Duloxetine (Page 10 of 13)

14.2 Major Depressive Disorder in Adults

The efficacy of duloxetine delayed-release capsules as a treatment for MDD in adults was established in 4 randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients (18 to 83 years) meeting DSM-IV criteria for MDD:
• In Studies MDD-1 and MDD-2, patients were randomized to duloxetine delayed-release capsules 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks
• In Study MDD-3, patients were randomized to duloxetine delayed-release capsules 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks
• In Study MDD-4, patients were randomized to duloxetine delayed-release capsules 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks.
In all four trials, duloxetine delayed-release capsules demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (see Table 8). There is no evidence that doses greater than 60 mg/day confer additional benefits.
In all of these clinical trials, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. Table 8: Summary of the Primary Efficacy Results for Adult Trials in MDD

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included.
^a Difference (drug minus placebo) in least-squares mean change from baseline.
^b Doses statistically significantly superior to placebo.
In Study MDD-5, 533 adult patients meeting DSM-IV criteria for MDD received duloxetine delayed-release capsules 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment [defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD] were randomly assigned to continuation of duloxetine delayed-release capsules at the same dosage (N=136) or to placebo (N=142) for 6 months.
In Study MDD-5, patients on duloxetine delayed-release capsules experienced a statistically significantly longer time to relapse of depression than did patients on placebo (see Figure 1). Relapse was defined as an increase in the CGI-S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. Figure 1: Cumulative Proportion ^a of Adult Patients with MDD Relapse (Study MDD-5)

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^a Kaplan-Meier estimator method.

14.3 Generalized Anxiety Disorder

GAD Trials in Adults (Including Geriatric Patients)
The efficacy of duloxetine delayed-release capsules in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD (Studies GAD-1, GAD-2, and GAD-3, respectively).
In Studies GAD-1 and GAD-2, the starting dose was 60 mg once daily (down titration to 30 mg once daily was allowed for tolerability reasons; the dosage could be increased to 60 mg once daily). Fifteen percent of patients were down titrated. Study GAD-3 had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.
Studies GAD-2 and GAD-3 involved dose titration with duloxetine delayed-release capsules doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dosage for completers at endpoint in these trials was 104.8 mg/day. Study GAD-1 evaluated duloxetine delayed-release capsules dosages of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.
In all 3 trials, duloxetine delayed-release capsules demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (see Table 8) and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a composite measurement of the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities.
In Study GAD-4, 887 patients meeting DSM-IV-TR criteria for GAD received duloxetine delayed-release capsules 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment [defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement (CGI-Improvement) score of 1 or 2] were randomly assigned to continuation of duloxetine delayed-release capsules at the same dosage (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking duloxetine delayed-release capsules experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo (see Figure 2).
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
GAD Trial in Geriatric Patients
The efficacy of duloxetine delayed-release capsules in the treatment of patients ≥65 years of age with GAD was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults ≥65 years of age meeting the DSM-IV criteria for GAD (Study GAD-5). In Study GAD-5, the starting dose was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments at treatment weeks 2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dosage for patients completing the 10-week acute treatment phase was 51 mg. Patients treated with duloxetine delayed-release capsules (N=151) demonstrated significantly greater improvement compared with placebo (N=140) on mean change from baseline to endpoint as measured by the HAM-A total score (see Table 8).
GAD Trial in Pediatric Patients 7 to 17 Years Old
The efficacy of duloxetine delayed-release capsules in the treatment of pediatric patients 7 to 17 years of age with GAD was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria) (Study GAD-6).
In Study GAD-6, the starting dosage was 30 mg once daily for 2 weeks. Further dosage increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dosage for patients completing the 10-week treatment phase was 57.6 mg/day. In this study, duloxetine delayed-release capsules (N=135) demonstrated superiority over placebo (N=137) from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score (see Table 9).
Table 9: Summary of the Primary Efficacy Results for GAD Trials

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included.
a Difference (drug minus placebo) in least squares mean change from baseline.
b Dose statistically significantly superior to placebo. Figure 2: Cumulative Proportiona of Adult Patients with GAD Relapse (Study GAD-4)

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a Kaplan-Meier estimator method.