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`
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`022567Orig1s000
`
`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`
`STATISTICAL REVIEW AND EVALUATION
`CLINICAL STUDIES
`
`
`NDA/Serial Number:
`Drug Name:
`Indication:
`Applicant:
`Date(s):
`
`22-567 N000
`Vilazodone
`Major depressive disorder
`PGxHealth
`Received: March 22, 2010;
`PDUFA Due Date: January 22, 2011
`Review Priority:
`Standard
`Biometrics Division:
`Biometrics I, HFD-710
`Statistical Reviewer:
`Phillip Dinh, Ph.D.
`Concurring Reviewers: Peiling Yang, Ph.D.
`
`H.M. James Hung, Ph.D.
`Medical Division:
`Division of Psychiatry Products, HFD-130
`Clinical Team:
`Cheri Lindberg M.D., Medical Reviewer, HFD-130
`Robert Levin M.D., Medical Team Leader, HFD-130
`Project Manager:
`Bill Bender, HFD-130
`
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`
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`Keywords: Clinical studies; NDA review
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`Reference ID: 2870273
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`Table of Contents
`1. EXECUTIVE SUMMARY ..............................................................................................................................4
`1.1
`CONCLUSIONS AND RECOMMENDATIONS ....................................................................................................4
`1.2
`BRIEF OVERVIEW OF CLINICAL STUDIES.....................................................................................................4
`1.3
`STATISTICAL ISSUES AND FINDINGS ............................................................................................................4
`2.
`INTRODUCTION ............................................................................................................................................4
`2.1
`OVERVIEW...................................................................................................................................................4
`2.2
`DATA SOURCES ...........................................................................................................................................5
`3. STATISTICAL EVALUATION .....................................................................................................................6
`3.1
`EVALUATION OF EFFICACY .........................................................................................................................6
`3.1.1 Study CLDA-07-DP-02 .............................................................................................................................6
`3.1.1.1 Objectives .............................................................................................................................................................6
`3.1.1.2 Study Design.........................................................................................................................................................6
`3.1.1.3 Efficacy Endpoints and Analyses ..........................................................................................................................6
`3.1.1.4 Efficacy Results.....................................................................................................................................................6
`3.1.1.4.1 Study Population................................................................................................................................................6
`3.1.1.4.2 Sponsor’s Efficacy Results for Primary Efficacy Measure ................................................................................8
`3.1.1.4.3 Sponsor’s Other Efficacy Results.......................................................................................................................8
`3.1.1.4.4 Reviewer’s Results and Comments ....................................................................................................................9
`3.1.2 Study GNSC-04-DP-02 ...........................................................................................................................11
`3.1.2.1 Objective............................................................................................................................................................. 11
`3.1.2.2 Study Design....................................................................................................................................................... 11
`3.1.2.3 Efficacy Endpoints and Analyses ........................................................................................................................ 12
`3.1.2.4 Efficacy Results................................................................................................................................................... 12
`3.1.2.4.1 Study Population.............................................................................................................................................. 12
`3.1.2.4.2 Sponsor’s Efficacy Results for the Primary Efficacy Measure......................................................................... 13
`3.1.1.4.3 Sponsor’s Other Efficacy Results..................................................................................................................... 14
`3.1.2.4.4 Reviewer’s Results and Comments .................................................................................................................. 15
`3.1.3 Summary of primary efficacy results of phase II studies ......................................................................17
`EVALUATION OF SAFETY...........................................................................................................................19
`3.2
`4.
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS .........................................................................19
`4.1
`GENDER, RACE AND AGE ..........................................................................................................................19
`4.1.1
`Study CLDA-07-DP-02 ....................................................................................................................19
`4.1.1.1 Gender .......................................................................................................................................................... 19
`4.1.1.2
`Race .............................................................................................................................................................. 19
`4.1.1.3
`Age ................................................................................................................................................................ 20
`4.1.1.4
`Baseline disease severity............................................................................................................................... 20
`4.1.1.5 Disease history.............................................................................................................................................. 21
`4.1.2
`Study GNSC-04-DP-02 ....................................................................................................................21
`4.1.2.1 Gender .......................................................................................................................................................... 21
`4.1.2.2
`Race .............................................................................................................................................................. 22
`4.1.2.3
`Age ................................................................................................................................................................ 22
`4.1.2.4
`Baseline disease severity............................................................................................................................... 23
`4.1.2.5 Disease history.............................................................................................................................................. 23
`5. SUMMARY AND CONCLUSIONS .............................................................................................................24
`5.1
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE ....................................................................................24
`5.2
`CONCLUSIONS AND RECOMMENDATIONS ..................................................................................................24
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`LIST OF TABLES
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`Table 1. Study CLDA-07-DP-02: Disposition of patients..........................................................................................7
`Table 2. Study CLDA-07-DP-02: Demographic characteristics (Safety sample).......................................................7
`Table 3. Study CLDA-07-DP-02: Sponsor’s primary efficacy results: change from baseline to week 8 in the
`MADRS total score (LOCF) in the ITT sample .........................................................................................................8
`Table 4. Study CLDA-07-DP-02: Sponsor’s efficacy results: change from baseline to week 8 in the CGI-S (LOCF)
`in the ITT sample........................................................................................................................................................8
`Table 5. Study CLDA-07-DP-02: Sponsor’s efficacy results: CGI-I at week 8 (LOCF) in the ITT sample..............9
`Table 6. Study CLDA-07-DP-02: Sponsor’s efficacy results: change from baseline to week 8 in the HAM-D17
`(LOCF) in the ITT sample..........................................................................................................................................9
`Table 7. Study CLDA-07-DP-02: Reviewer’s efficacy analysis: change from baseline in the MADRS total score
`(MMRM analysis) over time in the ITT sample.......................................................................................................10
`Table 8. Study GNSC-04-DP-02: Disposition of patients ........................................................................................12
`Table 9. Study GNSC-04-DP-02: Demographic characteristics (Safety sample).....................................................13
`Table 10. Study GNSC-04-DP-02: Sponsor’s primary analysis: change from baseline to week 8 in the MADRS
`total score (LOCF) in the ITT sample ......................................................................................................................13
`Table 11. Study GNSC-04-DP-02: Sponsor’s efficacy results: change from baseline to week 8 in the CGI-S
`(LOCF) in the ITT sample........................................................................................................................................14
`Table 12. Study GNSC-04-DP-02: Sponsor’s efficacy results: CGI-I at week 8 (LOCF) in the ITT sample ..........14
`Table 13. Study GNSC-04-DP-02: Sponsor’s efficacy results: change from baseline to week 8 in the HAM-D17
`total score (LOCF) in the ITT sample ......................................................................................................................14
`Table 14. Study GNSC-04-DP-02: Reviewer’s efficacy analysis: change from baseline in the MADRS total score
`(MMRM analysis) over time in the ITT sample.......................................................................................................15
`Table 15. Study GNSC-04-DP-02: Reviewer’s analysis: change from baseline to week 8 in the MADRS total score
`(LOCF) in the ITT sample for the first 266 subjects ................................................................................................16
`Table 16. Summary of results on the primary efficacy variables of phase II studies ...............................................18
`Table 17. Study CLDA-07-DP-02: Reviewer’s primary efficacy results by gender: change from baseline to week 8
`in the MADRS total score (LOCF) in the ITT sample .............................................................................................19
`Table 18. Study CLDA-07-DP-02: Reviewer’s primary efficacy results by race: change from baseline to week 8 in
`the MADRS total score (LOCF) in the ITT sample..................................................................................................19
`Table 19. Study CLDA-07-DP-02: Reviewer’s primary efficacy results by age: change from baseline to week 8 in
`the MADRS total score (LOCF) in the ITT sample..................................................................................................20
`Table 20. Study CLDA-07-DP-02: Reviewer’s primary efficacy results by baseline disease severity: change from
`baseline to week 8 in the MADRS total score (LOCF) in the ITT sample...............................................................20
`Table 21. Study CLDA-07-DP-02: Reviewer’s primary efficacy results by disease history: change from baseline to
`week 8 in the MADRS total score (LOCF) in the ITT sample .................................................................................21
`Table 22. Study GNSC-04-DP-02: Reviewer’s primary efficacy results by gender: change from baseline to week 8
`in the MADRS total score (LOCF) in the ITT sample .............................................................................................21
`Table 23. Study GNSC-04-DP-02: Reviewer’s primary efficacy results by race: change from baseline to week 8 in
`the MADRS total score (LOCF) in the ITT sample..................................................................................................22
`Table 24. Study GNSC-04-DP-02: Reviewer’s primary efficacy results by age: change from baseline to week 8 in
`the MADRS total score (LOCF) in the ITT sample..................................................................................................22
`Table 25. Study GNSC-04-DP-02: Reviewer’s primary efficacy results by baseline disease severity: change from
`baseline to week 8 in the MADRS total score (LOCF) in the ITT sample...............................................................23
`Table 26. Study GNSC-04-DP-02: Reviewer’s primary efficacy results by disease history: change from baseline to
`week 8 in the MADRS total score (LOCF) in the ITT sample .................................................................................23
`
`LIST OF FIGURES
`
`
`Figure 1. Study CLDA-07-DP-02: Cumulative distribution function .....................................................................11
`Figure 2. Study GNSC-04-DP-02: Cumulative distribution function......................................................................17
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`1.
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`2.
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`EXECUTIVE SUMMARY
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`1.1 Conclusions and Recommendations
`Vilazodone at a 40 mg/day was positive in the acute treatment of major depressive disorder,
`as measured by the change from baseline to week 8 in the Montgomery-Asberg Depression
`Rating Scale (MADRS) total score, based on two pivotal studies.
`
`1.2 Brief Overview of Clinical Studies
`This submission contains two pivotal, phase III studies to support the efficacy and safety of
`vilazodone in the acute treatment of major depressive disorder (MDD). Both studies were
`randomized, double-blind, placebo-controlled, parallel-group, multicenter, U.S. studies.
`Both studies investigated the efficacy and safety of vilazodone at a target dose of 40
`mg/day. Patients went through a titration period to the target dose. The primary efficacy
`measure was the change from baseline to week 8 in the MADRS total score.
`
`This NDA also contains five other studies that were either negative or failed and are not
`subject to this review.
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`1.3 Statistical Issues and Findings
`Both pivotal studies were positive based on the primary efficacy variable pre-specified.
`None of the secondary efficacy measures were specified as key secondary efficacy
`measures or agreed upon a priori
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`The long-term efficacy of vilazodone has not been adequately assessed. The current data
`are based on a one year open-label study (Study CLDA-07-DP-04). Because this was an
`open-label and there was no control group, the efficacy evaluation is limited and is subject
`to biases.
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`INTRODUCTION
`2.1 Overview
`
`This review provides a statistical evaluation of the efficacy of vilazodone as an acute
`treatment of major depressive disorder (MDD).
`
`As defined in the DSM-IV-TR, major depressive disorder (MDD) is a mental illness
`characterized by one or more major depressive episodes. A major depressive episode
`implies a prominent and relatively persistent (nearly every day for at least 2 weeks)
`depressed or dysphoric mood that usually interferes with daily functioning. MDD includes
`at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities,
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`significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor
`agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed
`thinking or impaired concentration, or a suicide attempt or suicidal ideation.
`
`According to the sponsor, MDD is the leading cause of disability in the United States for
`people aged 15 to 44 years old and contributes to functional impairment and increases in
`morbidity and mortality.
`
`According to the sponsor, vilazodone HCl (vilazodone), a dual-acting potent and selective
`serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is a new chemical entity
`belonging to the structural chemical group of the indolalkylamines.
`
`Vilazodone is currently under development for the treatment of major depressive disorder
`(MDD). Vilazodone has been investigated in 5 phase II studies conducted in MDD patients
`where the safety of vilazodone was confirmed, but efficacy was not established. Two of
`these studies were negative and three were considered failed
`
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`
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`Vilazodone was also studied in two phase III studies:
`- Study CLDA-07-DP-02 was a U.S., randomized, double-blind, placebo-controlled,
`multicenter, 8-week study. The study consisted of three periods: a washout period, a
`screening period, and an 8-week double-blind treatment period. Patients were titrated to
`the target dose by Day 15. The primary efficacy variable was the change from baseline
`to week 8 in the MADRS total score.
`- Study GNSC-04-DP-02 was a U.S., randomized, double-blind, placebo-controlled,
`multicenter, 8-week study. After an appropriate washout and screening, patients were
`randomly assigned to receive either placebo or vilazodone in a 1:1 ratio. Patients were
`titrated to the target dose by Day 15. The primary efficacy variable was the change
`from baseline to week 8 in the MADRS total score.
`
`
`This review will focus on the efficacy evaluation of studies CLDA-07-DP-02 and GNSC-
`04-DP-02, with a brief summary of the primary efficacy results of other five phase II
`studies.
`
`2.2 Data Sources
`
`The sponsor’s submitted data are stored in the following directory of the CDER’s electronic
`document room: \\Cdsesub1\evsprod\NDA022567\0000\m5\datasets.
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`3.
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`STATISTICAL EVALUATION
`3.1 Evaluation of Efficacy
`3.1.1 Study CLDA-07-DP-02
`
`3.1.1.1 Objectives
`Primary: The primary objective of this study was to compare the efficacy
`between vilazodone and placebo using the change from baseline in the MADRS
`total score at week 8.
`
`3.1.1.2 Study Design
`This was a U.S., randomized, double-blind, placebo-controlled, multicenter, 8-
`week study. The study consisted of three periods: a washout period, a screening
`period, and an 8-week double-blind treatment period. Patients were titrated to
`their target dose by Day 15. The primary efficacy variable was the MADRS total
`score. The MADRS was evaluated at baseline, weeks 1, 2, 4, 6, and 8, or at early
`termination.
`
`Eligible patients were male and female between the age of 18 and 70; diagnosed
`with MDD, single episode or recurrent, according to DSM-IV-TR; had a HAM-D
`score ≥ 22 on the first 17 items of the 21 item HAM-D at screening and baseline
`visits; and had a HAM-D item 1 (depressed mood) score ≥ 2 at screening and
`baseline visits.
`
`The study was planned for 235 patients per arm to provide 90% power to detect
`an effect size of 0.3 on the change from baseline to week 8 in the MADRS total
`score.
`
`3.1.1.3 Efficacy Endpoints and Analyses
`Primary efficacy measure and analysis: The primary efficacy measure was the
`change from baseline to week 8 in the MADRS total score. Missing values were
`imputed by the Last Observation Carried Forward (LOCF) method. The primary
`analysis was an ANCOVA model with terms for treatment and center, and
`baseline MADRS total score as a covariate. Center was pooled as necessary for
`the analysis.
`
`Sensitivity analyses on the primary efficacy variable include an ANCOVA model
`as above with the treatment-by-center interaction and a mixed-effects model for
`repeated measures (MMRM). For the MMRM analysis, the model included fixed
`categorical effect terms for treatment, center, visit, and treatment-by-visit
`interaction, as well as continuous fixed covariates for baseline MADRS and
`baseline-by-visit interaction.
`
`3.1.1.4 Efficacy Results
`
`3.1.1.4.1 Study Population
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`The disposition of patients is summarized in Table 1. A total of 481 subjects
`were randomized. Ninety three subjects (19.3%) discontinued from the study
`prematurely. The main reasons for dropping out were lost to follow-up (37%),
`consent withdrawal (24%), and adverse event (17%). There were about three
`times more dropouts due to adverse events in vilazodone arm than in the placebo
`arm. On the contrary, there were about twice more patients who dropped out due
`to lack of efficacy in the placebo arm than in vilazodone arm.
`
`
`
`Table 1. Study CLDA-07-DP-02: Disposition of patients
`Placebo
`Vilazodone Total
`
`241
`240
`481
`Randomized
`
`
`93 (19.3)
`47 (19.6)
`Discontinued study: n (%) 46 (19.1)
`16 (17.2)
`12 (25.5)
` Adverse event
`4 (8.7)
`22 (23.7)
`11 (23.4)
` Withdrawal of consent
`11 (23.9)
`34 (36.6)
`17 (36.2)
` Lost to follow-up
`17 (37.0)
`10 (10.8)
`3 (6.4)
` Lack of therapeutic effect
`7 (15.2)
`1 (1.1)
`0 (0.0)
` Investigator decision
`1 (2.2)
`8 (8.6)
`3 (6.4)
` Non compliance
`5 (10.9)
`2 (2.2)
`1 (2.1)
` Other
`1 (2.2)
`388 (80.7)
`193 (80.4)
`Completed study: n (%)
`195 (80.9)
`Patients 2080-058 and 2020-173 were excluded because the same patients participated in two
`clinical sites.
`(Source: CLDA-07-DP-02 Study Report; Table 6, page 51)
`
`
`The demographic characteristics in the safety sample are presented in Table 2.
`The majority of the patients were white (80%). There were slightly more females
`than males. The average age was 42 years old and ranged from 18 to 70.
`
`
`Table 2. Study CLDA-07-DP-02: Demographic characteristics (Safety sample)
`
`Placebo
`Vilazodone
`Total
`N = 233
`N = 235
`N = 468
`
`41.1 (12.2)
`42 (18 – 69)
`
`41.7 (12.3)
`42 (18 - 70)
`
`139 (59.2)
`96 (40.9)
`
`263 (56.2)
`205 (43.8)
`
`Age at entry (yr) n
`
`42.4 (12.5)
` Mean (SD)
`43 (19 – 70)
` Median (min-max)
`Sex – n (%)
`
`124 (53.2)
` Female
`109 (46.8)
` Male
`Race – n (%)
`
`373 (79.7)
`182 (77.5)
`191 (82.0)
` White
`66 (14.1)
`35 (14.9)
`31 (13.3)
` Black
`16 (3.4)
`8 (3.4)
`8 (3.4)
` Asian
`13 (2.8)
`10 (4.3)
`3 (1.3)
` Others
`Patients 2080-058 and 2020-173 were excluded because the same patients participated in two
`clinical sites.
`(Source: CLDA-07-DP-02 Study Report; Tables 9 & 10, pages 54 & 55)
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`3.1.1.4.2 Sponsor’s Efficacy Results for Primary Efficacy Measure
`The sponsor’s primary efficacy analysis is summarized in Table 3. Vilazodone
`was superior to placebo on the change from baseline in the MADRS total score.
`
`Table 3. Study CLDA-07-DP-02: Sponsor’s primary efficacy results: change from baseline
`to week 8 in the MADRS total score (LOCF) in the ITT sample
`Placebo
`Vilazodone
`
`231
`232
`Sample size
`
`
`Baseline MADRS total score
` Mean (Standard deviation)
`32.0 (3.6)
`31.9 (3.5)
` Median (Min – Max)
`32 (24 – 42)
`32 (22 – 42)
`
`
`Change from baseline
` LS Means
`-10.8
`-13.3
` Difference from placebo (SE)
`
`-2.5 (0.96)
` (95% confidence interval)
`
`(-4.4, -0.6)
` P-value
`
`0.009
`The data for Patient IDs of 2080-058, 2020-173, and 2080-074 were excluded from
`analysis. Patient IDs 2020-016 (vilazodone) and 2080-058 (vilazodone) were the same
`patient enrolled at 2 different clinical sites and participation was consecutive. Patient IDs
`2020-173 (placebo) and 2080-074 (vilazodone) were the same patient and participation
`was overlapping at 2 different clinical sites.
`(Source: CLDA-07-DP-02 Study Report; Table 11, page 57)
`
`3.1.1.4.3 Sponsor’s Other Efficacy Results
`Change from baseline in the CGI-Severity of Illness (LOCF):
`An analysis of covariance on the change from baseline to week 8 in the CGI-S
`with missing values imputed by the LOCF method is summarized in Table 11.
`The results suggested the efficacy of vilazodone over placebo.
`
`
`Table 4. Study CLDA-07-DP-02: Sponsor’s efficacy results: change from baseline to week 8
`in the CGI-S (LOCF) in the ITT sample
`Placebo
`Vilazodone
`
`231
`231
`Sample size
`-1.1
`-1.4
`LS Means
`
`-0.4
`Difference from placebo
`
`(-0.6, -0.1)
`(95% confidence interval)
`
`0.004
`Unadjusted p-value
`(Source: CLDA-07-DP-02 Study Report; Table 18, page 70)
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`CGI-Improvement (LOCF):
`An analysis of covariance on the CGI-I at week 8 with missing values imputed by
`the LOCF method is summarized in Table 5. The results suggested the efficacy
`of vilazodone over placebo.
`
`
`Table 5. Study CLDA-07-DP-02: Sponsor’s efficacy results: CGI-I at week 8 (LOCF) in the
`ITT sample
`Vilazodone
`Placebo
`
`231
`231
`Sample size
`2.5
`2.8
`LS Means
`-0.3
`
`Difference from placebo
`(-0.5, -0.1)
`
`(95% confidence interval)
`0.004
`
`Unadjusted p-value
`(Source: CLDA-07-DP-02 Study Report; Table 19, page 71)
`
`Change from baseline in the HAM-D17 total score (LOCF):
`An analysis of covariance on the change from baseline to week 8 in the HAM-
`D17 total score with missing values imputed by the LOCF method is summarized
`in Table 6 The results supported the primary efficacy results.
`
`
`Table 6. Study CLDA-07-DP-02: Sponsor’s efficacy results: change from baseline to week 8
`in the HAM-D17 (LOCF) in the ITT sample
`Placebo
`Vilazodone
`
`231
`231
`Sample size
`-9.1
`-10.7
`LS Means
`
`-1.6
`Difference from placebo
`
`(-3.1, -0.2)
`(95% confidence interval)
`
`0.0256
`Unadjusted p-value
`(Source: CLDA-07-DP-02 Study Report; Table 17 page 69)
`
`
`3.1.1.4.4 Reviewer’s Results and Comments
`This reviewer confirmed the findings based on the primary efficacy variable as
`presented in Table 3. Vilazodone was statistically significantly superior to
`placebo.
`
`Sensitivity analysis on the primary efficacy variable: Table 7 summarizes an
`MMRM analysis of the treatment effects of vilazodone over the duration of the
`study. The model included baseline MADRS total score as a fixed covariate, a
`baseline-by-visit interaction, treatment group and visit as fixed factors, and
`treatment-by-visit interaction. Patients were treated as a random effect. An
`unstructured covariance matrix was used. It is noted that these results are slightly
`different from the sponsor’s results reported on page 62 of the CLDA-07-DP-02
`Study Report. However, the conclusion is the same and is supportive of the
`primary efficacy analysis.
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`Table 7. Study CLDA-07-DP-02: Reviewer’s efficacy analysis: change from baseline in the
`MADRS total score (MMRM analysis) over time in the ITT sample
`Placebo
`Vilazodone
`Vilazodone - Placebo
`
`N
`Mean
`N
`Mean
`Diff
`P-value*
`visit
`231
`-3.3
`232
`-3.7
`-0.4
`0.347
`Week 1
`223
`-5.7
`224
`-6.7
`-1.0
`0.087
`Week 2
`216
`-9.2
`213
`-10.8
`-1.6
`0.050
`Week 4
`207
`-11.4
`203
`-13.7
`-2.3
`0.017
`Week 6
`196
`-11.9
`194
`-14.8
`-2.9
`0.006
`Week 8
`(Source: Reviewer’s results).
`Subjects 2080-058, 2020-173, and 2080-047 were excluded from this analysis.
`*P-values are not adjusted for multiplicity
`
`
`The sponsor stated that after the completion of the study, two sets of identical
`genotypes were noted during the DNA analysis. Further investigation found that
`two sets of patients were the same individuals. Patients 020-016 and 2080-058
`were the same individual participating in two different, nearby sites, in a
`sequential manner. This individual was randomized to vilazodone both times. It
`was decided that only efficacy data from the first time to be included in the
`analysis. Patients 2020-173 and 2080-074 were the same individual participating
`in two different, nearby sites, during overlapping periods. This individual was
`randomized to placebo and vilazodone, respectively. This patient was excluded
`from all efficacy analysis.
`
`Figure 1 captures the empirical cumulative distribution functions (CDFs) of the
`two arms of the study. The horizontal axis captures the range of the changes from
`baseline in the MADRS total score at the last visit (LOCF). The use of the LOCF
`approach to handle the premature dropouts appears sensible because of the
`relatively low dropouts in the study for this indication. This is further supported
`by the consistencies of the treatment effects across several sensitivity and
`secondary analyses. The vertical axis depicts the proportion of patients whose
`changes from baseline score were less than or equal to a given score on the
`horizontal axis. The CDF plots attempt to capture the entire distributions of the
`responses whereas the means (as in Table 3) capture the central tendency of the
`distributions only. It should be noted that the variations associated with the CDF
`curves were not captured and presented in Figure 1. Thus, these curves are
`mainly for descriptive purposes only. Separations between vilazodone and
`placebo were observed in these two curves.
`
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`Figure 1. Study CLDA-07-DP-02: Cumulative distribution function
`(Source: Reviewer’s results)
`
`3.1.2 Study GNSC-04-DP-02
`
`
`
`3.1.2.1 Objective
`Primary: The primary objective of this study was to compare the efficacy of
`vilazodone and placebo in the treatment of MDD, as measured by the mean
`change from baseline in the Montgomery-Asberg Depression Rating Scale
`(MADRS) total score after 8 weeks of treatment.
`
`3.1.2.2 Study Design
`This was a U.S., randomized, double-blind, placebo-controlled, multicenter study.
`After an appropriate washout and screening, patients were randomly assigned to
`receive either placebo or vilazodone in a 1:1 ratio. Doses of vilazodone or
`matching placebo were titrated according to the following schedule: 10 mg/day
`for 7 days (Days 1-7), 20 mg/day for 7 days (Days 8-14), and 40 mg/day for 42
`days (Days 15-56). Dose modification was permitted: patients experiencing
`intolerable adverse events (AEs) at 20 mg/day could remain at 20 mg/day if
`indicated, and patients who developed intolerable adverse events at 40 mg/day
`were permitted to reduce the dosage to 20 mg/day.
`
`Patients were eligible to enroll if they were male or female between the age of 18-
`65 years; had a diagnosis of MDD, single episode or recurrent; had a HAM-D
`score ≥ 22 on the first 17 items of the 21-item HAM-D at screening and baseline
`visits; and had a HAM-D item 1 (depressed mood) score ≥ 2 at the screening and
`baseline visits.
`
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`The study was planned to enroll 408 patients with 266 patients randomized (133
`per arm) to detect a 4.0 difference with a standard deviation of 10.
`
`3.1.2.3 Efficacy Endpoints and Analyses
`Primary efficacy measure and analysis: The primary efficacy measure was the
`change from baseline to week 8 in the MADRS total score, with dropout values
`imputed by the last observation carried forward (LOCF) method. The primary
`analysis model was ANCOVA with treatment and center factors, and baseline
`MADRS total score as a covariate. The primary efficacy measure was assessed at
`baseline, weeks 1, 2, 4, 6, and 8 or at early termination.
`
`3.1.2.4 Efficacy Results
`
`
`
`3.1.2.4.1 Study Population
`A total of 561 patients were screened. Of these, 410 patients were randomized to
`either vilazodone or placebo (205 patients in each group). The disposition of
`patients is summarized in Table 8. Seventy five percent