A Study of Ketamine in Patients With Treatment-resistant Depression

Primary Outcomes

• 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 Outcomes

• 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.

• 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.

• 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.

• 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).