Effects of Initial Dosing Strategies of Duloxetine on Tolerability and Efficacy in Patients with Major Depressive Disorder

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

• METHODS continued
• 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.
• Fishers 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.
• 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.

Mean Change of Common Adverse Event Score at Week
1 By Food and Dose
Mean Common Adverse Event Score Over Acute Phase
by Food and Dose
p .35 for main effect of food
p.02
6.0
All groups at
End of
1
60 mg QD
5.5
Placebo
lead in
p.01
5.0
4.5
0.87
4.0
0.82
3.5
Mean Score
3.0
1
-
week at
Improvement
starting
Demographics
2.5
doses
2.0
Mean Change from Baseline
DLX 30mg QAM (N219)
DLX 30mg BID (N213)
DLX 60mg QAM (N215)
0.50
Characteristic
1.5
1.0
0.37
Gender, N () Female 136 (62.1) 145 (68.1) 134
(62.3) Age, y, mean 42.2 42.8 43.9 Age, y,
range 18.9 - 80.1 18.7 - 82.7 18.6
77.5 Ethnicity, n () Caucasian 169 (77.2)
162 (76.1) 174 (80.9) African descent 28
(12.8) 26 (12.2) 15 (7.0) Hispanic 15
(6.8) 20 (9.4) 19 (8.8) Others 7
(3.2) 5 (2.3) 7 (3.3) HAMD-17 total,
mean 21.6 21.7 21.2 IDS-30 total, mean
35.5 35.9 35.1 CGI-S, mean 4.4 4.3
4.3
0.5
0.24
0.0
0
1
2
3
4
5
6
Weeks
0
0
30 mg QAM with Food
30 mg QAM w/o Food
30 mg BID with Food
30 mg
30 mg
30 mg
30 mg
60 mg
60 mg
30 mg BID w/o Food
60 mg QAM w/ food
60 mg QAM w/o Food
BID
QAM
QAM
QAM
BID
QAM
Baseline Scores 30mg QD w/food 4.6
30mg QD w/out food 4.7
30mg BID w/food 4.9 30mg BID w/out food
4.8
60mg QD w/food 4.5 60mg QD w/out food 4.5
Without Food
With Food
Incidence of Common Adverse Events (AMDP-5) at
Week 1 by Dose
Discontinuation Due to Adverse Event in Acute
Phase by Dose and Food
35
10
Duloxetine
p .07 (
30 QAM
vs
60 QAM w/o food)
Incidence of Treatment-Emergent Nausea at Week 1
and Acute Phase by Dose
Mean Nausea Score Over Acute Phase by Dose
30 mg QAM
30
Duloxetine
30 mg BID
25
p .01 (
30 QAM
vs
30 BID w/o food)
Duloxetine

• BACKGROUND
• Major depressive disorder (MDD) has a lifetime
  prevalence ranging from 10 to 25 in females and
  5 to 12 in males (APA 2000).
• 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).
• 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.
• 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.
• 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.
• 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.
• OBJECTIVES
• Primary objective
• Compared the incidence of treatment-emergent
  nausea for patients initially dosed at duloxetine
  30 mg QAM, versus duloxetine 60 mg QAM.
• Secondary objectives
• 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.
• Compared tolerability and efficacy after 1 week
  at the starting dose and at the end of the
  treatment (5 weeks).
• METHODS
• Double-blind parallel design trial conducted in
  male and female adult outpatients (18 years or
  older) with MDD as defined by DSM-IV-TR.
• Patients were randomized in a 3 x 2 complete
  factorial arrangement to
• Starting dose groups 30mg QAM (n219) 30mg BID
  (n213) 60mg QAM (n215)
• Food groups by instruction to take study drug
  with food or not within one hour of eating
  (without food).

-
50
Weeks 2
6
30 mg QAM
60 mg QAM
7.0
20
Starting Dose
Week 1
0.7
30 mg BID
Percent Incidence

5
40
15
Percent of Patients
5.1
0.6
60 mg QAM
After Week 1

all patients were
10
Starting Dose
3
dosed at 60 mg QD
30
3.8
5
0.5
3.7
9
p

.04 (60mg QAM starting dose vs
5
2.7
Percent
0.4
20
30 mg QAM starting dose)
Mean Score
1.8
Improvement
0
n11
29
0.3
n15
n8
n8
n6
27
n 4
23
0
10
0.2
30 mg
30 mg
30 mg
30 mg
60 mg
60 mg
Increased
Gastric
Events
Dry Mouth
Dizziness
Any
Insomnia
Drowsiness
Perspiration
Constipation
QAM
QAM
BID
QAM
QAM
BID
0
0.1
Without Food
With Food
30 mg QAM
30 mg BID
60 mg QAM

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
0.0
At Week 1, there were no statistically
significant differences between starting doses
within each food group in discontinuation rates
due to adverse events
0
1
2
3
4
5
6
Pooled Across Food
Weeks
Groups
Mean Change in HAMD17 Total Score Over Acute Phase
Mean Change of IDS-30 Total Score Over Acute Phase
Nausea Score Change Among Patients Reporting
New Nausea at Week 1
Incidence of Treatment-Emergent Nausea at Week 1
by Food and Dose
Weeks
Weeks
50
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Duloxetine
0
Duloxetine
30 mg QAM
-1
30 mg QAM
40
-1
Duloxetine

-2
-3
Duloxetine
30 mg BID
-3
30 mg BID
30
33

-5
Duloxetine

30
-4
60 mg QAM

-7
Week 1 p.05 (60 QAM vs 30 QAM) p lt .005
(60 QAM vs 30 BID) Week 2 p.03 (60 QAM vs
30 QAM) p..001 (60 QAM vs 30 BID)

Duloxetine
Percent
-5
26
Mean Change from Baseline
Improvement
Mean Change from Baseline
Improvement
24
24
20
60 mg QAM

-6
-9
19
p .01 (60 QAM vs 30 QAM) plt .001 (60 QAM
vs 30 BID)
-7
-11
10
-8
-13
-9
0
-10
-15
30 mg
30 mg
60 mg
30 mg
30 mg
60 mg
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.
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
QAM
BID
QAM
BID
With Food
QAM
QAM
Without Food
HMDR Study Design Acute Phase
With Food
There were no differences within or between dose
and food groups in the incidence of
treatment-emergent nausea
Mean Change of Nausea Score at Week 1 by Food and
Dose
DLX 30 mg QAM (
n111)
DLX 30 mg QAM (
n111)
DLX 30 mg BID (n
107
DLX 30 mg BID (n
107
)


Take with food

Take with food
1
DLX 60 mg QAM (n
108
DLX 60 mg QAM (n
108
)
p .01 for main effect of food
8 week
8 week
vs
p .03 (30 QAM
After 1 week all patients
After 1 week all patients
extension
extension
60 QAM)
60mg QD dose
Duloxetine
60mg QD dose
Duloxetine
DLX 30 mg QAM (n
106
DLX 30 mg QAM (n
106
)
(
60 QAM w/out food
p .06 (30 BID
vs

p.006
vs
60 QAM)
60 QAM w/food)
DLX 30 mg BID (n
107
DLX 30 mg BID (n
107
)

Do not take within

Do not take within
Mean Change from Baseline

an hour of eating
an hour of eating

DLX 60 mg QAM (n
108
DLX 60 mg QAM (n
108
)
0.50
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2003. Montvale (NJ) Medical Economics Data
Production Co. Wong DT, Bymaster FP. 2002. Dual
serotonin and noradrenaline uptake inhibitor
class of antidepressants potential for greater
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58169-222. APA. 2000. Diagnostic and
Statistical Manual of Mental Disorders Fourth
Edition - Text Revision. Washington DC.
1 week
1 week
0.28
0.26
0.18
0.20
0.15
Week 0 Week 1

Week 6
Week 0 Week 1

Week 6
0
Acute phase 6 weeks
30 mg
30 mg
60 mg
30 mg
30 mg
60 mg
BID
QAM
QAM
QAM
BID
QAM
Funding provided by Eli Lilly and Company
Without Food
With Food