Transcript Slide 1

Effects of Initial Dosing Strategies of Duloxetine on Tolerability and Efficacy in Patients with
Major Depressive Disorder
David Dunner, MD1 (sponsor); Susan Kornstein,MD2; Virgil Whitmyer, PhD3; Adam Meyers, MS3; Craig Mallinckrodt, PhD3; Madelaine Wohlreich, MD3; Millie Hollandbeck, BS3; John Greist, MD4
1) Center for Anxiety and Depression, Mercer Island, WA; 2) Virginia Commonwealth University, Richmond, VA; 3) Lilly Research Laboratories, Indianapolis, IN; 4) Healthcare Technology Systems, Inc., Madison, WI
• Efficacy was primarily evaluated by the 17-item HAMD and the 30-item Inventory of Depressive Symptoms Clinician Rated (IDS-30) total score.
Statistical Methods
• All patients with a baseline and at least one post-baseline measure were included in the analysis.
145 (68.1)
42.2
18.9 - 80.1
169 (77.2)
28 (12.8)
15 (6.8)
7 (3.2)
21.6
IDS-30 total, mean
162 (76.1)
26 (12.2)
20 (9.4)
5 (2.3)
21.7
35.9
35.1
4.4
4.3
4.3
*p = .04 (60mg QAM
starting dose vs
30 mg QAM
starting dose)
0.4
0.3
Pooled Across Food
Groups
Primary objective
*
0
1
25
30
Percent
• Double-blind parallel design trial conducted in male and female adult outpatients (18 years or older) with MDD as defined by DSM-IV-TR.
Percent
5
6
33
30
26
24
20
8
15
7
22
19
17
14
15
12
Mean change on AMDP-5 item 112 (nausea)
HMDR Study Design – Acute Phase
30 mg
QAM
30 mg
BID
60 mg
QAM
30 mg
QAM
Without Food
30 mg
BID
60 mg
QAM
30 mg
QAM
30 mg
BID
60 mg
QAM
Without food
Mean Change of Nausea Score at Week 1 by
Food and Dose
DLX 30 mg BID (n= 107)
107
1
8 week
extension
After 1 week all patients:
60mg QD dose Duloxetine
DLX 30 mg QAM (n=106)
(n=106
“Do not take within
an hour of eating”
eating
DLX 30 mg BID (n=107)
(n=107
DLX 60 mg QAM (n=108)
(n=108
1 week
Week 0
Week 1
Week 6
Acute phase = 6 weeks
Funding provided by Eli Lilly and Company
p = .01 for main effect of food
Mean Change from Baseline
DLX 60 mg QAM (n= 108)
108
p = .03 (30 QAM vs
60 QAM)
p =.06 (30 BID vs
60 QAM)
* p=.006
( 60 QAM w/out food
vs
60 QAM w/food)
0.50
30 mg 30 mg 60 mg
BID
QAM
QAM
Without Food
Mean Score
p = .07 (30 QAM vs 60 QAM w/o food)
7.0
5.1
3.8
30 mg
BID
With Food
60 mg
QAM
3.7
2.7
n= 4
n=11
n=6
60 mg
QAM
30 mg
QAM
n=15
n=8
n=8
0
30 mg
QAM
30 mg
BID
Without Food
30 mg
BID
60 mg
QAM
With Food
Weeks
1
2
3
4
5
6
0
Duloxetine
30 mg QAM
-1
-2
Duloxetine
30 mg BID
-3
-4
-5
**
*
Duloxetine
60 mg QAM
-6
-7
-8
-9
-10
*p =.01 (60 QAM
vs 30 QAM)
**p< .001 (60
QAM vs 30
BID)
Baseline Mean Score = 17.55 (after placebo lead in)
Mean change in HAMD17 Total Score at endpoint was statistically significant for each starting dose
group
1
2
3
4
5
6
Duloxetine
30 mg QAM
-1
-3
**
-5
*
-7
-9
Duloxetine
30 mg BID
Duloxetine
60 mg QAM
**
*
-11
-13
-15
Baseline Mean Score = 29.20 (after placebo lead in)
Mean change in IDS-30 Total Score at endpoint was statistically significant for
each starting dose group.
Week 1: * p=.05
(60 QAM vs 30
QAM)
**p < .005 (60
QAM vs 30 BID)
Week 2: * p=.03
(60 QAM vs 30
QAM)
**p.=.001 (60
QAM vs 30 BID)
CONCLUSIONS
• Overall, duloxetine was efficacious and well-tolerated regardless of starting dose.
• In this study, instructing patients to take duloxetine with food improved initial tolerability, particularly in patients started at 60mg-QAM.
• Starting patients at 30mg-QAM resulted in a transitory delay in efficacy which was not significant after Week 2.
• Remission rates at the end of the treatment period were not different among the 3 starting doses and were 39.6% (30mg QAM), 35.9%
(30mg BID), and 42.1% (60mg QAM).
REFERENCES
[PDR] Physicians’ Desk Reference. 2003. Montvale (NJ): Medical Economics Data Production Co.
0.28
0.20
0
10
• Starting patients at 30mg-QAM improved tolerability compared to starting doses of 30mg-BID and 60mg-QAM.
*
0.26
30 mg
QAM
2 units of change of
3 units of change
1 unit of change in
severity: 0-2 or 1-3
of severity: 0-3
severity: 0 -1, 1-2, or 2-3
Nausea Severity: 0 = no nausea; 1 = mild; 2 = moderate; 3 = severe
With Food
There were no differences within or between dose and food groups in the incidence of
treatment-emergent nausea
DLX 30 mg QAM (n=111)
“Take with food ”
0
4.9 60mg QD w/food
4.5
4.8 60mg QD w/out food 4.5
Mean Change of IDS-30 Total Score Over
Acute Phase
2
3
5
0
30mg BID w/food
30mg BID w/out food
30 mg BID with Food
60 mg QAM w/o Food
Mean Change in HAMD17 Total Score Over
Acute Phase
4
4
10
10
1
30 mg QAM w/o Food
60 mg QAM w/ food
At Week 1, there were no statistically significant differences between starting doses within each
food group in discontinuation rates due to adverse events
0
16
6
*p =.04 (30mg QD vs 30mg BID)
Any Insomnia - Mean of difficulty falling asleep, interrupted sleep, shortened sleep, and early
waking; Gastric Events - Mean of nausea and vomiting
0
5
5
1.8
3
24
19
• After 1 week on the starting dose, all patients were dosed at 60mg once daily (QD) for the remaining 5 weeks of treatment.
• The “common adverse events score” is the mean of items from the AMDP-5 (defined a priori) that are commonly associated with duloxetine. These items include:
nausea, vomiting, dry mouth, constipation, mean of insomnia items, drowsiness, increased perspiration, and decreased appetite.
10
3
2
4
5
*
15
Mean Change from Baseline
40
• Assessment of nausea was done by the AMPD-5 and included:
4
Baseline Scores:
30mg QD w/food
4.6
30mg QD w/out food 4.7
Weeks
30
20
20
35
50
• Compared tolerability and efficacy after 1 week at the starting dose and at the end of the treatment (5 weeks).
Food groups: by instruction to take study drug with food or not within one hour of eating (without food).
3
Weeks
Nausea Score – Change Among Patients
Reporting New Nausea at Week 1
Incidence of Treatment-Emergent Nausea
at Week 1 by Food and Dose
METHODS
2
3
p = .01 (30 QAM vs 30 BID w/o food)
0
0.2
60 mg QAM
2
Discontinuation Due to Adverse Event in
Acute Phase by Dose and Food
5
0.1
30 mg BID
1
30 mg QAM with Food
30 mg BID w/o Food
Constipation
0.5
60 mg
QAM
Duloxetine
60 mg QAM
Dizziness
0
60 mg QAM
Starting Dose
25
Increased
Perspiration
10
29
27
23
After Week 1 – all patients were
dosed at 60 mg QD
0
Duloxetine
30 mg BID
Any
Insomnia
20
OBJECTIVES
Starting dose groups: 30mg QAM (n=219); 30mg BID (n=213); 60mg QAM (n=215)
30 mg
BID
With Food
Dry Mouth
30 mg BID
3
5
9
Improvement
Mean Score
Percent
30
0.0
• Patients were randomized in a 3 x 2 complete factorial arrangement to:
30 mg
QAM
Duloxetine
30 mg QAM
Drowsiness
0.7
0.6
30 mg QAM
• Examined effects of dose and food on tolerability and efficacy in a 3 x 2 factorial design. Starting Doses: 30 mg QAM; 30 mg BID; and 60 mg QAM
compared with taking starting dose with or without food.
60 mg
QAM
30
30 mg QAM
Starting Dose
Week 1
40
• Starting duloxetine at lower doses or taking duloxetine with food is often recommended to mitigate initial adverse events but has not been well-studied. This study
aimed to examine these dosing strategies.
Secondary objectives
30 mg 30 mg
BID
QAM
Incidence of Common Adverse Events
(AMDP-5) at Week 1 by Dose
Weeks 2-6
2.5
2.0
0
Without Food
Mean Nausea Score Over Acute Phase by
Dose
1-week at
starting
doses
Weeks
Gastric
Events
Incidence of Treatment-Emergent Nausea at
Week 1 and Acute Phase by Dose
3.5
3.0
0.5
0.0
0.24
35
• Treatment-emergent nausea associated with initial antidepressant treatment is one reason for treatment discontinuation and is reported at a rate of  20% for
selective serotonin reuptake inhibitors (SSRIs), with rates as high as 31% for venlafaxine, a dual-reuptake inhibitor of serotonin and norepinephrine (SNRI) (PDR
2003).
• Compared the incidence of treatment-emergent nausea for patients initially dosed at duloxetine 30 mg QAM, versus duloxetine 60 mg QAM.
174 (80.9)
15 (7.0)
19 (8.8)
7 (3.3)
21.2
35.5
CGI-S, mean
• Major depressive disorder (MDD) has a lifetime prevalence ranging from 10% to 25% in females and 5% to 12% in males (APA 2000).
• A recent open-label study further suggested that taking duloxetine 30 mg QD for one week followed by escalation to doses of 60 mg or higher may lessen the risk
of adverse events with only a short-lived impact on efficacy compared with starting at 60 mg QD.
18.6 – 77.5
18.7 - 82.7
4.5
4.0
1.5
1.0
0.37
0
50
• In trials starting duloxetine at the effective treatment dose for MDD of 60 mg QD, the nausea rate was 38%, which appeared to be short-lived and dose related.
43.9
0.50
Mean Change from Baseline
Age, y, range
Ethnicity, n (%)
Caucasian
African descent
Hispanic
Others
HAMD-17 total, mean
42.8
0.82
Improvement
Age, y, mean
134 (62.3)
Improvement
136 (62.1)
DLX 60mg QAM
(N=215)
0.87
Percent of Patients
DLX 30mg BID
(N=213)
Gender, N (%) Female
BACKGROUND
• Duloxetine is a potent dual reuptake inhibitor of serotonin and norepinephrine; exhibits a low affinity for most neurotransmitter receptors (Wong and Bymaster
2002); thus, suggesting a favorable side effect potential.
p=.01
Demographics
DLX 30mg QAM
(N=219)
6.0 End of All groups at
5.5 Placebo 60 mg QD
lead in
5.0
1
• HAMD and IDS-30 mean changes from baseline to all post baseline visits were analyzed using a restricted maximum likelihood (REML)-based repeated
measures approach (MMRM). Analyses included the fixed, categorical effects of dose group, investigator, visit, and dose group-by-visit interaction, as well as
the continuous, fixed covariate of baseline score. AMDP-5 outcomes were analyzed as described above with the addition of food group, food group-by-visit
interaction, and food group-by-dose group-by-visit interaction as categorical effects to the model.
Characteristic
Mean Common Adverse Event Score Over
Acute Phase by Food and Dose
p = .35 for main effect of food
p=.02
• Fisher’s exact test was used to assess the equality of dose groups in the incidence of treatment-emergent nausea based on changes in AMDP-5 item 112 at
Week 1. The primary analysis was the contrast between the 30 mg QAM and 60 mg QAM dose groups.
Results: No significant differences were found between starting doses of 30mg QAM and 60mg QAM on the primary analysis of rate of
treatment-emergent nausea. However, on the secondary mean change analysis, both the main effect of food group and the starting dose
group by food group interaction were significant at week 1. These results differed from the primary analysis because the mean change
analysis assessed changes in both rate and severity of nausea. Further, there was a main effect of food - taking duloxetine with food
reduced (improved) initial nausea—with the greatest benefit of food among those patients who started at 60 mg QAM. When taking
duloxetine without food, patients starting at 30mg QAM had improved nausea compared with those at 60mg QD. In patients taking
duloxetine without food discontinuation rates due to adverse events were 3.6%, 14.0%, 10.2% versus those taking it with food at 5.4%,
7.5%, and 7.4% for 30mg QAM, 30mg BID, and 60mg QAM respectively. All starting dose groups showed significant baseline to endpoint
improvements, as measured by mean changes in the HAMD. However, patients initially dosed at 60mg QAM showed significantly greater
improvement at weeks 1and 2 (IDS) and 2 (HAMD) than those initially dosed at 30mg QAM or 30mg BID. For the remaining 4 weeks of
treatment, mean change did not differ among initial dose groups.
Conclusions: Taking duloxetine with food or starting at 30mg QAM appeared to improve initial tolerability. Starting 30mg BID did not
improve tolerability compared to 60mg QAM. The starting dose of 30mg QAM in the first week produced a transient disadvantage in
efficacy compared to a starting dose of 60mg QAM.
Mean Change of Common Adverse Event
Score at Week 1 By Food and Dose
Mean Change from Baseline
Methods: This double-blind, parallel design trial was conducted in adult outpatients with major depressive disorder (MDD). Patients were
randomized in a 3 x 2 complete factorial arrangement to one of three starting dose groups: 30mg once daily in the morning (QAM;
n=219), 30mg twice daily (BID; n=213), or 60mg QAM (n=215) and to one of two food groups: by instruction to take study drug with food
or not within one hour of eating. After one week on the starting dose, all patients were dosed at 60mg QD for the remaining five weeks of
treatment. The primary objective of the study was to compare the rate of treatment emergent nausea in the 30mg QAM group versus the
60mg QAM group based on item 112 (nausea) of the Association for Methodology and Documentation in Psychiatry adverse event scale
(AMDP-5). A key secondary objective was to evaluate mean changes on AMDP-5 item 112 using an analysis that included dose group,
food group, and their interaction. Other secondary objectives included mean changes on an a priori determined common adverse events
list and discontinuations due to adverse events. Efficacy was primarily evaluated by the 17-item Hamilton Depression Rating Scale
(HAMD) and the Inventory of Depressive Symptoms-Clinician Rated (IDS).
METHODS continued
Percent Incidence
Background: Patients often discontinue antidepressant treatment due to early side effects. Starting at a lower dose or taking the
medication with food is often recommended to mitigate initial adverse events, but these strategies have not been well studied. Duloxetine
is a serotonin-norepinephrine reuptake inhibitor with an efficacious (recommended) dose of 60mg once daily (QD). A previous open-label
duloxetine study suggested that starting duloxetine at 30mg QD for one week followed by escalation to 60mg QD may lessen the risk of
initial nausea with only a short-lived impact on efficacy. This study compared starting doses of duloxetine taken with or without food.
Improvement
ABSTRACT
0.15
0.18
30 mg 30 mg 60 mg
QAM BID
QAM
With Food
Wong DT, Bymaster FP. 2002. Dual serotonin and noradrenaline uptake inhibitor class of antidepressants potential for greater efficacy or just hype? Prog
Drug Res 58:169-222.
APA. 2000. Diagnostic and Statistical Manual of Mental Disorders Fourth Edition - Text Revision. Washington DC.