E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Major depressive disorder |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 |
|
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 (450 mg IV) versus placebo and rapastinel (225 mg IV) versus placebo in the treatment of MDD, as measured by the change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score at end of treatment (end of week 6) |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of rapastinel (450 mg IV) versus placebo and rapastinel (225 mg IV) versus placebo in the treatment of MDD, as measured by the change from baseline MADRS total score at 1 day post-first dose of treatment
To evaluate the safety and tolerability of rapastinel (450 mg IV) versus placebo and rapastinel (225 mg IV) versus placebo in the treatment of MDD, as evaluated by adverse events (AEs), clinical laboratory measures, electrocardiograms (ECGs), vital signs, and Columbia-Suicide Severity Rating Scale (C-SSRS) |
|
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 |
Pharmacogenetic
Blood samples will be collected at any time between Visits 2 and 9, inclusive, to determine individual genotype status and for pharmacogenetic biobanking. Participation is optional.
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. |
|
E.3 | Principal inclusion criteria |
Criteria to be assessed at Visit 1 (Screening)
1. Written informed consent, obtained from the patient before the initiation of any study-specific procedures
2. Male or female outpatients, 18 to 75 (inclusive) years of age at Visit 1
3. Meet DSM-5 criteria for MDD (based on confirmation from the MINI), with a current major depressive episode of at least 8 weeks and not exceeding 18 months in duration at Visit 1
4. Have a minimum score of 26 on the rater-administered MADRS and a minimum score of 24 on the computer-administered MADRS at Visit 1
5. Have a difference of no greater than 7 points between the rater-administered MADRS and computer-administered MADRS at Visit 1
6. Have a CGI-S score ≥ 4 at Visit 1
7. Treatment naive in the present episode or have failed to respond (< 50% reduction in depressive symptoms as documented using the ATRQ) to 1 to 3 ADTs given at adequate doses (as defined by the ADT package insert) and duration of > 8 weeks during the present episode
8. Normal physical-examination findings, clinical-laboratory test results, and ECG results from Screening (Visit 1) or abnormal results that are determined to be not clinically significant by the investigator and documented as such in the eCRF
9. If female of childbearing potential, have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at Visit 1
10. Ability to follow study instructions and likely to complete all required visits
Criteria to be assessed at Visit 2 (Baseline)
11. Have a minimum score of 26 on the rater-administered MADRS and a minimum score of 24 on the computer-administered MADRS at Visit 2
12. Have a difference of no greater than 7 points between the rater-administered MADRS and computer-administered MADRS at Visit 2
13. Have a CGI-S score ≥ 4 at Visit 2 |
|
E.4 | Principal exclusion criteria |
1. DSM-5–based diagnosis of any disorder other than MDD that was the primary focus of treatment within 6 months before Visit 1.
2. Lifetime history of meeting DSM-5 criteria for:
a. Schizophrenia spectrum or other psychotic disorder
b. Bipolar or related disorder
c. Major neurocognitive disorder
d. Neurodevelopmental disorder of greater than mild severity or of a severity that impacts the patient’s ability to consent, follow study directions, or otherwise safely participate in the study
e. Dissociative disorder
f. Posttraumatic stress disorder
g. MDD with psychotic features
3. History of meeting DSM-5 criteria for alcohol or substance use disorder (other than nicotine or caffeine) within the 6 months before Visit 1
4. DSM-5–based diagnosis of any personality disorder of sufficient severity to interfere with participation in this study in the opinion of the investigator
5. History of:
a. Inadequate response to electroconvulsive therapy (ECT), a monoamine oxidase inhibitor, ketamine, or adjunctive treatment with an antipsychotic
b. Treatment with clozapine or any depot antipsychotic
c. ECT, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment during the current episode or in the 6 months before Visit 1 (whichever is longer)
d. Tardive dyskinesia, serotonin syndrome, or neuroleptic malignant syndrome
e. Intolerance or hypersensitivity to rapastinel
6. Having received:
a. Anticonvulsant/mood stabilizer, within 1 year prior to Visit 1
b. Antipsychotic in the current episode, with the exception of quetiapine given for insomnia ≤ 50 mg/day provided it can be safely discontinued prior to Visit 2
c. Combination therapy of 2 or more ADTs in the current episode if given for depression at adequate dose and duration
d. ADT augmentation agent in the current episode
7. 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, cannabinoids or episodic use of benzodiazepines may be allowed as described more detailed in the protocol
8. 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 or Visit 2
c. MADRS Item 10 score ≥ 5 at Visit 1 or Visit 2 on the MADRS
9. At imminent risk of injuring self or others or causing significant damage to property, as judged by the investigator
10. Requiring concomitant treatment with any of the prohibited medications, supplements, or herbal products listed in Appendix III
11. Prior participation in any investigational study of rapastinel/GLYX-13
12. Initiation or termination of psychotherapy for depression within the 3 months preceding Visit 1, or plans to initiate, terminate, or change such therapy during the course of the study
13. Ongoing treatment with phototherapy, or termination of phototherapy within 1 month of Visit 1
14. Weight < 40 kg or > 125 kg at screening
15. Females who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study
16. Females of childbearing potential and male partners of females of childbearing potential, not using a reliable means of contraception
17. Any cardiovascular disease that is clinically significant, unstable, or decompensated
18. Heart rate (supine) of ≤ 45 bpm or ≥ 120 bpm, or any heart rate that is clinically symptomatic at Visit 1 or Visit 2 based upon vital signs
19. Any systolic and/or diastolic blood pressure (BP) that is symptomatic or clinically significant in the opinion of the investigator
20. History of congenital QTc prolongation or QTc prolongation (screening ECG with QTcF ≥ 450 msec for men and QTcF ≥ 470 msec for women)
21. Hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change in dosage for at least 1 month before Visit 1
22. History of seizure disorder, stroke, significant head injury, tumor of the central nervous system, or any other condition that predisposes to seizure
23. Known human immunodeficiency virus (HIV) infection
24. Positive hepatitis C antibody on screening, with the exception of patients for whom the reflex HCV RNA test is negative
25. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody immunoglobulin M
26. Screening liver enzyme test (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT]) results > 2 times the upper limit of normal (ULN)
27. Current enrollment in an investigational drug or device study or participation in such a study within 6 months of entry into this study
28. 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 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in MADRS total score at the end of the double-blind treatment period (end of Week 6) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 6 weeks of treatment |
|
E.5.2 | Secondary end point(s) |
Key secondary endpoint:
Change from baseline in MADRS total score at 1 day after first dose of investigational product (IP)
Other:
• Change from baseline in MADRS at 7 days after first dose of treatment
• Change from baseline in CGI-S at 1 and 7 days after first dose of treatment, and end of treatment
• Rate of sustained responders during treatment
• Rate of responders at 1 and 7 days after first dose of treatment, and end of treatment (end of Week 6)
• Rate of sustained remitters during treatment
• Rate of remitters at 1 and 7 days after first dose of treatment, and end of treatment (end of Week 6)
• Time to first response
• Time to first sustained response
• Time to first remission
• Time to first sustained remission
• Change from baseline in Sheehan Disability Scale (SDS) at end of treatment
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary endpoint:
Change from baseline in MADRS total score at 1 day after first dose of
investigational product (IP)
Additional endpoints:
At each visit and the final analysis will be done at the end of the study |
|
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 | Yes |
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 | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Hungary |
Japan |
Poland |
Russian Federation |
Slovakia |
Ukraine |
|
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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
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 |