A Study of Intermittent Doses of CERC-301 in MDD

Study Overview
=================
Brief Summary
-----------------
There is a significant unmet medical need for rapidly acting treatment of subjects with severe major depressive disorder (MDD) who have not adequately responded to antidepressant therapy. Alternative therapies require weeks to achieve full efficacy, may have significant side effects, and still fail in a high percentage of subjects. Rapid reduction of severe depression by pharmacological therapy is important to reduce the need for hospitalization and risk of self-harm and mortality. CERC-301, a highly selective, orally bioavailable, N-methyl-D-aspartate (NMDA) receptor subunit 2B (NR2B), also referred to as Glutamate NMDA receptor subunit epsilon-2 (GluN2B) antagonist, would be a therapeutic breakthrough if it provides rapid onset of antidepressant effects and an effect size similar to that seen with experimental intravenous NMDA modulators.

Detailed Description
-----------------
The study will evaluate the antidepressant effect of one or two administrations of two doses of CERC-301 (12 mg and 20 mg) in subjects with MDD who are currently experiencing a severe depressive episode despite stable ongoing treatment with a selective serotonin- or serotonin-norepinephrine reuptake inhibitor (SSRI or SNRI).

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Study of Intermittent Doses of CERC-301 in the Treatment of Subjects With Severe Depression Despite Antidepressant Treatment

Conditions
-----------------
Major Depressive Disorder

Intervention / Treatment
-----------------
* Drug: CERC-301
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of MDD recurrent without psychotic features according to DSM-IV-TR criteria with diagnosis confirmed using the Structured Clinical Interview for DSM-IV Axis I Disorders Clinical Trials Version (SCID-CT). Lifetime history of ≥2 major depressive episodes, for which at least one required treatment with SSRI or SNRI antidepressants. History during the current major depressive episode of failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to ≤3 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration during the current episode, according to the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. Exclusion Criteria: Duration of current depression episode ≥2 years or diagnosis of Persistent Depressive Disorder (DSM-V) or Dysthymic Disorder (DSM-IV) Use of other NMDA-receptor modulators (e.g., dextromethorphan, ketamine, amantadine, memantine) within 30 days of screening and throughout the study. History of use of an NMDA-receptor modulator for the treatment of MDD. Use of bupropion, tricyclic antidepressants, antipsychotics, stimulants, or lithium within 8 weeks prior to screening Initiation of psychotherapy or a change in intensity of psychotherapy or other non-drug therapies (e.g., hypnosis, acupuncture) within 8 weeks prior to screening. Electroconvulsive therapy, transcranial magnetic stimulation, or vagal nerve stimulation during the current depressive episode. Excessive alcohol use, which is defined by the Centers for Disease Control as >1 drink per day for women and >2 drinks per day for men. Current diagnosis of a Substance Use (including alcohol) Disorder (Abuse or Dependence, as defined by DSM-IV/V), with the exception of nicotine dependence, at screening or within 6 months prior to screening. Active, comorbid disease that might limit the ability of the subject to participate in the study as determined by the Investigator (i.e., poorly controlled diabetes mellitus, congestive heart failure, etc.). Current neurologic or neuropsychiatric disorder which could interfere with the ability to diagnose or assess MDD or which could cause or contribute to depressive symptomatology (e.g., Alzheimer's disease, Parkinson's diseases, chronic pain syndromes, including fibromyalgia, substance use disorder, post-partum depression). Lifetime history of the following disorders: Bipolar I, II, or Not Otherwise Specified (NOS) mood disorders, eating disorders , schizophrenia and other psychotic disorders, sleep disorders , significant cognitive disorders, dissociative disorders, impulse control disorders, and borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorders. Subjects with suicidal behavior within 6 months prior to screening as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening version. Elevated seated blood pressure at screening and prior to randomization Lifetime history of stroke or congestive heart failure, atrial fibrillation or coronary artery disease. Clinically significant current liver disease or liver enzyme (GGT, ALT, AST, total bilirubin) elevations at screening above 2 × the ULN. Clinically significant renal impairment defined as estimated creatinine clearance [CrCl] <50 mL/min at screening measured using Cockcroft-Gault formula. Fasting serum glucose >140 mg/dL. Subjects who, in the opinion of the Investigator, are not appropriate for a 21-day placebo-controlled study due to risk of significant threat to self or others during screening or study conduct. Previous participation in an investigational study using CERC-301. Participation in an investigational drug or device study within the 6 months prior to screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CERC-301 12mg<br>The study includes two dose administrations 7 days apart (Day 0 and Day 7) followed by 14 days of observation for a total of 21 days. | Drug: CERC-301<br>* CERC-301, a highly selective, orally bioavailable, NMDA receptor subunit 2B (NR2B), also referred to as Glutamate NMDA receptor subunit epsilon-2 (GluN2B) antagonist<br>|
| Experimental: CERC-301 20mg<br>The study includes two dose administrations 7 days apart (Day 0 and Day 7) followed by 14 days of observation for a total of 21 days. | Drug: CERC-301<br>* CERC-301, a highly selective, orally bioavailable, NMDA receptor subunit 2B (NR2B), also referred to as Glutamate NMDA receptor subunit epsilon-2 (GluN2B) antagonist<br>|
| Placebo Comparator: Placebo<br>The study includes two dose administrations 7 days apart (Day 0 and Day 7) followed by 14 days of observation for a total of 21 days. | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bech-6 from baseline | To evaluate the antidepressant effect of CERC-301 (12 or 20 mg) compared to placebo averaged between 2 and 4 days post-treatment with study drug assessed by the 6-item unidimensional subset (Bech-6) of the 17-item Hamilton Depression Rating Scale (HDRS-17) | average of 2 and 4 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Santen-7 | To evaluate the antidepressant effect of a single dose of CERC-301 (12 or 20 mg) compared to placebo averaged between 2 and 4 days post-treatment with study drug assessed by the 7-item unidimensional subset of the HDRS-17, the Santen-7 | averaged between 2 and 4 days post treatment | 
| Change from baseline in HDRS-17 | To evaluate the antidepressant effect of a single dose of CERC-301 (12 or 20 mg) compared to placebo averaged between 2 and 4 days post-treatment with study drug assessed by the HDRS-17 | averaged between 2 and 4 days post treatment | 
| Change from baseline in Bech-6 | To evaluate the antidepressant effect of CERC-301 at 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment assessed by the Bech-6. | 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment | 
| Change from baseline in Santen-7 | To evaluate the antidepressant effect of CERC-301 at 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment assessed by the Santen-7. | 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment | 
| Change from baseline in HDRS-17 | To evaluate the antidepressant effect of CERC-301 at 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment assessed by the HDRS-17. | 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment | 
| Change from baseline in CUDOS-A | To evaluate the antidepressant effect of CERC-301 at 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment assessed by the Clinically Useful Depression Outcome Scale-Anxiety (CUDOS-A). | 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment | 
| Change from baseline in SHAPS-SR | To evaluate the antidepressant effect of CERC-301 at 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment assessed by the Snaith-Hamilton Pleasure Scale Self Report (SHAPS-SR) | 2, 4, 7 days after each dose, and 14 days after last dose of study drug treatment | 
| Change from baseline in QIDS-SR | To evaluate the antidepressant effect of CERC-301 at 7 days after each dose and 14 days after last dose of study drug treatment assessed by the Quick Inventory of Depressive Symptomatology Self Report (QIDS-SR) | 7 days after each dose and 14 days after last dose of study drug treatment | 
| Change from baseline in CGI-I | To evaluate the antidepressant effect of CERC-301 at 7 days after each dose and 14 days after last dose of study drug treatment assessed by the Clinical Global Impression-Improvement (CGI-I) | 7 days after each dose and 14 days after last dose of study drug treatment | 
| Change from baseline in CGI-S | To evaluate the antidepressant effect of CERC-301 at 7 days after each dose and 14 days after last dose of study drug treatment assessed by the Clinical Global Impression -Severity (CGI-S) | 7 days after each dose and 14 days after last dose of study drug treatment |