A Study to Test the Effect of Different Doses of BI 1358894 and Quetiapine in People With Depression

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: BI 1358894
* Drug: Placebo
* Drug: Quetiapine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group 1<br>BI 1358894 | Drug: BI 1358894<br>* BI 1358894<br>|
| Placebo Comparator: Placebo group<br>Placebo | Drug: Placebo<br>* Placebo<br>|
| Experimental: Treatment group 2<br>Quetiapine | Drug: Quetiapine<br>* quetiapine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score | The MADRS consists of 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thought, suicidal thoughts. MADRS items are rated on a 0-6 continuum (0=no abnormality, 6=severe). The possible total score could range from 0 to 60 (from normal with absence of symptoms to severe depression). | At week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response defined as ≥ 50% MADRS reduction from baseline |  | At week 6 | 
| Change from baseline in State-Trait Anxiety Inventory (STAI) State and Trait version scores | The S-Anxiety scale (STAI Form Y-1) consists of twenty statements that evaluate how respondents feel right now, at this moment. The T-Anxiety scale (STAI Form Y-2) consists of twenty statements that assess how people generally feel. Each STAI item is given a weighted score of 1 to 4. A rating of 4 indicates the presence of a high level of anxiety for ten S-Anxiety items and eleven T-Anxiety items (e.g., I feel frightened, I feel upset). A high rating indicates the absence of anxiety for the remaining ten S-Anxiety items and nine T-Anxiety items (e.g., I feel calm, I feel relaxed).Scores for both the S-Anxiety and the T-Anxiety scales can vary from a minimum of 20 to a maximum of 80. Higher scores indicate greater anxiety. | At week 6 | 
| Change from baseline in Clinical Global Impression Severity Scale (CGI-S) score | The CGI-S 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. Higher scores indicate worsening. | At week 6 | 
| Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) total score | The different categories and associated 16 items are: Negative Emotions/Mood: sadness, hopeless/helpless, irritability, anhedonia; Anxiety: feeling overwhelmed, worry; Low Energy: tiredness; Cognition: intrusive thoughts, poor concentration; Sleep Disturbances: general sleep adequacy; Self Harm/Suicide: life not worth living; Low Motivation: lack of drive, no interest in activities; Sense of Self: self-blame; Eating Behavior: poor appetite, overeating. 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. | At week 6 |