Poster NR4-2

Efficacy and Tolerability of Vilazodone, a Dual-Acting Serotonergic Antidepressant, in the Treatment of Patients With Major Depressive Disorder (MDD)

Arif Khan, MD,^1,2 Andrew J. Cutler, MD,^3,4 Daniel K. Kajdasz, PhD,⁵ Maria Athanasiou, PhD,⁵ Donald S. Robinson, MD,⁶ Heidi Whalen, MHS,⁵ Carol R. Reed, MD⁵

¹Northwest Clinical Research Center, Bellevue, Washington; ²Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina; ³University of Florida, Gainesville, Florida; ⁴Florida Clinical Research Center, LLC, Bradenton, Florida; ⁵PGxHealth, LLC, New Haven, Connecticut; ⁶Worldwide Drug Development, Burlington, Vermont

Abstract

Objective

To assess the efficacy, safety, and tolerability of vilazodone HCl (VLZ), a dual-acting selective serotonin reuptake inhibitor and 5-HT_1A receptor partial agonist, in the treatment of major depressive disorder (MDD).

Method

This phase 3, randomized, double-blind, placebo (PBO)-controlled study enrolled patients (pts) 18-70 years of age with MDD and a baseline HAM-D-17 score ³22. Pts received VLZ or PBO QD titrated to 40 mg over 2 weeks and continued for up to 8 weeks (ITT population, n = 463; 388 completers). The primary objective was to assess VLZ efficacy measured by change in MADRS score. Secondary efficacy measures included MADRS response, HAM-D, HAM-A, CGI-S, and CGI-I. Safety and tolerability assessments included treatment-emergent adverse events (AEs) and labs, ECGs, and the Changes in Sexual Function Questionnaire (CSFQ).

Results

VLZ-treated pts had significantly greater improvement from baseline in MADRS total score at end point (P = 0.009) than PBO (ITT, LS mean changes, -13.3 and -10.8, respectively). Significantly more VLZ-treated than PBO pts (44% vs 30%, P = 0.002) were MADRS responders (decrease in MADRS total score ³50%). VLZ-treated pts also had significant improvements from baseline in HAM-D-17 (P = 0.026), HAM-A (P = 0.037), CGI-S (P = 0.004), and CGI-I (P = 0.004) at end point vs PBO. Discontinuations due to AEs were VLZ 5.1% and PBO 1.7%. The most frequent AEs in VLZ vs PBO pts were headache (13% vs 10%), nausea (26% vs 6%), and diarrhea (31% vs 11%) (>93% of these judged to be mild or moderate in intensity). There were no clinically significant changes in weight, vital signs, ECGs, or labs. No clinically significant treatment-related effects on sexual function were seen on the CSFQ in males or females. Libido decrease was the most common AE related to sexual function (11 [4.7%] VLZ pts and 0 PBO pts).

Conclusions

Vilazodone treatment was associated with significant improvement in depression and anxiety symptoms and was safe and well tolerated in this study of adult patients with MDD.

Introduction

•		Despite a variety of available antidepressants, most patients with major depressive disorder (MDD) do not experience an adequate response to their first course of treatment
•		In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study

	—		47% of patients responded to SSRI treatment1
	—		Switching to different regimens was associated with increased intolerability2,3

•		Alternative agents offering good efficacy and tolerability are needed
•		Vilazodone HCl is a dual-acting potent and selective serotonin reuptake inhibitor and 5-HT1A receptor partial 1A agonist that exerts its effects at the serotonin transporter and at pre- and post-synaptic 5-HT1A receptors4,5

—

The unique dual modulation of serotonin neurotransmission by vilazodone is hypothesized to decrease endogenous serotonin negative feedback and enhance post-synaptic 5-HT effects

•

A previous placebo-controlled, phase 3 study found vilazodone effective for the treatment of patients with MDD, with good tolerability at a dose of 40 mg/day6

Objectives

•

Primary

—

To compare efficacy between vilazodone-treated and placebo groups using change from baseline to end of treatment (EOT) on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score up to 8 weeks of treatment

•

Secondary

	—		To assess the safety and tolerability profile of vilazodone
	—		To evaluate the efficacy of vilazodone compared with placebo on the following secondary measures: 17-item Hamilton Depression Scale (HAM-D-17), Hamilton Anxiety Scale (HAM-A), and Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales

Presented at the 163rd Annual Meeting of the American Psychiatric Association, May 22-26, 2010, New Orleans, Louisiana		Supported by PGxHealth, LLC

Methods

•		All patients provided written informed consent before study procedures
•		The protocol was approved by the institutional review board of each center

Study Population

•

Selected inclusion criteria

	—		Male and female patients; 18 to 70 years of age
	—		Diagnosis of MDD, single episode or recurrent, according to DSM-IV-TR criteria
	—		Current episode ³4 weeks’ and <2 years’ duration
	—		HAM-D-17 score ³22 and HAM-D item 1 (depressed mood) score ³2 at screening and baseline visits

•

Selected exclusion criteria

	—		Axis I disorder of posttraumatic stress disorder, obsessive-compulsive disorder, or eating disorder within 6 months
	—		History of schizophrenia, schizoaffective disorder, or bipolar I or II disorder
	—		Psychotherapy within 12 weeks of screening
	—		Failure to respond to 2 consecutive antidepressants of different classes during the present episode

Study Design

•		Placebo-controlled, randomized, double-blind, multicenter, parallel-group study of 8 weeks’ duration (Figure 1)
•		Patients randomized to vilazodone were titrated to the target dose of 40 mg once daily (QD) over a 2-week period according to a fixed-titration schedule
•		A sample of 470 patients with 1:1 randomization to vilazodone or placebo provided 90% power to detect a 3-point difference in mean change from baseline between treatments (2-sided testing at 0.05 significance level)

Figure 1. Study design and treatment.

V, study visit.

• Efficacy Assessments

—   —

MADRS, HAM-D-17, HAM-A, and CGI-S at baseline and at weeks 1, 2, 4, 6, and 8 (or EOT)   CGI-I at postbaseline visits

•

Safety Assessments

	—		Adverse events (AEs), clinical laboratory evaluations, electrocardiography (ECG), physical examinations, and vital signs
	—		Patient-rated Changes in Sexual Function Questionnaire (CSFQ) for change in sexual function during treatment
	—		Columbia-Suicide Severity Rating Scale to assess risk for suicidal ideation and/or behavior

Statistical Analysis

•		Efficacy evaluations were based on the intent-to-treat (ITT) population, defined as all randomized patients dispensed study drug with ³1 postbaseline efficacy assessment
•		Safety evaluations were based on the safety population, defined as all randomized patients dispensed study drug with ³1 postbaseline safety measure
•		Treatment group comparisons of continuous measures were based on differences in least-squares mean (LSM) changes from baseline to EOT from an analysis of covariance model containing terms for treatment and center, with baseline included as a covariate
•		A mixed-effects model repeated measures (MMRM) analysis was conducted with terms for treatment, center, visit, and treatment-by-visit interaction, with baseline and baseline-by-visit interaction included as covariates
•		Statistical comparisons were 2-sided and considered significant at the 0.05 level
•		No statistical testing for safety measures was performed

Results

•

481 patients were randomized, and 388 (80.7%) completed the study (Figure 2)

Figure 2. Patient disposition.

 

^a n (%) of randomized patients in each group.

•

Demographic characteristics were similar between vilazodone-treated and placebo groups (Table 1)

Table 1. Baseline Demographics and Disease Characteristics (Safety Population)

Characteristic		Vilazodone n = 235				Placebo n = 233
Sex, n (%)
Male			96 (40.9	)			109 (46.8	)
Female			139 (59.1	)			124 (53.2	)
Race, n (%)
White			182 (77.4	)			191 (82.0	)
Black/African American			35 (14.9	)			31 (13.3	)
Other			18 (7.7	)			11 (4.7	)
Mean age, y (SD)			41.1 (12.2	)			42.4 (12.5	)
Range, y			18-69				19-70
Duration of current MDD episode, n (%)
1-6 mo			110 (46.8	)			120 (51.5	)
>6-12 mo			61 (26.0	)			59 (25.3	)
>12 mo			63 (26.8	)			54 (23.2	)
Severity of current episode, n (%)
Moderate			175 (74.5	)			165 (70.8	)
Severe			60 (25.5	)			68 (29.2	)

• Treatment compliance was >90% for vilazodone-treated and placebo patients at each visit

Efficacy

•		Vilazodone-treated patients showed significantly greater improvement at EOT in MADRS scores than did placebo patients (Table 2)
•		Vilazodone-treated patients also experienced significantly greater improvement at EOT in HAM-D-17, HAM-A, and CGI-S and CGI-I scores than did placebo patients (Table 2)

Table 2. Mean Change in Efficacy Assessments From Baseline to EOT
(ITT Population, Last-Observation-Carried-Forward Analysis)

Baseline

LSM Change at EOT

Vilazodone

Placebo

Vilazodone

Placebo

Assessment

n = 231

n = 232

n = 231

n = 232

P

MADRS

31.9 ± 3.5

32.0 ± 3.6

-13.3 ± 0.9

-10.8 ± 0.9

0.009

HAM-D-17

25.0 ± 2.4

25.3 ± 2.6

-10.7 ± 0.7

-9.1 ± 0.7

0.026

HAM-A

18.0 ± 5.3

18.1 ± 5.8

-7.0 ± 0.55

-5.7 ± 0.55

0.037

CGI-S

4.5 ± 0.5

4.5 ± 0.5

-1.4 ± 0.1

-1.1 ± 0.1

0.004

CGI-I

—

—

2.5 ± 0.1

2.8 ± 0.1

0.004

•		MMRM analysis showed greater improvement in MADRS total score for vilazodone-treated patients than for placebo patients at week 6 (P = 0.019) and week 8 (P = 0.007) (Figure 3)
•		MADRS response rate (³50% decrease from baseline at EOT) was significantly greater (P = 0.002) for vilazodone-treated patients (44%) than for placebo patients (30%); remission (EOT score <10) was not significantly greater for vilazodone-treated patients (27%) than for placebo patients (20%)

Figure 3. Mean change from baseline in MADRS total score by week (ITT Population, MMRM Analysis)

Safety and Tolerability

•		Most treatment-emergent adverse events (TEAEs) were mild or moderate in intensity (>93% in both groups)
•		The most frequent TEAEs in the vilazodone group (compared with the placebo group) were diarrhea (31% vs 11%), nausea (26% vs 6%), and headache (13% vs 10%) (Table 3)

Table 3. TEAEs Occurring in ³5% of Vilazodone Patients (Safety Population)

		Vilazodone				Placebo
		n = 235				n = 233
MedDRA Preferred Term		Patients, n (%)
Diarrhea			72 (30.6	)			25 (10.7	)
Nausea			61 (26.0	)			13 (5.6	)
Headache			30 (12.8	)			24 (10.3	)
Dry mouth			21 (8.9	)			9 (3.9	)
Dizziness			21 (8.9	)			9 (3.9	)
Insomnia			17 (7.2	)			7 (3.0	)
Abnormal dreams			14 (6.0	)			4 (1.7	)
Vomiting			12 (5.1	)			1 (0.4	)

MedDRA, Medical Dictionary for Regulatory Activities.

•		12 of 235 (5.1%) vilazodone patients and 4 of 233 (1.7%) placebo patients discontinued due to TEAEs
•		Overall, mean changes in laboratory values from screening (hematology, chemistry, and urinalysis) were similar and clinically unimportant between vilazodone and placebo groups
•		No clinically significant treatment-related ECG abnormalities were reported; vital sign and weight changes were not clinically remarkable (Table 4)

Table 4. Blood Pressure (Sitting), Pulse, and Weight at Baseline and Change From Baseline (Safety Population)

		Vilazodone								Placebo
		n = 235								n = 233
						Mean Change From								Mean Change From
Parameter		Mean				Baseline				Mean				Baseline
SBP, mm Hg
Baseline			120.3				—				119.9				—
Week 8			119.3				-1.3				119.8				-0.1
Early termination			122.8				-0.1				120.9				1.9
DBP, mm Hg
Baseline			76.2				—				77.1				—
Week 8			76.5				0.2				76.4				-0.5
Early termination			79.2				2.2				77.8				0.3
Pulse, bpm
Baseline			73.4				—				72.9				—
Week 8			74.4				1.2				74.3				1.6
Early termination			74.2				-0.4				76.6				3.7
Weight, kg
Baseline			86.36				—				88.86				—
Week 8			87.80				0.21				90.26				0.36
Early termination			83.64				0.19				87.46				-0.25

SBP, systolic blood pressure; DBP, diastolic blood pressure; bpm, beats per minute.

•		Overall sexual function for men and women (as measured by CSFQ) was similar for vilazodone and placebo groups
•		The TEAE decreased libido was more common among patients treated with vilazodone (11 [4.7%]) than among those given placebo (0%)

Conclusions

•		Vilazodone produced statistically significant and clinically meaningful improvement of symptoms in patients with MDD based on disease-specific and global improvement measures (MADRS, HAM-D, HAM-A, and CGI) during 8 weeks of treatment in this study
•		Vilazodone treatment at a dose of 40 mg/day was safe and well-tolerated
•		This study replicates efficacy, safety, and tolerability findings demonstrated in a previous 8-week, phase 3, placebo-controlled study of vilazodone in adults with MDD6

References

1.		Trivedi MH et al. Am J Psychiatry. 2006;163:28-40.
2.		Rush AJ. Am J Psychiatry. 2007;164:201-204.
3.		Rush AJ et al. Am J Psychiatry. 2006;163:1905-1917.
4.		Hughes A et al. Eur J Pharmacol. 2005;510:49-57.
5.		Dawson L et al. CNS Neurosci Ther. 2009;15:107-117.
6.		Rickels K et al. J Clin Psychiatry. 2009;70:326-333.