A Noninferiority Comparison of Duloxetine and Venlafaxine XR for the Treatment of Adult Patients with Generalized Anxie

1. FIGURE 5. Treatment-Emergent Adverse Events (ITT Sample) Poster presented at ACNP, Boca Raton, FL, USA; December 9–13, 2007 A Noninferiority Comparison of Duloxetine and Venlafaxine XR for the Treatment of Adult Patients with Generalized Anxiety Disorder Sponsored by: Dr. Michael J Detke Michael J Detke MD, PhD1,2,3; David Nutt MD4; Christer Allgulander MD5; Janelle Erickson PhD1*; Melissa Spann PhD1; Daniel WalkerPhD1; Susan G. Ball PhD1,2; James M. Russell MD1 1 Lilly Research Laboratories, Indianapolis, IN; 2 Indiana University School of Medicine, Indianapolis, IN; 3 Harvard Medical School, Boston, MA; 4 University of Bristol, Bristol, UK; 5 Karolinska Institutet, Stockholm, Sweden; * Current affiliation Orexigen Therapeutics, San Diego, CA Outcome Measures ABSTRACT Purpose:The present study is a noninferiority comparison of the efficacy of duloxetine 60–120 mg/day and venlafaxine extended-release (XR) 75–225 mg/day, compared with placebo, for the treatment of adults with generalized anxiety disorder (GAD). Methods:Data for these analyses were pooled, as planned a priori for adequate powering, from 2 nearly identical 10-week, multicenter, randomized, double-blind studies that each assessed duloxetine 60–120 mg/day and venlafaxine XR 75–225 mg/day compared with placebo. Male or female outpatients ≥ 18 years of age had to meet DSM‑IV-TR criteria for GAD. The primary efficacy outcome measure was the Hamilton Anxiety Scale (HAMA) total score. An expert consensus panel recommended 6 statistical and clinical criteria for determination of noninferiority between a test medication and an active comparator. These criteria were 1) Requirement of at least one 3-arm double-blind placebo-controlled comparison trial for the test intervention with an active comparator, 2) Improvements from the test and active comparator interventions must be superior compared with placebo by a clinically meaningful difference in HAMA total score from baseline to endpoint (≥ 2 points), 3) Treatment response rates (defined as ≥ 50% reduction in HAMA total score) of test and active comparator groups should be at least 10 percentage points greater than the response rate of placebo group, 4) Both the test and active comparator treatments have to be statistically significantly better than placebo on the primary outcome measure, 5) The noninferiority test should use a noninferiority margin (1.5 HAMA points) between the active comparator and the test treatment that is < 50% of the difference between the comparator treatment and placebo, and 6) The response rate of the test intervention is no less than 5 percentage points of the response rate of the active comparator group. Noninferiority analysis was done using the per-protocol population of patients who had at least 4 weeks of treatment, HAMA ratings after at least 4 weeks, and did not have any protocol violations. Assessments of safety and tolerability included discontinuation rates, treatment-emergent adverse events (TEAEs), vital signs, and laboratory analyses. Results:In the pooled sample, patients were randomly assigned to receive duloxetine (N=320), venlafaxine (N=333), or placebo (N=331). For the noninferiority analysis, the per-protocol patients who were treated with duloxetine (N=239) or venlafaxine (N=262) were significantly more improved (mean HAMA reductions -15.4 and -15.2, respectively) compared with placebo (-11.6, P ≤ .001, both comparisons). Response rates for the intent-to-treat sample were 56%, 58%, and 40% respectively. The lower bound of the 1‑sided 97.5% confidence intervals for the point estimate was -1.28 for the per-protocol population, which remained within the pre-specified -1.5 point noninferiority margin. Adverse event-related discontinuation was significantly higher for duloxetine (13.4%, P ≤.001) and venlafaxine XR (11.4%, P ≤ .01) groups compared with placebo (5.4%). Nausea was the most common TEAE in the duloxetine (26.9%) and venlafaxine XR (20.1%) groups. No clinically significant differences were detected in vital signs in the active treatment groups compared with placebo. Conclusions:Duloxetine 60–120 mg/day met all statistical and clinical criteria for noninferiority and exhibited a similar safety profile compared with venlafaxine XR 75–225 mg for the treatment of adults with GAD. FIGURE 1. HAMA Total Score Mean Change Baseline to Endpoint FIGURE 4. Noninferiority Analysis Criteria CONCLUSIONS • The strengths of this study include: • – a placebo control group • – a carefully considered set of clinically relevant and statistically rigorous criteria for noninferiority, established a priori, by an external panel • – double-blind parallel treatment groups • – the use of a protocol-specified population to reduce potential bias • – pooling of data from 2 nearly identical studies to ensure adequate statistical power • Duloxetine 60–120 mg/day treatment met all of the recommended statistical and clinical criteria for establishing noninferiority in terms of efficacy for GAD in reference to venlafaxine XR 75–225 mg/day treatment. • Both active medications had similar tolerability in treatment-emergent adverse event profiles and mean changes in vital signs. • Duloxetine treatment can be considered to be similar to venlafaxine XR treatment for efficacy and tolerability in adult patients with GAD. • Hamilton Anxiety Rating Scale (HAMA)7 total score • Response rate defined as ≥ 50% reduction in HAMA total score from baseline to endpoint • Spontaneously reported adverse events, vital signs and weight at each visit Criterion Met? 1. Duloxetine and venlafaxine XR both significantly better than placebo at endpoint on HAMA total score   2. Both active drugs better than placebo by ≥ 2 HAMA total score points Study Designs Per-protocol SampleIntent-to-treat Sample • 10-week acute double-blind, randomized, placebo-controlled study of duloxetine 60–120 mg once daily, venlafaxine XR 75–225 mg once daily, or placebo • Study 1: Starting doses were: duloxetine 30 mg/day first week, then 60-120 mg/day thereafter; venlafaxine XR 37.5 mg/day first week then 75-225 mg/day thereafter • Dose was flexibly managed, but patients were required to have an increase in dose if they were judged to have minimal or no improvement after 4 weeks of treatment and if they could tolerate a dose increase; maximum daily doses were duloxetine 120 mg/day and venlafaxine XR 225 mg/day • Study 2: Same design, but also included a duloxetine 20 mg/day dose arm that did not titrate during the acute treatment (not included in the noninferiority analyses)  3. Response rates for active drugs ≥ 10 percentage points better than placebo. Improvement Least-square Mean Change 4. Response rate for duloxetine not > 5 percentage points lower than venlafaxine XR  5. The noninferiority margin < 50% of the difference between venlafaxine XR and placebo in previous trials ***  *** *** *** 6. Noninferiority margin lower bound of one-sided 97.5% CI is within -1.5 HAMA total score points  Baseline Mean HAMA Total Score: ~26-27 ***P ≤ .001 vs. placebo Consensus Panel Guidelines for Noninferiority Trials† FIGURE 2. HAMA Response Rates at Endpoint(ITT Sample) • Duloxetine 60–120 mg/day and venlafaxine XR 75-225 mg/day both significantly better than placebo at endpoint on HAMA total score. • Both active drugs better than placebo by clinically meaningful difference (≥ 2 HAMA total score points). • Response rates for active drugs ≥ 10 percentage points better than placebo. • Response rate for duloxetine 60–120 mg/day not more than 5 percentage points lower than venlafaxine XR 75–225 mg/day. • The noninferiority margin (the difference between endpoint least-squares mean change on HAMA total score between duloxetine 60–120 mg/day and placebo and the endpoint least-squares mean change on HAMA total score for venlafaxine XR 75–225 mg/day and placebo) is < 50% of the difference between venlafaxine XR and placebo found in previously published trials. Analysis should use the per-protocol population defined by patients who had ≥ 4 weeks of treatment, HAMA ratings after at least 4 weeks, compliant with study drug, and had no protocol violations. • One sided 97.5% confidence interval of the noninferiority margin difference between duloxetine 60–120 mg/day and venlafaxine XR 75–225 mg/day is within an a priori defined interval of 1.5 HAMA total score points. *** † ** *** *** *** ** *** *** ** * ** *** *** *** ** *** † ** ** Percent of Patients ** • BACKGROUND • Duloxetine and venlafaxine XR have both been demonstrated to be efficacious for the treatment of adults with generalized anxiety disorder (GAD).1,2,3,4 • Establishing similar efficacy between 2 medications can provide guidance for treatment planning by allowing consideration of other patient care issues, such as adverse event profile, comorbidities, cost, access, and preference. • Noninferiority trials are designed to show that a treatment is no worse than an already established treatment and may be required for drug registration programs by regulatory agencies. Given their complexity, they require careful consideration of statistical and clinical criteria.5 *P ≤ .05 **P ≤ .01 ***P ≤ .001 vs. placebo †P ≤ .05, duloxetine vs venlafaxine XR CMH test controlling for study HAMA Response was defined as a 50% or greater reduction in the HAMA total score. All events that occurred in  5% of duloxetine-treated patients and at twice the rate of placebo during the 10-week acute treatment phase. † Consensus panel membership consisted of David P. Nutt, MD; Tim Peters, PhD; Christer Allgulander, MD; Yves Lecrubier, MD; and Hans-Ulrich Wittchen, PhD. All criteria considered necessary for conclusive noninferiority. REFERENCES FIGURE 3. Noninferiority: Observed Difference (Per-protocol Population) • Rynn M, et al. Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial. Depress Anxiety 2007; Feb 20; [Epub ahead of print]. • Koponen H, et al. Efficacy of duloxetine for the treatment of generalized anxiety disorder: Implications for primary care physicians. Prim Care Comp JClin Psychiatry 2007;9:100-107. • Hartford J, et al. Duloxetine as an SNRI treatment for generalized anxiety disorder: results from a placebo and active-controlled trial. Int ClinPsychopharmacol 2007; 22(3):167-174. • Rickels K, Pollack MH, Sheehan DV, Haskins JT. Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry 2000; 157: 968-974. • Gotzsche PC. Lessons from and cautions about noninferiority and equivalence randomized trials. JAMA 2006; 295:1172-1174. • Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59(suppl 20):22-33. • Hamilton M. Development of a rating scale for primary depressive illness. BrtJ Clin Soc Psych 1959; 6:278-296. FIGURE 6. Mean Changes in Vital Signs and Weight (ITT Sample) RESULTS TABLE 1. Patient Demographics (Intent-to-treat, ITT) Study Objective Duloxetine 60-120 mg/day (N = 320) Venlafaxine XR 75-225 mg/day (N = 333) Placebo (N = 331) * To conduct a noninferiority comparison of duloxetine 60 to 120 mg once daily with venlafaxine XR 75 mg to 225 mg once daily for the treatment of adults with GAD. Age, mean (SD) 41.5 (13.1) 41.1 (13.3) 42.2 (13.2) Ethnicity, n (%) METHODS Caucasian 214 (67.1) 231 (69.4) 228 (68.9) ** ** African 36 (11.3) 20 ( 6.0) 27 ( 8.2) Patients Hispanic 51 (16.0) 62 (18.6) 54 (16.3) • Males and females ≥ 18 years recruited globally • Inclusion criteria: Primary diagnosis of DSM-IV-TR GAD that was assessed by Mini International Neuropsychiatric Interview6 and confirmed by psychiatrist • Exclusion criteria: comorbid psychiatric diagnoses, medications that contraindicate treatment with either duloxetine or venlafaxine XR Other 18 (5.6) 20 (6.0) 22 (6.6) Gender, n (%) CI, confidence interval Duloxetine 60–120 mg (N = 238) is shown to be non-inferior to Venlafaxine XR 75–225 mg (N = 255) Key: Sys BP, Systolic Blood Pressure (mm/Hg); Dia BP, Diastolic Blood Pressure (mm/Hg); bpm, beats per minute * P ≤ .05, ** P ≤ .01 versus placebo Female 194 (60.6) 195 (58.6) 207 (62.5) No significant differences between treatment groups.