Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)

Study Overview
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Brief Summary
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This study is looking at the efficacy, durability, safety, and tolerability of multiple single doses of Ketamine vs. active placebo for treating patients with treatment resistant depression who are taking an antidepressant that is not working for them.

Detailed Description
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The primary objective is to investigate whether all doses (0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, and 1.0 mg/kg) of ketamine are superior to active placebo (midazolam 0.045 mg/kg) therapy in the acute treatment of patients with treatment resistant depression within 72 hours (Day 3), when added to ongoing and stable antidepressant therapy.

Official Title
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Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Drug: Ketamine
* Drug: Ketamine
* Drug: Ketamine
* Drug: Ketamine
* Drug: Placebo Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18-70 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 TRD 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 (Day -7/-28 and Day 0), 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 18-35 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 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 >7 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 6 months prior to screening Current Axis I disorder that is the principal focus of treatment and MDD the secondary focus of 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 Has failed to respond to electroconvulsive therapy (ECT) during the current depressive episode Has received vagus nerve stimulation (VNS) at any time prior to screening Has 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 Current episode of: Hypertension, Stage 1 as defined by a systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90 mmHg at screening on two of three measurements (standing and supine) at least 15 minutes apart. Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥99 mmHg at the Baseline Visit (Visit 1) within 1.5 hours prior to randomization on two of three measurements (standing and supine) at least 15 minutes apart. Recent myocardial infarction (within one year) or a history of myocardial infarction. Syncopal event within the past year. Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2 Angina pectoris. Heart rate <50 or >105 beats per minute at screening or randomization (Baseline Visit). QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline Visit). Current history of hypertension, or on antihypertensives for the purpose of lowering blood pressure, who have either had an increase in antihypertensive dose or increase in the number of antihypertensive drugs used to treat hypertension over the last 2 months. Chronic lung disease excluding asthma. 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 any of the following lab abnormalities: Thyroid stimulating hormone outside of the normal limits and clinically significant as determined by the investigator. Free thyroxine (T4) levels may be measured if TSH level is high. Subject will be excluded if T4 level is clinically significant. Patients with diabetes mellitus fulfilling any of the following criteria: i. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% at screening ii. Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus related illness in the past 12 weeks iii. Not under physician care for diabetes mellitus iv. 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. c. 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 for less than 2 months prior to screening. (Subjects on a stable dosage of thyroid replacement medication for at least 2 months or more prior to screening are eligible for enrollment.) 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 study results interpretation History of positive screening urine test for drugs of abuse at screening Patients with exclusionary laboratory values, or requiring treatment with exclusionary concomitant medications Patients on exclusionary concomitant psychotropic medications, the half-life of which would not allow sufficient time for patients to have been free of the medication post-taper for five half-lives within the maximum screening period (28 days). Patient who have participated in studies of ketamine or AZD6765 or other NMDA receptor antagonists for depression and received active treatment. Patients with narrow angle glaucoma Patients with a lifetime history of PCP/Ketamine drug use Liver Function Tests higher than 2.5 times upper limit of normal

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ketamine 0.1mg<br>Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion | Drug: Ketamine<br>* Dose of Ketamine will be 0.1 mg/kg - one single infusion<br>|
| Active Comparator: Ketamine 0.2mg<br>Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion | Drug: Ketamine<br>* Dose of Ketamine will be 0.2 mg/kg - one single infusion<br>|
| Active Comparator: Ketamine 0.5mg<br>Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion | Drug: Ketamine<br>* Dose of Ketamine will be 0.5 mg/kg - one single infusion<br>|
| Active Comparator: Ketamine 1.0mg<br>Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion | Drug: Ketamine<br>* Dose of Ketamine will be 1.0 mg/kg - one single infusion<br>|
| Placebo Comparator: Midazolam (Active Placebo)<br>Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion | Drug: Placebo Midazolam<br>* Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Rating Scale for Depression - 6 Items | The HAMD6 is a 6-item clinician-rated scale, where clinicians rate the presence of depression symptoms (i.e., depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, somatic symptoms) on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. One item (i.e., somatic symptoms) is rated on only a 3-point scale, ranging from 0-2. The possible scale range is 0-22, where higher values represent more severe depression. 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. In this study, the HAMD6 was used to assess symptoms occurring in the past 24 hours. | A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Scale (MADRS) | The MADRS is a 10-item clinician-rated scale measuring depression severity. Symptoms are rated on a 7-point scale, where 0 = not present, and 1-6 represent increasing severity. Values 2, 4, and 6 have specific anchoring text (e.g., 2=Difficulties in starting activities. 4=Difficulties in starting simple routine activities which are carried out with effort, 6=Complete lassitude. Unable to do anything without help.) Values 1, 3, and 5 do not have specific text. The possible scale range is 0-60, where higher values represent higher severity. In this study, the MADRS was used to rate symptoms occurring in the past 3 days. | A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0 and 3. | 
| Clinical Global Impressions-Severity (CGI-S) | The CGI-S is a clinician rated single-item scale: How depressed is the patient at this time?, rated on a 7-point response scale: 1 = Normal, not at all depressed, 2 = Borderline depressed, 3 = Mildly depressed, 4 = Moderately depressed. 5 = Markedly depressed, 6 = severely depressed, 7 = Among the most severely depressed patients. When rating patients, clinicians were asked to consider the past 24 hours. | A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3 | 
| Clinical Global Impressions-Improvement (CGI-I) Scale | The CGI-I is a clinician rated single-item scale: Compared to the patient's condition at admission, how much has the patient changed?, rated on a 7-point response scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. In this case, admission referred to the CGI-S screening assessments performed between Day -28 an -7, one conducted during the screening visit, and a second rating conducted by a remote, independent rater. | A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3 | 
| Symptoms of Depression Questionnaire (SDQ) | The SDQ is a 44-item self-report scale, which aims to measure depression more comprehensively by including the assessment of symptoms in the anxiety-depression spectrum, including symptoms of irritability, anger attacks, and anxiety. Items are rated on an 6-point Likert scale, where participants are asked to rate if a specific symptom (e.g. How has your mood been over the past 24 hours?) is normal for him or her (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The total scale score is calculated by averaging across the items, resulting in a possible range from 1 to 6. Higher scores indicate greater depression severity. When rating, patients were asked to consider their symptoms during the past 24 hours. | A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3 | 
| Clinical Positive Affect Scale (CPAS) | The CPAS is a 16-item self-report scale to assess the level to which participants experience persistent distress due to feeling that they have not returned to their normal or premorbid state. Items (e.g., I look forward to things) are rated on a 5-point scale (0=not at all, 1=very much less than normal, 2=much less than normal, 3=slightly less than normal, 4=same as best or normal self). The possible scale range is 0 to 64, with higher scores indicating greater recovery from depression. Patients were asked to rate their experience of the past 24 hours. | A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3 | 
| Snaith-Hamilton Pleasure-Scale (SHAPS) | The SHAPS is a 14-item self-report scale to measure hedonic tone. Items (e.g., I would enjoy reading a book, magazine, or newspaper.) are rated on a 4-point scale (1=strongly disagree, 2=disagree, 3=agree, 4=strongly agree). Either of the 'disagree' responses scores 1 point, and either of the 'agree' responses scores 0 points, for a total scale range of 0-14. Higher scores indicate greater inability to experience pleasure. Patients were asked to rate their experience of the past 24 hours. | A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3 | 
| Clinician-Administered Dissociative States Scale (CADSS) Scores During Infusion | The CADSS is a 23-item self-report scale for the assessment of dissociative states. It is a reliable, valid self-report instrument. The severity of each dissociative symptom ranges from 0 (not present) to 4 (extreme). The total score is calculated by summing across items, with a total possible range of 0-92. The CADSS was administered right before infusion, and 40, 80 minute and 120 minutes after the start of infusion. The timeframe is at this moment. | Day 0/baseline at 0, 40, 80, and 120 minutes | 
| Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS) | The Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. 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 can also be used during treatment to monitor for clinical worsening or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale. | Screening Visit and Days 0, 1, 3, 5, 7, 14 and 30 combined | 
| Number of Participants With Abnormal and Clinically Significant CBC and Chemistry Labs by Treatment | CBC Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, Glucose, Uric Acid) Testing was performed by study site laboratories and used institutional normal lab value ranges. | Day 3 and Early Termination Visit (approximately 3 weeks following intervention) | 

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