Depressive Disorder, Major
Conditions
Keywords
Major Depressive Disorder, Depression, Drug Therapy
Brief summary
The purpose of this study is to evaluate the efficacy, safety and tolerability 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 469 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 15 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 14 weeks. Participants made 7 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 (MDE) recurrent as the primary diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria. * The reported duration of the current MDE is at least 3 months. * 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 received any investigational compound \<30 days before Screening or 5 half-lives prior to Screening. * Has received Lu AA21004 in a previous clinical study. * Has 1 or more the following: 1. Any current psychiatric disorder other than MDD as defined in the DSM-IV-TR . 2. Current or history of: manic or hypomanic episode, schizophrenia or any other psychotic disorder, including major depression with psychotic features, mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR. 3. Diagnosis of alcohol or other substance abuse or dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that had not been in sustained full remission for at least 2 years prior to Screening. 4. Presence or history of a clinically significant neurological disorder (including epilepsy). 5. Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc). 6. Any Axis II disorder that might compromise the study. * The current depressive symptoms of the patient were considered by the investigator to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each. * Has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening. * Was currently receiving formal cognitive or behavioral therapy, systematic psychotherapy, or planned to initiate such therapy during the study. * Has a significant risk of suicide according to the investigator's clinical judgment or had a score ≥5 on item 10 (suicidal thoughts) of the MADRS or had made a suicide attempt in the previous 6 months. * Was required to take excluded medications or it was anticipated that would require treatment with at least 1 of the disallowed concomitant medications during the study. * Has a clinically significant unstable illness, for example hepatic impairment or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, hematological, infectious, dermatological disorder or metabolic disturbance. NOTE: For the purposes of this study, the following conditions were considered unstable due to the potential impact on assessment of MDD response: pain disorder, chronic fatigue syndrome, fibromyalgia, and obstructive sleep apnea. * Has 1 or more laboratory value outside the normal range, based on the blood or urine samples taken at the Screening Visit, that were considered by the investigator to be clinically significant; or the patient has any of the following values at the Screening Visit: 1. A serum creatinine value \>1.5 times the upper limits of normal (× ULN). 2. A total serum total bilirubin value \>1.5 × ULN. 3. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value \>2 × ULN. * Has a thyroid stimulating hormone value outside the normal range. * Has clinically significant abnormal vital signs. * Has an abnormal electrocardiogram.
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 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 (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. 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 | 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 65 investigative sites in the United States from 11 August 2010 to 04 June 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 15 mg vortioxetine.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks. | 160 |
| Vortioxetine 10 mg Vortioxetine 10 mg, encapsulated tablets, orally, once daily for up to 8 weeks. | 157 |
| Vortioxetine 15 mg Vortioxetine 10 mg, encapsulated tablets, orally, once daily for one week, then vortioxetine 15 mg, encapsulated tablets, orally, once daily for up to 7 weeks. | 152 |
| Total | 469 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 4 | 2 | 0 |
| Overall Study | Lost to Follow-up | 7 | 7 | 3 |
| Overall Study | Noncompliance with Study Drug | 2 | 0 | 1 |
| Overall Study | Other | 2 | 0 | 2 |
| Overall Study | Pretreatment Event or Adverse Event | 6 | 8 | 12 |
| Overall Study | Protocol Deviations | 4 | 3 | 3 |
| Overall Study | Withdrawal of Consent | 2 | 6 | 10 |
Baseline characteristics
| Characteristic | Total | Placebo | Vortioxetine 15 mg | Vortioxetine 10 mg |
|---|---|---|---|---|
| Age Continuous | 45.1 years STANDARD_DEVIATION 12.44 | 46.2 years STANDARD_DEVIATION 11.79 | 43.8 years STANDARD_DEVIATION 13.51 | 45.2 years STANDARD_DEVIATION 11.94 |
| Age, Customized ≤55 years | 371 participants | 122 participants | 120 participants | 129 participants |
| Age, Customized >55 years | 98 participants | 38 participants | 32 participants | 28 participants |
| Alcohol Consumption 2 to 6 times per week | 60 participants | 24 participants | 14 participants | 22 participants |
| Alcohol Consumption Daily | 10 participants | 1 participants | 4 participants | 5 participants |
| Alcohol Consumption Never | 154 participants | 49 participants | 51 participants | 54 participants |
| Alcohol Consumption Once monthly or less often | 178 participants | 60 participants | 62 participants | 56 participants |
| Alcohol Consumption Once per week | 67 participants | 26 participants | 21 participants | 20 participants |
| Body Mass Index (BMI) | 31.07 kg/m^2 STANDARD_DEVIATION 7.771 | 31.14 kg/m^2 STANDARD_DEVIATION 7.533 | 30.78 kg/m^2 STANDARD_DEVIATION 7.752 | 31.29 kg/m^2 STANDARD_DEVIATION 8.063 |
| Clinical Global Impression - Severity scale score | 4.7 sores on a scale STANDARD_DEVIATION 0.59 | 4.7 sores on a scale STANDARD_DEVIATION 0.61 | 4.6 sores on a scale STANDARD_DEVIATION 0.59 | 4.7 sores on a scale STANDARD_DEVIATION 0.56 |
| Hamilton Anxiety Scale Total Score | 19.9 scores on a scale STANDARD_DEVIATION 5.78 | 20.0 scores on a scale STANDARD_DEVIATION 6.14 | 19.5 scores on a scale STANDARD_DEVIATION 5.42 | 20.1 scores on a scale STANDARD_DEVIATION 5.77 |
| Height | 167.92 cm STANDARD_DEVIATION 9.92 | 168.85 cm STANDARD_DEVIATION 10.407 | 167.52 cm STANDARD_DEVIATION 9.789 | 167.35 cm STANDARD_DEVIATION 9.523 |
| Montgomery Åsberg Depression Rating Scale (MADRS) Total Score | 33.7 scores on a scale STANDARD_DEVIATION 4.37 | 33.4 scores on a scale STANDARD_DEVIATION 4.53 | 33.7 scores on a scale STANDARD_DEVIATION 4.51 | 34.1 scores on a scale STANDARD_DEVIATION 4.07 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 6 participants | 1 participants | 4 participants | 1 participants |
| Race/Ethnicity, Customized Black | 112 participants | 35 participants | 38 participants | 39 participants |
| Race/Ethnicity, Customized Caucasian (White, including Hispanic) | 348 participants | 124 participants | 109 participants | 115 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 54 participants | 20 participants | 18 participants | 16 participants |
| Race/Ethnicity, Customized Non-Hispanic and non-Latino | 415 participants | 140 participants | 134 participants | 141 participants |
| Region of Enrollment United States | 469 participants | 160 participants | 152 participants | 157 participants |
| Sex: Female, Male Female | 329 Participants | 108 Participants | 108 Participants | 113 Participants |
| Sex: Female, Male Male | 140 Participants | 52 Participants | 44 Participants | 44 Participants |
| Smoking Classification Current smoker | 138 participants | 46 participants | 52 participants | 40 participants |
| Smoking Classification Ex-smoker | 100 participants | 31 participants | 38 participants | 31 participants |
| Smoking Classification Never smoked | 231 participants | 83 participants | 62 participants | 86 participants |
| Waist Circumference | 99.31 cm STANDARD_DEVIATION 17.37 | 99.93 cm STANDARD_DEVIATION 17.82 | 97.93 cm STANDARD_DEVIATION 17.536 | 100.02 cm STANDARD_DEVIATION 16.762 |
| Weight | 87.81 kg STANDARD_DEVIATION 23.678 | 89.14 kg STANDARD_DEVIATION 24.01 | 86.49 kg STANDARD_DEVIATION 23.154 | 87.74 kg STANDARD_DEVIATION 23.914 |
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 | 92 / 160 | 99 / 154 | 96 / 151 |
| serious Total, serious adverse events | 1 / 160 | 1 / 154 | 0 / 151 |
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 post-baseline 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 | -12.87 scores on a scale | Standard Error 1.043 |
| Vortioxetine 10 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -13.66 scores on a scale | Standard Error 1.064 |
| Vortioxetine 15 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -13.36 scores on a scale | Standard Error 1.087 |
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 for each dose was applied to compare 10 mg and 15 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: 0.59795% CI: [-3.71, 2.14]Mixed model for repeated measurements
p-value: 0.74595% CI: [-3.44, 2.46]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. 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 | -14.11 scores on a scale | Standard Error 1.611 |
| 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 | -15.07 scores on a scale | Standard Error 1.65 |
| Vortioxetine 15 mg | Change From Baseline in MADRS Total Score at Week 8 in Participants With Baseline Hamilton Anxiety Scale (HAM-A) Total Score ≥ 20 | -12.37 scores on a scale | Standard Error 1.689 |
p-value: 0.6795% CI: [-5.43, 3.5]Mixed model for repeated measurements
p-value: 0.45195% CI: [-2.8, 6.26]Mixed model for repeated measurements
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) Total Score
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 | -9.38 scores on a scale | Standard Error 0.877 |
| Vortioxetine 10 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score | -10.30 scores on a scale | Standard Error 0.959 |
| Vortioxetine 15 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score | -8.69 scores on a scale | Standard Error 0.99 |
p-value: 0.46495% CI: [-3.38, 1.55]Mixed model for repeated measurements
p-value: 0.695% CI: [-1.91, 3.3]Mixed model for repeated measurements
Secondary
Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8
The Clinical Global Impression - global improvement 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 (CGI-S) score-by-week as fixed effects.
Time frame: Week 8
Population: The 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 | 2.65 scores on a scale | Standard Error 0.105 |
| Vortioxetine 10 mg | Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8 | 2.56 scores on a scale | Standard Error 0.107 |
| Vortioxetine 15 mg | Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8 | 2.60 scores on a scale | Standard Error 0.11 |
p-value: 0.55495% CI: [-0.38, 0.21]Mixed model for repeated measurements
p-value: 0.73995% CI: [-0.35, 0.25]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 | 22.1 percentage of participants |
| Vortioxetine 10 mg | Percentage of Participants in MADRS Remission at Week 8 | 26.6 percentage of participants |
| Vortioxetine 15 mg | Percentage of Participants in MADRS Remission at Week 8 | 23.9 percentage of participants |
p-value: 0.35295% CI: [0.754, 2.211]Regression, Logistic
p-value: 0.69495% CI: [0.646, 1.928]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 | 32.9 percentage of participants |
| Vortioxetine 10 mg | Percentage of Participants With a MADRS Response at Week 8 | 37.8 percentage of participants |
| Vortioxetine 15 mg | Percentage of Participants With a MADRS Response at Week 8 | 37.3 percentage of participants |
p-value: 0.39695% CI: [0.761, 1.995]Regression, Logistic
p-value: 0.43595% CI: [0.748, 1.963]Regression, Logistic