E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Major Depressive Disorder |
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E.1.1.1 | Medical condition in easily understood language |
Major Depressive Disorder |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025458 |
E.1.2 | Term | Major depressive disorder, recurrent episode, moderate degree |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10081270 |
E.1.2 | Term | Major depressive disorder |
E.1.2 | System Organ Class | 100000004873 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of lumateperone 42 mg administered once daily compared withplacebo as adjunctive treatment to antidepressant therapy in patients with Major Depressive Disorder (MDD) who have an inadequate response to ongoing antidepressant therapy (ADT) as measured by change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of lumateperone 42 mg administered once daily compared with placebo as adjunctive treatment to ADT in patients with MDD who have an inadequate response to ongoing ADT as measured by change from baseline to Day 43 in the Clinical Global Impression Scale-Severity (CGI-S).
Safety Objectives The safety objective of this study is to determine the safety and tolerability of lumateperone 42 mg administered orally once daily compared with that of placebo in patients with MDD who have an inadequate response to ongoing ADT as assessed by AEs; clinical laboratory results; vital sign measures; ECG results; suicidality as assessed by the C-SSRS; and extrapyramidal symptoms (EPS) as assessed by Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson Angus Scale (SAS). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Main Inclusion Criteria 1. Provides written informed consent; 2. Male or female patients between the ages of 18 and 65 years, inclusive; 3. Meets DSM-5 criteria for MDD (MDD with psychotic features will be acceptable) as confirmed by the Investigator or Sponsor- approved rater using the MINI and meets all of the following criteria: a. The start of the current major depressive episode (MDE) is at least 8 weeks but not more than 18 months prior to Screening (Visit 1); b. Has at least moderate severity of illness based on rater- administered MADRS total score ≥ 24 at Screening (Visit 1) and at Baseline (Visit 2); c. Has at least moderate severity of illness based on CGI-S score ≥ 4 at Screening (Visit 1) and at Baseline (Visit 2); d. Has a Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score ≥14 at Screening (Visit 1) and at Baseline (Visit 2); e. Has sufficient history and medical record confirmation verifying the ADT and the current MDE is causing clinically significant distress or impairment in social, occupational, or other important areas of functioning. 4. Currently having an inadequate response to ADT (less than 50% improvement) as confirmed by the Investigator using ATRQ and taking at least the minimum effective dose (per package insert) of one of the following antidepressants as monotherapy treatment for at least 6 weeks duration: a. citalopram/escitalopram b. fluoxetine c. paroxetine d. sertraline e. duloxetine f. levomilnacipran/milnacipran (if locally approved for MDD) g. venlafaxine/desvenlafaxine h. bupropion I. vilazodone j. vortioxetine All Inclusion Criteria are presented in Section 6.3.1. of the enclosed protocol |
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E.4 | Principal exclusion criteria |
Main Exclusion Criteria Patients who meet any of the following exclusion criteria will not be able to participate in the study: 1. Within the patient’s lifetime, has a confirmed DSM-5 psychiatric diagnosis other than MDD, including: a. Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder or other psychotic disorder; b. Bipolar Disorder; 2. Within 6 months of Screening, has a confirmed DSM-5 psychiatric diagnosis other than MDD including: a. Anxiety disorders such as Panic Disorder or Generalized Anxiety Disorder; Obsessive-compulsive Disorder; Posttraumatic Stress Disorder as primary diagnoses. Note: Anxiety symptoms may be allowed if secondary to MDD, provided these symptoms do not require concurrent treatment; b. Eating disorder; c. Substance use disorders (excluding nicotine); d. Personality disorder of sufficient severity to have a major impact on the patient’s psychiatric status; e. Within 12 months of Screening, has had any other psychiatric condition (other than MDD) that has been the main focus of treatment; 3. The patient experiences a ≥ 25% decrease in the MADRS total score between Screening (Visit 1) and Baseline (Visit 2); 4. The patient experiences a ≥ 25% decrease in the QIDS-SR-16 total score between Screening (Visit 1) and Baseline (Visit 2); 5. In the opinion of the Investigator, the patient has a significant risk for suicidal behavior during participation in the study or: a. At Screening (Visit 1), the patient scores “yes” on Suicidal Ideation Items 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) within 6 months prior to Screening, or at Baseline (Visit 2), the patient scores “yes” on Suicidal Ideation Items 4 or 5 since the Screening Visit; b. At Screening (Visit 1), the patient has had 1 or more suicide attempts within 2 years prior to Screening; c. At Screening (Visit 1) or Baseline (Visit 2), the patient scores ≥ 5 on MADRS Item 10 (Suicidal Thoughts), or d. The patient is considered to be in imminent danger to him/herself or others. 6. The patient has a first MDE at age 60 years or older. All Exclusion Criteria are presented in Section 6.3.2. of the enclosed protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is change from baseline to Day 43 in the MADRS total score. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Baseline (Visit 2) to Day 43 (Visit 8) |
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E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint is the, change from baseline to Day 43 in the CGI-S score.
Additional efficacy analysis are included, below: Analysis of additional efficacy parameters will be based on the mITT population for the on-treatment effect and include the following: - The proportion of patients who are treatment responders where response is defined as a ≥ 50% decrease from baseline in MADRS total score at Day 43; - The proportion of remitters, where remission is defined as a MADRS total score ≤ 10 at Day 43; - By-visit mean change from baseline in the MADRS total score; - By-visit mean change from baseline in the GAD-7 total score; - By-visit mean change from baseline in CGI-S score; - Change from baseline in MADRS individual item scores at each assessment time point, including Day 43 Supportive analyses of the on-treatment effects of the additional efficacy endpoints will also be performed based on the ITT Population using all efficacy data, including assessments collected after patients stopped study treatment, except those assessed after starting a new ADT.
Safety endpoints: Safety analyses will be performed using the Safety Population. The safety parameters will include AEs, clinical laboratory, vital signs, ECG, and EPS (AIMS, BARS, and SAS) and C-SSRS scales. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoint: from Baseline (Visit 2) to Day 43 (Visit 8) in CGI-S score. Additional efficacy parameters: every visit Safety: every visit |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Colombia |
Finland |
Germany |
Poland |
Sweden |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial days | 18 |