Major Depressive Disorder
Conditions
Keywords
Major depressive disorder, Treatment-resistant depression, Ketamine
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.
Interventions
DRUGPlacebo
Form= intravenous infusion, route= intravenous (IV) use. IV infusions of placebo 2 times weekly or IV infusions of placebo 3 times weekly.
DRUGKetamine
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.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | 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 | 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 | 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) | 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 | 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) | 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 | 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. |
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | 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. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ketamine | 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]) | 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]) | 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 | 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 | 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) | 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). |
| Maximum Observed Plasma Concentration (Cmax) of Ketamine | 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. |
Countries
United States
Participant flow
Pre-assignment details
A total of 165 participants were screened and 68 participants were randomized into the study. Of these 68 participants randomized, 67 participants received at least 1 dose of the study agent (Intent-To-Treat analysis set).
Participants by arm
| Arm | Count |
|---|---|
| Placebo: 2 Times Per Week Participants received Intravenous (IV) infusion of placebo 2 times weekly for 4 weeks. | 16 |
| Ketamine: 2 Times Per Week Participants received 0.50 milligram per kilogram (mg/kg) ketamine IV infusion 2 times weekly for 4 weeks. | 18 |
| Placebo: 3 Times Per Week Participants received IV infusion of placebo 3 times weekly for 4 weeks. | 16 |
| Ketamine: 3 Times Per Week Participants received 0.50 mg/kg ketamine IV infusion 3 times weekly for 4 weeks. | 17 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 0 | 1 |
| Overall Study | Lack of Efficacy | 11 | 1 | 15 | 2 |
| Overall Study | Other | 0 | 2 | 0 | 3 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
| Overall Study | Randomized But Not Treated | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo: 2 Times Per Week | Ketamine: 2 Times Per Week | Placebo: 3 Times Per Week | Ketamine: 3 Times Per Week | Total |
|---|---|---|---|---|---|
| Age, Continuous | 40.3 years STANDARD_DEVIATION 11.79 | 45.7 years STANDARD_DEVIATION 9.58 | 46.1 years STANDARD_DEVIATION 10.51 | 43.3 years STANDARD_DEVIATION 11.99 | 43.9 years STANDARD_DEVIATION 10.9 |
| Region of Enrollment USA | 16 participants | 18 participants | 16 participants | 17 participants | 67 participants |
| Sex: Female, Male Female | 12 Participants | 12 Participants | 9 Participants | 12 Participants | 45 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 7 Participants | 5 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 16 | 15 / 18 | 8 / 16 | 13 / 17 |
| serious Total, serious adverse events | 0 / 16 | 2 / 18 | 0 / 16 | 0 / 17 |
Outcome results
Primary
Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to 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.
Time frame: Baseline (Day 1) and Day 15
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | Baseline (n=16,18,16,17) | 35.6 Units on a scale | Standard Deviation 3.79 |
| Placebo: 2 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | Change at Day 15 (n=13,16,16,13) | -5.7 Units on a scale | Standard Deviation 10.23 |
| Ketamine: 2 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | Change at Day 15 (n=13,16,16,13) | -18.4 Units on a scale | Standard Deviation 12.01 |
| Ketamine: 2 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | Baseline (n=16,18,16,17) | 33.3 Units on a scale | Standard Deviation 4.91 |
| Placebo: 3 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | Baseline (n=16,18,16,17) | 36.8 Units on a scale | Standard Deviation 5.83 |
| Placebo: 3 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | Change at Day 15 (n=13,16,16,13) | -3.1 Units on a scale | Standard Deviation 5.67 |
| Ketamine: 3 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | Baseline (n=16,18,16,17) | 35.4 Units on a scale | Standard Deviation 5.28 |
| Ketamine: 3 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 15 | Change at Day 15 (n=13,16,16,13) | -17.7 Units on a scale | Standard Deviation 7.27 |
p-value: <0.00170% CI: [-20, -12.01]Mixed Effect Model Repeated Measure
p-value: <0.00170% CI: [-18.96, -13.84]Mixed Effect Model Repeated Measure
Secondary
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity])
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.
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
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) | Day 1 (n=13,13) | 369 hour*nanogram per milliliter | Standard Deviation 79.9 |
| Placebo: 2 Times Per Week | Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) | Day 15 (n=9,8) | 416 hour*nanogram per milliliter | Standard Deviation 68.9 |
| Ketamine: 2 Times Per Week | Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) | Day 1 (n=13,13) | 344 hour*nanogram per milliliter | Standard Deviation 47.3 |
| Ketamine: 2 Times Per Week | Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) | Day 15 (n=9,8) | 340 hour*nanogram per milliliter | Standard Deviation 94 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC[0-last])
The AUC(0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time.
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
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC[0-last]) | Day 1 (n=16,15) | 312 hour*nanogram per milliliter | Standard Deviation 67.9 |
| Placebo: 2 Times Per Week | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC[0-last]) | Day 15 (n=14,14) | 342 hour*nanogram per milliliter | Standard Deviation 66.7 |
| Ketamine: 2 Times Per Week | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC[0-last]) | Day 1 (n=16,15) | 295 hour*nanogram per milliliter | Standard Deviation 42.8 |
| Ketamine: 2 Times Per Week | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC[0-last]) | Day 15 (n=14,14) | 293 hour*nanogram per milliliter | Standard Deviation 65.6 |
Secondary
Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to 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.
Time frame: Baseline (Day 1) and Endpoint (Day 29)
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) | Baseline (n=15,18,16,17) | 5.0 Units on a scale | Full Range 3.79 |
| Placebo: 2 Times Per Week | Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) | Change at Endpoint (n=15,18,16,17) | 0.0 Units on a scale | Full Range 10.61 |
| Ketamine: 2 Times Per Week | Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) | Change at Endpoint (n=15,18,16,17) | -2.0 Units on a scale | Full Range 6.6 |
| Ketamine: 2 Times Per Week | Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) | Baseline (n=15,18,16,17) | 5.0 Units on a scale | Full Range 4.91 |
| Placebo: 3 Times Per Week | Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) | Change at Endpoint (n=15,18,16,17) | 0.0 Units on a scale | — |
| Placebo: 3 Times Per Week | Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) | Baseline (n=15,18,16,17) | 5.0 Units on a scale | Full Range 5.83 |
| Ketamine: 3 Times Per Week | Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) | Baseline (n=15,18,16,17) | 5.0 Units on a scale | Full Range 5.28 |
| Ketamine: 3 Times Per Week | Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Endpoint (Day 29) | Change at Endpoint (n=15,18,16,17) | -2.0 Units on a scale | Full Range 10.61 |
Secondary
Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to 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.
Time frame: Baseline (Day 1) and Day 29
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | Baseline (n=16,18,16,17) | 35.6 Units on a scale | Standard Deviation 3.79 |
| Placebo: 2 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | Change at Day 29 (n=2,13,1,13) | -23.5 Units on a scale | Standard Deviation 10.61 |
| Ketamine: 2 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | Change at Day 29 (n=2,13,1,13) | -27.1 Units on a scale | Standard Deviation 6.6 |
| Ketamine: 2 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | Baseline (n=16,18,16,17) | 33.3 Units on a scale | Standard Deviation 4.91 |
| Placebo: 3 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | Baseline (n=16,18,16,17) | 36.8 Units on a scale | Standard Deviation 5.83 |
| Placebo: 3 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | Change at Day 29 (n=2,13,1,13) | -1 Units on a scale | — |
| Ketamine: 3 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | Baseline (n=16,18,16,17) | 35.4 Units on a scale | Standard Deviation 5.28 |
| Ketamine: 3 Times Per Week | Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 29 | Change at Day 29 (n=2,13,1,13) | -22.9 Units on a scale | Standard Deviation 10.61 |
Secondary
Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to 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.
Time frame: Baseline (Day 1) and Endpoint (Day 29)
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) | Baseline (n=15,18,16,17) | 8.0 Units on a scale | Full Range 3.79 |
| Placebo: 2 Times Per Week | Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) | Change at Endpoint (n=15,18,16,17) | 0.0 Units on a scale | Full Range 10.61 |
| Ketamine: 2 Times Per Week | Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) | Change at Endpoint (n=15,18,16,17) | -4.0 Units on a scale | Full Range 6.6 |
| Ketamine: 2 Times Per Week | Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) | Baseline (n=15,18,16,17) | 7.5 Units on a scale | Full Range 4.91 |
| Placebo: 3 Times Per Week | Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) | Baseline (n=15,18,16,17) | 8.0 Units on a scale | Full Range 5.83 |
| Placebo: 3 Times Per Week | Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) | Change at Endpoint (n=15,18,16,17) | -1.0 Units on a scale | — |
| Ketamine: 3 Times Per Week | Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) | Baseline (n=15,18,16,17) | 7.0 Units on a scale | Full Range 5.28 |
| Ketamine: 3 Times Per Week | Change in Patient Global Impression-Severity (PGI-S) Score From Baseline to Endpoint (Day 29) | Change at Endpoint (n=15,18,16,17) | -3.0 Units on a scale | Full Range 10.61 |
Secondary
Clinical Global Impression of Improvement (CGI-I) Score at Endpoint of Double Blind Phase
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.
Time frame: Endpoint (Day 29)
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo: 2 Times Per Week | Clinical Global Impression of Improvement (CGI-I) Score at Endpoint of Double Blind Phase | 4.0 Units on a scale | Full Range 3.79 |
| Ketamine: 2 Times Per Week | Clinical Global Impression of Improvement (CGI-I) Score at Endpoint of Double Blind Phase | 2.0 Units on a scale | Full Range 4.91 |
| Placebo: 3 Times Per Week | Clinical Global Impression of Improvement (CGI-I) Score at Endpoint of Double Blind Phase | 4.0 Units on a scale | Full Range 5.83 |
| Ketamine: 3 Times Per Week | Clinical Global Impression of Improvement (CGI-I) Score at Endpoint of Double Blind Phase | 2.0 Units on a scale | Full Range 5.28 |
Secondary
Elimination Half-Life (t1/2)
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).
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
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Elimination Half-Life (t1/2) | Day 1 (n=13,13) | 2.18 hour | Standard Deviation 0.43 |
| Placebo: 2 Times Per Week | Elimination Half-Life (t1/2) | Day 15 (n=9,8) | 2.39 hour | Standard Deviation 0.36 |
| Ketamine: 2 Times Per Week | Elimination Half-Life (t1/2) | Day 15 (n=9,8) | 2.21 hour | Standard Deviation 0.36 |
| Ketamine: 2 Times Per Week | Elimination Half-Life (t1/2) | Day 1 (n=13,13) | 2.18 hour | Standard Deviation 0.4 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Ketamine
The Cmax is the maximum observed plasma concentration of drug.
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
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Maximum Observed Plasma Concentration (Cmax) of Ketamine | Day 1 (n=16,16) | 207 nanogram per milliliter (ng/ml) | Standard Deviation 83 |
| Placebo: 2 Times Per Week | Maximum Observed Plasma Concentration (Cmax) of Ketamine | Day 15 (n=14,15) | 219 nanogram per milliliter (ng/ml) | Standard Deviation 69.4 |
| Ketamine: 2 Times Per Week | Maximum Observed Plasma Concentration (Cmax) of Ketamine | Day 1 (n=16,16) | 168 nanogram per milliliter (ng/ml) | Standard Deviation 34.4 |
| Ketamine: 2 Times Per Week | Maximum Observed Plasma Concentration (Cmax) of Ketamine | Day 15 (n=14,15) | 189 nanogram per milliliter (ng/ml) | Standard Deviation 74.4 |
Secondary
Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
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.
Time frame: Day 15 and Day 29
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 15 (n=13,16,16,13) | 1 Participants | 3.79 |
| Placebo: 2 Times Per Week | Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 29 (n=2,13,1,13) | 1 Participants | 10.61 |
| Ketamine: 2 Times Per Week | Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 29 (n=2,13,1,13) | 12 Participants | 6.6 |
| Ketamine: 2 Times Per Week | Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 15 (n=13,16,16,13) | 6 Participants | 4.91 |
| Placebo: 3 Times Per Week | Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 29 (n=2,13,1,13) | 0 Participants | — |
| Placebo: 3 Times Per Week | Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 15 (n=13,16,16,13) | 0 Participants | 5.83 |
| Ketamine: 3 Times Per Week | Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 15 (n=13,16,16,13) | 3 Participants | 5.28 |
| Ketamine: 3 Times Per Week | Number of Remitters Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 29 (n=2,13,1,13) | 5 Participants | 10.61 |
Secondary
Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
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.
Time frame: Day 15 and Day 29
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 15 (n=13,16,16,13) | 2 Participants | 3.79 |
| Placebo: 2 Times Per Week | Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 29 (n=2,13,1,13) | 1 Participants | 10.61 |
| Ketamine: 2 Times Per Week | Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 29 (n=2,13,1,13) | 13 Participants | 6.6 |
| Ketamine: 2 Times Per Week | Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 15 (n=13,16,16,13) | 11 Participants | 4.91 |
| Placebo: 3 Times Per Week | Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 15 (n=13,16,16,13) | 1 Participants | 5.83 |
| Placebo: 3 Times Per Week | Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 29 (n=2,13,1,13) | 0 Participants | — |
| Ketamine: 3 Times Per Week | Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 15 (n=13,16,16,13) | 7 Participants | 5.28 |
| Ketamine: 3 Times Per Week | Number of Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Day 29 (n=2,13,1,13) | 9 Participants | 10.61 |
Secondary
Number of Sustained Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
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.
Time frame: Day 15
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here, N (Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo: 2 Times Per Week | Number of Sustained Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | 1 Participants | 3.79 |
| Ketamine: 2 Times Per Week | Number of Sustained Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | 7 Participants | 4.91 |
| Placebo: 3 Times Per Week | Number of Sustained Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | 0 Participants | 5.83 |
| Ketamine: 3 Times Per Week | Number of Sustained Responders Based on Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | 4 Participants | 5.28 |
Secondary
Patient Global Impression-Change (PGI-C) Score at Endpoint of Double Blind Phase
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.
Time frame: Endpoint (Day 29)
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo: 2 Times Per Week | Patient Global Impression-Change (PGI-C) Score at Endpoint of Double Blind Phase | 4.0 Units on a scale | Full Range 3.79 |
| Ketamine: 2 Times Per Week | Patient Global Impression-Change (PGI-C) Score at Endpoint of Double Blind Phase | 2.0 Units on a scale | Full Range 4.91 |
| Placebo: 3 Times Per Week | Patient Global Impression-Change (PGI-C) Score at Endpoint of Double Blind Phase | 4.0 Units on a scale | Full Range 5.83 |
| Ketamine: 3 Times Per Week | Patient Global Impression-Change (PGI-C) Score at Endpoint of Double Blind Phase | 3.0 Units on a scale | Full Range 5.28 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ketamine
The Tmax is defined as actual sampling time to reach maximum observed drug concentration.
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
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ketamine | Day 1 (n=16,16) | 0.67 Hour | Full Range 83 |
| Placebo: 2 Times Per Week | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ketamine | Day 15 (n=14,15) | 0.67 Hour | Full Range 69.4 |
| Ketamine: 2 Times Per Week | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ketamine | Day 15 (n=14,15) | 0.67 Hour | Full Range 74.4 |
| Ketamine: 2 Times Per Week | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ketamine | Day 1 (n=16,16) | 0.66 Hour | Full Range 34.4 |
Secondary
Total Systemic Clearance (CL) of Ketamine
The CL is a quantitative measure of the rate at which a drug substance is removed from the body.
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
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Total Systemic Clearance (CL) of Ketamine | Day 1 (n=13,13) | 113 liter per hour | Standard Deviation 35.1 |
| Placebo: 2 Times Per Week | Total Systemic Clearance (CL) of Ketamine | Day 15 (n=9,8) | 93.9 liter per hour | Standard Deviation 15.6 |
| Ketamine: 2 Times Per Week | Total Systemic Clearance (CL) of Ketamine | Day 1 (n=13,13) | 108 liter per hour | Standard Deviation 21.4 |
| Ketamine: 2 Times Per Week | Total Systemic Clearance (CL) of Ketamine | Day 15 (n=9,8) | 117 liter per hour | Standard Deviation 22.3 |
Secondary
Volume of Distribution at Steady-State (Vss) of Ketamine
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.
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
Population: An intent-to-treat (ITT) analysis set is defined as all participants who receive at least 1 dose of study drug and have both Day 1 (baseline) and at least 1 post-baseline MADRS total score. Here,N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: 2 Times Per Week | Volume of Distribution at Steady-State (Vss) of Ketamine | Day 1 (n=13,13) | 275 liter | Standard Deviation 114 |
| Placebo: 2 Times Per Week | Volume of Distribution at Steady-State (Vss) of Ketamine | Day 15 (n=9,8) | 239 liter | Standard Deviation 61.2 |
| Ketamine: 2 Times Per Week | Volume of Distribution at Steady-State (Vss) of Ketamine | Day 1 (n=13,13) | 276 liter | Standard Deviation 77.2 |
| Ketamine: 2 Times Per Week | Volume of Distribution at Steady-State (Vss) of Ketamine | Day 15 (n=9,8) | 290 liter | Standard Deviation 64.9 |