Proof-of-Concept Trial of CERC-501 Augmentation of Antidepressant Therapy in Treatment-Resistant Depression

Study Overview
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Brief Summary
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This study is looking at the efficacy, rapidity, safety, and tolerability of two doses of oral CERC-501 for treating patients with treatment resistant depression who are taking an antidepressant that is not working for them.

Detailed Description
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This study will involve 10 visits to the clinical site over approximately 1.5 months. There will be a screening visit (7-28 days may pass between the screening visit and the first treatment visit), a baseline/treatment visit (first day of study drug treatment), followed by 5 consecutive days of treatment visits. Follow-up visits will occur 6, 13, and 20 days after first receiving study drug.

Official Title
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Double-Blind, Placebo-Controlled, Proof-of-Concept (POC) Trial of CERC-501, a Kappa-Selective Opioid Receptor Antagonist, Augmentation of Antidepressant Therapy in Treatment-Resistant Depression (TRD)

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Drug: CERC-501
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18-65 years old. Able to read, understand, and provide written, dated informed consent prior to screening. Diagnosed with Major Depressive Disorder (MDD), single or recurrent, and currently experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior to screening. Has a history of treatment resistance during the current MDE. Meet the threshold on the total MADRS score of greater than or equal to 20 at both screening and baseline visits, as confirmed by the remote centralized MGH CTNI rater between the screen visit and the baseline visit. In good general health For female participants, status of non-childbearing potential or use of an acceptable form of birth control Body mass index between 18-40 kg/m2 Concurrent psychotherapy will be allowed if the type and frequency of the therapy has been stable for at least three months prior to screening and is expected to remain stable during participation in the study Concurrent benzodiazepine and hypnotic therapy will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study. Exclusion Criteria: Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study Female that is pregnant or breastfeeding Female with a positive pregnancy test at screening or baseline History during the current MDE of failure to achieve a satisfactory response to >3 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration during the current episode Total MADRS score of <20 at the screen or baseline visits, or as assessed by the remote, independent MGH CTNI rater and reported to the site Current diagnosis of a Substance Use Disorder (Abuse or Dependence) with the exception of nicotine dependence, at screening or within six months prior to screening Current diagnosis of Axis I disorders other than Dysthymic Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder or Specific Phobia (unless one of these is comorbid and clinically unstable, and/or the focus of the participant's treatment for the past 6 months or more) History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes History of eating disorders within five years of screening Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant at any time within 6 months prior to screening Subject is considered at significant risk for suicidal behavior during the course of their participation in the study Subject has had electroconvulsive therapy in the current episode of depression Has received vagus nerve stimulation (VNS) at any time prior to screening Dementia, delirium, amnestic, or any other cognitive disorder Has a clinically significant abnormality on the screening physical examination Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation Known history or current episode of: Uncontrolled hypertension, Recent myocardial infarction (within one year) or a history of more than one myocardial infarction, Syncopal event within the past year, Congestive heart failure, Angina pectoris, Systolic BP <85 or >160 mmHg or diastolic BP >95 mmHg or heart rate <50 or >105 beats per minute at screening or randomization, or QTcF greater than or equal to 450 msec at screening or randomization. Chronic lung disease Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder, epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system, or a history of significant head trauma within the past 2 years Presents with a history of Thyroid stimulating hormone outside of the normal limits and clinically significant as determined by the investigator Patients with diabetes mellitus fulfilling any of the following criteria: Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% at screening Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus related illness in the past 12 weeks Not under physician care for diabetes mellitus Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to screening. For thiazolidinediones (glitazones) this period should not be less than 8 weeks. Any other clinically significant abnormal laboratory result (as determined after evaluation by study investigator and MGH CTNI medical monitor) at the time of the screening exam. History of hypothyroidism and has been on a stable dosage of thyroid replacement medication, or was surgically treated less than six months prior to screening History of hyperthyroidism which was treated (medically or surgically) less than six months prior to screening Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with the interpretation of study results History of positive screening urine test for drugs of abuse Patients with exclusionary laboratory values, or requiring treatment with exclusionary concomitant medications, including tricyclic antidepressants and monoamine oxidase inhibitors, or on two or more concomitant antidepressant therapies Patients currently taking a proton pump inhibitor (PPI)/histamine 2 (H2) blocker or with a history of chronic NSAID use Patients with a positive test for Helicobacter pylori (urea breath test) Patients with any of the following GI-related findings: Clinically evident GI complaints or GI disease at Screening or Visit 1 Past history of gastric disease (including but not limited to peptic ulcer disease, gastritis (including atrophic gastritis), upper GI bleeding, any other GI precancerous conditions), and of any other clinically relevant GI disease.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: sequential parallel comparison design (SPCD) with two phases
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Dose Drug-Drug Arm<br>Patients in this arm will receive CERC-501 10.0 mg/day for 3 days (in Phase 1) and for 3 subsequent days (in Phase 2) | Drug: CERC-501<br>* Low dose of CERC-501 will be 10 mg/day during the first phase (3 days) and during the second phase (3 days). High Dose of CERC-501 will be 20 mg/day during the first phase (3 days) and during the second phase (3 days). For patients randomly assigned to the placebo/low-dose drug sequence, the patient will receive placebo for 3 days and then 10 mg/day CERC-501 for the following 3 days. For patients randomly assigned to the placebo/high-dose drug sequence, the patient will receive placebo for 3 days and then 20 mg/day CERC-501 for the following 3 days.<br>|
| Active Comparator: High Dose Drug-Drug Arm<br>Patients in this arm will receive CERC-501 20.0 mg/day for 3 days (in Phase 1) and for 3 subsequent days (in Phase 2) | Drug: CERC-501<br>* Low dose of CERC-501 will be 10 mg/day during the first phase (3 days) and during the second phase (3 days). High Dose of CERC-501 will be 20 mg/day during the first phase (3 days) and during the second phase (3 days). For patients randomly assigned to the placebo/low-dose drug sequence, the patient will receive placebo for 3 days and then 10 mg/day CERC-501 for the following 3 days. For patients randomly assigned to the placebo/high-dose drug sequence, the patient will receive placebo for 3 days and then 20 mg/day CERC-501 for the following 3 days.<br>|
| Other: Placebo/Low-Dose Drug Arm<br>Patients in this arm will receive placebo for 3 days (in Phase 1) and CERC-501 10.0 mg/day for 3 days (in Phase 2) | Drug: CERC-501<br>* Low dose of CERC-501 will be 10 mg/day during the first phase (3 days) and during the second phase (3 days). High Dose of CERC-501 will be 20 mg/day during the first phase (3 days) and during the second phase (3 days). For patients randomly assigned to the placebo/low-dose drug sequence, the patient will receive placebo for 3 days and then 10 mg/day CERC-501 for the following 3 days. For patients randomly assigned to the placebo/high-dose drug sequence, the patient will receive placebo for 3 days and then 20 mg/day CERC-501 for the following 3 days.<br>Drug: Placebo<br>* For patients randomly assigned to the placebo/ placebo sequence, study medication will be placebo during the first phase (3 days) and during the second phase (3 days). For patients randomly assigned to the placebo/low-dose drug sequence, the patient will receive placebo for 3 days and then 10 mg/day CERC-501 for the following 3 days. For patients randomly assigned to the placebo/high-dose drug sequence, the patient will receive placebo for 3 days and then 20 mg/day CERC-501 for the following 3 days.<br>|
| Other: Placebo/High-Dose Drug Arm<br>Patients in this arm will receive placebo for 3 days (in Phase 1) and CERC-501 20.0 mg/day for 3 days (in Phase 2) | Drug: CERC-501<br>* Low dose of CERC-501 will be 10 mg/day during the first phase (3 days) and during the second phase (3 days). High Dose of CERC-501 will be 20 mg/day during the first phase (3 days) and during the second phase (3 days). For patients randomly assigned to the placebo/low-dose drug sequence, the patient will receive placebo for 3 days and then 10 mg/day CERC-501 for the following 3 days. For patients randomly assigned to the placebo/high-dose drug sequence, the patient will receive placebo for 3 days and then 20 mg/day CERC-501 for the following 3 days.<br>Drug: Placebo<br>* For patients randomly assigned to the placebo/ placebo sequence, study medication will be placebo during the first phase (3 days) and during the second phase (3 days). For patients randomly assigned to the placebo/low-dose drug sequence, the patient will receive placebo for 3 days and then 10 mg/day CERC-501 for the following 3 days. For patients randomly assigned to the placebo/high-dose drug sequence, the patient will receive placebo for 3 days and then 20 mg/day CERC-501 for the following 3 days.<br>|
| Placebo Comparator: Placebo/Placebo Arm<br>Patients in this arm will receive placebo for 3 days (in Phase 1) and for 3 subsequent days (in Phase 2) | Drug: Placebo<br>* For patients randomly assigned to the placebo/ placebo sequence, study medication will be placebo during the first phase (3 days) and during the second phase (3 days). For patients randomly assigned to the placebo/low-dose drug sequence, the patient will receive placebo for 3 days and then 10 mg/day CERC-501 for the following 3 days. For patients randomly assigned to the placebo/high-dose drug sequence, the patient will receive placebo for 3 days and then 20 mg/day CERC-501 for the following 3 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hamilton Rating Scale for Depression - 6 Items (HAM-D-6) | This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. Scale items are assessed based on symptoms within the past 24 hours. A higher score indicates more depression symptoms. Total scores range from 0 (normal) to 22 (severe). To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. | Baseline and 72 hours after initiating treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Response on Hamilton Rating Scale for Depression - 6 Items (HAM-D-6) | Compare response rates at 72 hours for of patients treated with either dose (10 mg/day or 20 mg/day) of CERC-501 to those assigned to placebo therapy, using the Sequential Parallel Comparison Design (SPCD), with response defined as a 50% or greater reduction from baseline to Day 3 on the HAM-D-6 total score). To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. The HAM-D-6 instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. Scale items are assessed based on symptoms within the past 24 hours. A higher score indicates more depression symptoms. | 72 hours after treatment initiation | 
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) | The 10-item Montgomery-Asberg Depression Rating Scale (MADRS), which measures depression severity (in past 3 days), was completed by clinicians using an MGH structured interview. Each item is measured on a scale from 0 to 6, and the items are summed to find the total score. The total minimum score is 0 units on a scale and the total maximum score is 60 units on a scale, where higher scores indicate more severe depression. To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. | Baseline and 72 hours and 20 days after initiating treatment | 
| Change in Clinical Global Impression -Severity (CGI-S) | The CGI-S scale was administered by clinicians to measure depressive severity (CGI-S). Each item is rated on a seven-point scale (1=normal to 7=among the most severe), so a higher total score indicates greater depressive severity. Severity is assessed based on the last 24 hours. To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. | Baseline and 72 hours and 20 days after initiating treatment | 
| Clinical Global Impression-Improvement (CGI-I) | The CGI-I scale was administered by clinicians to measure improvement in depressive severity (CGI-I). Each item is rated on a seven-point scale (1=very much improved to 7=very much worse), so a higher total score indicates less improvement in depressive severity. Improvement is assessed based on the last 24 hours. | 72 hours and 20 days after initiating treatment | 
| Change in Symptoms of Depression Questionnaire (SDQ) | This validated self-rating instrument has 44 items on a scale of 1-6, measuring multiple depressive symptom domains. Each item is rated based on a subject's perception of what is normal for the individual (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). This scale is rated based on the past 24 hours. A total score is calculated by summing the 44 item scores, for a range of 0-264. To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. | Baseline and 72 hours and 20 days after initiating treatment | 
| Change in Perceived Stress Scale (PSS) | This is a 10-item, validated, self-rated measure of perceived stress, that is of the degree to which the subjects perceives things to be stressful and overwhelming. Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived stress. Scores ranging from 0-13 would be considered low stress. Scores ranging from 14-26 would be considered moderate stress. Scores ranging from 27-40 would be considered high perceived stress. This scale is rated based on the past 24 hours. To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. | Baseline and 72 hours and 20 days after treatment initiation | 
| Change in Positive Affect Scale (PAS) | This is a validated, self-rated measure of positive affect uses 5-point scales (1 = very slightly/not at all to 5 = extremely). Higher scores represent higher levels of positive affect. The scale is rated based on the past 24 hours. The total score is the sum of 10 items, for a range of 10-50. To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. | Baseline and 72 hours and 20 days after initiating treatment | 
| Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Satisfaction With Participation in Social Roles and Discretionary Activities | These are two well-validated 7-item self-rating scales that measure social health. A higher score represents higher satisfaction on each scale. The scales are rated based on the past 24 hours. Each item is rated 1-5 (1=Not at all, 2=A little bit, 3=Somewhat, 4=Quite a bit, 5=Very much). Each 7-item subscale score is the sum of each of the 7 items and ranges from 7-35. To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. | Baseline and 72 hours and 20 days after initiating treatment | 
| Change in the Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior. It is a clinical interview providing a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS will be performed to assess suicidal ideation and behavior. It contains a 5-item rating scale for suicidal ideation and a 7-item rating scale for suicidal behavior. Higher total scores indicate higher severity. Each item is coded 1=yes, 0=no, so a total score of 0 on each scale means that a no response was entered for each of the 5 suicidal ideation and for each of the 7 suicidal behavior questions, i.e., 0=lowest severity score. Total suicidal ideation score ranges from 0 (least severe) to 5 (most severe). Total suicidal behavior score ranges from 0 (least severe) to 7 (most severe). | Baseline and 72 hours after initiating treatment | 
| Number of Participants With Clinically Significant Abnormal ECG | Number of Participants with clinically significant abnormal electrocardiogram (ECG) | 72 hours after treatment initiation | 
| Number of Participants With Clinically Significant Abnormal Labs | Total number of participants with clinically significant abnormal labs | 72 hours after treatment initiation | 
| Change in Hamilton Rating Scale for Depression - 6 Items (HAM-D-6), Day 20 | This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. Scale items are assessed based on symptoms within the past 24 hours. A higher score indicates more depression symptoms. Total scores range from 0 (normal) to 22 (severe). To better estimate the baseline, we did not use simply the cross-sectional assessment at baseline, but we estimated the average during the screening period as the true baseline. | Baseline and 20 days after initiating treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Treatment Resistant Depression, Antidepressant, Major Depression, MDD