Depressive Disorder, Major
Conditions
Keywords
Major Depressive Disorder, Depression, Melancholia, Drug Therapy
Brief summary
The purpose of this study is to evaluate the efficacy of vortioxetine, once daily (QD), compared with placebo in adults with major depressive disorder.
Detailed description
The drug that was tested in this study is called Vortioxetine. Vortioxetine is being tested to treat depression in adults who have major depressive disorder (MDD). This study looked at MDD relief in people who took varying dosages of vortioxetine. The study enrolled 462 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need): * Vortioxetine 10 mg * Vortioxetine 20 mg * Placebo (dummy inactive capsule) - this was a capsule that looked like the study drug but had no active ingredient. All participants were asked to take one capsule at the same time each day throughout the study. This multi-center trial was conducted in the United States. The overall time to participate in this study was up to 13 weeks. Participants made 9 visits to the clinic, and were contacted by telephone 4 weeks after the last dose of study drug for a follow-up assessment.
Interventions
DRUGVortioxetine
Encapsulated vortioxetine immediate release tablets
DRUGPlacebo
Vortioxetine placebo-matching capsules
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Suffers from a major depressive episode recurrent as the primary diagnosis according to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria. * Has a Montgomery Åsberg Depression Rating Scale (MADRS) total score of 26 or greater at Screening and Baseline Visits. * Has a Clinical Global Impression - Severity of Illness (CGI-S) score of 4 or greater at Screening and Baseline Visits.
Exclusion criteria
* Has previously participated in a Lu AA21004 clinical study. * Has 1 or more the following: * Any current psychiatric disorder other than Major Depressive Disorder as defined in the DSM-IV * Current or past history of: manic or hypomanic episode, schizophrenia or any other psychotic disorder defined in the DSM-IV-TR. * Diagnosis of alcohol or other substance disorder (except nicotine and caffeine) as defined in the DSM-IV-TR that has not been in sustained full remission for at least years prior to screening (participant must also have negative urine drug screen prior to Baseline). * Presence or history of a clinically significant neurological disorder (including epilepsy) * Neurodegenerative disorder. * Any Axis II disorder that might compromise the study. * Has a thyroid stimulating hormone value outside the normal range at the Screening Visit that is deemed clinically significant by the investigator. * Has clinically significant abnormal vital signs as determined by the investigator. * Has an abnormal Electrocardiogram. * Has an alanine aminotransferase, aspartate aminotransferase or total bilirubin level greater than 1.5 times the upper limits of normal. * Has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study medication. * Has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy. * Has a known history of or currently has increased intraocular pressure or is at risk of acute narrow-angle glaucoma. * Has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance. For the purposes of this protocol the following conditions are considered unstable due to the potential impact on assessment of MDD response: pain disorder, chronic fatigue syndrome, fibromyalgia, and obstructive sleep apnea. * Has a significant risk of suicide according to the investigator's opinion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | Baseline and Week 8 | The MADRS is a depression rating scale consisting of 10 items, each rated 0 (normal) to 6 (most abnormal). The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). A decrease in the total score or on individual items indicates improvement. Least squares (LS) means are from a mixed model for repeated measurements (MMRM) analysis of covariance (ANCOVA) with treatment, center, week, treatment-by-week interaction, Baseline MADRS total score-by-week as fixed effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a MADRS Response at Week 8 | Baseline and Week 8 | Response is defined as a participant with a ≥50% decrease in Montgomery Åsberg Depression Rating Scale (MADRS) total score from Baseline. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement. |
| Mean Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 8 | Week 8 | The Clinical Global Impression-Global Improvement scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. LS means were from a mixed model for repeated measurements (MMRM) ANCOVA with treatment, center, week, treatment-by-week interaction, Baseline Clinical Global Impression Scale-Severity of Illness Scale (CGI-S) score-by-week as fixed effects. |
| Change From Baseline in MADRS Total Score at Week 8 in Participants With Baseline Hamilton Anxiety Scale (HAM-A) Total Score ≥20 | Baseline and Week 8 | The MADRS is a depression rating scale consisting of 10 items, each rated 0 (normal) to 6 (most abnormal). The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). A decrease in the total score or on individual items indicates improvement. LS means are from a mixed model for repeated measurements (MMRM) ANCOVA with treatment, center, week, treatment-by-week interaction, Baseline MADRS total score-by-week as fixed effects. The HAM-A is a 14 item rating scale to quantify anxiety severity rated on a 5-point scale from 0 (not present) to 4 (severe) with a total score range from 0 to 56, where lower scores indicate mild severity. |
| Percentage of Participants in MADRS Remission at Week 8 | Week 8 | Remission is defined as a participant with a Montgomery Åsberg Depression Rating Scale (MADRS) total score ≤10. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement. |
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | Baseline and Week 8 | The Sheehan Disability Scale assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. LS means were from mixed model for repeated measurements (MMRM) ANCOVA with treatment, center, week, treatment-by-week interaction, Baseline SDS total score-by-week as fixed effects. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 37 investigative sites in the United States from 15 July 2010 to 17 January 2012.
Pre-assignment details
Participants with a diagnosis of major depressive disorder were enrolled equally in 1 of 3 treatment groups, once a day placebo, 10 mg, or 20 mg vortioxetine.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo-matching capsules, orally, once daily for up to 8 weeks. | 157 |
| Vortioxetine 10 mg Vortioxetine 10 mg, encapsulated tablets, orally, once daily for up to 8 weeks. | 155 |
| Vortioxetine 20 mg Vortioxetine 10 mg, encapsulated tablets, orally, once daily for one week then vortioxetine 20 mg, encapsulated tablets, orally, once daily for up to 7 weeks. | 150 |
| Total | 462 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 3 | 1 |
| Overall Study | Lost to Follow-up | 7 | 7 | 10 |
| Overall Study | Noncompliance with Study Drug | 0 | 2 | 0 |
| Overall Study | Other | 1 | 1 | 2 |
| Overall Study | Pretreatment Event or Adverse Event | 2 | 9 | 7 |
| Overall Study | Protocol Deviations | 2 | 2 | 5 |
| Overall Study | Withdrawal of Consent | 5 | 7 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Vortioxetine 20 mg | Vortioxetine 10 mg |
|---|---|---|---|---|
| Age Continuous | 42.3 years STANDARD_DEVIATION 11.61 | 42.8 years STANDARD_DEVIATION 12.23 | 43.1 years STANDARD_DEVIATION 13.09 | 43.1 years STANDARD_DEVIATION 12.04 |
| Age, Customized ≤55 years | 130 participants | 387 participants | 124 participants | 133 participants |
| Age, Customized >55 years | 27 participants | 75 participants | 26 participants | 22 participants |
| Alcohol Consumption 2-to-6 times per week | 15 participants | 50 participants | 14 participants | 21 participants |
| Alcohol Consumption Daily | 3 participants | 6 participants | 0 participants | 3 participants |
| Alcohol Consumption Never | 54 participants | 169 participants | 52 participants | 63 participants |
| Alcohol Consumption Once monthly or less often | 63 participants | 175 participants | 65 participants | 47 participants |
| Alcohol Consumption Once per week | 22 participants | 62 participants | 19 participants | 21 participants |
| Body Mass Index (BMI) | 31.31 kg/m^2 STANDARD_DEVIATION 7.262 | 31.36 kg/m^2 STANDARD_DEVIATION 7.622 | 30.84 kg/m^2 STANDARD_DEVIATION 7.836 | 31.92 kg/m^2 STANDARD_DEVIATION 7.779 |
| Clinical Global Impression - Severity scale score | 4.5 scores on a scale STANDARD_DEVIATION 0.55 | 4.5 scores on a scale STANDARD_DEVIATION 0.55 | 4.5 scores on a scale STANDARD_DEVIATION 0.54 | 4.5 scores on a scale STANDARD_DEVIATION 0.55 |
| Hamilton Anxiety Scale Total Score | 17.8 scores on a scale STANDARD_DEVIATION 5.41 | 18.4 scores on a scale STANDARD_DEVIATION 5.44 | 18.9 scores on a scale STANDARD_DEVIATION 5.64 | 18.5 scores on a scale STANDARD_DEVIATION 5.25 |
| Height | 167.46 cm STANDARD_DEVIATION 9.265 | 167.41 cm STANDARD_DEVIATION 9.21 | 167.92 cm STANDARD_DEVIATION 9.194 | 166.86 cm STANDARD_DEVIATION 9.199 |
| Montgomery Åsberg Depression Rating Scale (MADRS) total score | 32.0 scores on a scale STANDARD_DEVIATION 3.99 | 32.2 scores on a scale STANDARD_DEVIATION 4.27 | 32.4 scores on a scale STANDARD_DEVIATION 4.3 | 32.3 scores on a scale STANDARD_DEVIATION 4.52 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 5 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 3 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black | 37 participants | 129 participants | 49 participants | 43 participants |
| Race/Ethnicity, Customized Caucasian (White, including Hispanic) | 120 participants | 323 participants | 97 participants | 106 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 17 participants | 37 participants | 10 participants | 10 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Non-Hispanic and non-Latino | 140 participants | 425 participants | 140 participants | 145 participants |
| Region of Enrollment United States | 157 participants | 462 participants | 150 participants | 155 participants |
| Sex: Female, Male Female | 110 Participants | 335 Participants | 107 Participants | 118 Participants |
| Sex: Female, Male Male | 47 Participants | 127 Participants | 43 Participants | 37 Participants |
| Smoking Classification Current smoker | 52 participants | 143 participants | 45 participants | 46 participants |
| Smoking Classification Ex-smoker | 40 participants | 95 participants | 28 participants | 27 participants |
| Smoking Classification Never smoked | 65 participants | 224 participants | 77 participants | 82 participants |
| Waist Circumference | 100.20 cm STANDARD_DEVIATION 18.64 | 98.93 cm STANDARD_DEVIATION 17.426 | 96.76 cm STANDARD_DEVIATION 16.434 | 99.76 cm STANDARD_DEVIATION 16.996 |
| Weight | 88.28 kg STANDARD_DEVIATION 23.29 | 88.13 kg STANDARD_DEVIATION 23.277 | 87.08 kg STANDARD_DEVIATION 23.582 | 89.00 kg STANDARD_DEVIATION 23.076 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 80 / 157 | 103 / 155 | 94 / 150 |
| serious Total, serious adverse events | 0 / 157 | 2 / 155 | 0 / 150 |
Outcome results
Primary
Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score
The MADRS is a depression rating scale consisting of 10 items, each rated 0 (normal) to 6 (most abnormal). The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). A decrease in the total score or on individual items indicates improvement. Least squares (LS) means are from a mixed model for repeated measurements (MMRM) analysis of covariance (ANCOVA) with treatment, center, week, treatment-by-week interaction, Baseline MADRS total score-by-week as fixed effects.
Time frame: Baseline and Week 8
Population: The full analysis set (FAS) included all randomized patients who received at least 1 dose of study drug, and had at least 1 valid postbaseline value for assessment of primary efficacy. A mixed model for repeated measurements (MMRM) based on observed cases was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -10.77 scores on a scale | Standard Error 0.807 |
| Vortioxetine 10 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -12.96 scores on a scale | Standard Error 0.832 |
| Vortioxetine 20 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -14.41 scores on a scale | Standard Error 0.845 |
Comparison: All statistical tests were 2-sided with the estimated P-values at the 5% level of significance. To control for multiplicity, a pre-specified sequential testing procedure was applied to compare 10 mg and 20 mg vortioxetine to placebo. Efficacy endpoints were tested for each dose in sequential order at significance level 0.025; as soon as an endpoint was non-significant at 0.025, the testing procedure stopped for all subsequent endpoints.p-value: 0.05895% CI: [-4.45, 0.08]Mixed model for repeated measurements
p-value: 0.00295% CI: [-5.92, -1.35]Mixed model for repeated measurements
Secondary
Change From Baseline in MADRS Total Score at Week 8 in Participants With Baseline Hamilton Anxiety Scale (HAM-A) Total Score ≥20
The MADRS is a depression rating scale consisting of 10 items, each rated 0 (normal) to 6 (most abnormal). The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). A decrease in the total score or on individual items indicates improvement. LS means are from a mixed model for repeated measurements (MMRM) ANCOVA with treatment, center, week, treatment-by-week interaction, Baseline MADRS total score-by-week as fixed effects. The HAM-A is a 14 item rating scale to quantify anxiety severity rated on a 5-point scale from 0 (not present) to 4 (severe) with a total score range from 0 to 56, where lower scores indicate mild severity.
Time frame: Baseline and Week 8
Population: Full analysis set patients with a HAM-A Baseline score ≥20. A mixed model for repeated measurements (MMRM) based on observed cases was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MADRS Total Score at Week 8 in Participants With Baseline Hamilton Anxiety Scale (HAM-A) Total Score ≥20 | -10.26 scores on a scale | Standard Error 1.392 |
| Vortioxetine 10 mg | Change From Baseline in MADRS Total Score at Week 8 in Participants With Baseline Hamilton Anxiety Scale (HAM-A) Total Score ≥20 | -14.55 scores on a scale | Standard Error 1.369 |
| Vortioxetine 20 mg | Change From Baseline in MADRS Total Score at Week 8 in Participants With Baseline Hamilton Anxiety Scale (HAM-A) Total Score ≥20 | -17.52 scores on a scale | Standard Error 1.331 |
p-value: 0.02595% CI: [-8.03, -0.56]Mixed model for repeated measurements
p-value: <0.00195% CI: [-10.92, -3.6]Mixed model for repeated measurements
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8
The Sheehan Disability Scale assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. LS means were from mixed model for repeated measurements (MMRM) ANCOVA with treatment, center, week, treatment-by-week interaction, Baseline SDS total score-by-week as fixed effects.
Time frame: Baseline and Week 8
Population: Full analysis set. A mixed model for repeated measurements (MMRM) based on observed cases was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | -5.86 scores on a scale | Standard Error 0.771 |
| Vortioxetine 10 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | -7.25 scores on a scale | Standard Error 0.747 |
| Vortioxetine 20 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | -8.26 scores on a scale | Standard Error 0.794 |
p-value: 0.18395% CI: [-3.44, 0.66]Mixed model for repeated measurements
p-value: 0.02595% CI: [-4.5, -0.3]Mixed model for repeated measurements
Secondary
Mean Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 8
The Clinical Global Impression-Global Improvement scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. LS means were from a mixed model for repeated measurements (MMRM) ANCOVA with treatment, center, week, treatment-by-week interaction, Baseline Clinical Global Impression Scale-Severity of Illness Scale (CGI-S) score-by-week as fixed effects.
Time frame: Week 8
Population: Full Analysis Set. A mixed model for repeated measurements (MMRM) based on observed cases was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 8 | 2.89 scores on a scale | Standard Error 0.09 |
| Vortioxetine 10 mg | Mean Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 8 | 2.69 scores on a scale | Standard Error 0.093 |
| Vortioxetine 20 mg | Mean Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 8 | 2.59 scores on a scale | Standard Error 0.094 |
p-value: 0.11995% CI: [-0.45, 0.05]Mixed model for repeated measurements
p-value: 0.02495% CI: [-0.55, -0.04]Mixed model for repeated measurements
Secondary
Percentage of Participants in MADRS Remission at Week 8
Remission is defined as a participant with a Montgomery Åsberg Depression Rating Scale (MADRS) total score ≤10. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement.
Time frame: Week 8
Population: Full analysis set, last observation carried forward was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants in MADRS Remission at Week 8 | 14.2 percentage of participants |
| Vortioxetine 10 mg | Percentage of Participants in MADRS Remission at Week 8 | 21.4 percentage of participants |
| Vortioxetine 20 mg | Percentage of Participants in MADRS Remission at Week 8 | 22.3 percentage of participants |
p-value: 0.09395% CI: [0.918, 3.018]Regression, Logistic
p-value: 0.05995% CI: [0.979, 3.233]Regression, Logistic
Secondary
Percentage of Participants With a MADRS Response at Week 8
Response is defined as a participant with a ≥50% decrease in Montgomery Åsberg Depression Rating Scale (MADRS) total score from Baseline. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement.
Time frame: Baseline and Week 8
Population: Full analysis set, last observation carried forward was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a MADRS Response at Week 8 | 28.4 percentage of participants |
| Vortioxetine 10 mg | Percentage of Participants With a MADRS Response at Week 8 | 33.8 percentage of participants |
| Vortioxetine 20 mg | Percentage of Participants With a MADRS Response at Week 8 | 39.2 percentage of participants |
p-value: 0.30195% CI: [0.796, 2.093]Regression, Logistic
p-value: 0.04495% CI: [1.013, 2.652]Regression, Logistic