline in STAI State and Trait version scores at Week 6 is reported. The STAI comprises separate self-report scales for measuring state and trait anxiety. Both consist of 20 statements. 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 weighted score of 1 to 4. Scores for both scales can vary from 20 (minimum) to 80 (maximum). Higher scores indicate greater anxiety. Least squares mean and adjusted standard error 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. |
| Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 6 | 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. | 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. Least squares mean and adjusted standard error 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. |
| Change From Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Week 6 | 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. | 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. Least squares mean and adjusted standard error 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. |
Countries
Argentina, Australia, Bulgaria, Canada, Czechia, France, Germany, Hungary, Japan, Poland, Russia, Slovakia, Spain, United States
Participant flow
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 Major Depressive Disorder (MDD) with inadequate response to ongoing treatment with a Selective Serotonin Reuptake Inhibitor (SSRI) or a Serotonin Norepinephrine Reuptake Inhibitor (SNRI) or bupropion.
Pre-assignment 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 patient was randomized to the placebo arm but treated with 125 mg BI 1358894.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 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). | 128 |
| 5 mg BI 1358894 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. | 36 |
| 25 mg BI 1358894 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. | 39 |
| 75 mg BI 1358894 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. | 39 |
| 125 mg BI 1358894 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. | 75 |
| Quetiapine 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. | 71 |
| Total | 388 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 0 | 2 | 1 | 2 | 7 |
| Overall Study | Burden of Study Procedures | 1 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | No Reason Available | 0 | 2 | 0 | 0 | 1 | 0 |
| Overall Study | Not treated | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other than listed | 3 | 3 | 3 | 2 | 3 | 3 |
| Overall Study | Protocol Violation | 2 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Technical Problems | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | 5 mg BI 1358894 | 25 mg BI 1358894 | 75 mg BI 1358894 | 125 mg BI 1358894 | Quetiapine | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 42.9 Years STANDARD_DEVIATION 13 | 39.7 Years STANDARD_DEVIATION 13.8 | 44.7 Years STANDARD_DEVIATION 12.1 | 42.7 Years STANDARD_DEVIATION 12.2 | 47.7 Years STANDARD_DEVIATION 11.7 | 43.6 Years STANDARD_DEVIATION 12.4 | 43.8 Years STANDARD_DEVIATION 12.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 5 Participants | 2 Participants | 5 Participants | 8 Participants | 12 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 109 Participants | 31 Participants | 37 Participants | 34 Participants | 67 Participants | 59 Participants | 337 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Montgomery-Åsberg Depression Rating Scale (MADRS) total score | 32.0 Score on a scale STANDARD_DEVIATION 6.4 | 34.0 Score on a scale STANDARD_DEVIATION 4.8 | 34.1 Score on a scale STANDARD_DEVIATION 5.6 | 32.1 Score on a scale STANDARD_DEVIATION 6.4 | 33.1 Score on a scale STANDARD_DEVIATION 6 | 33.6 Score on a scale STANDARD_DEVIATION 5.6 | 32.9 Score on a scale STANDARD_DEVIATION 6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 24 Participants | 5 Participants | 6 Participants | 6 Participants | 15 Participants | 12 Participants | 68 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 2 Participants | 3 Participants | 1 Participants | 7 Participants | 6 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 98 Participants | 29 Participants | 30 Participants | 32 Participants | 53 Participants | 53 Participants | 295 Participants |
| Sex: Female, Male Female | 82 Participants | 27 Participants | 28 Participants | 26 Participants | 51 Participants | 49 Participants | 263 Participants |
| Sex: Female, Male Male | 46 Participants | 9 Participants | 11 Participants | 13 Participants | 24 Participants | 22 Participants | 125 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 128 | 0 / 36 | 0 / 39 | 0 / 39 | 0 / 75 | 0 / 71 |
| other Total, other adverse events | 32 / 128 | 16 / 36 | 22 / 39 | 24 / 39 | 34 / 75 | 43 / 71 |
| serious Total, serious adverse events | 7 / 128 | 0 / 36 | 2 / 39 | 2 / 39 | 1 / 75 | 1 / 71 |
Outcome results
Primary
Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6
Change from baseline in MADRS total score at Week 6 is reported. 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). Least squares mean and adjusted standard error 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.
Time frame: 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.
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6 | -13.0 Units on a scale | Standard Error 1 |
| 5 mg BI 1358894 | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6 | -12.4 Units on a scale | Standard Error 2 |
| 25 mg BI 1358894 | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6 | -10.8 Units on a scale | Standard Error 1.9 |
| 75 mg BI 1358894 | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6 | -10.8 Units on a scale | Standard Error 1.9 |
| 125 mg BI 1358894 | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6 | -11.5 Units on a scale | Standard Error 1.4 |
Comparison: 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.p-value: 0.763690% CI: [-3, 4.3]Mixed Models Analysis
Comparison: 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.p-value: 0.30490% CI: [-1.4, 5.9]Mixed Models Analysis
Comparison: 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.p-value: 0.30990% CI: [-1.4, 5.7]Mixed Models Analysis
Comparison: 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.p-value: 0.369490% CI: [-1.3, 4.4]Mixed Models Analysis
Comparison: 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 %.p-value: 0.9158MCPMod Linear model
Comparison: 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 %.p-value: 0.8676MCPMod Exponential model
Comparison: 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 %.p-value: 0.9552MCPMod Emax1 model
Comparison: 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 %.p-value: 0.9619MCPMod Emax2 model
Comparison: 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 %.p-value: 0.9507MCPMod Sigmoid Emax model
Secondary
Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 6
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. Least squares mean and adjusted standard error 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.
Time frame: 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.
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 6 | -1.3 Units on a scale | Standard Error 0.1 |
| 5 mg BI 1358894 | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 6 | -1.2 Units on a scale | Standard Error 0.2 |
| 25 mg BI 1358894 | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 6 | -1.2 Units on a scale | Standard Error 0.2 |
| 75 mg BI 1358894 | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 6 | -1.1 Units on a scale | Standard Error 0.2 |
| 125 mg BI 1358894 | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 6 | -1.1 Units on a scale | Standard Error 0.2 |
Comparison: 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.p-value: 0.621190% CI: [-0.3, 0.5]Mixed Models Analysis
Comparison: 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.p-value: 0.515890% CI: [-0.2, 0.6]Mixed Models Analysis
Comparison: 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.p-value: 0.451890% CI: [-0.2, 0.6]Mixed Models Analysis
Comparison: 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.p-value: 0.234790% CI: [-0.1, 0.6]Mixed Models Analysis
Secondary
Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6
Change from baseline in STAI State and Trait version scores at Week 6 is reported. The STAI comprises separate self-report scales for measuring state and trait anxiety. Both consist of 20 statements. 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 weighted score of 1 to 4. Scores for both scales can vary from 20 (minimum) to 80 (maximum). Higher scores indicate greater anxiety. Least squares mean and adjusted standard error 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.
Time frame: 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.
Population: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | S-Anxiety | -11.3 Units on a scale | Standard Error 1.2 |
| Placebo | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | T-Anxiety | -11.0 Units on a scale | Standard Error 1.1 |
| 5 mg BI 1358894 | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | S-Anxiety | -7.0 Units on a scale | Standard Error 2.3 |
| 5 mg BI 1358894 | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | T-Anxiety | -6.9 Units on a scale | Standard Error 2.1 |
| 25 mg BI 1358894 | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | S-Anxiety | -8.9 Units on a scale | Standard Error 2.3 |
| 25 mg BI 1358894 | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | T-Anxiety | -10.2 Units on a scale | Standard Error 2.1 |
| 75 mg BI 1358894 | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | T-Anxiety | -9.9 Units on a scale | Standard Error 2.1 |
| 75 mg BI 1358894 | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | S-Anxiety | -12.3 Units on a scale | Standard Error 2.2 |
| 125 mg BI 1358894 | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | S-Anxiety | -8.6 Units on a scale | Standard Error 1.6 |
| 125 mg BI 1358894 | Change From Baseline in State-Trait Anxiety Inventory (STAI) State and Trait Version Scores at Week 6 | T-Anxiety | -7.2 Units on a scale | Standard Error 1.5 |
Comparison: 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.p-value: 0.101390% CI: [0, 8.6]Mixed Models Analysis
Comparison: 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.p-value: 0.359690% CI: [-1.9, 6.6]Mixed Models Analysis
Comparison: 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.p-value: 0.674590% CI: [-5.2, 3.1]Mixed Models Analysis
Comparison: 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.p-value: 0.18790% CI: [-0.7, 6]Mixed Models Analysis
Comparison: 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.p-value: 0.092190% CI: [0.1, 8.1]Mixed Models Analysis
Comparison: 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.p-value: 0.739590% CI: [-3.2, 4.8]Mixed Models Analysis
Comparison: 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.p-value: 0.629690% CI: [-2.7, 5]Mixed Models Analysis
Comparison: 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.p-value: 0.042990% CI: [0.7, 6.9]Mixed Models Analysis
Secondary
Change From Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Week 6
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. Least squares mean and adjusted standard error 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.
Time frame: 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.
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Week 6 | -13.3 Units on a scale | Standard Error 1.2 |
| 5 mg BI 1358894 | Change From Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Week 6 | -9.9 Units on a scale | Standard Error 2.2 |
| 25 mg BI 1358894 | Change From Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Week 6 | -8.9 Units on a scale | Standard Error 2.2 |
| 75 mg BI 1358894 | Change From Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Week 6 | -12.3 Units on a scale | Standard Error 2.1 |
| 125 mg BI 1358894 | Change From Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Week 6 | -10.5 Units on a scale | Standard Error 1.6 |
Comparison: 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.p-value: 0.172390% CI: [-0.7, 7.6]Mixed Models Analysis
Comparison: 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.p-value: 0.075790% CI: [0.3, 8.5]Mixed Models Analysis
Comparison: 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.p-value: 0.686490% CI: [-3, 5]Mixed Models Analysis
Comparison: 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.p-value: 0.158590% CI: [-0.5, 6]Mixed Models Analysis
Secondary
Number of Participants With Response Defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) Reduction From Baseline at Week 6
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.
Time frame: Prior to the first intake of the trial medication (week 0, baseline) and after 6 weeks of treatment.
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Response Defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) Reduction From Baseline at Week 6 | 40 Participants |
| 5 mg BI 1358894 | Number of Participants With Response Defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) Reduction From Baseline at Week 6 | 10 Participants |
| 25 mg BI 1358894 | Number of Participants With Response Defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) Reduction From Baseline at Week 6 | 9 Participants |
| 75 mg BI 1358894 | Number of Participants With Response Defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) Reduction From Baseline at Week 6 | 12 Participants |
| 125 mg BI 1358894 | Number of Participants With Response Defined as ≥ 50% Montgomery-Åsberg Depression Rating Scale (MADRS) Reduction From Baseline at Week 6 | 23 Participants |
Comparison: Logistic regression model, including the fixed categorical effects of treatment and baseline MDD severity.p-value: 0.888990% CI: [0.4709, 1.8873]Regression, Logistic
Comparison: Logistic regression model, including the fixed categorical effects of treatment and baseline MDD severity.p-value: 0.328490% CI: [0.3255, 1.3307]Regression, Logistic
Comparison: Logistic regression model, including the fixed categorical effects of treatment and baseline MDD severity.p-value: 0.804890% CI: [0.5757, 2.1114]Regression, Logistic
Comparison: Logistic regression model, including the fixed categorical effects of treatment and baseline MDD severity.p-value: 0.98290% CI: [0.5968, 1.6999]Regression, Logistic