A Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment-resistant Depression

MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement.

Time frame: Baseline (Day 1) and Endpoint (Day 8) of Period 1

Population: Period 1 Intent-to-treat (ITT) analysis set included all participants randomly assigned to treatment in period 1.

MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement.

Time frame: Baseline (Day 8) and Endpoint (Day 15) of Period 2

Population: Period 2 ITT analysis set included non-responders (QIDS-SR16 total score \>=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score \>= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.

CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness 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 most extremely ill patients. CGI-S permits global evaluation of participant's condition at given time. A negative change in score indicates improvement.

Time frame: Baseline (Day 1) and Endpoint (Day 8) of Period 1

Population: Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.

GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21).

Time frame: Baseline (Day 1) and Endpoint (Day 8) of Period 1

Population: Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.

PGI-S is a patient-rated scale that assesses the severity of their illness at the time of assessment, relative to participants past experience. It is a 4-point (1 to 4) scale in response to the question 'Considering all aspects of your depression right now would you say your depression is?' with scores as follows: 1: none; 2: mild; 3: moderate; 4: severe. A higher score implies a more severe condition.

Time frame: Baseline (Day 1) and Endpoint (Day 8) of Period 1

Population: Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.

QIDS-SR16 is self-rated scale assesses severity of depressive symptoms. Total scores range from 0-27. Higher score indicates greater severity of depression. Negative change in score indicates improvement. Total score obtained by adding scores for each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders-4th edition major depressive disorder (DSM-IV MDD) criteria: depressed mood, loss of interest/pleasure, concentration/decision making, self-outlook, suicidal ideation, energy/fatigability, sleep, weight/appetite change, psychomotor changes. 16 items used to rate 9 criterion domains: 4 items used to rate sleep disturbance (early/middle/late insomnia/hypersomnia); 2 items used to rate psychomotor disturbance (agitation, retardation); 4 items used to rate appetite/weight disturbance. 1 item used to rate 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, suicidal ideation). Each item was rated 0-3.

Time frame: Baseline (Day 1) and Endpoint (Day 8) of Period 1

Population: Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.

CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness 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 most extremely ill patients. CGI-S permits global evaluation of participant's condition at given time. A negative change in score indicates improvement.

Time frame: Baseline (Day 8) and Endpoint (Day 15) of Period 2

Population: Period 2 ITT analysis set included non-responders (QIDS-SR16 total score \>=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score \>= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.

GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21).

Time frame: Baseline (Day 8) and Endpoint (Day 15) of Period 2

Population: Period 2 ITT analysis set included non-responders (QIDS-SR16 total score \>=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score \>= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.

PGI-S is a patient-rated scale that assesses the severity of their illness at the time of assessment, relative to participants past experience. It is a 4-point (1 to 4) scale in response to the question 'Considering all aspects of your depression right now would you say your depression is?' with scores as follows: 1: none; 2: mild; 3: moderate; 4: severe. A higher score implies a more severe condition. A negative change in score indicates improvement.

Time frame: Baseline (Day 8) and Endpoint (Day 15) of Period 2

Population: Period 2 ITT analysis set included non-responders (QIDS-SR16 total score \>=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score \>= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.

QIDS-SR16 is self-rated scale assesses severity of depressive symptoms. Total scores range from 0-27. Higher score indicates greater severity of depression. Negative change in score indicates improvement. Total score obtained by adding scores for each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders-4th edition major depressive disorder (DSM-IV MDD) criteria: depressed mood, loss of interest/pleasure, concentration/decision making, self-outlook, suicidal ideation, energy/fatigability, sleep, weight/appetite change, psychomotor changes. 16 items used to rate 9 criterion domains: 4 items used to rate sleep disturbance (early/middle/late insomnia/hypersomnia); 2 items used to rate psychomotor disturbance (agitation, retardation); 4 items used to rate appetite/weight disturbance. 1 item used to rate 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, suicidal ideation). Each item was rated 0-3.

Time frame: Baseline (Day 8) and Endpoint (Day 15) of Period 2

Population: Period 2 ITT analysis set included non-responders (QIDS-SR16 total score \>=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score \>= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.

Participants who had a MADRS total score of \<=10 were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

Time frame: Days 1, 2 and 8 of Double-blind Phase of Period 1

Population: Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.

Participants who had a MADRS total score of less than or equal to (\<=10) were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement.

Time frame: Days 1, 2 and 8 of Double-blind Phase of Period 2

Population: Period 2 ITT analysis set included non-responders (QIDS-SR16 total score \>=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score \>= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.

A participant is defined a responder at a given time point if the percent improvement in MADRS is \>=50%. Participant who do not meet such criterion, worsen or discontinue during the DB phase for any reason was considered as non-responders, that is, was assigned a value of 0. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

Time frame: Period 2: Days 1 (2 hour), 2 and 8 of Double-blind Phase

Population: Period 2 ITT analysis set included non-responders (QIDS-SR16 total score \>=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score \>= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.

A participant is defined a responder at a given time point if the percent improvement in MADRS is greater than or equal to (\>=) 50%. Participant who do not meet such criterion, worsen or discontinue during the DB phase for any reason was considered as non-responders, that is, was assigned a value of 0. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

Time frame: Period 1: Days 1 (2 hour), 2 and 8 of Double-blind Phase

Population: Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.

Sustained response was defined as at least 50% improvement from baseline in the MADRS total score with onset by Day 2 that is maintained to study Day 15. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

Time frame: Day 2 Up to Day 15

Population: Population analyzed included participants from double-blind (DB) ITT (who were randomly assigned to treatment during the double-blind phase) who completed the double-blind phase and received the same treatment for both periods.

Sustained response was defined as at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 that is maintained to study Day 15. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

Time frame: Day 2 Up to Day 15

Population: Population analyzed included participants from DB ITT (who were randomly assigned to treatment during the double-blind phase) who received the same treatment for both periods, including participants who did not complete the double-blind Phase.