Transcript Document

Duloxetine 60 to 120 mg Once Daily for the Prevention of Relapse in Adults with Generalized Anxiety Disorder:
A Double-blind Placebo-controlled Trial
Sponsored by
Dr. Jonathan Davidson
Jonathan RT Davidson MD1, Hans-Ulrich Wittchen PhD2, Pierre-Michel Llorca MD3, Janelle Erickson PhD4*, Michael J Detke MD, PhD.4,5,6, Susan G Ball PhD4,6, James M Russell MD4
Duke University Medical Center, Durham, NC; 2 Technische Universitat Dresden, Dresden, Germany; 3 C.H.U. Clermont-Ferrand, France; 4 Lilly Research Laboratories, Indianapolis, IN; 5 McLean Hospital/Harvard Medical School, Boston, MA; 6 Indiana University School of Medicine, Indianapolis, IN; * Current affiliation Orexigen Therapeutics, San Diego, CA
Key Inclusion Criteria
ABSTRACT
Purpose: To examine treatment with duloxetine 60–120 mg once daily for relapse prevention in
adults with generalized anxiety disorder (GAD) using a 26-week open-label, flexible-dose acute
therapy followed by a 26-week, double-blind, placebo-controlled, randomized withdrawal
continuation phase.
Methods: 887 patients ≥ 18 years of age [mean age = 43.3 yrs; 61% female] with a DSM-IVTR-defined GAD diagnosis entered open-label treatment with duloxetine 60–120 mg for 26 weeks.
Treatment response was defined as a Hamilton Anxiety Rating Scale (HAMA) total score reduction
from baseline ≥ 50% to a score of ≤ 11 and clinician improvement rating of “much” or “very much
improved” for the last 2 visits of open-label treatment. Patients who completed open-label phase
and met this definition were randomly assigned to receive either duloxetine (N = 216) or placebo
(N = 213) for the 26-week double-blind continuation phase. Relapse was defined as an increase in
the Clinical Global Impression Severity rating of at least 2 points from randomization (end of openlabel phase) to a score ≥ 4 (moderate) while meeting criteria for GAD or by discontinuation due to
lack of efficacy.
Results: At the open-label endpoint, 78.8% of patients met the responder criteria and 44.3% met
remission criteria (a HAMA total score ≤ 7). During the double-blind continuation phase, 41.8% of
placebo-treated patients relapsed compared with 13.7% of duloxetine-treated patients (P ≤ .001).
Among patients who did relapse, duloxetine-treated patients had a longer time to relapse compared
with patients who were switched to placebo (log-rank test, P ≤ .001). On both primary and
secondary measures, placebo-treated patients significantly worsened from randomization to study
endpoint compared with duloxetine-treated patients in their illness severity and functioning
(P ≤ .001, all comparisons). Discontinuation due to adverse events was 13.6% during open-label
phase, and 1.9% in the double-blind continuation phase for duloxetine-treated patients. During the
double-blind continuation phase, there was no significant difference between duloxetine and
placebo groups in the frequency of emergent adverse events (P = .629), except for dizziness which
was more frequent in the placebo group (9.9% vs 3.7%, P ≤ .05) for whom medication was
withdrawn during the double-blind phase.
Conclusions: The 3-fold greater relapse rate with placebo during the continuation phase indicates
the need for on-going treatment for patients with GAD. Duloxetine was efficacious and welltolerated for long-term treatment and significantly reduced the risk of relapse.
BACKGROUND
• Generalized anxiety disorder (GAD) is a chronic disorder with low probability
of spontaneous recovery1.
• Long-term medication is often required for optimal management of GAD2.
• Duloxetine has shown efficacy compared to placebo in 3 acute (9–10 week)
therapy trials3,4,5.
Study Objectives
Primary: To examine the long-term efficacy of duloxetine 60–120 mg once
daily for the prevention of relapse in patients with GAD who responded
therapeutically to an initial 26-week course of duloxetine treatment.
Secondary: To compare changes in efficacy and functioning measures
between patients who were maintained on duloxetine with patients who were
switched to placebo during the 26-week double-blind continuation phase.
METHODS
Study Design
Screening
Open-Label Acute Phase
Double-Blind Phase
• Male and female outpatients at least 18 years of age
• All patients must meet DSM-IV criteria for GAD with disease severity as
follows:
– Hospital Anxiety and Depression Scale (HADS) anxiety subscale
score of ≥ 10 at Visit 1
– Clinical Global Impressions-Severity ≥ 4 at Visits 1 and 2
– Covi Anxiety Scale (CAS) score of ≥ 9; no item in the Raskin
Depression Scale (RDS) > 3; and CAS score > RDS score
• To be continued into double-blind phase, patients must meet response
criteria:
– Decrease ≥ 50% from baseline on the Hamilton Anxiety Rating Scale
(HAMA) total score to ≤ 11
– Clinical Global Impressions of Improvement ratings of “much” or “very
much improved” for the last 2 consecutive visits
Table 2. Mean Changes from Double-blind Randomization to
Study Endpoint for Efficacy and Functioning Measures
Figure 1. Patient Disposition
• Diagnostic exclusions:
– Any current and primary DSM-IV Axis I diagnosis other than GAD
– Major depressive disorder within the past 6 months
– Panic disorder, post-traumatic stress disorder, or an eating disorder
diagnosis in past year
– Lifetime diagnosis of obsessive-compulsive disorder, bipolar affective
disorder, psychosis, factitious, or somatoform disorder
• Medical exclusions:
– Any medical condition that would contraindicate the use of duloxetine
– Any excluded concomitant or psychotropic medication
Outcome Measures
Secondary:
• Hospital Anxiety and Depression Scale (HADS)7
• Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I)8
Figure 2. Relapse Rate by Treatment (Double-blind Continuation
Phase)
Functioning:
• Sheehan Disability Scale (SDS) Global Functioning Score9
• Quality of Life Enjoyment and Satisfaction Scale (Q-LESQ-SF)10
• Primary analysis compared time to relapse for duloxetine and placebo using
a log-rank test.
• Relapse was defined as ≥ 2-point increase in CGI-S ratings from doubleblind randomization baseline to ≥ 4 (moderate) or as discontinuation due to
loss of efficacy.
• For most measures, differences between groups in the double-blind phase
were examined using analysis of covariance (ANCOVA) model that included
treatment and investigator as main effects and baseline score as a
covariate.
Open-label Phase
DLX 60 mg QD
15 8
DLX = Duloxetine
Weeks
26
Age, mean (SD)
Randomization
of Responders
52
55
7.52
***
HAMA psychic factora
1.23
4.52
***
HAMA somatic factora
0.34
2.98
***
HADS anxietya
0.05
3.53
***
HADS depressiona
0.00
2.23
***
SDS global functioning scorea
0.60
5.03
***
Q-LESQ-SF maximum percent scoreb
-0.29
-12.53
***
Female
Ethnicity, n (%)
Caucasian
Nausea
Headache
Dry Mouth
Diarrhea
Dizziness
Constipation
Fatigue
Hyperhidrosis
Insomnia
Somnolence
Decreased appetite
Upper respiratory
Decreased libido
Vomiting
Nasopharyngitis
Double-Blind Phase
Adverse Events
28.3%
18.7%
14.3%
14.2%
13.4%
12.5%
11.5%
10.0%
9.8%
8.2%
6.1%
5.5%
5.4%
5.4%
5.0%
0%
100%
10%
30%
*
Headache
5.6%
5.2%
Nasopharyngitis
3.7%
6.1%
Duloxetine 60-120 mg/d (N = 887)
20%
3.7%
Dizziness
40%
Percent of Patients
† Events occurring
at frequency > 5%
9.9%
2.8%
Anxiety
6.6%
0%
10%
Duloxetine 60-120 mg/d (N = 216)
Placebo (N = 213) * P ≤ .05
20%
80%
30%
40%
Percent of Patients
† Events occurring at frequency > 5%
Placebo (N=201)
60%
***
41.8%
40%
20%
13.7%
0%
*** P ≤ .001
Treatment Group
Serious Adverse Events
Serious Adverse Events
• Alcohol intoxication
• Alcohol dependency
• Anxiety
• Arrythmia
• Cellulitis
• Cerebral hemorrhage
(resulted in death)
• Depression
Duloxetine
Placebo
• Bronchitis
• Diarrhea
• Worsening of GAD
• Acute fall
• Ruptured
tendon
• Diverticulitis
• Mania
• Nephrolithasis
• Attempted suicide (2)
• Suicide (fatal)
• Stress
• Syncope
ACKNOWLEDGMENT
Duloxetine
Duloxetine
60–120 mg/day
60–120 mg/day
Placebo
(N = 887)
(N = 216)
(N = 213)
43.3 (13.4)
45.0 (13.2)
45.7 (14.1)
541 (61.0)
132 (61.1)
125 (58.7)
754 (85.0)
185 (85.7)
191 (89.7)
No significant differences between treatment groups in patients entering double-blind phase.
Research supported by Eli Lilly and Company and Boehringer Ingelheim GmbH
a***P ≤ .001, within group; b***P ≤ .001, placebo vs. duloxetine.
–Prevention
endpoint)
of
relapse
(primary
•Duloxetine 60–120 mg once daily
treatment was efficacious, associated
with significantly lower relapse rates
than placebo, greater maintenance of
quality of life and daily functioning, and
was generally well tolerated during this
one year study.
REFERENCES
Figure 3. Mean Hamilton Anxiety Rating Scale Total Score
Double-blind Phase
•Among GAD patients who responded to
duloxetine during 26-week open-label
phase and then received double-blind
treatment for 26 weeks, duloxetine 60–
120 mg once daily was superior to
placebo on the following endpoints:
–Change from baseline to endpoint
on
secondary
efficacy
and
functioning measures
Duloxetine 60-120 mg/day (N=204)
Statistical Analyses
Sex, n (%)
0
1.63
Open Label Phase
Adverse Events
Table 1. Patient Demographics
Placebo
HAMA total scorea
Figure 4. Adverse Events†
RESULTS
Primary: Hamilton Anxiety Rating Scale (HAMA)6
Taper
-3 to -30 DLX 30
days
mg QD
P value
Key Exclusion Criteria
DLX 90 mg QD
All
Patients
Placebo
N = 211
Key: HAMA, Hamilton Anxiety Rating Scale; HADS, Hospital Anxiety and Depression Scale; SDS,
Sheehan Disability Scale; Q-LESQ-SF, Quality of Life Enjoyment and Satisfaction Scale Short Form
a higher scores indicate greater worsening; b lower scores indicate greater worsening; *** P ≤ .001,
between groups
DLX 120 mg QD
DLX 60-120 mg QD
CONCLUSIONS
Duloxetine
N = 213
Measure
Percent of Patients who
met Relapse Criteria
1
We thank the patients who participated in the study. We would like to acknowledge our
appreciation to the following principal investigators and their clinical research staff: Dr.
Voker Arolt, Dr. Borwin Bandelow, Dr. Bertrand Baranosvsky, Dr. Benny Barnhard, Dr.
Bettina Bergthold, Dr. J Alexander Bodkin, Dr. Joan Busner, Dr. Osvaldo Caro, Dr. WA
de Backer, Dr. Anthony Dietrich, Dr. Bernadette D’Souza, Dr. Luisa Figueira, Dr.
Christian Gaussares, Dr. Hermann-Josef Gertz, Dr. Francis Ghysen, Dr. Paul Gross, Dr.
Thomas Gualtieri, Dr. Peter Halama, Dr. Ulrich Hegerl, Dr. Fritz Henn, Dr. Ethan Kass,
Dr. Arif Khan, Dr. Saaid Khojasteh, Dr. Stephanie Kutler, Dr. Philippe Leclercq, Dr. Pierre
Le Goubey, Dr. Robert Levine, Dr. Bruce Lydiard, Dr. Silva Marques, Dr. John Marshall,
Dr. Carla Mendez, Dr. K Mulder, Dr. Pascal Pannetier, Dr. Franck Peyre, Dr. Jain
Rakesh, Dr. Angelo Samubnaris, Dr. Thomas Shiovitz, Dr. Margot Schmitz, Dr. Martin
Schuster, Dr. Georg Schonbeck, Dr. Andreas Strohle, Dr. Marques Teixeira, Dr. Mikel
Thomas, Dr. Harry Van Mierilo, Dr. W Veerman, Dr. Hans-Peter Volz, Dr. Jim Whalen
and Dr. Marcel Zins-Ritter.
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Poster presented at ACNP, Boca Raton, FL, USA; November 9-13, 2007