Major Depressive Disorder
Conditions
Brief summary
This randomized, double-blind, placebo-controlled, multicenter, 8-week, clinical trial is designed to assess the efficacy and safety of vilazodone and to evaluate genetic biomarkers of treatment response associated with vilazodone use in adult patients diagnosed with MDD by the DSM-IV-TR criteria.
Detailed description
This randomized, double-blind, placebo-controlled, multicenter, 8-week, clinical trial is designed to assess the efficacy and safety of vilazodone and to evaluate genetic biomarkers of treatment response associated with vilazodone use in adult patients diagnosed with MDD by the DSM-IV-TR criteria. This study will enroll approximately 470 patients at approximately 10 clinical sites. Safety and efficacy will be assessed at each visit. A DNA sample will be collected and analyzed for response to vilazodone.
Interventions
DRUGvilazodone
titration to 40 mg tablets qd (once a day) for 8 weeks
DRUGplacebo
placebo
Sponsors
Forest Laboratories
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 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients 18-70 years of age. * A diagnosis of MDD, single episode or recurrent, according to DSM-IV-TR (296.2/296.3) with a current Major Depressive Episode of less than two year's duration with a minimum duration of at least 4 weeks. * Meets DSM-IV-TR criteria for Major Depressive Disorder. * HAM-D score ≥ 22 on the first 17 items of the 21-item HAM-D. * HAM-D item 1 (depressed mood) score ≥ 2. * Patients must be able to provide written informed consent * Patients must be able to speak, read and understand English
Exclusion criteria
* Patients with a current (or within 6 months prior to the Screening Visit) Axis I disorder of Post Traumatic Stress Disorder, Eating Disorder, Obsessive Compulsive Disorder. * Patients with a history of schizophrenia, schizoaffective disorder or bipolar I or II disorder (with a history of hypomanic or manic episodes). * Patients who meet DSM-IV-TR criteria for substance abuse (alcohol or drugs) within 3 months prior to the Screening Visit or substance dependence within 6 months prior to the Screening Visit. * Patients who meet criteria for any of the following DSM-IV-TR MDD Specifiers: \[a\] With Catatonic Features; \[b\] With Postpartum Onset; \[c\] With Seasonal Pattern \[d\]severe with Psychotic Features. * Patients who are receiving formal psychotherapy or have had psychotherapy within the 12 weeks prior to the Screening Visit. * Patients who have any one of the following: * In the month prior to screening, have had active suicidal ideation with some intent to act, without specific plan. * In the month prior to screening, have had suicidal ideation with specific plan and intent. * Have made a suicide attempt within the 6 months prior to the screening visit. * In the opinion of the Investigator, is currently at significant risk of suicide. * Patients who have had an inadequate response to at least 2 consecutive antidepressants from different classes given at adequate doses for an adequate duration. * Patients who have received electroconvulsive therapy within the 6 months prior to the Screening Visit. * Patients currently taking a psychotropic drug. Patients who have taken psychotropic drugs must have discontinued these prior to the Screening Visit. The minimum discontinuation periods are outlined in the study protocol. * Patients taking migraine medications with a serotonergic mechanism of action * Patients taking CYP3A4 inhibitors such as grapefruit juice, ketoconazole, diltiazem, and macrolide antibiotics or montelukast * Patients with known hypersensitivity to SSRIs (selective serotonin reyptake inhibitors) or 5-HT1a agonists. * Patients previously treated with vilazodone (also known as SB-659746-A or EMD 68 843). * Patients with a history of clinically significant cardiac, renal, neurologic, cerebrovascular, hepatic, hematologic, metabolic or pulmonary disorders. * Patients with any serious medical disorder or condition that would, in the investigator's opinion, preclude the administration of study medication. * Female patients must not be pregnant, lactating, or planning to become pregnant during the time of study participation. All female patients must be at least 1 year post menopausal or irreversibly surgically sterilized (by hysterectomy, oophorectomy, or bilateral tubal ligation with resection) or determined not to be at risk of pregnancy. * Patients with clinically significant abnormalities on electrocardiogram. * Patients having clinically significant abnormal laboratory findings. * Patients with a positive drug screen. * Patients who, in the opinion of the investigator, would be noncompliant with the visit schedule or study procedures. * Patients that have taken an investigational drug or participated in an investigational drug trial within the past 30 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 8 in the MADRS (Montgomery-Asberg Depression Rating Scale) Total Score. | Baseline, Week 1, Week 2, Week 4, Week 6, Week 8 | The MADRS is an observer rating scale that has proven to be an efficient and practical measure of depression. The scale was constructed to be sensitive to treatment effects. The change from baseline in MADRS total score has a possible range of -60 to 60 where negative values reflect improvement in depression symptom severity. The method of last observation carried forward was utilized for subjects who discontinued prematurely. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 8 in the HAM-D 17 (17-Item Hamilton Rating Scale for Depression) Total Score | Baseline, week 1, week 2, week 4, week 6, week 8 | The HAM-D 17 is a 17-item subscale of the HAM-D 21, which is designed to be completed by a trained rater. It is designed for rating depressive symptom severity in patients with a confirmed diagnosis of depressive disorder. The change in HAM-D 17 has a possible range of -52 to 52 with negative values indicating improvment in depression symptom severity. The method of last observation carried forward was utilized for subjects who discontinued prematurely. |
| The CGI-I (Clinician's Global Impression of Improvement) Score at Week 8 | Week 1, Week 2, Week 4, Week 6, Week 8 | The CGI-I scale measures change from the baseline state at every visit after the baseline visit. It permits a global evaluation of the patient's improvement over time. At the scheduled clinic visits, the clinician assessed the patient's improvement relative to the symptoms at baseline on a CGI-I item using a 7-point scale, where 1 = very much improved and 7 = very much worse. The method of last observation carried forward was utilized for subjects who discontinued prematurely. |
| Change From Baseline to Week 8 in the HAM-A ( Hamilton Anxiety Rating Scale) Total Score | Baseline, Week 1, Week 2, Week 4, Week 6, Week 8 | The HAM-A is a rating scale developed to quantify the severity of anxiety. It consists of 14 items, each defined by a series of symptoms. Each item is rated on a 5-point scale, ranging from 0 (not present) to 4 (severe). Change from baseline in the HAM-A total score may range from -52 to 52 with negative value indicating improvement in anxiety symptom severity. The method of last observation carried forward was utilized for subjects who discontinued prematurely. |
| MADRS (Montgomery-Asberg Depression Rating Scale) Response Rate at Week 8 | Baseline, Week 1, Week 2, Week 4, Week 6, Week 8 | MADRS response was defined as ≥ 50% decrease from baseline in MADRS total score at Week 8. The response rate is the percentage of subjects in each treatment group meeting the criteria for response. The method of last observation carrier forward was utilized for subjects who discontinued prematurely. |
| MADRS (Montgomery-Asberg Depression Rating Scale) Remission Rate at Week 8 | Baseline, Week 1, Week 2, Week 4, Week 6, Week 8 | MADRS remission was defined as a MADRS total score \< 10 at Week 8. The remission rate is the percentage of subjects in each treatment group who met the criteria for remission. The method of last observation carried forward was utilized for subjects who discontinued prematurely. |
Countries
United States
Participant flow
Recruitment details
Recruitment period was 31Mar2008 to 10Feb2009.
Pre-assignment details
This study included a washout period to allow patients to discontinue their current antidepressant medications and any additional medications prohibited by the protocol, if applicable.
Participants by arm
| Arm | Count |
|---|---|
| Vilazodone (ITT Population) Vilazodone, 40 mg | 231 |
| Placebo (ITT Population) placebo to match vilazodone | 232 |
| Total | 463 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 4 |
| Overall Study | Lack of Efficacy | 3 | 7 |
| Overall Study | Lost to Follow-up | 17 | 17 |
| Overall Study | Non-compliance | 3 | 5 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 11 | 11 |
Baseline characteristics
| Characteristic | Vilazodone (ITT Population) | Placebo (ITT Population) | Total |
|---|---|---|---|
| Age Continuous | 41.1 years STANDARD_DEVIATION 12.22 | 42.4 years STANDARD_DEVIATION 12.49 | 41.7 years STANDARD_DEVIATION 12.36 |
| Region of Enrollment United States | 231 participants | 232 participants | 463 participants |
| Sex: Female, Male Female | 138 Participants | 123 Participants | 261 Participants |
| Sex: Female, Male Male | 93 Participants | 109 Participants | 202 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 148 / 235 | 85 / 233 |
| serious Total, serious adverse events | 4 / 235 | 2 / 233 |
Outcome results
Primary
Change From Baseline to Week 8 in the MADRS (Montgomery-Asberg Depression Rating Scale) Total Score.
The MADRS is an observer rating scale that has proven to be an efficient and practical measure of depression. The scale was constructed to be sensitive to treatment effects. The change from baseline in MADRS total score has a possible range of -60 to 60 where negative values reflect improvement in depression symptom severity. The method of last observation carried forward was utilized for subjects who discontinued prematurely.
Time frame: Baseline, Week 1, Week 2, Week 4, Week 6, Week 8
Population: Intent-to-Treat (ITT): the ITT population consisted of patients who were randomized, took at least 1 dose of study drug, and had at least 1 post-baseline efficacy endpoint measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Vilazodone (ITT Population) | Change From Baseline to Week 8 in the MADRS (Montgomery-Asberg Depression Rating Scale) Total Score. | -13.3 Units on a scale |
| Placebo (ITT Population) | Change From Baseline to Week 8 in the MADRS (Montgomery-Asberg Depression Rating Scale) Total Score. | -10.8 Units on a scale |
Comparison: The model was an analysis of covariance (ANCOVA), with terms for treatment group and center, adjusting for baseline MADRS total score. Missing values at week 8 were handled using the last observation carried forward (LOCF) approach.p-value: 0.00995% CI: [-4.4, -0.6]ANCOVA
Secondary
Change From Baseline to Week 8 in the HAM-A ( Hamilton Anxiety Rating Scale) Total Score
The HAM-A is a rating scale developed to quantify the severity of anxiety. It consists of 14 items, each defined by a series of symptoms. Each item is rated on a 5-point scale, ranging from 0 (not present) to 4 (severe). Change from baseline in the HAM-A total score may range from -52 to 52 with negative value indicating improvement in anxiety symptom severity. The method of last observation carried forward was utilized for subjects who discontinued prematurely.
Time frame: Baseline, Week 1, Week 2, Week 4, Week 6, Week 8
Population: Intent-to-Treat (ITT): the ITT population consisted of patients who were randomized, took at least 1 dose of study drug, and had at least 1 post-baseline efficacy endpoint measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Vilazodone (ITT Population) | Change From Baseline to Week 8 in the HAM-A ( Hamilton Anxiety Rating Scale) Total Score | -7.0 Units on a scale |
| Placebo (ITT Population) | Change From Baseline to Week 8 in the HAM-A ( Hamilton Anxiety Rating Scale) Total Score | -5.7 Units on a scale |
Comparison: The model was an analysis of covariance (ANCOVA), with terms for treatment group and center, adjusting for baseline HAM-A total score. Missing values at week 8 were handled using the last observation carried forward (LOCF) approach.p-value: 0.03795% CI: [-2.4, -0.1]ANCOVA
Secondary
Change From Baseline to Week 8 in the HAM-D 17 (17-Item Hamilton Rating Scale for Depression) Total Score
The HAM-D 17 is a 17-item subscale of the HAM-D 21, which is designed to be completed by a trained rater. It is designed for rating depressive symptom severity in patients with a confirmed diagnosis of depressive disorder. The change in HAM-D 17 has a possible range of -52 to 52 with negative values indicating improvment in depression symptom severity. The method of last observation carried forward was utilized for subjects who discontinued prematurely.
Time frame: Baseline, week 1, week 2, week 4, week 6, week 8
Population: Intent-to-Treat (ITT): the ITT population consisted of patients who were randomized, took at least 1 dose of study drug, and had at least 1 post-baseline efficacy endpoint measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Vilazodone (ITT Population) | Change From Baseline to Week 8 in the HAM-D 17 (17-Item Hamilton Rating Scale for Depression) Total Score | -10.7 Units on a scale |
| Placebo (ITT Population) | Change From Baseline to Week 8 in the HAM-D 17 (17-Item Hamilton Rating Scale for Depression) Total Score | -9.1 Units on a scale |
Comparison: The model was an analysis of covariance (ANCOVA), with terms for treatment group and center, adjusting for baseline HAM-D 17 total score. Missing values at week 8 were handled using the last observation carried forward (LOCF) approach.p-value: 0.02695% CI: [-3.1, -0.2]ANCOVA
Secondary
MADRS (Montgomery-Asberg Depression Rating Scale) Remission Rate at Week 8
MADRS remission was defined as a MADRS total score \< 10 at Week 8. The remission rate is the percentage of subjects in each treatment group who met the criteria for remission. The method of last observation carried forward was utilized for subjects who discontinued prematurely.
Time frame: Baseline, Week 1, Week 2, Week 4, Week 6, Week 8
Population: Intent-to-Treat (ITT): the ITT population consisted of patients who were randomized, took at least 1 dose of study drug, and had at least 1 post-baseline efficacy endpoint measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vilazodone (ITT Population) | MADRS (Montgomery-Asberg Depression Rating Scale) Remission Rate at Week 8 | 63 Participants |
| Placebo (ITT Population) | MADRS (Montgomery-Asberg Depression Rating Scale) Remission Rate at Week 8 | 47 Participants |
Comparison: Cochran-Mantel-Haenszel tests were used to compare MADRS remission rates between the treatment groups, stratifying by center. The asymptotic confidence interval of the risk difference was estimated by the normal approximation to the binomial distribution.p-value: 0.06695% CI: [-0.008, 0.147]Cochran-Mantel-Haenszel
Secondary
MADRS (Montgomery-Asberg Depression Rating Scale) Response Rate at Week 8
MADRS response was defined as ≥ 50% decrease from baseline in MADRS total score at Week 8. The response rate is the percentage of subjects in each treatment group meeting the criteria for response. The method of last observation carrier forward was utilized for subjects who discontinued prematurely.
Time frame: Baseline, Week 1, Week 2, Week 4, Week 6, Week 8
Population: Intent-to-Treat (ITT): the ITT population consisted of patients who were randomized, took at least 1 dose of study drug, and had at least 1 post-baseline efficacy endpoint measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vilazodone (ITT Population) | MADRS (Montgomery-Asberg Depression Rating Scale) Response Rate at Week 8 | 101 Participants |
| Placebo (ITT Population) | MADRS (Montgomery-Asberg Depression Rating Scale) Response Rate at Week 8 | 70 Participants |
Comparison: Cochran-Mantel-Haenszel tests were used to compare MADRS response rates between the treatment groups, stratifying by center. The asymptotic confidence interval of the risk difference was estimated by the normal approximation to the binomial distribution.p-value: 0.00295% CI: [0.047, 0.221]Cochran-Mantel-Haenszel
Secondary
The CGI-I (Clinician's Global Impression of Improvement) Score at Week 8
The CGI-I scale measures change from the baseline state at every visit after the baseline visit. It permits a global evaluation of the patient's improvement over time. At the scheduled clinic visits, the clinician assessed the patient's improvement relative to the symptoms at baseline on a CGI-I item using a 7-point scale, where 1 = very much improved and 7 = very much worse. The method of last observation carried forward was utilized for subjects who discontinued prematurely.
Time frame: Week 1, Week 2, Week 4, Week 6, Week 8
Population: Intent-to-Treat (ITT): the ITT population consisted of patients who were randomized, took at least 1 dose of study drug, and had at least 1 post-baseline efficacy endpoint measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Vilazodone (ITT Population) | The CGI-I (Clinician's Global Impression of Improvement) Score at Week 8 | 2.5 Units on a scale |
| Placebo (ITT Population) | The CGI-I (Clinician's Global Impression of Improvement) Score at Week 8 | 2.8 Units on a scale |
Comparison: The model was an analysis of variance (ANOVA), with terms for treatment group and center. Missing values at week 8 were handled using the last observation carried forward (LOCF) approach.p-value: 0.00495% CI: [-0.5, -0.1]ANOVA