| 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 (MDD) 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. |
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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 | 14.0 |
| 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 | 10037175 - Psychiatric disorders |
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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 compare the efficacy of OPC-34712 (2.0 mg/day) to placebo as adjunctive therapy to an assigned open-label antidepressant therapy (ADT) in subjects who demonstrate an incomplete response after 8 weeks of prospective treatment with the same assigned open-label ADT. |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of OPC 34712 (2.0 mg/day) as adjunctive therapy to ADT in the proposed subject population with MDD. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Pharmacogenomic sample collection will be performed for subjects who provide separate consent under protocol 331-10-228. This pharmacogenomic sampling is optional and subjects who do not choose to sign the applicable ICF for this blood draw may still participate in trial 331-10-228. The genotype of each voluntarily participating subject in the pharmacogenomic portion of this trial will be determined for CYP2D6. |
|
| E.3 | Principal inclusion criteria |
Subjects are required to meet the following 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 one and no more than three 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.
Inclusion Criteria Required for Entry into Phase B (Double-blind Randomization Phase):
7. HAM-D17 Total Score >= 14 at the Week 8 visit
8. HAM-D17 Total Score at the Week 8 visit that is less than a 50% reduction from baseline value
9. CGI-I score >= 3 at the Week 8 visit
10. As evaluated by the investigator, the subject is suitable for randomization based on all available clinical, efficacy, and safety data collected during Phase A in addition to HAM-D17 and CGI-I scores. |
|
| 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.
|
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| 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, LOCF) in MADRS Total Score. The trial will compare the placebo-plus-ADT arm to the OPC-34712-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 from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit, LOCF) in Sheehan Disability Scale (SDS) Mean Score (the mean of 3 individual item scores). |
|
| 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. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Canada |
| Czech Republic |
| France |
| 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 page 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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