Treatment Resistant Depression
Conditions
Brief summary
The purpose of this study is to determine whether olanzapine and fluoxetine combination (OFC) if used for a long time (47 weeks) makes patients suffering from Treatment Resistant Depression stable, determine if OFC is safe when used to treat patients with Treatment Resistant Depression for a long time (up to 47 weeks), to determine whether olanzapine and fluoxetine combination or fluoxetine alone is better to treat Treatment Resistant Depression when treated for a long time (up to 47 weeks) and to assess the quality of life during treatment.
Detailed description
This is a multicenter, randomized, double-blind, active comparator-controlled, parallel study of participants with Treatment Resistant Depression (TRD), comparing the efficacy and safety of olanzapine and fluoxetine Combination (OFC) versus fluoxetine in relapse prevention of stabilized participants with TRD. The study will consist of 4 phases: a screening phase; a 6- to 8-week open-label acute treatment phase; a 10- to 12-week open-label stabilization phase; and a 27- to 29-week double-blind relapse prevention treatment phase. Participants who demonstrate response to open-label OFC during the acute treatment phase will continue into the stabilization phase. Participants who remain stable while receiving open-label OFC during this phase will be randomized to receive either OFC or fluoxetine during the double-blind relapse prevention phase. Investigators and participants will be blinded to the precise duration of the stabilization period, the definition of remission, and the criteria for entry into the relapse prevention phase; this information is described in a supplement given to Ethical Review Boards (ERBs) and regulatory authorities.
Interventions
DRUGOlanzapine and Fluoxetine combination (OFC)
Open label acute phase: introductory dose for 4 days then 3 milligram (mg) Olanzapine and 25 mg Fluoxetine Combination (3/25), 6/25, 12/25, 6/50, 12/50 or 18/50, oral, daily, for 6-8 weeks. Open label stabilization phase: 6/25, 12/25, 6/50, 12/50 or 18/50 mg, oral, daily for 16-20 weeks. Double blind relapse prevention phase: dose determined during stabilization phase at Week 17, oral, daily, for 27 weeks.
DRUGFluoxetine
25 or 50 mg/day fixed dosing for 27 weeks
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Have single or recurrent unipolar Major Depressive Disorder (MDD), without psychotic features by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) clinical assessment, confirmed by the structured clinician Interview for DSM-IV Axis 1 disorders (SCID-I). * If female and of childbearing potential, test negative for pregnancy and agree to abstain from sexual activity or use a medically accepted means of contraception during the study. Use of any oral or injectable contraception must be initiated prior to receiving treatment. * Have 17-item Hamilton Depression (HAM-D) score greater than or equal to 18 at screening and the day treatment is due to be received for the first time. * Have treatment-resistant depression, as defined by having demonstrated failure to achieve satisfactory antidepressant response to adequate separate treatment courses of at least 2 different antidepressants within the current episode of MDD.
Exclusion criteria
* Have a diagnosis of Parkinson's disease or related disorders. * Have a current or lifetime diagnosis of any of the following according to DSM-IV criteria: Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Psychotic Disorder Not Otherwise Specified, Bipolar Disorder I or II, Delirium of any type, Dementia of any type, Amnestic Disorder, any Substance-Induced Disorder, or any Psychotic Disorder due to a General Medical Condition. * Have current diagnosis of post-partum depression, MDD with atypical features, or MDD with a seasonal pattern as defined in the DSM-IV. * Have paranoid, schizoid, schizotypal, antisocial, and borderline personality disorders (Axis II) as a comorbid or primary diagnosis, based on DSM-IV criteria. * Have had psychotic symptoms within 1 month prior to Screening or demonstrate psychotic features at screening and on the day treatment is due to be assigned for the first time as determined by the investigator. * Have DSM-IV substance dependence/abuse or not willing to avoid use of the substance (not including dependence on nicotine or caffeine), as defined by the SCID-I, within the past 30 days. * Are actively suicidal in the judgment of the investigator. * Have had one or more seizures without a clear and resolved etiology. * Have leukopenia or history of leukopenia without a clear and resolved etiology, or known history of agranulocytosis during the participant's lifetime. * Have alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) values greater than or equal to 2 times the upper limit of normal (ULN) of the performing laboratory or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) values greater than or equal to 2 times the ULN or total bilirubin values greater than or equal to 1.5 times the ULN at any time during screening. * Have acute, serious, or unstable medical conditions. * Have any illness such that death is anticipated within 1 year or intensive care unit hospitalization for the illness is anticipated within 6 months. * Have elevated prolactin levels at screening. * Have Bazett's corrected QT interval (QTc) greater than 450 milliseconds (male) or greater than 470 milliseconds (female) at screening and when treatment is due to be received for the first time. * Have received electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) treatment within the current episode; have a history of failure to adequate treatment courses of ECT or VNS; or will require ECT or VNS at any time during study participation. * If receiving psychotherapy, light therapy, or both, are anticipated to require changes in frequency/intensity of treatment regimen or to cease treatment regimen over the duration of the study. Participants who are not receiving any of these therapies upon study entry may not begin any of these therapies during screening, or during any treatment phases of the study. * Have received previous treatment with clozapine. * Have used a monoamine oxidase inhibitor (MAOI) within 14 days prior to screening or are expected to need MAOI treatment at any time during this study through 5 weeks after the participant discontinues from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Relapse by Any Criteria | Randomization (Week 20) to Week 47 | Relapse defined as meeting any of these criteria: 50% increase in Montgomery-Asberg Depression Rating Scale (MADRS) score from randomization with a Clinical Global Impressions-Severity (CGI-S) of Depression score increase to a score of 4 or more; Hospitalized for depression or suicidality; Discontinued due to lack of efficacy/worsening of depression/suicidality. MADRS is a 10-item rating scale for depressive mood symptoms severity, items rated on 0-6 scale, with total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). Lack of Efficacy/Worsening of depression was at discretion of investigator based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator. Those who did not relapse were censored at their last observation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Relapse by Any Criteria | Randomization (Week 20) to Week 47 | Relapse is defined as meeting any of the following criteria: 50% increase in Montgomery-Asberg Depression Rating Scale (MADRS) score from randomization with concomitant Clinical Global Impressions-Severity (CGI-S) of Depression score increase to a score of 4 or more; Hospitalization for depression or suicidality; Discontinuation due to lack of efficacy/worsening of depression/suicidality. MADRS is a rating scale for severity of depressive mood symptoms with 10 items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). Lack of Efficacy/Worsening of depression was at the discretion of the investigator and based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator. |
| Percentage of Participants Who Relapse Based on Montgomery-Åsberg Depression Rating Scale (MADRS) Score With Concomitant Clinical Global Impressions-Severity (CGI-S) of Depression Score | Randomization (Week 20) to Week 47 | Relapse is defined as a 50% increase in the Montgomery-Asberg Depression Rating Scale (MADRS) score from randomization with concomitant Clinical Global Impressions-Severity (CGI-S) of Depression score increase to a score of 4 or more. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). |
| Percentage of Participants Who Relapse as Measured by Hospitalization for Depression or Suicidality | Randomization (Week 20) to Week 47 | — |
| Percentage of Participants Who Relapse as Measured by Discontinuation Due to Lack of Efficacy/Worsening of Depression/Suicidality | Randomization (Week 20) to Week 47 | Lack of Efficacy/Worsening of depression was at the discretion of the investigator and was based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator. |
| Time to Relapse Based on the Montgomery-Åsberg Depression Rating Scale (MADRS) Score With Concomitant Clinical Global Impressions-Severity (CGI-S) of Depression Score | Randomization (Week 20) to Week 47 | Relapse is defined as a 50% increase in the Montgomery-Asberg Depression Rating Scale (MADRS) score from randomization with concomitant Clinical Global Impressions-Severity (CGI-S) of Depression score increase to a score of 4 or more. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). Those who did not relapse were censored at their last observation. |
| Time to Relapse as Measured by Hospitalization for Depression or Suicidality | Randomization (Week 20) to Week 47 | Those who did not relapse were censored at their last observation. |
| Time to Relapse as Measured by Discontinuation Due to Lack of Efficacy/Worsening of Depression/Suicidality | Randomization (Week 20) to Week 47 | Lack of Efficacy/Worsening of depression was at the discretion of the investigator and was based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator. Those who did not relapse were censored at their last observation. |
| Percentage of Participants Responding to Treatment During Open-Label Acute Treatment Phase | Week 0 to Week 8 | A 50% or greater improvement from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) and a Clinical Global Impressions-Severity (CGI-S) of Depression score ≤3 will be considered as response criteria met. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). |
| Percentage of Participants Maintaining Response at Any Point During Stabilization Treatment Phase | Week 8 to Week 20 | A 50% or greater improvement from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) and a Clinical Global Impressions-Severity (CGI-S) of Depression score ≤3 will be considered as response criteria met. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). |
| Percentage of Participants Achieving Remission at Any Point During Stabilization Treatment Phase | Week 8 to Week 20 | Remission is defined as the Montgomery-Asberg Depression Rating Scale (MADRS) score ≤8. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). |
| Percentage of Participants Maintaining Remission | Randomization (Week 20) to Week 47 | Remission is defined as the Montgomery-Asberg Depression Rating Scale (MADRS) score ≤8. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). |
| Mean Change From Week 20 to Week 47 in Montgomery-Asberg Depression Rating Scale (MADRS) Using Mixed-Effects Model Repeated Measures (MMRM) Analysis | Randomization (Week 20), Week 47 | The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Mean Change From Week 20 to Week 47 in Montgomery-Asberg Depression Rating Scale (MADRS) Using Last Observation Carried Forward (LOCF) Analysis | Randomization (Week 20), up to Week 47 | The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) Mean values were controlled for baseline (Week 20), treatment and country. |
| Mean Change From Week 20 to Week 47 in Clinical Global Impressions - Severity (CGI-S) of Depression Using Mixed-Effects Model Repeated Measures (MMRM) Analysis | Randomization (Week 20), Week 47 | CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Resource Utilization - Average Number of Hours Worked for Pay Per Week at Week 47 | Week 47 | — |
| Resource Utilization (Number of Psychiatric Visits, Number of Emergency Room or Equivalent Facility Visits for Psychiatric Illness) | Randomization (Week 20) to Week 47 | Resource utilization is defined as the average number of psychiatric visits and number of emergency room or equivalent facility visits for psychiatric illness. |
| Change From Week 20 to Week 47 Endpoint in the Sheehan Disability Scale (SDS) | Randomization (Week 20), up to Week 47 | The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work or school (Item 1), social (Item 2), and family life and home responsibilities (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Mean values were controlled for baseline (Week 20), treatment and country. |
| Percent of Participants With Treatment-Emergent Akathisia | Randomization (Week 20) to Week 47 | Barnes Akathisia Scale (BAS) rates observable, restless movements of drug-induced akathisia as well as the subjective awareness of restlessness and any distress associated with the akathisia. It consists of 4 items. 3 items (objective akathisia, subjective awareness of restlessness and subjective distress related to restlessness) rated on a 4-point scale, with 0 being no akathisia and 3 being severe akathisia. Item 4 (global clinical assessment of Akathisia) is derived from the responses on Items 1-3 rated on a 6-point scale, with 0 being absence and 5 being extreme Akathisia. Treatment emergent akathisia is defined as a global clinical assessment score on BAS \<2 at baseline (Week 20) and a global clinical assessment score on BAS ≥2 post-baseline (Weeks 21-47). |
| Percent of Participants With Treatment-Emergent Dyskinesia | Randomization (Week 20) to Week 47 | Abnormal Involuntary Movement Scale (AIMS) is a 12-item scale designed to record the occurrence of dyskinetic movements. Items 1 through 10 are rated on a 5-point scale, with 0 being no dyskinetic movements and 4 being severe dyskinetic movements. Items 11 and 12 are yes/no questions regarding the dental condition of the participants. Treatment emergent dyskinesia is defined as a score ≥3 on any one of the AIMS items 1-7 post-baseline (Weeks 21-47) or scores ≥2 on any two of the AIMS items 1-7 post-baseline (Weeks 21-47) among participants without either criteria at baseline (Week 20). |
| Mean Change From Week 20 to Week 47 in Fasting Total Cholesterol | Randomization (Week 20), Week 47 | Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Percent of Participants With Treatment-Emergent High Fasting Total Cholesterol | Randomization (Week 20) to Week 47 | Borderline to High fasting total cholesterol: ≥200 milligrams/deciliter (mg/dL) and \<240 mg/dL at baseline and ≥240 mg/dL any time post baseline; Normal to Borderline fasting total cholesterol: \<200 mg/dL at baseline, ≥200 mg/dL and \<240 mg/dL any time post baseline; Normal to High fasting total cholesterol: \<200 mg/dL at baseline and ≥240 mg/dL any time post baseline. |
| Mean Change From Week 20 to Week 47 in Fasting Low-Density Lipoprotein (LDL) Cholesterol | Randomization (Week 20), Week 47 | Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Percent of Participants With Treatment-Emergent High Fasting Low-Density Lipoprotein (LDL) Cholesterol | Randomization (Week 20) to Week 47 | Borderline to High fasting LDL cholesterol: ≥100 milligrams/deciliter (mg/dL) and \<160 mg/dL at baseline and ≥160 mg/dL any time post baseline; Normal to Borderline fasting LDL cholesterol: \<100 mg/dL at baseline, ≥100 mg/dL and \<160 mg/dL any time post baseline; Normal to High fasting LDL cholesterol: \<100 mg/dL at baseline and ≥160 mg/dL any time post baseline. |
| Mean Change From Week 20 to Week 47 in Fasting High-Density Lipoprotein (HDL) Cholesterol | Randomization (Week 20), Week 47 | Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Percent of Participants With Treatment-Emergent Low Fasting High-Density Lipoprotein (HDL) Cholesterol | Randomization (Week 20) to Week 47 | Normal to Low fasting HDL cholesterol is ≥40 milligrams/deciliter (mg/dL) at baseline and \<40 mg/dL anytime post baseline. |
| Percent of Participants With Treatment-Emergent Hepatic Events | Randomization (Week 20) to Week 47 | Participants with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<=3 times the upper limit of normal (ULN) at baseline, with ALT or AST \>=3 times the ULN post-baseline and total bilirubin \>=2 times ULN at the same time are considered having treatment-emergent hepatic events. |
| Mean Change From Week 20 to Week 47 in Fasting Triglycerides | Randomization (Week 20), Week 47 | Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Percent of Participants With Treatment-Emergent High Fasting Triglycerides | Randomization (Week 20) to Week 47 | Borderline to High fasting triglycerides: ≥150 milligrams/deciliter (mg/dL) and \<200 mg/dL at baseline and ≥200 mg/dL any time post baseline; Normal to Borderline fasting triglycerides: \<150 mg/dL at baseline, ≥150 mg/dL and \<200 mg/dL any time post baseline; Normal to High fasting triglycerides: \<150 mg/dL at baseline and ≥200 mg/dL any time post baseline. |
| Mean Change From Week 20 to Week 47 in Fasting Glucose | Randomization (Week 20), Week 47 | Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Percent of Participants With Treatment-Emergent High Fasting Glucose | Randomization (Week 20) to Week 47 | Impaired to High fasting glucose: ≥100 milligrams/deciliter (mg/dL) and \<126 mg/dL at baseline and ≥126 mg/dL any time post baseline; Normal to High glucose: \<100 mg/dL at baseline and ≥126 mg/dL any time post baseline; Normal to Impaired fasting glucose is \<100 mg/dL at baseline, ≥100 mg/dL and \<126 mg/dL any time post baseline; Normal/Impaired to High fasting glucose: \<126 mg/dL at baseline and ≥126 mg/dL any time post baseline. |
| Mean Change From Week 20 to Week 47 in Weight | Randomization (Week 20), Week 47 | Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Percent of Participants With Week 20-to-Week 47 Endpoint Increase in Weight of at Least 7% | Week 20 to Week 47 | — |
| Percent of Participants With Suicide-Related Thoughts and Behaviors | Randomization (Week 20) to Week 47 | Columbia Suicide Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a yes answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. |
| Mean Change in Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) on Electrocardiogram | Randomization (Week 20), Week 47 | Least Squares (LS) Mean values were obtained from a mixed model repeated measures (MMRM) analysis. Model includes baseline (Week 20), treatment, country, visit, and treatment by visit interaction. |
| Percent of Participants With Treatment-Emergent Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) on Electrocardiogram ≥500 Milliseconds (Msec) | Randomization (Week 20) to Week 47 | Data presented are the percent of participants whose baseline corrected (for rate) cardiac QT interval \<500 msec with post-baseline corrected (for rate) cardiac QT interval ≥500 msec. |
| Percent of Participants With a 60 Milliseconds (Msec) Increase in Fridericia-Corrected (for Rate) Cardiac QT Interval (QTcF) on Electrocardiogram | Randomization (Week 20) to Week 47 | — |
| Percent of Participants With Treatment-Emergent Parkinsonism | Randomization (Week 20) to Week 47 | Simpson-Angus Scale is used to measure Parkinsonian-type symptoms in participants exposed to neuroleptics. The scale consists of 10 items, each rated on a 5-point scale, with 0 meaning complete absence of the condition and 4 meaning the presence of the condition in extreme form. The total score is obtained by adding the items and ranges from 0-40 with higher scores indicating worse conditions. Treatment emergent parkinsonism is defined as total score ≤3 of items 1 through 10 of the Simpson-Angus scale at baseline (Week 20) and a total score \>3 of items 1 through 10 post-baseline (Weeks 21-47). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Randomization (Week 20) to Week 27 | Relapse is defined as meeting any of the following criteria (Relapse-any reason): 50% increase in MADRS score from randomization with concomitant CGI-S of Depression score increase to a score of 4 or more (MADRS score/CGI-S Depression Score); Hospitalization for depression or suicidality; Discontinuation due to lack of efficacy/worsening of depression/suicidality. MADRS is a rating scale for severity of depressive mood symptoms with 10 items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). Lack of Efficacy/Worsening of depression was at the discretion of the investigator and based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator. |
Countries
Argentina, India, Mexico, Puerto Rico, Russia, South Africa, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
The study consisted of 4 treatment phases: a screening phase (Study Period I \[SPI\]) of 3 to 14 days; a 6- to 8-week (wk) acute open-label treatment phase (SPII); a 12-week open-label stabilization treatment phase (SPIII); and a 27-week double-blind (DB) randomized relapse prevention treatment phase (SPIV).
Participants by arm
| Arm | Count |
|---|---|
| OFC (SPII-Wk 0-8, Acute Open-label) Olanzapine and Fluoxetine Combination (OFC): 3 milligram (mg) Olanzapine and 25 mg Fluoxetine Combination (3/25), 6/25, 12/25, 6/50, 12/50 or 18/50, oral, daily, for 6-8 weeks during open-label acute treatment phase (SPII). Flexible dosing with initial forced titration. | 892 |
| Total | 892 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| SPIII (Wk 9-20,Open-label Stabilization) | Adverse Event | 0 | 28 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Blinded Randomization Criteria Not Met | 0 | 30 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Entry Criteria Not Met | 0 | 6 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Lost to Follow-up | 0 | 9 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Physician Decision | 0 | 4 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Protocol Violation | 0 | 24 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Relapse Criteria Met | 0 | 1 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Sponsor Decision | 0 | 5 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Stabilization Criteria Not Met | 0 | 62 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Unknown, Not Otherwise Specified | 0 | 1 | 0 | 0 |
| SPIII (Wk 9-20,Open-label Stabilization) | Withdrawal by Subject | 0 | 41 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Adverse Event | 44 | 0 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Entry Criteria Not Met | 34 | 0 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Lost to Follow-up | 14 | 0 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Physician Decision | 4 | 0 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Protocol Violation | 13 | 0 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Response Criteria Not Met | 80 | 0 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Sponsor Decision | 8 | 0 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Unknown, Not Otherwise Specified | 1 | 0 | 0 | 0 |
| SPII (Wk 0-8, Acute Open-label) | Withdrawal by Subject | 39 | 0 | 0 | 0 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Adverse Event | 0 | 0 | 19 | 10 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Death | 0 | 0 | 1 | 0 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Entry Criteria Not Met | 0 | 0 | 2 | 1 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Lost to Follow-up | 0 | 0 | 3 | 8 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Physician Decision | 0 | 0 | 1 | 0 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Protocol Violation | 0 | 0 | 11 | 5 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Relapse Criteria Met | 0 | 0 | 24 | 63 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Sponsor Decision | 0 | 0 | 5 | 4 |
| SPIV (Wk 21-47, DB Relapse Prevention) | Withdrawal by Subject | 0 | 0 | 16 | 15 |
Baseline characteristics
| Characteristic | OFC (SPII-Wk 0-8, Acute Open-label) |
|---|---|
| Age, Continuous | 44.38 years STANDARD_DEVIATION 11.98 |
| Body Mass Index (BMI) | 29.12 kilograms/square meter (kg/m²) STANDARD_DEVIATION 7.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 167 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 725 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 27 Participants |
| Race (NIH/OMB) Asian | 115 Participants |
| Race (NIH/OMB) Black or African American | 101 Participants |
| Race (NIH/OMB) More than one race | 11 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 634 Participants |
| Region of Enrollment Argentina | 53 participants |
| Region of Enrollment India | 108 participants |
| Region of Enrollment Mexico | 44 participants |
| Region of Enrollment Puerto Rico | 20 participants |
| Region of Enrollment Russian Federation | 66 participants |
| Region of Enrollment South Africa | 40 participants |
| Region of Enrollment Turkey | 28 participants |
| Region of Enrollment United States | 533 participants |
| Sex: Female, Male Female | 591 Participants |
| Sex: Female, Male Male | 301 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 | 606 / 892 | 348 / 655 | 100 / 221 | 105 / 223 |
| serious Total, serious adverse events | 13 / 892 | 9 / 655 | 9 / 221 | 7 / 223 |
Outcome results
Primary
Time to Relapse by Any Criteria
Relapse defined as meeting any of these criteria: 50% increase in Montgomery-Asberg Depression Rating Scale (MADRS) score from randomization with a Clinical Global Impressions-Severity (CGI-S) of Depression score increase to a score of 4 or more; Hospitalized for depression or suicidality; Discontinued due to lack of efficacy/worsening of depression/suicidality. MADRS is a 10-item rating scale for depressive mood symptoms severity, items rated on 0-6 scale, with total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). Lack of Efficacy/Worsening of depression was at discretion of investigator based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator. Those who did not relapse were censored at their last observation.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants are included in the time to event analyses. The numbers of participants censored are 186 and 152 for OFC and Flu groups, respectively.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Time to Relapse by Any Criteria | NA days | Full Range 10 |
| Flu (SPIV) | Time to Relapse by Any Criteria | NA days | Full Range 5.9 |
Comparison: Power estimate assumes approximately 1230 participants enter SPII. With a 60% drop-out/disqualification rate in SPII, then 492 participants enter SPIII. If 26% of participants drop out during SPIII, then 364 participants enter SPIV. Assuming 20% drop-out rate, 25% relapse rate on OFC and 40% relapse rate for fluoxetine (hazard ratio = 0.56), the log-rank test is 80% powered to detect a difference at a 2-sided 0.05 level. A total of 95 relapse events during SPIV should satisfy these assumptions.p-value: <0.001Log Rank
Secondary
Change From Week 20 to Week 47 Endpoint in the Sheehan Disability Scale (SDS)
The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work or school (Item 1), social (Item 2), and family life and home responsibilities (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Mean values were controlled for baseline (Week 20), treatment and country.
Time frame: Randomization (Week 20), up to Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) SDS score measurements. Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Change From Week 20 to Week 47 Endpoint in the Sheehan Disability Scale (SDS) | 1.30 units on a scale | Standard Error 0.72 |
| Flu (SPIV) | Change From Week 20 to Week 47 Endpoint in the Sheehan Disability Scale (SDS) | 3.24 units on a scale | Standard Error 0.73 |
p-value: 0.00795% CI: [-3.36, -0.53]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Clinical Global Impressions - Severity (CGI-S) of Depression Using Mixed-Effects Model Repeated Measures (MMRM) Analysis
CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) CGI-S measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Clinical Global Impressions - Severity (CGI-S) of Depression Using Mixed-Effects Model Repeated Measures (MMRM) Analysis | 0.20 units on a scale | Standard Error 0.08 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Clinical Global Impressions - Severity (CGI-S) of Depression Using Mixed-Effects Model Repeated Measures (MMRM) Analysis | 0.54 units on a scale | Standard Error 0.08 |
p-value: 0.00295% CI: [-0.55, -0.12]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Fasting Glucose
Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) glucose measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Fasting Glucose | 3.67 milligrams/deciliter (mg/dL) | Standard Error 1.36 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Fasting Glucose | -2.22 milligrams/deciliter (mg/dL) | Standard Error 1.47 |
p-value: 0.00295% CI: [2.22, 9.56]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Fasting High-Density Lipoprotein (HDL) Cholesterol
Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) HDL cholesterol measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Fasting High-Density Lipoprotein (HDL) Cholesterol | -1.71 milligrams/deciliter (mg/dL) | Standard Error 0.84 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Fasting High-Density Lipoprotein (HDL) Cholesterol | 2.02 milligrams/deciliter (mg/dL) | Standard Error 0.92 |
p-value: 0.00195% CI: [-5.99, -1.47]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Fasting Low-Density Lipoprotein (LDL) Cholesterol
Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) LDL cholesterol measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Fasting Low-Density Lipoprotein (LDL) Cholesterol | -0.72 milligrams/deciliter (mg/dL) | Standard Error 2.96 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Fasting Low-Density Lipoprotein (LDL) Cholesterol | 0.85 milligrams/deciliter (mg/dL) | Standard Error 3.2 |
p-value: 0.70395% CI: [-9.69, 6.54]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Fasting Total Cholesterol
Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) cholesterol measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Fasting Total Cholesterol | -2.65 milligrams/deciliter (mg/dL) | Standard Error 3.24 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Fasting Total Cholesterol | -1.74 milligrams/deciliter (mg/dL) | Standard Error 3.52 |
p-value: 0.83995% CI: [-9.71, 7.89]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Fasting Triglycerides
Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) triglycerides measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Fasting Triglycerides | -8.24 milligrams/deciliter (mg/dL) | Standard Error 5.7 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Fasting Triglycerides | -21.51 milligrams/deciliter (mg/dL) | Standard Error 6.2 |
p-value: 0.08395% CI: [-1.72, 28.26]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Montgomery-Asberg Depression Rating Scale (MADRS) Using Last Observation Carried Forward (LOCF) Analysis
The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) Mean values were controlled for baseline (Week 20), treatment and country.
Time frame: Randomization (Week 20), up to Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) MADRS measurements. LOCF principle was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Montgomery-Asberg Depression Rating Scale (MADRS) Using Last Observation Carried Forward (LOCF) Analysis | 3.03 units on a scale | Standard Error 0.71 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Montgomery-Asberg Depression Rating Scale (MADRS) Using Last Observation Carried Forward (LOCF) Analysis | 6.84 units on a scale | Standard Error 0.73 |
p-value: <0.00195% CI: [-5.39, -2.24]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Montgomery-Asberg Depression Rating Scale (MADRS) Using Mixed-Effects Model Repeated Measures (MMRM) Analysis
The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) MADRS measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Montgomery-Asberg Depression Rating Scale (MADRS) Using Mixed-Effects Model Repeated Measures (MMRM) Analysis | 2.06 units on a scale | Standard Error 0.56 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Montgomery-Asberg Depression Rating Scale (MADRS) Using Mixed-Effects Model Repeated Measures (MMRM) Analysis | 4.97 units on a scale | Standard Error 0.61 |
p-value: <0.00195% CI: [-4.46, -1.36]t-test, 2 sided
Secondary
Mean Change From Week 20 to Week 47 in Weight
Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and standard error (SE). LS Mean values were controlled for baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) weight measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change From Week 20 to Week 47 in Weight | 1.14 kilograms (kg) | Standard Error 0.33 |
| Flu (SPIV) | Mean Change From Week 20 to Week 47 in Weight | -2.78 kilograms (kg) | Standard Error 0.36 |
p-value: <0.00195% CI: [2.96, 4.88]t-test, 2 sided
Secondary
Mean Change in Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) on Electrocardiogram
Least Squares (LS) Mean values were obtained from a mixed model repeated measures (MMRM) analysis. Model includes baseline (Week 20), treatment, country, visit, and treatment by visit interaction.
Time frame: Randomization (Week 20), Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) electrocardiogram (ECG) measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Mean Change in Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) on Electrocardiogram | -3.12 milliseconds (msec) | Standard Error 1.48 |
| Flu (SPIV) | Mean Change in Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) on Electrocardiogram | -1.55 milliseconds (msec) | Standard Error 1.6 |
p-value: 0.42195% CI: [-5.42, 2.27]t-test, 2 sided
Secondary
Percentage of Participants Achieving Remission at Any Point During Stabilization Treatment Phase
Remission is defined as the Montgomery-Asberg Depression Rating Scale (MADRS) score ≤8. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time frame: Week 8 to Week 20
Population: All participants who entered open-label stabilization treatment phase (SPIII).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percentage of Participants Achieving Remission at Any Point During Stabilization Treatment Phase | 77.9 percentage of participants |
Secondary
Percentage of Participants Maintaining Remission
Remission is defined as the Montgomery-Asberg Depression Rating Scale (MADRS) score ≤8. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percentage of Participants Maintaining Remission | 86.4 percentage of participants |
| Flu (SPIV) | Percentage of Participants Maintaining Remission | 78.9 percentage of participants |
p-value: 0.047Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Maintaining Response at Any Point During Stabilization Treatment Phase
A 50% or greater improvement from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) and a Clinical Global Impressions-Severity (CGI-S) of Depression score ≤3 will be considered as response criteria met. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants).
Time frame: Week 8 to Week 20
Population: All participants who entered open-label stabilization treatment phase (SPIII).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percentage of Participants Maintaining Response at Any Point During Stabilization Treatment Phase | 68.2 percentage of participants |
Secondary
Percentage of Participants Responding to Treatment During Open-Label Acute Treatment Phase
A 50% or greater improvement from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) and a Clinical Global Impressions-Severity (CGI-S) of Depression score ≤3 will be considered as response criteria met. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants).
Time frame: Week 0 to Week 8
Population: All participants who entered open-label acute treatment phase (SPII).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percentage of Participants Responding to Treatment During Open-Label Acute Treatment Phase | 78.0 percentage of participants |
Secondary
Percentage of Participants Who Relapse as Measured by Discontinuation Due to Lack of Efficacy/Worsening of Depression/Suicidality
Lack of Efficacy/Worsening of depression was at the discretion of the investigator and was based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percentage of Participants Who Relapse as Measured by Discontinuation Due to Lack of Efficacy/Worsening of Depression/Suicidality | 10.9 percentage of participants |
| Flu (SPIV) | Percentage of Participants Who Relapse as Measured by Discontinuation Due to Lack of Efficacy/Worsening of Depression/Suicidality | 28.3 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Relapse as Measured by Hospitalization for Depression or Suicidality
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percentage of Participants Who Relapse as Measured by Hospitalization for Depression or Suicidality | 1.8 percentage of participants |
| Flu (SPIV) | Percentage of Participants Who Relapse as Measured by Hospitalization for Depression or Suicidality | 1.3 percentage of participants |
p-value: 0.713Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Relapse Based on Montgomery-Åsberg Depression Rating Scale (MADRS) Score With Concomitant Clinical Global Impressions-Severity (CGI-S) of Depression Score
Relapse is defined as a 50% increase in the Montgomery-Asberg Depression Rating Scale (MADRS) score from randomization with concomitant Clinical Global Impressions-Severity (CGI-S) of Depression score increase to a score of 4 or more. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill).
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percentage of Participants Who Relapse Based on Montgomery-Åsberg Depression Rating Scale (MADRS) Score With Concomitant Clinical Global Impressions-Severity (CGI-S) of Depression Score | 14.0 percentage of participants |
| Flu (SPIV) | Percentage of Participants Who Relapse Based on Montgomery-Åsberg Depression Rating Scale (MADRS) Score With Concomitant Clinical Global Impressions-Severity (CGI-S) of Depression Score | 28.3 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Relapse by Any Criteria
Relapse is defined as meeting any of the following criteria: 50% increase in Montgomery-Asberg Depression Rating Scale (MADRS) score from randomization with concomitant Clinical Global Impressions-Severity (CGI-S) of Depression score increase to a score of 4 or more; Hospitalization for depression or suicidality; Discontinuation due to lack of efficacy/worsening of depression/suicidality. MADRS is a rating scale for severity of depressive mood symptoms with 10 items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). Lack of Efficacy/Worsening of depression was at the discretion of the investigator and based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percentage of Participants Who Relapse by Any Criteria | 15.8 percentage of participants |
| Flu (SPIV) | Percentage of Participants Who Relapse by Any Criteria | 31.8 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percent of Participants With a 60 Milliseconds (Msec) Increase in Fridericia-Corrected (for Rate) Cardiac QT Interval (QTcF) on Electrocardiogram
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) electrocardiogram (ECG) measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percent of Participants With a 60 Milliseconds (Msec) Increase in Fridericia-Corrected (for Rate) Cardiac QT Interval (QTcF) on Electrocardiogram | 0 percentage of participants |
| Flu (SPIV) | Percent of Participants With a 60 Milliseconds (Msec) Increase in Fridericia-Corrected (for Rate) Cardiac QT Interval (QTcF) on Electrocardiogram | 0 percentage of participants |
Secondary
Percent of Participants With Suicide-Related Thoughts and Behaviors
Columbia Suicide Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a yes answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) C-SSRS measurements.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OFC (SPIV) | Percent of Participants With Suicide-Related Thoughts and Behaviors | Suicidal Ideation | 4.1 percentage of participants |
| OFC (SPIV) | Percent of Participants With Suicide-Related Thoughts and Behaviors | Suicidal Behavior | 0 percentage of participants |
| Flu (SPIV) | Percent of Participants With Suicide-Related Thoughts and Behaviors | Suicidal Ideation | 6.3 percentage of participants |
| Flu (SPIV) | Percent of Participants With Suicide-Related Thoughts and Behaviors | Suicidal Behavior | 0 percentage of participants |
p-value: 0.392Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent Akathisia
Barnes Akathisia Scale (BAS) rates observable, restless movements of drug-induced akathisia as well as the subjective awareness of restlessness and any distress associated with the akathisia. It consists of 4 items. 3 items (objective akathisia, subjective awareness of restlessness and subjective distress related to restlessness) rated on a 4-point scale, with 0 being no akathisia and 3 being severe akathisia. Item 4 (global clinical assessment of Akathisia) is derived from the responses on Items 1-3 rated on a 6-point scale, with 0 being absence and 5 being extreme Akathisia. Treatment emergent akathisia is defined as a global clinical assessment score on BAS \<2 at baseline (Week 20) and a global clinical assessment score on BAS ≥2 post-baseline (Weeks 21-47).
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) BAS measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent Akathisia | 0.9 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent Akathisia | 0.9 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) on Electrocardiogram ≥500 Milliseconds (Msec)
Data presented are the percent of participants whose baseline corrected (for rate) cardiac QT interval \<500 msec with post-baseline corrected (for rate) cardiac QT interval ≥500 msec.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had \<500 msec QTc interval at baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) electrocardiogram (ECG) measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) on Electrocardiogram ≥500 Milliseconds (Msec) | 0 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) on Electrocardiogram ≥500 Milliseconds (Msec) | 0 percentage of participants |
Secondary
Percent of Participants With Treatment-Emergent Dyskinesia
Abnormal Involuntary Movement Scale (AIMS) is a 12-item scale designed to record the occurrence of dyskinetic movements. Items 1 through 10 are rated on a 5-point scale, with 0 being no dyskinetic movements and 4 being severe dyskinetic movements. Items 11 and 12 are yes/no questions regarding the dental condition of the participants. Treatment emergent dyskinesia is defined as a score ≥3 on any one of the AIMS items 1-7 post-baseline (Weeks 21-47) or scores ≥2 on any two of the AIMS items 1-7 post-baseline (Weeks 21-47) among participants without either criteria at baseline (Week 20).
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) AIMS measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent Dyskinesia | 0.5 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent Dyskinesia | 0.0 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent Hepatic Events
Participants with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<=3 times the upper limit of normal (ULN) at baseline, with ALT or AST \>=3 times the ULN post-baseline and total bilirubin \>=2 times ULN at the same time are considered having treatment-emergent hepatic events.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had baseline (Week 20) and post-baseline (Weeks 21-47) hepatic function measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent Hepatic Events | 0.0 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent Hepatic Events | 0.0 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent High Fasting Glucose
Impaired to High fasting glucose: ≥100 milligrams/deciliter (mg/dL) and \<126 mg/dL at baseline and ≥126 mg/dL any time post baseline; Normal to High glucose: \<100 mg/dL at baseline and ≥126 mg/dL any time post baseline; Normal to Impaired fasting glucose is \<100 mg/dL at baseline, ≥100 mg/dL and \<126 mg/dL any time post baseline; Normal/Impaired to High fasting glucose: \<126 mg/dL at baseline and ≥126 mg/dL any time post baseline.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had impaired or normal glucose value at baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) glucose measurements.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Glucose | Impaired to High (n=98, 97) | 18.4 percentage of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Glucose | Normal to High (n=90, 96) | 4.4 percentage of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Glucose | Normal to Impaired (n=90, 96) | 35.6 percentage of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Glucose | Normal/Impaired to High (n= 188, 193) | 11.7 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Glucose | Normal/Impaired to High (n= 188, 193) | 6.2 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Glucose | Impaired to High (n=98, 97) | 7.2 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Glucose | Normal to Impaired (n=90, 96) | 28.1 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Glucose | Normal to High (n=90, 96) | 5.2 percentage of participants |
p-value: 0.031Fisher Exact
p-value: 1Fisher Exact
p-value: 0.344Fisher Exact
p-value: 0.072Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent High Fasting Low-Density Lipoprotein (LDL) Cholesterol
Borderline to High fasting LDL cholesterol: ≥100 milligrams/deciliter (mg/dL) and \<160 mg/dL at baseline and ≥160 mg/dL any time post baseline; Normal to Borderline fasting LDL cholesterol: \<100 mg/dL at baseline, ≥100 mg/dL and \<160 mg/dL any time post baseline; Normal to High fasting LDL cholesterol: \<100 mg/dL at baseline and ≥160 mg/dL any time post baseline.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had borderline or normal LDL cholesterol value at baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) LDL cholesterol measurements.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Low-Density Lipoprotein (LDL) Cholesterol | Borderline to High (n= 115, 134) | 17.4 percent of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Low-Density Lipoprotein (LDL) Cholesterol | Normal to Borderline (n=22, 26) | 22.7 percent of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Low-Density Lipoprotein (LDL) Cholesterol | Normal to High (n=22, 26) | 4.5 percent of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Low-Density Lipoprotein (LDL) Cholesterol | Borderline to High (n= 115, 134) | 10.4 percent of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Low-Density Lipoprotein (LDL) Cholesterol | Normal to Borderline (n=22, 26) | 30.8 percent of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Low-Density Lipoprotein (LDL) Cholesterol | Normal to High (n=22, 26) | 0.0 percent of participants |
p-value: 0.139Fisher Exact
p-value: 0.746Fisher Exact
p-value: 0.458Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent High Fasting Total Cholesterol
Borderline to High fasting total cholesterol: ≥200 milligrams/deciliter (mg/dL) and \<240 mg/dL at baseline and ≥240 mg/dL any time post baseline; Normal to Borderline fasting total cholesterol: \<200 mg/dL at baseline, ≥200 mg/dL and \<240 mg/dL any time post baseline; Normal to High fasting total cholesterol: \<200 mg/dL at baseline and ≥240 mg/dL any time post baseline.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had borderline or normal cholesterol level at baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) cholesterol measurements.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Total Cholesterol | Borderline to High (n= 75, 83) | 28.0 percentage of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Total Cholesterol | Normal to Borderline (n=47, 59) | 17.0 percentage of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Total Cholesterol | Normal to High (n=47, 59) | 2.1 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Total Cholesterol | Borderline to High (n= 75, 83) | 20.5 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Total Cholesterol | Normal to Borderline (n=47, 59) | 16.9 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Total Cholesterol | Normal to High (n=47, 59) | 3.4 percentage of participants |
p-value: 0.352Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent High Fasting Triglycerides
Borderline to High fasting triglycerides: ≥150 milligrams/deciliter (mg/dL) and \<200 mg/dL at baseline and ≥200 mg/dL any time post baseline; Normal to Borderline fasting triglycerides: \<150 mg/dL at baseline, ≥150 mg/dL and \<200 mg/dL any time post baseline; Normal to High fasting triglycerides: \<150 mg/dL at baseline and ≥200 mg/dL any time post baseline.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had borderline or normal triglycerides value at baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) triglyceride measurements.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Triglycerides | Borderline to High (n=47, 41) | 51.1 percentage of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Triglycerides | Normal to Borderline (n= 68, 74) | 22.1 percentage of participants |
| OFC (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Triglycerides | Normal to High (n=68, 74) | 16.2 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Triglycerides | Borderline to High (n=47, 41) | 26.8 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Triglycerides | Normal to Borderline (n= 68, 74) | 6.8 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent High Fasting Triglycerides | Normal to High (n=68, 74) | 5.4 percentage of participants |
p-value: 0.029Fisher Exact
p-value: 0.014Fisher Exact
p-value: 0.054Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent Low Fasting High-Density Lipoprotein (HDL) Cholesterol
Normal to Low fasting HDL cholesterol is ≥40 milligrams/deciliter (mg/dL) at baseline and \<40 mg/dL anytime post baseline.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had normal HDL cholesterol value at baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) HDL cholesterol measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent Low Fasting High-Density Lipoprotein (HDL) Cholesterol | 39.2 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent Low Fasting High-Density Lipoprotein (HDL) Cholesterol | 25.5 percentage of participants |
p-value: 0.004Fisher Exact
Secondary
Percent of Participants With Treatment-Emergent Parkinsonism
Simpson-Angus Scale is used to measure Parkinsonian-type symptoms in participants exposed to neuroleptics. The scale consists of 10 items, each rated on a 5-point scale, with 0 meaning complete absence of the condition and 4 meaning the presence of the condition in extreme form. The total score is obtained by adding the items and ranges from 0-40 with higher scores indicating worse conditions. Treatment emergent parkinsonism is defined as total score ≤3 of items 1 through 10 of the Simpson-Angus scale at baseline (Week 20) and a total score \>3 of items 1 through 10 post-baseline (Weeks 21-47).
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who had baseline (Week 20) and at least 1 post-baseline (Weeks 21-47) Simpson-Angus Scale measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percent of Participants With Treatment-Emergent Parkinsonism | 1.4 percentage of participants |
| Flu (SPIV) | Percent of Participants With Treatment-Emergent Parkinsonism | 0.0 percentage of participants |
p-value: 0.248Fisher Exact
Secondary
Percent of Participants With Week 20-to-Week 47 Endpoint Increase in Weight of at Least 7%
Time frame: Week 20 to Week 47
Population: All randomized participants who had Week 20 and at least 1 post-baseline (Weeks 21-47) weight measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OFC (SPIV) | Percent of Participants With Week 20-to-Week 47 Endpoint Increase in Weight of at Least 7% | 11.8 percentage of participants |
| Flu (SPIV) | Percent of Participants With Week 20-to-Week 47 Endpoint Increase in Weight of at Least 7% | 2.3 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Resource Utilization - Average Number of Hours Worked for Pay Per Week at Week 47
Time frame: Week 47
Population: All randomized participants who worked for pay at Week 47.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Resource Utilization - Average Number of Hours Worked for Pay Per Week at Week 47 | 37.49 hours | Standard Deviation 16.95 |
| Flu (SPIV) | Resource Utilization - Average Number of Hours Worked for Pay Per Week at Week 47 | 37.76 hours | Standard Deviation 14.58 |
Secondary
Resource Utilization (Number of Psychiatric Visits, Number of Emergency Room or Equivalent Facility Visits for Psychiatric Illness)
Resource utilization is defined as the average number of psychiatric visits and number of emergency room or equivalent facility visits for psychiatric illness.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants who provided information of psychiatric visits and emergency room or equivalent facility visits for psychiatric illness from Week 21 to Week 47.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OFC (SPIV) | Resource Utilization (Number of Psychiatric Visits, Number of Emergency Room or Equivalent Facility Visits for Psychiatric Illness) | Psychiatric visits (n=136, 113) | 0.65 visits per participant | Standard Deviation 1.43 |
| OFC (SPIV) | Resource Utilization (Number of Psychiatric Visits, Number of Emergency Room or Equivalent Facility Visits for Psychiatric Illness) | Emergency room or equivalent facility visits | 0.00 visits per participant | Standard Deviation 0 |
| Flu (SPIV) | Resource Utilization (Number of Psychiatric Visits, Number of Emergency Room or Equivalent Facility Visits for Psychiatric Illness) | Emergency room or equivalent facility visits | 0.00 visits per participant | Standard Deviation 0 |
| Flu (SPIV) | Resource Utilization (Number of Psychiatric Visits, Number of Emergency Room or Equivalent Facility Visits for Psychiatric Illness) | Psychiatric visits (n=136, 113) | 0.81 visits per participant | Standard Deviation 1.52 |
Secondary
Time to Relapse as Measured by Discontinuation Due to Lack of Efficacy/Worsening of Depression/Suicidality
Lack of Efficacy/Worsening of depression was at the discretion of the investigator and was based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator. Those who did not relapse were censored at their last observation.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants are included in the time to event analyses. The numbers of participants censored are 197 and 160 for OFC and Flu groups, respectively.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Time to Relapse as Measured by Discontinuation Due to Lack of Efficacy/Worsening of Depression/Suicidality | NA days | Full Range 11.8 |
| Flu (SPIV) | Time to Relapse as Measured by Discontinuation Due to Lack of Efficacy/Worsening of Depression/Suicidality | NA days | Full Range 5.3 |
p-value: <0.001Log Rank
Secondary
Time to Relapse as Measured by Hospitalization for Depression or Suicidality
Those who did not relapse were censored at their last observation.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants are included in the time to event analyses. The numbers of participants censored are 217 and 220 for OFC and Flu groups, respectively.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Time to Relapse as Measured by Hospitalization for Depression or Suicidality | NA days | Full Range 29.9 |
| Flu (SPIV) | Time to Relapse as Measured by Hospitalization for Depression or Suicidality | NA days | Full Range 4.3 |
p-value: 0.831Log Rank
Secondary
Time to Relapse Based on the Montgomery-Åsberg Depression Rating Scale (MADRS) Score With Concomitant Clinical Global Impressions-Severity (CGI-S) of Depression Score
Relapse is defined as a 50% increase in the Montgomery-Asberg Depression Rating Scale (MADRS) score from randomization with concomitant Clinical Global Impressions-Severity (CGI-S) of Depression score increase to a score of 4 or more. The MADRS has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). Those who did not relapse were censored at their last observation.
Time frame: Randomization (Week 20) to Week 47
Population: All randomized participants are included in the time to event analyses. The numbers of participants censored are 190 and 160 for OFC and Flu groups, respectively.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| OFC (SPIV) | Time to Relapse Based on the Montgomery-Åsberg Depression Rating Scale (MADRS) Score With Concomitant Clinical Global Impressions-Severity (CGI-S) of Depression Score | NA days | Full Range 10.4 |
| Flu (SPIV) | Time to Relapse Based on the Montgomery-Åsberg Depression Rating Scale (MADRS) Score With Concomitant Clinical Global Impressions-Severity (CGI-S) of Depression Score | NA days | Full Range 6.2 |
p-value: <0.001Log Rank
Other Pre-specified
Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189)
Relapse is defined as meeting any of the following criteria (Relapse-any reason): 50% increase in MADRS score from randomization with concomitant CGI-S of Depression score increase to a score of 4 or more (MADRS score/CGI-S Depression Score); Hospitalization for depression or suicidality; Discontinuation due to lack of efficacy/worsening of depression/suicidality. MADRS is a rating scale for severity of depressive mood symptoms with 10 items rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). CGI-S measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (the most extremely ill). Lack of Efficacy/Worsening of depression was at the discretion of the investigator and based on clinical observation. Suicidality is thoughts or actions of self-harm as determined by the investigator.
Time frame: Randomization (Week 20) to Week 27
Population: All randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OFC (SPIV) | Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Relapse-any criteria | 83.6 percentage of participants |
| OFC (SPIV) | Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Relapse-MADRS score/CGI-S Depression Score | 85.3 percentage of participants |
| OFC (SPIV) | Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Relapse-Hospitalization for depression/suicidality | 97.7 percentage of participants |
| OFC (SPIV) | Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Relapse-Discontinued for lack efficacy/worsening | 87.4 percentage of participants |
| Flu (SPIV) | Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Relapse-Discontinued for lack efficacy/worsening | 69.8 percentage of participants |
| Flu (SPIV) | Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Relapse-any criteria | 66.5 percentage of participants |
| Flu (SPIV) | Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Relapse-Hospitalization for depression/suicidality | 98.6 percentage of participants |
| Flu (SPIV) | Kaplan-Meier Estimate of Percentage of Subjects Not Relapsing at Week 27 (Day 189) | Relapse-MADRS score/CGI-S Depression Score | 69.6 percentage of participants |