Duloxetine (Page 12 of 16)

14 CLINICAL STUDIES

The efficacy of duloxetine delayed-release capsules has been established in the following adequate and well-controlled trials:

Major Depressive Disorder (MDD): 4 short-term and 1 maintenance trial in adults [see Clinical Studies (14.1)].
Generalized Anxiety Disorder (GAD): 3 short-term trials in adults, 1 maintenance trial in adults, and 1 short-term trial in children and adolescents [see Clinical Studies (14.2)].
Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults [see Clinical Studies (14.3)].
Fibromyalgia (FM): Two trials in adults (one of 3 months duration and one of 6 months duration) [see Clinical Studies (14.4)].
Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) and one 13-week trial in adult patients with chronic pain due to osteoarthritis [see Clinical Studies (14.5)].

14.1 Major Depressive Disorder

The efficacy of duloxetine delayed-release capsules as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies, 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 the third study, 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 the fourth study, 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. There is no evidence that doses greater than 60 mg/day confer additional benefits.

In all 4 studies, duloxetine delayed-release capsules demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (Studies 1 to 4 in Table 7).

In all of these clinical studies, 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 7: Summary of the Primary Efficacy Results for Studies in Major Depressive Disorder
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.

Study Number

Treatment Group

Primary Efficacy Measure: HAMD-17

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

Duloxetine delayed-release capsules (60 mg/day)b Placebo

21.5 (4.1)

21.1 (3.71)

-10.9 (0.7)

-6.1 (0.69)

-4.9 (-6.8, -2.9)

Study 2

Duloxetine delayed-release capsules (60 mg/day)b Placebo

20.3 (3.32)

20.5 (3.42)

-10.5 (0.71)

-8.3 (0.67)

-2.2 (-4, -0.3)

Study 3

Duloxetine delayed-release capsules (20 mg BID) b Duloxetine delayed-release capsules (40 mg BID) b Placebo

18.6 (5.85)

18.1 (4.52)

17.2 (5.11)

-7.4 (0.8)

-8.6 (0.81)

-5 (0.81)

-2.4 (-4.7, -0.2)

-3.6 (-5.9, -1.4)

Study 4

Duloxetine delayed-release capsules (40 mg BID) b Duloxetine delayed-release capsules (60 mg BID) b Placebo

19.9 (3.54)

20.2 (3.41)

19.9 (3.58)

-11 (0.49)

-12.1 (0.49)

-8.8 (0.5)

-2.2 (-3.6, -0.9)

-3.3 (-4.7, -1.9)

In another study, 533 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 dose (N=136) or to placebo (N=142) for 6 months. Patients on duloxetine delayed-release capsules experienced a statistically significantly longer time to relapse of depression than did patients on placebo (Study 5 in 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. The effectiveness of duloxetine delayed-release capsules in hospitalized patients with major depressive disorder has not been studied.

Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (MDD Study 5)
(click image for full-size original)

14.2 Generalized Anxiety Disorder

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.

In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.

The 2 flexible-dose studies 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 dose for completers at endpoint in the flexible-dose studies was 104.75 mg/day. The fixed-dose study evaluated duloxetine delayed-release capsules doses 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 studies, duloxetine delayed-release capsules demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (Studies 1 to 3 in 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 another study, 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 dose (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 (Study 4 in Figure 2).

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

The efficacy of duloxetine delayed-release capsules in the treatment of patients ≥65 years of age with generalized anxiety disorder 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. In this study, 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 dose for patients completing the 10-week acute treatment phase was 50.95 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 Hamilton Anxiety Rating Scale total score (Study 5 in Table 8).

The efficacy of duloxetine delayed-release capsules in the treatment of pediatric patients 7 to 17 years of age with generalized anxiety disorder (GAD) was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria).

In this study, the starting dose was 30 mg once daily for 2 weeks. Further dose increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose 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 (Study 6 in Table 8).

Table 8: Summary of the Primary Efficacy Results for Studies in General Anxiety Disorder

Study Number

Treatment Group

Primary Efficacy Measure

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1 (HAM-A)

Duloxetine delayed-release capsules (60 mg/day)b

25.1 (7.18)

-12.8 (0.68)

-4.4 (-6.2, -2.5)

Duloxetine delayed-release capsules (120 mg/day) b

25.1 (7.24)

-12.5 (0.67)

-4.1 (-5.9, -2.3)

Placebo

25.8 (7.66)

-8.4 (0.67)

Study 2 (HAM-A)

Duloxetine delayed-release capsules (60 to 120 mg/day) b

22.5 (7.44)

-8.1 (0.7)

-2.2 (-4.2, -0.3)

Placebo

23.5 (7.91)

-5.9 (0.7)

Study 3 (HAM-A)

Duloxetine delayed-release capsules (60 to 120 mg/day) b

25.8 (5.66)

-11.8 (0.69)

-2.6 (-4.5, -0.7)

Placebo

25 (5.82)

-9.2 (0.67)

Study 5(Elderly) (HAM-A)

Duloxetine delayed-release capsules (60 to 120 mg/day) b

24.6 (6.21)

-15.9 (0.63)

-4.2 (-5.9, -2.5)

Placebo

24.5 (7.05)

-11.7 (0.67)

Study 6(Pediatric) (PARS for GAD)

Duloxetine delayed-release capsules (30 to 120 mg/day) b

17.5 (1.98)

-9.7 (0.5)

-2.7 (-4, -1.3)

Placebo

17.4 (2.24)

-7.1 (0.5)

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: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (GAD Study 4)

fig2
(click image for full-size original)

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