Major Depressive Disorder
Conditions
Brief summary
This study will evaluate the safety and effectiveness of fluoxetine flexible dosing in the treatment of MDD in adult Japanese participants. Participants who complete the short-term treatment phase of Study B1Y-JE-HCLV (NCT#: NCT01808612) will be allowed to enroll in this study, and receive fluoxetine treatment for an additional 52 weeks.
Interventions
DRUGFluoxetine
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have completed Study B1Y-JE-HCLV (NCT#:NCT01808612) * Agree to abstain from sexual activity or to use a reliable method of birth control
Exclusion criteria
* Significant suicidal risk * Have a current or previous diagnosis of bipolar disorder, psychotic depression, schizophrenia or other psychotic disorder, anorexia, bulimia, obsessive compulsive disorder, or post-traumatic stress disorder * Have a history of substance abuse or dependence within the past 6 months, excluding caffeine and nicotine * Need to use thioridazine or pimozide during the study * Have a positive urine drug screen for drugs with abuse potential * Female participants who are either pregnant, nursing, or have recently given birth, or male participants who are planning for their partners to be or become pregnant * Have frequent or severe allergic reactions to multiple medications * Have a serious or unstable medical illness or condition, or psychological condition * Participants deemed ineligible by the investigator or sub-investigator for other reasons
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) | Baseline through Week 52. | — |
| Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia - Suicide Severity Rating Scale (C-SSRS) | Baseline through Week 52 | C-SSRS captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior is defined as a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation is defined as a yes answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving a Remission at Week 52 | up to Week 52 | The percentage of participants achieving a remission (defined as a HAMD21 total score ≤7) was calculated by dividing the number of participants achieving a remission at last observation by the total number of participants at risk, multiplied by 100. |
| Mean Change From Baseline to Week 52 on the Clinical Global Impression of Severity (CGI-S) Scale | Baseline, Week 52 | CGI-S measures severity of illness at the time of assessment with scores ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). LS means were calculated using MMRM adjusting for the random effect of participant and fixed categorical effects of treatment, pooled investigative site, visit, and treatment-by-visit interaction, as well as the continuous fixed covariate of baseline CGI-S score. |
| Mean Change From Baseline to Week 52 on the 21-Item Hamilton Depression Rating Scale (HAMD21) Total Score | Baseline, Week 52 | HAMD21 is a 21-item assessment used to measure depression severity. Items were rated on a scale from 0 (symptoms not present) to a maximum of 2 to 4 (symptom extremely severe) for a total score ranging from 0 (not at all depressed) to 64 (severely depressed). Least squares (LS) means were calculated using mixed-model repeated measures (MMRM) adjusting for the random effect of participant and fixed categorical effects of treatment, pooled investigative site, visit, and treatment-by-visit interaction, as well as the continuous fixed covariate of baseline HAMD21 total score. |
| Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Baseline up to 52 weeks | SDS was completed by the participant and was used to assess the effect of the participant's symptoms on their work/school (Item 1), social life/leisure activities (Item 2), and family life/home responsibilities (Item 3). Each item was measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total score was the sum of the 3 items and ranged from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. LS means were calculated using analysis of covariance (ANCOVA) adjusting for treatment, pooled investigative site, and baseline SDS score. |
| Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Baseline, Week 52 | HAMD17 total scores and subscale scores from the HAMD21 are presented. HAMD17 is a 17-item assessment of depression severity (total scores range from 0-52). The Maier subscale (Items 1, 2, 7-10) represents the core symptoms of depression (0-24). Anxiety/Somatization subscale (Items 10-13, 15, 17) evaluates severity of psychic and somatic manifestations of anxiety as well as agitation (0-18). Retardation/Somatization subscale (Items 1, 7, 8, 14) evaluates dysfunction in mood, work, and sexual activity, as well as overall motor retardation (0-14). Sleep subscale (Items 4-6) assesses insomnia (0-6). Individual item scores may range from 0-4 or 0-2. Higher scores indicate more severe symptoms. LS means were calculated using MMRM adjusting for the random effect of participant and fixed categorical effects of treatment, pooled investigative site, visit, and treatment-by-visit interaction, as well as the continuous fixed covariate of baseline score. |
| Percentage of Participants Achieving a Response at Week 52 | Baseline, up to Week 52 | The percentage of participants achieving a response (defined as a ≥50% improvement from baseline on the HAMD21 total score) was calculated by dividing the number of participants achieving a response at last observation by the total number of participants at risk, multiplied by 100. |
Countries
Japan
Participant flow
Pre-assignment details
This study consisted of 2 study periods for Japanese participants who completed acute treatment in Study B1Y-JE-HCLV(NCT#: NCT01808612): Study period I was a 52-week open-label treatment period with fluoxetine 20 to 40 milligrams (mg), administered once daily, and Study period II was a 2-wk observation phase following discontinuation of fluoxetine.
Participants by arm
| Arm | Count |
|---|---|
| PLA/FLX (Placebo/Fluoxetine) Participants randomized to placebo in Study B1Y-JE-HCLV and transitioned to fluoxetine (20-40 mg/day) in Study B1Y-JE-HCLW. | 98 |
| FLX20/FLX Participants randomized to fluoxetine 20 mg/day in Study B1Y-JE-HCLV and continued on fluoxetine (20-40 mg/day) in Study B1Y-JE-HCLW. | 65 |
| FLX40/FLX Participants randomized to fluoxetine 40 mg/day in Study B1Y-JE-HCLV and continued on fluoxetine (20-40 mg/day) in Study B1Y-JE-HCLW. | 36 |
| Total | 199 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Study Period 1 | Adverse Event | 10 | 4 | 1 |
| Study Period 1 | Lack of Efficacy | 2 | 1 | 0 |
| Study Period 1 | Lost to Follow-up | 1 | 3 | 0 |
| Study Period 1 | Participant Decision | 9 | 7 | 3 |
| Study Period 1 | Physician Decision | 3 | 2 | 0 |
| Study Period 1 | Protocol Violation | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | PLA/FLX (Placebo/Fluoxetine) | FLX20/FLX | FLX40/FLX |
|---|---|---|---|---|
| Age, Continuous | 39.44 years STANDARD_DEVIATION 11.88 | 38.60 years STANDARD_DEVIATION 12.95 | 39.72 years STANDARD_DEVIATION 10.91 | 41.20 years STANDARD_DEVIATION 10.51 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 199 Participants | 98 Participants | 65 Participants | 36 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 199 participants | 98 participants | 65 participants | 36 participants |
| Sex: Female, Male Female | 99 Participants | 47 Participants | 33 Participants | 19 Participants |
| Sex: Female, Male Male | 100 Participants | 51 Participants | 32 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 74 / 98 | 46 / 65 | 29 / 36 | 5 / 77 | 7 / 52 | 1 / 33 |
| serious Total, serious adverse events | 2 / 98 | 1 / 65 | 0 / 36 | 0 / 77 | 1 / 52 | 0 / 33 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs)
Time frame: Baseline through Week 52.
Population: Participants who received at least 1 dose of the study drug were evaluated for AEs and SAEs. SAE reported for 1 participant (FLX20/FLX) was a pre-existing condition prior to Study Period 1 that became an SAE after Study Period 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PLA/FLX | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) | Participants with >=1 SAE | 2 participants |
| PLA/FLX | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) | Participants with >=1 AEs | 75 participants |
| FLX20/FLX | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) | Participants with >=1 SAE | 1 participants |
| FLX20/FLX | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) | Participants with >=1 AEs | 46 participants |
| FLX40/FLX | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) | Participants with >=1 SAE | 0 participants |
| FLX40/FLX | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) | Participants with >=1 AEs | 29 participants |
Primary
Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia - Suicide Severity Rating Scale (C-SSRS)
C-SSRS captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior is defined as a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation is defined as a yes answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation.
Time frame: Baseline through Week 52
Population: Participants who received at least 1 dose of study drug with at least 1 post-baseline C-SSRS score during Study Period 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLA/FLX | Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia - Suicide Severity Rating Scale (C-SSRS) | 8 participants |
| FLX20/FLX | Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia - Suicide Severity Rating Scale (C-SSRS) | 4 participants |
| FLX40/FLX | Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia - Suicide Severity Rating Scale (C-SSRS) | 0 participants |
Secondary
Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores
SDS was completed by the participant and was used to assess the effect of the participant's symptoms on their work/school (Item 1), social life/leisure activities (Item 2), and family life/home responsibilities (Item 3). Each item was measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total score was the sum of the 3 items and ranged from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. LS means were calculated using analysis of covariance (ANCOVA) adjusting for treatment, pooled investigative site, and baseline SDS score.
Time frame: Baseline up to 52 weeks
Population: Participants who received at least 1 dose of study drug with a baseline and at least 1 post-baseline SDS score. Missing endpoints were imputed with the last observation carried forward (LOCF) method, using only post-baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| PLA/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | SDS Total Score | -6.53 units on a scale | Standard Error 0.78 |
| PLA/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Work/School subscale (N:85, 60, 28) | -2.46 units on a scale | Standard Error 0.32 |
| PLA/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Social/Leisure subscale (N:98, 64, 36) | -2.11 units on a scale | Standard Error 0.28 |
| PLA/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Family/Home subscale (N:98,64,36) | -1.93 units on a scale | Standard Error 0.25 |
| FLX20/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Family/Home subscale (N:98,64,36) | -1.55 units on a scale | Standard Error 0.31 |
| FLX20/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | SDS Total Score | -6.17 units on a scale | Standard Error 0.97 |
| FLX20/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Social/Leisure subscale (N:98, 64, 36) | -2.11 units on a scale | Standard Error 0.35 |
| FLX20/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Work/School subscale (N:85, 60, 28) | -2.62 units on a scale | Standard Error 0.38 |
| FLX40/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Family/Home subscale (N:98,64,36) | -2.01 units on a scale | Standard Error 0.41 |
| FLX40/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Work/School subscale (N:85, 60, 28) | -2.24 units on a scale | Standard Error 0.56 |
| FLX40/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | Social/Leisure subscale (N:98, 64, 36) | -2.06 units on a scale | Standard Error 0.47 |
| FLX40/FLX | Change From Baseline to Week 52 in Sheehan Disability Scale (SDS) Total Score and Subscale Scores | SDS Total Score | -6.14 units on a scale | Standard Error 1.28 |
Secondary
Mean Change From Baseline to Week 52 on the 21-Item Hamilton Depression Rating Scale (HAMD21) Total Score
HAMD21 is a 21-item assessment used to measure depression severity. Items were rated on a scale from 0 (symptoms not present) to a maximum of 2 to 4 (symptom extremely severe) for a total score ranging from 0 (not at all depressed) to 64 (severely depressed). Least squares (LS) means were calculated using mixed-model repeated measures (MMRM) adjusting for the random effect of participant and fixed categorical effects of treatment, pooled investigative site, visit, and treatment-by-visit interaction, as well as the continuous fixed covariate of baseline HAMD21 total score.
Time frame: Baseline, Week 52
Population: Participants who received at least 1 dose of study drug with a baseline and at least 1 post-baseline HAMD21 total score during Study Period 1.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PLA/FLX | Mean Change From Baseline to Week 52 on the 21-Item Hamilton Depression Rating Scale (HAMD21) Total Score | -10.04 units on a scale | Standard Error 0.73 |
| FLX20/FLX | Mean Change From Baseline to Week 52 on the 21-Item Hamilton Depression Rating Scale (HAMD21) Total Score | -11.25 units on a scale | Standard Error 0.9 |
| FLX40/FLX | Mean Change From Baseline to Week 52 on the 21-Item Hamilton Depression Rating Scale (HAMD21) Total Score | -11.70 units on a scale | Standard Error 1.16 |
Secondary
Mean Change From Baseline to Week 52 on the Clinical Global Impression of Severity (CGI-S) Scale
CGI-S measures severity of illness at the time of assessment with scores ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). LS means were calculated using MMRM adjusting for the random effect of participant and fixed categorical effects of treatment, pooled investigative site, visit, and treatment-by-visit interaction, as well as the continuous fixed covariate of baseline CGI-S score.
Time frame: Baseline, Week 52
Population: Participants who received at least 1 dose of study drug with a baseline and at least 1 post-baseline CGI-S score during the Treatment Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PLA/FLX | Mean Change From Baseline to Week 52 on the Clinical Global Impression of Severity (CGI-S) Scale | -1.41 units on a scale | Standard Error 0.1 |
| FLX20/FLX | Mean Change From Baseline to Week 52 on the Clinical Global Impression of Severity (CGI-S) Scale | -1.45 units on a scale | Standard Error 0.13 |
| FLX40/FLX | Mean Change From Baseline to Week 52 on the Clinical Global Impression of Severity (CGI-S) Scale | -1.64 units on a scale | Standard Error 0.16 |
Secondary
Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores
HAMD17 total scores and subscale scores from the HAMD21 are presented. HAMD17 is a 17-item assessment of depression severity (total scores range from 0-52). The Maier subscale (Items 1, 2, 7-10) represents the core symptoms of depression (0-24). Anxiety/Somatization subscale (Items 10-13, 15, 17) evaluates severity of psychic and somatic manifestations of anxiety as well as agitation (0-18). Retardation/Somatization subscale (Items 1, 7, 8, 14) evaluates dysfunction in mood, work, and sexual activity, as well as overall motor retardation (0-14). Sleep subscale (Items 4-6) assesses insomnia (0-6). Individual item scores may range from 0-4 or 0-2. Higher scores indicate more severe symptoms. LS means were calculated using MMRM adjusting for the random effect of participant and fixed categorical effects of treatment, pooled investigative site, visit, and treatment-by-visit interaction, as well as the continuous fixed covariate of baseline score.
Time frame: Baseline, Week 52
Population: Participants who received at least 1 dose of study drug with a baseline and at least 1 post-baseline HAMD21 subscale score. LSM (least square mean) and SE (standard error) are from visit 16.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| PLA/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Sleep subscale score | -1.49 units on a scale | Standard Error 0.15 |
| PLA/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Retardation/Somatization subscale score | -3.45 units on a scale | Standard Error 0.26 |
| PLA/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | HAMD17 total scale | -9.06 units on a scale | Standard Error 0.67 |
| PLA/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Anxiety/Somatization subscale score | -3.08 units on a scale | Standard Error 0.25 |
| PLA/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Maier subscale score | -4.73 units on a scale | Standard Error 0.37 |
| FLX20/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Anxiety/Somatization subscale score | -3.16 units on a scale | Standard Error 0.31 |
| FLX20/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Retardation/Somatization subscale score | -3.98 units on a scale | Standard Error 0.32 |
| FLX20/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Sleep subscale score | -1.34 units on a scale | Standard Error 0.18 |
| FLX20/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | HAMD17 total scale | -10.20 units on a scale | Standard Error 0.83 |
| FLX20/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Maier subscale score | -5.55 units on a scale | Standard Error 0.46 |
| FLX40/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | HAMD17 total scale | -10.51 units on a scale | Standard Error 1.07 |
| FLX40/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Retardation/Somatization subscale score | -3.55 units on a scale | Standard Error 0.42 |
| FLX40/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Anxiety/Somatization subscale score | -3.61 units on a scale | Standard Error 0.39 |
| FLX40/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Sleep subscale score | -1.95 units on a scale | Standard Error 0.23 |
| FLX40/FLX | Mean Change From Baseline to Week 52 on the HAMD21 Subscale Scores | Maier subscale score | -5.02 units on a scale | Standard Error 0.6 |
Secondary
Percentage of Participants Achieving a Remission at Week 52
The percentage of participants achieving a remission (defined as a HAMD21 total score ≤7) was calculated by dividing the number of participants achieving a remission at last observation by the total number of participants at risk, multiplied by 100.
Time frame: up to Week 52
Population: Participants who received at least 1 dose of study drug with a baseline (which had not achieved remission threshold criteria) and had at least 1 post-baseline HAMD21 total score during the Treatment Period. Missing endpoints were imputed with the last observation carried forward (LOCF) method, using only post-baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLA/FLX | Percentage of Participants Achieving a Remission at Week 52 | 64 percentage of participants |
| FLX20/FLX | Percentage of Participants Achieving a Remission at Week 52 | 57 percentage of participants |
| FLX40/FLX | Percentage of Participants Achieving a Remission at Week 52 | 76 percentage of participants |
Secondary
Percentage of Participants Achieving a Response at Week 52
The percentage of participants achieving a response (defined as a ≥50% improvement from baseline on the HAMD21 total score) was calculated by dividing the number of participants achieving a response at last observation by the total number of participants at risk, multiplied by 100.
Time frame: Baseline, up to Week 52
Population: Participants who received at least 1 dose of study drug with a baseline and at least 1 post-baseline HAMD21 total score during the Treatment Period. Missing endpoints were imputed with the last observation carried forward (LOCF) method, using only post-baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLA/FLX | Percentage of Participants Achieving a Response at Week 52 | 68 Percentage of participants |
| FLX20/FLX | Percentage of Participants Achieving a Response at Week 52 | 65 Percentage of participants |
| FLX40/FLX | Percentage of Participants Achieving a Response at Week 52 | 83 Percentage of participants |