A Study of Ketamine in Patients With Treatment-resistant Depression

• ClinicalTrials.gov Identifier: NCT01627782
• Recruitment Status: Completed
• First Posted: June 26, 2012
• Results First Posted: August 5, 2016
• Last Update Posted: June 2, 2020
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: June 22, 2012
• First Posted Date: June 26, 2012
• Results First Submitted Date: May 10, 2016
• Results First Posted Date: August 5, 2016
• Last Update Posted Date: June 2, 2020
• Actual Study Start Date: August 6, 2012
• Actual Primary Completion Date: September 12, 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 24, 2016)

Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 [ Time Frame: Baseline (Day 1) and Day 15 ]

The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total score of 60. Higher scores represent a more severe condition.

Original Primary Outcome Measures (submitted: June 22, 2012)

The change from Day 1 (baseline) to Day 15 in depressive symptoms using the Montgomery Asberg Depression Rating Scale (MADRS) total score [ Time Frame: Day 1, Day 15 ]

The MADRS is a scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total score of 60. Higher scores represent a more severe condition.

Current Secondary Outcome Measures (submitted: June 24, 2016)

• Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 [ Time Frame: Baseline (Day 1) and Day 29 ]
  The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total score of 60. Higher scores represent a more severe condition.
• Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [ Time Frame: Day 15 and Day 29 ]
  Participants with a reduction in the MADRS total score of greater than or equal to (>=) 50 percent from baseline were defined as responders. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total score of 60. Higher scores represent a more severe condition.
• Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [ Time Frame: Day 15 and Day 29 ]
  Participants who had a MADRS total score of less than or equal to (<=) 10 were considered remitters. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total score of 60. Higher scores represent a more severe condition.
• Number of Sustained Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [ Time Frame: Day 15 ]
  Sustained response on Day 15 was defined as achieving an onset of antidepressant response within the first week that is maintained to the end of study Day 15. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total score of 60. Higher scores represent a more severe condition.
• Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) [ Time Frame: Baseline (Day 1) and Endpoint (Day 29) ]
  The CGI-S was used to rate the severity of the participants illness at the time of assessment, relative to the clinician's past experience with participants who had the same diagnosis and improvement with treatment. Considering total clinical experience, a participant was assessed on severity of mental illness at the time of rating according to: 0= not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill participants.
• Clinical Global Impression of Improvement (CGI-I) Score at Endpoint of Double Blind Phase [ Time Frame: Endpoint (Day 29) ]
  The CGI-I is a 7-point scale that was used to assess how much the participants illness was improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 0= not assessed; 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.
• Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) [ Time Frame: Baseline (Day 1) and Endpoint (Day 29) ]
  The PGI-S is an 11-point (0 to 10) scale that required the participant to rate the severity of their illness at the time of assessment, relative to the participants past experience. Considering their total experience, the participant was to assess the severity of their depression illness at the time of rating as none, mild, moderate or severe. The scale is rated as, 0=very well and 10=very poor.
• Patient Global Impression-Change (PGI-C) Score at Endpoint of Double Blind Phase [ Time Frame: Endpoint (Day 29) ]
  The PGI-C is a 7-point scale that required the subject to assess how much their illness had improved or worsened relative to a baseline state at the beginning of the intervention. The response options were: very much improved; much improved; improved (just enough to make a difference); no change; worse (just enough to make a difference); much worse; or very much worse. The scale is rated as, 1=very much improved and 7=very much worse.
• Maximum Observed Plasma Concentration (Cmax) of Ketamine [ Time Frame: Pre-infusion, 20, 40 (End of the Infusion), 45, 50, 60, 90, 120, 180, 240 and 360 minutes post-infusion on Day 1 and Day 15 ]
  The Cmax is the maximum observed plasma concentration of drug.
• Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ketamine [ Time Frame: Pre-infusion, 20, 40 (End of the Infusion), 45, 50, 60, 90, 120, 180, 240 and 360 minutes post-infusion on Day 1 and Day 15 ]
  The Tmax is defined as actual sampling time to reach maximum observed drug concentration.
• Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC[0-last]) [ Time Frame: Pre-infusion, 20, 40 (End of the Infusion), 45, 50, 60, 90, 120, 180, 240 and 360 minutes post-infusion on Day 1 and Day 15 ]
  The AUC(0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time.
• Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) [ Time Frame: Pre-infusion, 20, 40 (End of the Infusion), 45, 50, 60, 90, 120, 180, 240 and 360 minutes post-infusion on Day 1 and Day 15 ]
  The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC (last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
• Total Systemic Clearance (CL) of Ketamine [ Time Frame: Pre-infusion, 20, 40 (End of the Infusion), 45, 50, 60, 90, 120, 180, 240 and 360 minutes post-infusion on Day 1 and Day 15 ]
  The CL is a quantitative measure of the rate at which a drug substance is removed from the body.
• Volume of Distribution at Steady-State (Vss) of Ketamine [ Time Frame: Pre-infusion, 20, 40 (End of the Infusion), 45, 50, 60, 90, 120, 180, 240 and 360 minutes post-infusion on Day 1 and Day 15 ]
  The Vss is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of ketamine at steady state.
• Elimination Half-Life (t1/2) [ Time Frame: Pre-infusion, 20, 40 (End of the Infusion), 45, 50, 60, 90, 120, 180, 240 and 360 minutes post-infusion on Day 1 and Day 15 ]
  The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).

Original Secondary Outcome Measures (submitted: June 22, 2012)

• Number of patients with sustained response [ Time Frame: 15 days ]
  Sustained response is defined as achieving an onset of antidepressant response within the first week that is maintained to study Day 15.
• The change from Day 1 (baseline) to Day 29 in major depressive disorder (MMD) symptoms using the Montgomery Asberg Depression Rating Scale (MADRS) total score [ Time Frame: Day 1, Day 29 ]
  The MADRS is a scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total score of 60. Higher scores represent a more severe condition.
• The change from Day 1 (baseline) to Day 29 in severity of illness using the Clinical Global Impression - Severity (CGI-S) [ Time Frame: Day 1, Day 29 ]
  The CGI-S rating scale is a 7 point global assessment that measures the clinician's impression of the severity of illness exhibited by a patient. A rating of 1 is equivalent to "Normal, not at all ill" and a rating of 7 is equivalent to "Among the most extremely ill patients". Higher scores indicate worsening.
• The change from Day 29 through Day 47 in severity of illness using the Clinical Global Impression - Severity (CGI-S) [ Time Frame: Day 29, Day 47 ]
  The CGI-S rating scale is a 7 point global assessment that measures the clinician's impression of the severity of illness exhibited by a patient. A rating of 1 is equivalent to "Normal, not at all ill" and a rating of 7 is equivalent to "Among the most extremely ill patients". Higher scores indicate worsening.
• Assessment of major depressive disorder (MDD) as measured by the Clinical Global Impression - Improvement (CGI-I) [ Time Frame: 29 days ]
  The CGI-I is a 7-point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.
• The change from Day 1 (baseline) to Day 29 in severity of illness using the Patient Global Impression - Severity (PGI-S) [ Time Frame: Day 1, Day 29 ]
  The PGI-S is an 11-point (0= very well; 10= very poor) scale that requires the patients to rate the severity of their illness at the time of assessment, relative to the patient's past experience.
• The change from Day 29 through Day 47 in severity of illness using the Patient Global Impression - Severity (PGI-S) [ Time Frame: Day 29, Day 47 ]
  The PGI-S is an 11-point (0= very well; 10= very poor) scale that requires the patients to rate the severity of their illness at the time of assessment, relative to the patient's past experience.
• The change in patient perspective of global change in major depressive disorder (MDD) since start of study treatment, as measured by the Patient Global Impression of Change (PGI-C) [ Time Frame: 29 days ]
  The PGI-C is a 7-point scale that requires the patients to assess how much their illness has improved or worsened relative to a baseline state at the beginning of the intervention. The response options are: very much improved; much improved; improved (just enough to make a difference); no change; worse (just enough to make a difference); much worse; or very much worse.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Ketamine in Patients With Treatment-resistant Depression
• Official Title: A Double-blind, Randomized, Placebo-controlled, Parallel Group, Dose Frequency Study of Ketamine in Subjects With Treatment-resistant Depression
• Brief Summary: The purpose of this study is to explore the optimal dose frequency of ketamine in patients with treatment-resistant depression (TRD).
• Detailed Description: This is a double-blind (patients and study personnel do not know the identity of the administered treatments), randomized (the drug is assigned by chance), placebo-controlled (placebo is a substance that appears identical to the treatment and has no active ingredients), parallel arm study (each group of patients will be treated at the same time). The study will consist of a screening phase of up to 4 weeks, a 4-week double-blind treatment phase (Day 1 to Day 29), and a 3-week post treatment (follow up) phase. In the double-blind phase, patients will receive over 4 weeks either intravenous (IV) infusions of placebo (2 or 3 times weekly) or IV infusions of ketamine (2 or 3 times weekly). The total study duration for each patient will be a maximum of 13 weeks.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Major Depressive Disorder

Intervention

• Drug: Placebo
  Form= intravenous infusion, route= intravenous (IV) use. IV infusions of placebo 2 times weekly or IV infusions of placebo 3 times weekly.
• Drug: Ketamine
  Type= exact number, unit= mg/kg, number= 0.5, form= intravenous infusion, route= intravenous (IV) use. IV infusions of ketamine 0.50 mg/kg, 2 times weekly or IV infusions of ketamine 0.50 mg/kg, 3 times weekly.

Study Arms

• Placebo Comparator: Placebo 3 times/week
  Intervention: Drug: Placebo
• Experimental: Ketamine 3 times/week
  Intervention: Drug: Ketamine
• Experimental: Ketamine 2 times/week
  Intervention: Drug: Ketamine
• Placebo Comparator: Placebo 2 times/week
  Intervention: Drug: Placebo

Publications *

• Lewis S, Romano C, De Bruecker G, Murrough JW, Shelton R, Singh JB, Jamieson C. Analysis of Clinical Trial Exit Interview Data in Patients with Treatment-Resistant Depression. Patient. 2019 Oct;12(5):527-537. doi: 10.1007/s40271-019-00369-8.
• Johnson KM, Devine JM, Ho KF, Howard KA, Saretsky TL, Jamieson CA. Evidence to Support Montgomery-Asberg Depression Rating Scale Administration Every 24 Hours to Assess Rapid Onset of Treatment Response. J Clin Psychiatry. 2016 Dec;77(12):1681-1686. doi: 10.4088/JCP.15m10253.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 29, 2013): 68
• Original Estimated Enrollment (submitted: June 22, 2012): 56
• Actual Study Completion Date: September 12, 2013
• Actual Primary Completion Date: September 12, 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Be medically stable on the basis of clinical laboratory tests performed at screening
• Meet diagnostic criteria for recurrent major depressive disorder (MDD), without psychotic features
• Have a history of inadequate response, ie treatment was not successful, to at least 1 antidepressant
• Have an Inventory of Depressive Symptoms-Clinician rated, 30 item (IDS-C30) total score >= 40 at screening and predose at Day 1
• Inpatient or agreed to be admitted to the clinic on each dosing day

Exclusion Criteria:

• Has uncontrolled hypertension
• Has a history of, or current signs and symptoms of diseases, infections or conditions that in the opinion of the investigator, would make participation not be in the best interest (eg, compromise the well-being) of the patient or that could prevent, limit, or confound the protocol-specified assessments
• Has known allergies, hypersensitivity, or intolerance to ketamine or its excipients
• Is unable to read and understand the consent forms and patient reported outcomes, complete study-related procedures, and/or communicate with the study staff

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 64 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01627782
• Other Study ID Numbers: CR100886; KETIVTRD2002 ( Other Identifier: Janssen Research & Development, LLC )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: SENIOR DIRECTOR, CLINICAL RESEARCH, Janssen R&D US
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: May 2020