E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment Resistant Major Depression |
|
E.1.1.1 | Medical condition in easily understood language |
Depression is a mental disorder characterized by low mood and/or loss of interest or pleasure in nearly all activities. While there are many treatments available, not all subjects are helped by them. |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10057840 |
E.1.2 | Term | Major depression |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
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 |
The primary objective of the study is to evaluate the efficacy, safety, and tolerability of esketamine in subjects with treatment resistant depression. Efficacy in improving symptoms compared with a placebo will be assessed by the changes from randomisation to end of week 1 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. |
|
E.2.2 | Secondary objectives of the trial |
1. To assess the efficacy versus placebo of esketamine 0.20 mg/kg and 0.40 mg/kg i.v. infusion when administered on both Day 1 and Day 4. using the MADRS, the Clinical Global Impression – Severity and Clinical Global Impression – Improvement.
2. To assess the impact of esketamine 0.20 mg/kg and 0.40 mg/kg i.v. infusion on the patient administered Quick Inventory of Depressive Symptomatology- Self Report, the Patient Global Impression – Severity and the Patient Global Impression of Change.
3. To assess the proportion of responders (subjects who have a reduction in MADRS total score of >50% versus baseline on Day 2, 3, or 4 (prior to dosing) in each of the esketamine dose groups compared to placebo.
4. To evaluate the pharmacokinetics (PK) of esketamine, administered as an i.v. infusion, in subjects with TRD. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Be a man or woman, 18 to 64 years of age, inclusive.
- Be medically stable on the basis of clinical laboratory tests performed at screening.
- Meet Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition (DSM-IV-TR) diagnostic criteria for recurrent MDD, without psychotic features (DSM-IV, 296.32, or 296.33),
- Have an inadequate response to at least 1 antidepressant in the current episode of depression and at least one other inadequate treatment response to an antidepressant either in the current episode or in a previous episode.
- Have an IDS-C30 total score ≥ 34 at Screening and Day -1.
- Hospitalized or agreed to be hospitalized from Day -1 through the completion of study procedures on Day 2 and from Day 3 through the completion of study procedures on Day 4. |
|
E.4 | Principal exclusion criteria |
- Has a history of, or current signs and symptoms of, liver or renal insufficiency; hypothyroidism or hyperthyroidism, significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, or metabolic disturbances. Subjects with non-insulin dependent diabetes mellitus who are adequately controlled may participate in the study.
- Has uncontrolled hypertension (SBP> 160 mmHg or DBP > 90 mmHg despite diet, exercise or a stable dose of an allowed anti-hypertensive treatment) at Screening; or any past history of hypertensive crisis.
- Has a history of previous non-response of depressive symptoms to ketamine/esketamine.
- Has any contraindication to the use of esketamine, per local prescribing information.
- Has not responded to previous treatment with electroconvulsive therapy (ECT). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be improvement in depressive symptoms, as measured by the change in the MADRS total score from Day 1 (baseline) to Day 2 in the double-blind treatment phase. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 2, 24 hours after dosing |
|
E.5.2 | Secondary end point(s) |
1. Improvement in depressive symptoms, as measured by the change in the MADRS total score from Day 1 (baseline) to Day 3 and from Day 1 to Day 4 in the double-blind treatment phase.
2. Change from Day 1 (baseline) to Day 2 in MDD symptoms using the QIDS-SR16 for esketamine compared to placebo.
3. Change from Day 1 (baseline) to Day 2 in severity of illness using the PGI-S for esketamine compared to placebo.
4. Change from Day 1 (baseline) to Day 2 in patient perspective of global change in MDD since start of study treatment, as measured by the PGIC for esketamine compared to placebo.
5. Change from Day 1 (baseline) over time through Day 7 in the MADRS total score |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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 | 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 | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |