Venlafaxine Hydrochloride (Page 11 of 14)

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Major Depressive Disorder (MDD) was established in two placebo-controlled, short-term (8 weeks for study 1; 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225 mg per day in adult outpatients meeting DSM-III-R or DSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, venlafaxine hydrochloride extended-release capsules demonstrated superiority over placebo on the primary efficacy measure defined as change from baseline in the HAM-D-21 total score to the endpoint visit, venlafaxine hydrochloride extended-release capsules also demonstrated superiority over placebo on the key secondary efficacy endpoint, the Clinical Global Impressions (CGI) Severity of Illness scale. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing venlafaxine hydrochloride tablets in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of venlafaxine hydrochloride tablets over placebo based on the HAM-D-21 total score. The mean dose in completers was 350 mg per day (study 3).

In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg, once daily every morning) were randomized to continuation of their same venlafaxine hydrochloride extended-release capsules dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open-label phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason.

Patients receiving continued venlafaxine hydrochloride extended-release capsules treatment experienced statistically significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo (study 4).

In a second longer term trial, adult outpatients with MDD, recurrent type, who had responded (HAM-D 21 total score ≤ 12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥ 20; (2) no more than 2 HAM D-21 total scores > 10, and (3) no single CGI Severity of Illness item score ≥ 4 (moderately ill)] during an initial 26 weeks of treatment on venlafaxine hydrochloride tablets [100 to 200 mg per day, on a twice daily schedule] were randomized to continuation of their same venlafaxine hydrochloride tablets dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥ 4, was for up to 52 weeks. Patients receiving continued venlafaxine hydrochloride tablets treatment experienced statistically significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo (study 5).

Table 17 Major Depressive Disorder Studies

SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline
* Doses statistically significantly superior to placebo.
Study Number	Treatment Group	Primary Efficacy Measure: HAM-D Score
		Mean Baseline Score (SD)	LS Mean Change from Baseline	Placebo Subtracted Differencea (95%CI)
Study 1	Venlafaxine Hydrochloride Extended-release Capsules (75 to 225 mg/day)*	24.5	-11.7	-4.45(-6.66,-2.25)
	Placebo	23.6	-7.24	–
Study 2	Venlafaxine Hydrochloride Extended-release Capsules (75 to 225 mg/day)*	24.5	-15.11	-6.40(-8.45,-4.34)
	Placebo	24.9	-8.71	–
Study 3	Venlafaxine Hydrochloride Tablets (150 to 375 mg/day)*	28.2 (0.5)	-14.9	-10.2 (-14.4,-6)
	Placebo	28.6 (0.6)	-4.7	–

14.2 Generalized Anxiety Disorder

The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month, placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria for GAD.

In one 8-week study, venlafaxine hydrochloride extended-release capsules demonstrated superiority over placebo for the 75, 150, and 225 mg per day doses as measured by the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. However, the 75 and 150 mg per day doses were not as consistently effective as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg per day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg per day dose was more consistently effective than the 150 mg per day dose (study 2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg per day dose range studied.

Two 6-month studies, one evaluating venlafaxine hydrochloride extended-release capsules doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating venlafaxine hydrochloride extended-release capsules doses of 75 to 225 mg per day (study 4), showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg per day dose, this dose was not as consistently effective as the higher doses.

Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

Table 18 Generalized Anxiety Disorder Studies

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Doses statistically significantly superior to placebo.
*Difference (drug minus placebo) in least-squares mean change from baseline
Study Number	Treatment Group	Primary Efficacy Measure: HAM-A Score
		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo Subtracted Differencea (95% CI)
Study 1	Ven XR 75 mg	24.7	-11.1 (0.95)	-1.5 (-3.8, 0.8)
	Ven XR 150 mg	24.5	-11.7 (0.87)	-2.2 (-4.5, 0.1)
	Eff XR 225 mg	23.6	-12.1 (0.81)	-2.6 (-4.9, -0.3)
	Placebo	24.1	-9.5 (0.85)
Study 2	Ven XR 75 mg	23.7	-10.6 (0.82)	-2.6 (-4.6, -0.5)
	Ven XR 150 mg	23.0	-9.8 (0.86)	-1.7 (-3.8, 0.3)
	Placebo	23.7	-8.0 (0.73)
Study 3	Ven XR 37.5 mg	26.6 (0.4)	-13.8	-2.8 (-5.1, -0.6)
	Ven XR 75 mg	26.3 (0.4)	-15.5	-4.6 (-6.9, -2.3)
	Ven XR150 mg	26.3 (0.4)	-16.4	-5.5 (-7.8, -3.1)
	Placebo	26.7 (0.5)	-11.0
Study 4	Ven XR 75 to 225 mg	25.0	-13.4 (0.79)	— 4.7 (-6.6, -2.9)
	Placebo	24.9	-8.7 (0.70)