| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder (MDD) |
|
| E.1.1.1 | Medical condition in easily understood language |
Major Depressive Disorder is a mental disorder characterised by
an all-encompassing low mood accompanied by low self-esteem, and by
loss of interest or pleasure in normally enjoyable activities. |
|
| 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 | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025454 |
| E.1.2 | Term | Major depressive disorder, recurrent episode |
| E.1.2 | System Organ Class | 100000004873 |
|
| 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 compare the efficacy of brexpiprazole (2.0 mg/day) to placebo as adjunctive therapy to an assigned open-label antidepressant therapy (ADT) in subjects who demonstrate an inadequate response to a prospective 8-week trial of the same assigned open-label ADT. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of brexpiprazole (2.0 mg/day) as adjunctive therapy to ADT in the proposed subject population with MDD.
To characterize efficacy in subjects with anxious distress as well as those who demonstrated minimal improvements during the prospective 8-week trial. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Subjects who are able to provide written informed consent and/or consent obtained from a legally acceptable representative (as required by IRB/IEC) prior to the initiation of any protocol-required procedures.
2.Ability, in the opinion of the principal investigator, to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet/capsule ingestion, and discontinuation of prohibited concomitant medication; to read and understand the written word in order to complete subject-reported outcomes measures; and to be reliably rated on assessment
scales.
3.Male and female outpatients 18 to 65 years of age, inclusive, at the time of informed consent
4.Subjects with both a diagnosis of MDD, and in a current major depressive episode, as defined by DSM-IV-TR criteria and confirmed by both the MINI and an adequate clinical psychiatric evaluation. The current major depressive episode must be >= 8 weeks in duration. In addition, subjects must have reported a history for the current major depressive episode of an inadequate response to at least 1 and no more than 3 adequate antidepressant treatments. An inadequate
response is defined as < 50% reduction in depressive symptom severity, as assessed by the ATRQ.
Adequate treatment is defined as an antidepressant treatment for at least 6 weeks in duration at a minimum dose (or higher) as specified in the ATRQ. If the subject showed >= 50% improvement on any antidepressant treatment in the current episode, then the subject must have had an inadequate response to a subsequent adequate antidepressant treatment (as defined above by the ATRQ) of
another antidepressant drug prior to entry into the trial. For the most recent antidepressant treatment, the subject must not report >= 50% improvement (as defined above by the ATRQ).
5.Subjects with a HAM-D17 Total Score >= 18 at the screening and baseline visits.
6.Subjects willing to discontinue all prohibited psychotropic medications to meet protocol-required washouts prior to and during the trial period
|
|
| E.4 | Principal exclusion criteria |
For full details on exclusion criteria please refer to Section 3.4.3 of the
trial protocol.
Details of the exclusion criteria around the target population are
included below.
Subjects will be excluded if they meet any of the following exclusion
criteria:
• Subjects who report an inadequate response (less than 50% reduction
in depressive symptom severity) to more than three monotherapy
antidepressant treatments during the current Major Depressive Episode
at a therapeutic dose and for an adequate duration (minimum duration
of six weeks), including any antidepressant that the subject may be
taking at screening if it meets the criteria for adequate treatment.
• Subjects who report treatment with adjunctive antipsychotic
medication with an antidepressant for a minimum of three weeks during
the current Major Depressive Episode
• Subjects who have received ECT for the current Major Depressive
Episode.
• Subjects who have had an inadequate response to ECT at any time in
the past or who have had a vagus nerve stimulation or deep brain
stimulation device implanted for management of treatment-resistant
depression
• Subjects with a current need for involuntary commitment or who have
been hospitalized within four weeks of screening for the current Major
Depressive Episode.
• Subjects with a current Axis I (DSM-IV-TR) diagnosis of:
- Delirium, dementia, amnestic or other cognitive disorder
- Schizophrenia, schizoaffective disorder, or other psychotic disorder
- Bipolar I or II disorder
- Eating disorder (including anorexia nervosa or bulimia)
- Obsessive compulsive disorder
- Panic disorder
- Post-traumatic stress disorder
• Subjects with a current Axis II (DSM-IV-TR) diagnosis of borderline,antisocial, paranoid, schizoid, schizotypal or histrionic personality
disorder.
• Subjects experiencing hallucinations, delusions or any psychotic
symptomatology in the current Major Depressive Episode.
• Subjects who answer "Yes" on the C-SSRS either Suicidal Ideation
Item 4 or C-SSRS Suicidal Ideation Item 5 whose most recent episode
meeting criteria was within the past 6 months or Subjects who answer
"Yes" on any of the 5 C-SSRS Suicidal Behavior Items and whose most
recent episode meeting criteria for any of the occurred within the last 2
years
• Subjects who have met DSM-IV-TR criteria for substance abuse or
dependence within the past 180 days; including alcohol and
benzodiazepines, but excluding caffeine and nicotine.
Exclusion Criteria Assessed at the Week 8 Visit:
• Subjects who do not meet predetermined blinded criteria for
incomplete response according to the MST and/or the IVRS/IWRS.
•Subjects who, in the opinion of the investigator or medical monitor, are
not suitable for randomization for other reasons.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from the end of Phase A (Week 8 visit) to the end of Phase B (Week 14 visit) in MADRS Total Score. The trial will compare the placebo-plus-ADT arm to the brexpiprazole-plus-ADT arm, randomized at a ratio of 1:1, with an overall alpha of 0.05 for the primary endpoint. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy endpoint is evaluated as the change from the Week 8 visit to the Week 14 visit |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy variable is the change variables are as follows:
•Change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit,) in SDS Mean Score (the mean of 3 individual item scores).) for the Efficacy Sample.
•Change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with <25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8 visit) on MADRS Total Score.
•Change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulations with and without anxious distress as specified in DSM-V.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary efficacy endpoint is evaluated as the change from the
Week 8 visit to the Week 14 visit |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| 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 | 3 |
| 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 | 18 |
| 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 |
| Germany |
| Hungary |
| Poland |
| Slovakia |
| United States |
|
| 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
|
| The End of Trial Date is defined as the last Date of Contact or the Date of Final Contact Attempt from the Post-treatment Follow-up eCRF for the last subject completing or withdrawing from the trial. |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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