Major Depressive Disorder
Conditions
Brief summary
The purpose of this study is to find out if 60 mg of duloxetine given once a day by mouth for 8 weeks to patients diagnosed with major depressive disorder, who also report associated painful physical symptoms, is better than placebo when treating depression and its associated painful symptoms.
Interventions
DRUGDuloxetine
Participants received 30 mg duloxetine once daily (QD) by mouth (po) for 1 week followed by 60 mg QD, po for 7 weeks.
DRUGPlacebo
Participants received placebo QD, po for 8 weeks.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meets criteria for Major Depressive Disorder (MDD) as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) and confirmed by Mini International Neuropsychiatric Interview (MINI) * Montgomery-Asberg Depression Rating Scale (MADRS) total score of greater than or equal to 20 during the Screening Phase * At least 1 previous episode of depression * Painful physical symptoms with a score greater than or equal to 3 on the Brief Pain Inventory-Short Form (BPI-SF) average pain question during the Screening Phase * A Clinical Global Impression of Severity (CGI-S) score of greater than or equal to 4 during the Screening Phase * Written informed consent
Exclusion criteria
* Currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device * Previously completed or withdrawn from this study or any other study investigating duloxetine * Women of child-bearing potential who are not using a medically accepted means of contraception * Any current (within the past 6 months) DSM-IV-TR primary Axis I diagnosis other than MDD * History of alcohol abuse or dependence within 1 year immediately prior to being screened for the study * Any prior history of bipolar disorder, psychosis, or schizophrenia * Have an Axis II disorder that would interfere with study compliance * Lack of a response of any (lifetime of subject) episode of major depression greater than or equal to 2 adequate courses of antidepressant therapy, defined as a clinically appropriate dose for a minimum of 4 weeks or, alternatively, in the judgment of the investigator, the subject meets criteria for treatment-resistant depression * Have previously received treatment of MDD or Generalized Anxiety Disorder (GAD) with an adequate trial of duloxetine and did not respond or could not tolerate duloxetine * Diagnosis of acute liver injury or severe cirrhosis * Uncontrolled narrow-angle glaucoma * Positive urine drug screen for any substance of abuse. * A serious medical illness, including any cardiovascular, hepatic, renal, respiratory, hematologic, endocrinologic, or neurologic disease, or a clinically significant laboratory abnormality that is not stabilized or is anticipated to require intervention * A history of substance abuse or dependence within 1 year before being screened for the study * History of a serious suicide attempt or subject judged clinically to be at serious suicidal risk * Require continuous use of opioid analgesics for 6 or more months because of chronic pain * Pain of a known origin * Meets criteria for fibromyalgia as defined by the American College of Rheumatology * Experiences greater than or equal to 1 migraine headache per week * Have had electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or vagus nerve stimulation (VNS) within 1 year prior to being screened for the study * Initiating, changing, or stopping psychotherapy within 6 weeks prior to being screened for the study or at any time during the study * Investigator or subject anticipates initiating, changing, or stopping non-pharmacologic or alternative therapies for painful physical symptoms at any time during the study * Are taking any excluded medications within 7 days prior to randomization with the exception of fluoxetine which cannot be taken within 30 days prior to randomization * Treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to randomization or have the potential need to use an MAOI during the study or within 5 days of discontinuing study drug * Frequent and/or severe allergic reactions with multiple medications * Abnormal thyroid stimulating hormone concentration * Has epilepsy or history of seizure disorder or received treatment with anticonvulsant medication for epilepsy or seizures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 8 | Baseline, 8 weeks | The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are 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). The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction. |
| Change From Baseline in the Brief Pain Inventory-Short Form (BPI-SF) Average Pain Score During the 8-week Treatment Period | Day 1 through 8 weeks | A self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). The overall change is based on the estimated main treatment effect. The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Percentage of Participants Achieving Remission up to Week 8 | Baseline, up to 8 weeks | The Montgomery Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are 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). Remission is defined as achieving a MADRS total score ≤12. |
| Percentage of Participants Achieving Remission up to Week 8 | Up to 8 weeks | The Montgomery Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale from 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Remission is defined as achieving a MADRS total score ≤12 at the last 2 nonmissing consecutive visits (for example, visit 3 \[week 1\] and visit 4 \[week 2\], or visit 4 \[week 2\] and visit 5 \[week 4\], or visit 5 \[week 4\] and visit 6 \[week 8\]). |
| Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 4 | Baseline, 4 weeks | The MADRS is a rating scale for severity of depressive mood and symptoms. The MADRS has a 10-item checklist. Items are rated on a scale from 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction. |
| Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 2 | Baseline, 2 weeks | The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range from 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction. |
| Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | Baseline, 8 weeks | Measures pain severity and interference on function. Severity scores: 0 (no pain) to 10 (severe pain) on each question. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Average interference=average of nonmissing scores of individual interference items. LS Mean Value adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction. |
| Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During the Double-blind Treatment Phase | Baseline through 8 weeks | The C-SSRS captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal behaviors, ideations, and acts are provided. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, and completed suicide. Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions, which includes wish to be dead, and 4 different categories of active suicidal ideation. Suicidal acts: a yes answer to actual attempt or completed suicide. |
| Change From Baseline in Pulse Rate up to Week 8 | Baseline, up to week 8 | The change from baseline in pulse rate at week 8 is the primary analysis. For the primary analysis of pulse rate, the Least Squares (LS) Mean Value was adjusted for treatment, investigator, baseline, treatment\*visit interaction, and baseline\*visit interaction. The change from baseline in pulse rate up to week 8 is the secondary analysis. The LS Mean Value was adjusted for treatment, investigator, and baseline. |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Baseline, up to week 8 | The change from baseline in SBP and DBP at week 8 is the primary analysis. For the primary analysis of SBP and DBP, the Least Squares (LS) Mean Value was adjusted for treatment, investigator, baseline, treatment\*visit interaction, and baseline\*visit interaction. The change from baseline in SBP and DBP up to week 8 is the secondary analysis. The LS Mean Value was adjusted for treatment, investigator, and baseline. |
| Change From Baseline in Weight up to Week 8 | Baseline, up to week 8 | The change from baseline in weight at week 8 is the primary analysis. For the primary analysis of weight, the Least Squares (LS) Mean Value was adjusted for treatment, investigator, baseline, treatment\*visit interaction, and baseline\*visit interaction. The change from baseline in weight up to week 8 is the secondary analysis. The LS Mean Value was adjusted for treatment, investigator, and baseline. |
| Patient's Global Impressions of Improvement Scale (PGI-I) at Week 8 | 8 weeks | A scale that measures the participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, and treatment\*visit interaction. |
| Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | Baseline, 8 weeks | SDS is completed by participant; used to assess effect of the participant's symptoms on their work/social/family life. Total scores range from 0 to 30; higher values indicate greater disruption in the participant's work/social/family life. Each item score ranges from 0 to 10 with higher values indicating greater disruption in the participant's work/school life (item 1), social life/leisure activities (item 2), or family life/home responsibilities (item 3). The LS Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Abnormal Laboratory Values During the Double-blind Treatment Phase - High Alanine Amino Transferase/Serum Glutamate Pyruvate Transaminase (ALT/SGPT) | Baseline through 8 weeks | Laboratory assessment of ALT/SGPT during the double-blind treatment phase. Normal ALT/SGPT ranges for males are 6.00 units per liter (U/L) (low) to 43.00 U/L (high). Normal ALT/SGPT ranges for females are 6.00 U/L (low) to 34.00 U/L (high). |
Countries
France, Germany, Puerto Rico, Romania, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Duloxetine Participants received 30 mg duloxetine once daily (QD) by mouth (po) for 1 week followed by 60 mg QD, po for 7 weeks. | 262 |
| Placebo Participants received placebo QD, po for 8 weeks. | 266 |
| Total | 528 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 21 | 9 |
| Overall Study | Lack of Efficacy | 5 | 16 |
| Overall Study | Lost to Follow-up | 16 | 21 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 12 | 8 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 16 | 6 |
Baseline characteristics
| Characteristic | Duloxetine | Placebo | Total |
|---|---|---|---|
| Age Continuous | 46.15 years STANDARD_DEVIATION 13.27 | 45.73 years STANDARD_DEVIATION 12.85 | 45.94 years STANDARD_DEVIATION 13.05 |
| Brief Pain Inventory - Interference (BPI-I) | 5.65 units on a scale STANDARD_DEVIATION 2.2 | 5.67 units on a scale STANDARD_DEVIATION 2.11 | 5.66 units on a scale STANDARD_DEVIATION 2.16 |
| Brief Pain Inventory Severity: Average Pain Score (BPI-S: Average Pain) | 5.68 units on a scale STANDARD_DEVIATION 1.69 | 5.58 units on a scale STANDARD_DEVIATION 1.67 | 5.63 units on a scale STANDARD_DEVIATION 1.68 |
| Brief Pain Inventory Severity: Least Pain Score (BPI-S: Least Pain) | 4.27 units on a scale STANDARD_DEVIATION 2.17 | 4.11 units on a scale STANDARD_DEVIATION 2.22 | 4.19 units on a scale STANDARD_DEVIATION 2.19 |
| Brief Pain Inventory Severity: Pain Right Now Score (BPI-S: Pain Right Now) | 5.29 units on a scale STANDARD_DEVIATION 2.37 | 5.34 units on a scale STANDARD_DEVIATION 2.1 | 5.32 units on a scale STANDARD_DEVIATION 2.24 |
| Brief Pain Inventory Severity: Worst Pain Score (BPI-S: Worst Pain) | 6.93 units on a scale STANDARD_DEVIATION 1.65 | 6.86 units on a scale STANDARD_DEVIATION 1.7 | 6.89 units on a scale STANDARD_DEVIATION 1.67 |
| Clinical Global Impressions of Severity Scale (CGI-S) | 4.58 units on a scale STANDARD_DEVIATION 0.63 | 4.58 units on a scale STANDARD_DEVIATION 0.63 | 4.58 units on a scale STANDARD_DEVIATION 0.63 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 68 Participants | 63 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 194 Participants | 203 Participants | 397 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Montgomery Asberg Depression Rating Scale (MADRS) Total Score | 29.91 units on a scale STANDARD_DEVIATION 4.92 | 30.39 units on a scale STANDARD_DEVIATION 5.25 | 30.15 units on a scale STANDARD_DEVIATION 5.09 |
| Number of Previous Major Depressive Disorder (MDD) Episodes | 3.52 number of previous episodes STANDARD_DEVIATION 3.98 | 3.67 number of previous episodes STANDARD_DEVIATION 4.88 | 3.60 number of previous episodes STANDARD_DEVIATION 4.45 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants | 47 Participants | 78 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 222 Participants | 213 Participants | 435 Participants |
| Region of Enrollment France | 29 participants | 33 participants | 62 participants |
| Region of Enrollment Germany | 18 participants | 16 participants | 34 participants |
| Region of Enrollment Puerto Rico | 37 participants | 35 participants | 72 participants |
| Region of Enrollment Romania | 11 participants | 15 participants | 26 participants |
| Region of Enrollment Sweden | 22 participants | 22 participants | 44 participants |
| Region of Enrollment United States | 145 participants | 145 participants | 290 participants |
| Sex: Female, Male Female | 180 Participants | 184 Participants | 364 Participants |
| Sex: Female, Male Male | 82 Participants | 82 Participants | 164 Participants |
| Sheehan Disability Scale-Item 1 (SDS-Item 1), N=196,200,396 | 6.24 units on a scale STANDARD_DEVIATION 2.3 | 6.23 units on a scale STANDARD_DEVIATION 2.15 | 6.23 units on a scale STANDARD_DEVIATION 2.22 |
| Sheehan Disability Scale-Item 2 (SDS-Item 2), N=262,265,527 | 6.43 units on a scale STANDARD_DEVIATION 2.27 | 6.50 units on a scale STANDARD_DEVIATION 2.15 | 6.46 units on a scale STANDARD_DEVIATION 2.21 |
| Sheehan Disability Scale-Item 3 (SDS-Item 3), N=262,265,527 | 6.42 units on a scale STANDARD_DEVIATION 2.21 | 6.45 units on a scale STANDARD_DEVIATION 2.06 | 6.44 units on a scale STANDARD_DEVIATION 2.13 |
| Sheehan Disability Scale -Total Score (SDS Total), N=262,265,527 | 19.16 units on a scale STANDARD_DEVIATION 6 | 19.38 units on a scale STANDARD_DEVIATION 5.84 | 19.27 units on a scale STANDARD_DEVIATION 5.92 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 162 / 262 | 137 / 266 |
| serious Total, serious adverse events | 5 / 262 | 1 / 266 |
Outcome results
Primary
Change From Baseline in the Brief Pain Inventory-Short Form (BPI-SF) Average Pain Score During the 8-week Treatment Period
A self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). The overall change is based on the estimated main treatment effect. The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction.
Time frame: Day 1 through 8 weeks
Population: All randomized participants with a baseline and at least 1 post-baseline result.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Change From Baseline in the Brief Pain Inventory-Short Form (BPI-SF) Average Pain Score During the 8-week Treatment Period | -1.93 units on a scale | Standard Error 0.11 |
| Placebo | Change From Baseline in the Brief Pain Inventory-Short Form (BPI-SF) Average Pain Score During the 8-week Treatment Period | -1.31 units on a scale | Standard Error 0.1 |
p-value: <0.00195% CI: [-0.9, -0.33]Mixed Models Analysis
Primary
Change From Baseline in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 8
The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are 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). The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction.
Time frame: Baseline, 8 weeks
Population: All randomized participants with a baseline and at least 1 post-baseline result.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Change From Baseline in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 8 | -16.77 units on a scale | Standard Error 0.67 |
| Placebo | Change From Baseline in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 8 | -12.73 units on a scale | Standard Error 0.64 |
p-value: <0.00195% CI: [-5.83, -2.24]Mixed Models Analysis
Secondary
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 2
The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range from 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction.
Time frame: Baseline, 2 weeks
Population: All randomized participants with a baseline and at least 1 post-baseline result.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 2 | -9.90 units on a scale | Standard Error 0.49 |
| Placebo | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 2 | -7.71 units on a scale | Standard Error 0.47 |
p-value: 0.00195% CI: [-3.5, -0.89]Mixed Models Analysis
Secondary
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 4
The MADRS is a rating scale for severity of depressive mood and symptoms. The MADRS has a 10-item checklist. Items are rated on a scale from 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction.
Time frame: Baseline, 4 weeks
Population: All randomized participants with a baseline and at least 1 post-baseline result.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 4 | -14.15 units on a scale | Standard Error 0.58 |
| Placebo | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 4 | -10.49 units on a scale | Standard Error 0.55 |
p-value: <0.00195% CI: [-5.2, -2.11]Mixed Models Analysis
Secondary
Change From Baseline in Pulse Rate up to Week 8
The change from baseline in pulse rate at week 8 is the primary analysis. For the primary analysis of pulse rate, the Least Squares (LS) Mean Value was adjusted for treatment, investigator, baseline, treatment\*visit interaction, and baseline\*visit interaction. The change from baseline in pulse rate up to week 8 is the secondary analysis. The LS Mean Value was adjusted for treatment, investigator, and baseline.
Time frame: Baseline, up to week 8
Population: Primary analysis: All randomized participants with a baseline and at least 1 post-baseline result.~Secondary analysis: Intention-to-treat population (ITT) with nonmissing baseline value and at least 1 nonmissing post-baseline value, LOCF.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Duloxetine | Change From Baseline in Pulse Rate up to Week 8 | Change from Baseline in Pulse Rate up to Week 8 | 1.71 beats per minute (bpm) | Standard Error 0.54 |
| Duloxetine | Change From Baseline in Pulse Rate up to Week 8 | Change from Baseline in Pulse Rate at Week 8 | 1.58 beats per minute (bpm) | Standard Error 0.59 |
| Placebo | Change From Baseline in Pulse Rate up to Week 8 | Change from Baseline in Pulse Rate at Week 8 | -1.34 beats per minute (bpm) | Standard Error 0.57 |
| Placebo | Change From Baseline in Pulse Rate up to Week 8 | Change from Baseline in Pulse Rate up to Week 8 | -0.70 beats per minute (bpm) | Standard Error 0.53 |
p-value: <0.00195% CI: [1.34, 4.51]Mixed Models Analysis
p-value: 0.00195% CI: [0.97, 3.83]ANCOVA
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8
The change from baseline in SBP and DBP at week 8 is the primary analysis. For the primary analysis of SBP and DBP, the Least Squares (LS) Mean Value was adjusted for treatment, investigator, baseline, treatment\*visit interaction, and baseline\*visit interaction. The change from baseline in SBP and DBP up to week 8 is the secondary analysis. The LS Mean Value was adjusted for treatment, investigator, and baseline.
Time frame: Baseline, up to week 8
Population: Primary analysis: All randomized participants with a baseline and at least 1 post-baseline result.~Secondary analysis: Intention-to-treat population (ITT) with nonmissing baseline value and at least 1 nonmissing post-baseline value, Last Observation Carried Forward (LOCF).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Duloxetine | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Change from Baseline in SBP at Week 8 | 1.38 mm Hg | Standard Error 0.8 |
| Duloxetine | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Change from Baseline in DBP at Week 8 | 0.52 mm Hg | Standard Error 0.53 |
| Duloxetine | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Change from Baseline in SBP up to Week 8 | 1.41 mm Hg | Standard Error 0.74 |
| Duloxetine | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Change from Baseline in DBP up to Week 8 | 0.31 mm Hg | Standard Error 0.49 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Change from Baseline in DBP up to Week 8 | 0.01 mm Hg | Standard Error 0.48 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Change from Baseline in SBP at Week 8 | -0.52 mm Hg | Standard Error 0.77 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Change from Baseline in SBP up to Week 8 | -0.12 mm Hg | Standard Error 0.72 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Up to Week 8 | Change from Baseline in DBP at Week 8 | 0.05 mm Hg | Standard Error 0.51 |
p-value: 0.08395% CI: [-0.25, 4.04]Mixed Models Analysis
p-value: 0.51395% CI: [-0.95, 1.9]Mixed Models Analysis
p-value: 0.12495% CI: [-0.42, 3.47]ANCOVA
p-value: 0.63895% CI: [-0.98, 1.6]ANCOVA
Secondary
Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8
Measures pain severity and interference on function. Severity scores: 0 (no pain) to 10 (severe pain) on each question. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Average interference=average of nonmissing scores of individual interference items. LS Mean Value adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction.
Time frame: Baseline, 8 weeks
Population: All randomized participants with a baseline and at least 1 post-baseline result.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Severity for Worst Pain | -2.25 units on a scale | Standard Error 0.13 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Severity for Least Pain | -1.48 units on a scale | Standard Error 0.11 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Severity for Average Pain | -1.93 units on a scale | Standard Error 0.11 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Severity for Pain Right Now | -2.00 units on a scale | Standard Error 0.12 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with General Activity | -2.01 units on a scale | Standard Error 0.13 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Mood | -2.49 units on a scale | Standard Error 0.14 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Walking Ability | -1.52 units on a scale | Standard Error 0.13 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Normal Work | -2.02 units on a scale | Standard Error 0.13 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Relations With Others | -2.01 units on a scale | Standard Error 0.13 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Sleep | -1.94 units on a scale | Standard Error 0.14 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Enjoyment of Life | -2.44 units on a scale | Standard Error 0.14 |
| Duloxetine | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Mean Pain Interference Score | -2.03 units on a scale | Standard Error 0.12 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Sleep | -1.56 units on a scale | Standard Error 0.14 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Severity for Worst Pain | -1.60 units on a scale | Standard Error 0.12 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Walking Ability | -1.06 units on a scale | Standard Error 0.12 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Severity for Least Pain | -0.86 units on a scale | Standard Error 0.1 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Mean Pain Interference Score | -1.46 units on a scale | Standard Error 0.12 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Severity for Average Pain | -1.31 units on a scale | Standard Error 0.1 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Normal Work | -1.46 units on a scale | Standard Error 0.13 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Severity for Pain Right Now | -1.27 units on a scale | Standard Error 0.12 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Enjoyment of Life | -1.77 units on a scale | Standard Error 0.13 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with General Activity | -1.33 units on a scale | Standard Error 0.13 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Relations With Others | -1.31 units on a scale | Standard Error 0.13 |
| Placebo | Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 8 | BPI Pain Interference with Mood | -1.76 units on a scale | Standard Error 0.13 |
p-value: <0.00195% CI: [-0.97, -0.32]Mixed Models Analysis
p-value: <0.00195% CI: [-0.9, -0.34]Mixed Models Analysis
p-value: <0.00195% CI: [-0.9, -0.33]Mixed Models Analysis
p-value: <0.00195% CI: [-1.06, -0.42]Mixed Models Analysis
p-value: <0.00195% CI: [-1.03, -0.33]Mixed Models Analysis
p-value: <0.00195% CI: [-1.09, -0.37]Mixed Models Analysis
p-value: 0.00995% CI: [-0.79, -0.11]Mixed Models Analysis
p-value: 0.00295% CI: [-0.91, -0.21]Mixed Models Analysis
p-value: <0.00195% CI: [-1.06, -0.35]Mixed Models Analysis
p-value: 0.04295% CI: [-0.76, -0.01]Mixed Models Analysis
p-value: <0.00195% CI: [-1.03, -0.31]Mixed Models Analysis
p-value: <0.00195% CI: [-0.88, -0.25]Mixed Models Analysis
Secondary
Change From Baseline in the Percentage of Participants Achieving Remission up to Week 8
The Montgomery Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are 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). Remission is defined as achieving a MADRS total score ≤12.
Time frame: Baseline, up to 8 weeks
Population: All randomized participants with a post-baseline result, Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine | Change From Baseline in the Percentage of Participants Achieving Remission up to Week 8 | 47.0 percentage of participants |
| Placebo | Change From Baseline in the Percentage of Participants Achieving Remission up to Week 8 | 32.8 percentage of participants |
p-value: 0.001Cochran-Mantel-Haenszel
Secondary
Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8
SDS is completed by participant; used to assess effect of the participant's symptoms on their work/social/family life. Total scores range from 0 to 30; higher values indicate greater disruption in the participant's work/social/family life. Each item score ranges from 0 to 10 with higher values indicating greater disruption in the participant's work/school life (item 1), social life/leisure activities (item 2), or family life/home responsibilities (item 3). The LS Mean Value was adjusted for treatment, investigator, visit, baseline, treatment\*visit interaction, and baseline\*visit interaction.
Time frame: Baseline, 8 weeks
Population: All randomized participants with a baseline and at least 1 post-baseline result.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Duloxetine | Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | Disrupt Work/School Work (N=182, 196) | -2.82 units on a scale | Standard Error 0.22 |
| Duloxetine | Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | Disrupt Social Life/Leisure Activities | -3.04 units on a scale | Standard Error 0.19 |
| Duloxetine | Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | Disrupt Family/Home Responsibilities | -3.02 units on a scale | Standard Error 0.19 |
| Duloxetine | Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | SDS Total Score | -8.88 units on a scale | Standard Error 0.54 |
| Placebo | Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | SDS Total Score | -7.13 units on a scale | Standard Error 0.52 |
| Placebo | Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | Disrupt Work/School Work (N=182, 196) | -2.36 units on a scale | Standard Error 0.2 |
| Placebo | Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | Disrupt Family/Home Responsibilities | -2.49 units on a scale | Standard Error 0.18 |
| Placebo | Change From Baseline in the Sheehan Disability Scale (SDS) Total and Item Scores at Week 8 | Disrupt Social Life/Leisure Activities | -2.31 units on a scale | Standard Error 0.18 |
p-value: 0.11295% CI: [-1.03, 0.11]Mixed Models Analysis
p-value: 0.00595% CI: [-1.24, -0.22]Mixed Models Analysis
p-value: 0.0495% CI: [-1.04, -0.02]Mixed Models Analysis
p-value: 0.01995% CI: [-3.2, -0.29]Mixed Models Analysis
Secondary
Change From Baseline in Weight up to Week 8
The change from baseline in weight at week 8 is the primary analysis. For the primary analysis of weight, the Least Squares (LS) Mean Value was adjusted for treatment, investigator, baseline, treatment\*visit interaction, and baseline\*visit interaction. The change from baseline in weight up to week 8 is the secondary analysis. The LS Mean Value was adjusted for treatment, investigator, and baseline.
Time frame: Baseline, up to week 8
Population: Primary analysis: All randomized participants with a baseline and at least 1 post-baseline result.~Secondary analysis: All randomized participants with a baseline and at least 1 nonmissing post-baseline result, Last Observation Carried Forward (LOCF).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Duloxetine | Change From Baseline in Weight up to Week 8 | Change from Baseline in Weight at Week 8 | -0.77 kilograms (kg) | Standard Error 0.15 |
| Duloxetine | Change From Baseline in Weight up to Week 8 | Change from Baseline in Weight up to Week 8 | -0.74 kilograms (kg) | Standard Error 0.14 |
| Placebo | Change From Baseline in Weight up to Week 8 | Change from Baseline in Weight at Week 8 | 0.19 kilograms (kg) | Standard Error 0.15 |
| Placebo | Change From Baseline in Weight up to Week 8 | Change from Baseline in Weight up to Week 8 | 0.14 kilograms (kg) | Standard Error 0.13 |
p-value: <0.00195% CI: [-1.37, -0.54]Mixed Models Analysis
p-value: <0.00195% CI: [-1.24, -0.51]ANCOVA
Secondary
Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During the Double-blind Treatment Phase
The C-SSRS captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal behaviors, ideations, and acts are provided. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, and completed suicide. Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions, which includes wish to be dead, and 4 different categories of active suicidal ideation. Suicidal acts: a yes answer to actual attempt or completed suicide.
Time frame: Baseline through 8 weeks
Population: All randomized participants with at least 1 post-baseline C-SSRS result.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Duloxetine | Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During the Double-blind Treatment Phase | Suicidal Ideation | 26 participants |
| Duloxetine | Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During the Double-blind Treatment Phase | Suicidal Behavior | 1 participants |
| Duloxetine | Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During the Double-blind Treatment Phase | Suicidal Acts | 2 participants |
| Placebo | Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During the Double-blind Treatment Phase | Suicidal Ideation | 41 participants |
| Placebo | Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During the Double-blind Treatment Phase | Suicidal Behavior | 0 participants |
| Placebo | Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During the Double-blind Treatment Phase | Suicidal Acts | 0 participants |
p-value: 0.293Fisher Exact
Secondary
Patient's Global Impressions of Improvement Scale (PGI-I) at Week 8
A scale that measures the participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). The Least Squares (LS) Mean Value was adjusted for treatment, investigator, visit, and treatment\*visit interaction.
Time frame: 8 weeks
Population: All randomized participants with a baseline and at least 1 post-baseline result.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Patient's Global Impressions of Improvement Scale (PGI-I) at Week 8 | 2.56 units on a scale | Standard Error 0.08 |
| Placebo | Patient's Global Impressions of Improvement Scale (PGI-I) at Week 8 | 3.04 units on a scale | Standard Error 0.08 |
p-value: <0.00195% CI: [-0.71, -0.26]Mixed Models Analysis
Secondary
Percentage of Participants Achieving Remission up to Week 8
The Montgomery Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale from 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Remission is defined as achieving a MADRS total score ≤12 at the last 2 nonmissing consecutive visits (for example, visit 3 \[week 1\] and visit 4 \[week 2\], or visit 4 \[week 2\] and visit 5 \[week 4\], or visit 5 \[week 4\] and visit 6 \[week 8\]).
Time frame: Up to 8 weeks
Population: All randomized participants with a baseline and at least 1 post-baseline value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine | Percentage of Participants Achieving Remission up to Week 8 | 29.5 percentage of participants |
| Placebo | Percentage of Participants Achieving Remission up to Week 8 | 18.7 percentage of participants |
p-value: 0.0082Cochran-Mantel-Haenszel
Other Pre-specified
Number of Participants With Abnormal Laboratory Values During the Double-blind Treatment Phase - High Alanine Amino Transferase/Serum Glutamate Pyruvate Transaminase (ALT/SGPT)
Laboratory assessment of ALT/SGPT during the double-blind treatment phase. Normal ALT/SGPT ranges for males are 6.00 units per liter (U/L) (low) to 43.00 U/L (high). Normal ALT/SGPT ranges for females are 6.00 U/L (low) to 34.00 U/L (high).
Time frame: Baseline through 8 weeks
Population: All randomized participants with a normal baseline (respective to the specified direction) and at least 1 post-baseline result.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine | Number of Participants With Abnormal Laboratory Values During the Double-blind Treatment Phase - High Alanine Amino Transferase/Serum Glutamate Pyruvate Transaminase (ALT/SGPT) | 14 participants |
| Placebo | Number of Participants With Abnormal Laboratory Values During the Double-blind Treatment Phase - High Alanine Amino Transferase/Serum Glutamate Pyruvate Transaminase (ALT/SGPT) | 5 participants |
p-value: 0.033Fisher Exact