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 |
Moderate to severe depression |
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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 | PT |
E.1.2 | Classification code | 10057840 |
E.1.2 | Term | Major depression |
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 evaluate the efficacy of rapastinel (225 or 450 mg, IV, weekly or clinically driven schedule) versus placebo in the maintenance treatment of MDD, as measured by time to relapse during the 52 weeks of the double-blind treatment period (DBTP) |
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E.2.2 | Secondary objectives of the trial |
To characterize the efficacy of rapastinel (225 or 450 mg, IV, weekly or clinically driven schedule) versus placebo in the maintenance treatment of MDD, as measured by change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) at each postbaseline timepoint during the DBTP.
To evaluate the safety and tolerability of rapastinel (225 or 450 mg, IV, weekly or clinically driven schedule) in the maintenance treatment of MDD, as evaluated by AEs, clinical laboratory measures, electrocardiograms (ECGs), vital signs, and Columbia-Suicide Severity Rating Scale (C SSRS). |
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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 |
Pharmacokinetic
Sparse pharmacokinetic (PK) samples will be taken from patients
consenting to optional PK sampling to determine plasma concentrations
of rapastinel using a validated bioanalytical method. |
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E.3 | Principal inclusion criteria |
1. Written informed consent, obtained from the patient before the initiation of any study specific procedures
2. Completion of RAP-MD-30, RAP-MD-31, or RAP-MD-32
3. Male or female outpatients, 18 to 75 years of age (at time of entry to lead-in study)
4. Normal physical-examination findings, clinical-laboratory test results, and ECG results from Visit 1 or abnormal results that are determined to be not clinically significant with regard to participation in the study by the investigator (Note: Because Visit 1 ECG and laboratory results will not be available on the day of Visit 1, patients can be discontinued at Visit 2 if upon receipt of results the investigator determines clinically significant abnormalities are present.)
5. If female of childbearing potential, has a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test. Because Visit 1 pregnancy test results will not be available on the day of Visit 1, patients can be discontinued at Visit 2 if Visit 1 pregnancy test is positive.
6. Ability to follow study instructions and likely to complete all required visits
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E.4 | Principal exclusion criteria |
1. Positive result at Visit 1 from the urine drug screen (UDS) test for any prohibited medication. Exception: patients with a positive UDS at Visit 1 for opiates or episodic use of benzodiazepines may be allowed in the study as described more detailed in the protocol
(Note: Because Visit 1 UDS results will not be available on the day of Visit 1, patients can be discontinued at Visit 2 if upon receipt of results the investigator determines exclusionary results are present.)
2. Suicide risk, as determined by meeting any of the following criteria:
a. A suicide attempt within the past year
b. Significant risk, as judged by the investigator, based on the psychiatric interview or information collected in the C-SSRS at Visit 1
c. MADRS Item 10 score ≥ 5 on the MADRS at Visit 1 of this study or at any visit during participation in the lead-in study
3. At imminent risk of injuring self or others or causing significant damage to property, as judged by the investigator
4. Requiring concomitant treatment with any of the prohibited medications, supplements, or herbal products listed in Appendix III, including any psychotropic drug or any drug with psychotropic activity except as described in Section 9.4.9.1.
5. Females who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study
6. Females of childbearing potential, not using a reliable means of contraception
7. Any change in overall medical condition since entry in to the lead-in study that is determined by the investigator to be clinically significant with regard to participation in the study, including but not limited to: vital signs, ECG parameters, laboratory parameters, psychiatric status and neurological status
8. Current enrollment in an investigational drug or device study or participation in such a study within 6 months of entry into this study with the exception of the lead-in rapastinel study (RAP-MD-30, RAP-MD-31, or RAP-MD-32)
9. Employee, or immediate relative of an employee, of the sponsor, any of its affiliates or partners, or the study center
10. Inability to speak, read, and understand the local language sufficiently to understand the nature of the study, to provide written informed consent, or to allow the completion of all study assessments
11. Patient has a condition or is in a situation which, in the investigator's opinion, may put the patient at significant risk, may confound the study results, or may interfere significantly with the patient's participation in the study
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to first relapse during 52 weeks of the DBTP, defined as the number of days from the randomization date to the relapse date. Relapse during the DBTP is defined as meeting 1 or more of the following criteria within 52 weeks of randomization:
- Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 18 at 2 consecutive visits, or
- A ≥ 2 increase in Clinical Global Impressions-Severity (CGI-S) score compared with that obtained at randomization, or
- Risk of suicide as determined by the investigator, or
- Need for hospitalization due to worsening of depression as determined by the investigator, or
- Need for alternative treatment of depressive symptoms as determined by the investigator |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Measured after subject´s first relapse that has occurred during the 52 weeks of the Double Blind Treatment Period. |
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E.5.2 | Secondary end point(s) |
Additional efficacy endpoints:
- MADRS change from baseline
- CGI-S change from baseline
- Sheehan Disability Scale (SDS) change from baseline
Health Outcomes:
- EuroQol-5 Dimensions Scale 5L Version (EQ-5D-5L)
Safety:
- Adverse event (AE) recording, clinical laboratory measures, vital sign parameters, electrocardiograms (ECGs), and physical examinations
- Measure of sexual function: Changes in Sexual Functioning Questionnaire (CSFQ)
- Measure of psychotomimetic effects: Brief Psychiatric Rating Scale Positive Symptoms subscale (BPRS+)
- Measure of dissociative effects: Clinician Administered Dissociative States Scale (CADSS)
- Measure of suicidality: Columbia-Suicide Severity Rating Scale (C-SSRS)
- Measure of cognition/psychomotor function: Symbol Digit Coding (SDC) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Additional efficacy endpoints:
a change from baseline
Health Outcomes
Open-label: screening, week 8 and week 16
Double-blind period: baseline, week 12, week 24, week 36, week 48 and week 52
Safety:
At each visit and the final analysis will be done at the end of the study |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Two treatment periods: Open-label (OLTP) 8-16 weeks followed by double-blind (DBTP) for 52 weeks |
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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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
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 |
Bulgaria |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Japan |
Poland |
Russian Federation |
Serbia |
Slovakia |
Spain |
Sweden |
Ukraine |
United Kingdom |
United States |
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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
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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 | 5 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |