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EFFEXOR® XR (venlafaxine HCl) Clinical Studies

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

The efficacy of Effexor XR (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, Effexor XR 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, Effexor XR 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 Effexor in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of Effexor 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 Effexor XR (75, 150, or 225 mg, once daily every morning) were randomized to continuation of their same Effexor XR 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 Effexor XR 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 Effexor [100 to 200 mg per day, on a twice daily schedule] were randomized to continuation of their same Effexor 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 Effexor 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:
Study numberTreatment GroupPrimary Efficacy Measure: HAM-D Score
Mean Baseline Score (SD)LS Mean Change from BaselinePlacebo Subtracted Difference*(95%CI)
SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval.
*
Difference (drug minus placebo) in least-squares mean change from baseline
Doses statistically significantly superior to placebo.
Study 1Effexor(XR 75–225 mg/day)24.5-11.7-4.45(-6.66,-2.25)
Placebo23.6-7.24-
Study 2Effexor(XR 75–225 mg/day)24.5-15.11-6.40(-8.45,-4.34)
Placebo24.9-8.71
Study 3Effexor(IR 150–375 mg/day)28.2 (0.5)-14.9-10.2 (-14.4,-6.0)
Placebo28.6 (0.6)-4.7-

14.2 Generalized Anxiety Disorder

The efficacy of Effexor XR 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, Effexor XR 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 Effexor XR doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating Effexor XR 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:
Study NumberTreatment GroupPrimary Efficacy Measure: HAM-A Score
Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo Subtracted Difference* (95% CI)
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
* Doses statistically significantly superior to placebo.
*
Difference (drug minus placebo) in least-squares mean change from baseline
Study 1Ven XR 75 mg24.7-11.1 (0.95)-1.5 (-3.8, 0.8)
Ven XR 150 mg24.5-11.7 (0.87)-2.2 (-4.5, 0.1)
Eff XR 225 mg23.6-12.1 (0.81)-2.6 (-4.9, -0.3)
Placebo24.1-9.5 (0.85)
Study 2Ven XR 75 mg23.7-10.6 (0.82)-2.6 (-4.6, -0.5)
Ven XR 150 mg23.0-9.8 (0.86)-1.7 (-3.8, 0.3)
Placebo23.7-8.0 (0.73)
Study 3Ven XR 37.5 mg26.6 (0.4)-13.8-2.8 (-5.1, -0.6)
Ven XR 75 mg26.3 (0.4)-15.5-4.6 (-6.9, -2.3)
Ven XR150 mg26.3 (0.4)-16.4-5.5 (-7.8, -3.1)
Placebo26.7 (0.5)-11.0
Study 4Ven XR 75–225 mg25.0-13.4 (0.79)- 4.7 (-6.6, -2.9)
Placebo24.9-8.7 (0.70)

14.3 Social Anxiety Disorder (also known as Social Phobia)

The efficacy of Effexor XR as a treatment for Social Anxiety Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1–4) and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study, which included doses in a range of 75 to 225 mg per day in adult outpatients meeting DSM-IV criteria for SAD (study 5).

In these five studies, Effexor XR was statistically significantly more effective than placebo on change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to 225 mg per day group compared to the 75 mg per day group in the 6-month study.

Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.

Table 19: Social Anxiety Disorder Studies
Study NumberTreatment GroupPrimary Efficacy Measure: LSAS Score
Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo Subtracted Difference* (95% CI)
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
* Doses statistically significantly superior to placebo.
*
Difference (drug minus placebo) in least-squares mean change from baseline
Study 1Ven XR (75–225 mg)91.1-31.0(2.22)11.2 (-5.3, -17.1)
Placebo86.7-19.9 (2.22)-
Study 2Ven XR (75–225 MG)90.8-32.8 (2.69)-10.7 (-3.7,-17.6)
Placebo87.4-22.1 (2.66)-
Study 3Ven XR (75–225 MG)83.2-36.0 (2.35)-16.9(-22.6, -11.2)
Placebo83.6-19.1 (2.40)-12.7 (-6.5, -19.0)
Study 4Ven XR (75–225 mg)86.2-35.0 (2.64)-14.6 (-21.8, -7.4)
Placebo86.1-22.2 (2.47)
Study 5Ven XR 75 mg91.8-38.1 (3.16)-14.6 (-21.8, -7.4)
Ven XR (150–225 mg)86.2-37.6 (3.05)-14.1 (-21.3, -6.9)
Placebo89.3-23.5 (3.08)

14.4 Panic Disorder

The efficacy of Effexor XR as a treatment for Panic Disorder (PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg per day in one study (study 1) and 75 or 225 mg per day in the other study (study 2).

Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two studies, Effexor XR was statistically significantly more effective than placebo (for each fixed dose) on all three endpoints, but a dose-response relationship was not clearly established.

Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.

In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded during a 12-week open phase with Effexor XR (75 to 225 mg per day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued Effexor XR experienced a statistically significantly longer time to relapse.

Table 20: Panic Disorder Studies:
Study NumberTreatment Group Primary Efficacy Measure: Whether Free of Full-symptom Panic Attacks
Percent of patients Free of Full symptom panic attackAdjusted Odds Ratio* to placeboAdjusted Odds Ratio* 95% Confidence Interval
*
Odds ratio (drug to placebo) in terms of probability of free of full-symptom panic attacks based on logistic regression model.
95%CI: 95% confidence interval without adjusting for multiple dose arms.
Doses statistically significantly superior to placebo.
Study 1Ven XR 75 mg54.1% (85/157)2. 268(1.43, 3.59)
Ven XR 150 mg61.4% (97/158)3.035(1.91, 4.82)
Placebo34.4% (53/154)----
Study 2Ven XR 75 mg64.1% (100/156)2.350(1.46, 3.78)
Ven XR 225 mg70.0% (112/160)2.890(1.80, 4.64)
Placebo46.5% (73/157)----

14.5 Pediatric Patients

Two placebo-controlled studies in 766 pediatric patients with MDD and two placebo-controlled studies in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients.

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