Module 5

1
Module 5
2
Aripiprazole Pivotal Bipolar Clinical Trials
Program
3
Overview

• Acute mania efficacy in Bipolar I Disorder
• Trial 1 and 2
• Flexible-dose, 3-week, placebo-controlled trials
• Trial 3
• Fixed-dose, 3-week, placebo-controlled trial
• Pooled analysis of trials 1 and 2
• Safety profile of acute mania in Bipolar I
  Disorder
• Aripiprazole dosing information

4
Acute Mania Efficacy in Bipolar I
DisorderAripiprazole Clinical Trials
Baseline Baseline
Aripiprazole(mg/day) Placebo Active control (mg/day) Pure mania () Duration(wk) n MeanYMRS Total MedianCGI-BP
Trial 11 30 or 15 ? None 67 3 262 29 4
Trial 22,3 30 or 15 ? None 58 3 272 29 5
Trial 33 15, 30 ? None 61 3 401 28 5
Patients were diagnosed with Bipolar I Disorder
and were experiencing an acute manic or mixed
episode. Starting dose with option to decrease
to 15 mg for tolerability. Only the safety data
from this fixed-dose trial are included in the
ABILIFY (aripiprazole) package insert. CGI-BPCli
nical Global Impression-bipolar version
YMRSYoung Mania Rating Scale. 1. Keck PE et al.
Am J Psychiatry. 20031601651-1658 2. A poster
presented by Sachs et al. at the Institute of
Psychiatric Services, November 2003, Boston, MA
3. Data on file CN138-007.
5
Aripiprazole Acute Mania Trials
Aripiprazoledaily dose
Totalsample size
Duration of treatment
Comparator
Trial 1
254
Placebo
30 mg (mean 28 mg)
3 weeks
Trial 2
15 mg, 30 mgfixed
375
Placebo
3 weeks
Trial 3
272
Placebo
30 mg (mean 28 mg)
3 weeks
Trial 4
12 weeks
15 mg (mean 21.6 mg)
338
Haloperidol
Option to decrease to 15 mg for
tolerability. Option to increase to 30 mg.
6
Aripiprazole vs. Placebo in Acute Mania Study 1
Study Design

• Acute phase
• 3 weeks, inpatient, double-blind
• Patient characteristics
• Mean baseline YMRS 29
• Current episode 67 manic, 33 mixed
• Starting dose 30 mg with option to decrease to 15
  mg (mean dose, 28 mg)
• 262 randomized patients in 38 centers

Keck et al. Am J Psychiatry. 2003. In press.
7
Acute Mania Efficacy in Bipolar I Disorder
Evaluation Measures

• The YMRS is an 11-item, clinician-rated scale
  traditionally used to assess the degree of manic
  symptomatology in patients1
• The range is 0 (no manic features) to 60 (maximum
  score)
• Total score includes the following weighted items

• 4-point items
• Elevated mood
• Language/thought disorder
• Appearance
• Insight
• Increased activity
• Sexual interest
• Sleep

• 8-point items
• Irritability
• Speech
• Thought content
• Disruptive/aggressive behavior

• CGI-BP Severity of Illness Scale (1not ill at
  all, 7among the most extremely ill) assesses the
  clinicians impression of the patients current
  state of illness2

CGI-BPClinical Global Impressionbipolar
version YMRSYoung Mania Rating Scale. 1. Young
RC et al. Br J Psychiatry. 1978133429-435. 2.
Guy W, ed. ECDEU Assessment Manual for
Psychopharmacology, revised. Rockville, MD
National Institute of Mental Health 1976 DHEW
publication no. (ADM) 76-338.
8
Acute Mania Efficacy in Bipolar I Disorder Trial
1Clinical Trial Design

• Trial design
• 3 weeks, inpatient, double-blind, randomized,
  placebo-controlled
• Patient characteristics
• Aripiprazole mean baseline YMRS total score 28.2
• Placebo mean baseline YMRS total score 29.7
• Dosing
• Aripiprazole starting dose 30 mg/day, with option
  to decrease to 15 mg/day for tolerability (mean
  dose, 28 mg/day)
• Sample size
• 262 randomized patients in 38 centers

Patients not responding at the end of week 2
were discontinued from double-blind treatment and
offered the option of open-label aripiprazole
treatment during week 3. YMRSYoung Mania Rating
Scale (range 060). Keck PE et al. Am J
Psychiatry. 20031601651-1658.
9
Acute Mania Efficacy in Bipolar I Disorder Trial
2Clinical Trial Design

• Trial design
• 3 weeks, inpatient, double-blind, randomized,
  placebo-controlled
• Patient characteristics
• Aripiprazole mean baseline YMRS total score 28.8
• Placebo mean baseline YMRS total score 28.4
• Dosing
• Aripiprazole starting dose 30 mg/day, with option
  to decrease to 15 mg/day for tolerability (mean
  dose, 28 mg/day)
• Sample size
• 272 randomized patients in 29 US study centers

YMRSYoung Mania Rating Scale (range
060). Data on file CN138-074.
10
Acute Mania Efficacy
11
Study 074
12
Study CN138-074 A Multicenter, Randomized,
Double-Blind Study of Aripiprazole versus Placebo
in the Treatment of Patients with Acute Mania in
Bipolar Disorder
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
13
Study CN138-074 Overview

• A 3-week, multicenter, double-blind, randomized,
  placebo-controlled study to assess the efficacy
  and safety of aripiprazole in patients with
  bipolar I disorder experiencing an acute manic
  or mixed episode
• Patients were randomized to receive either
  aripiprazole (30 mg/day) or placebo

Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
14
Study CN138-074 Design

• 3-week, randomized, double-blind
  placebo-controlled trial
• Comparison of aripiprazole (30 mg/day) with
  placebo
• DSM-IV diagnosis of bipolar I disorder
• Currently experiencing manic or mixed episodes
• Aged 18 years or older
• Experiencing acute relapse requiring
  hospitalization
• YMRS score of 20

Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
15
Study CN138-074 Design
Hospitalization Screening weeks 12
Aripiprazole (30 mg/day)
Placebo
Study endweek 3
Screening Randomization Double-Blind Treatment
Phase(17 days)
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
16
Study CN138-074 Endpoints

• Primary endpoint
• Mean change in YMRS Total Score from baseline to
  week 3 using LOCF analysis
• Secondary endpoints
• Response rate (50 decrease in YMRS Total Score
  from baseline to week 3)
• Mean change from baseline in
• CGI-BP Severity of Illness (mania, depression,
  overall bipolar) scores
• CGI-BP Improvement from Baseline (mania,
  depression, overall bipolar) scores
• MontgomeryAsberg Depression Rating Scale total
  score
• PANSS Total and Hostility subscale score
• Rate of discontinuation due to lack of efficacy

LOCF, last observation carried forward PANSS,
Positive and Negative Syndrome Scale
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
17
Study CN138-074 Patient Disposition
Enrolled(n353)
Randomized(n272)
Aripiprazole (n137)
Placebo (n135)
Discontinued prior to week 363 (48) Adverse
events 12 (9) Lack of efficacy 12
(9) Withdrew consent 35 (25) Other 4 (3)
Completed week 375 (55)
Discontinued prior to week 365 (45) Adverse
events 10 (7) Lack of efficacy 28
(21) Withdrew consent 25 (19) Other 2 (2)
Completed week 370 (52)
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
18
Study CN138-074 Baseline Demographics
Aripiprazole group Placebo group Total
Patients, n 137 135 272
Male/female, n/n 69/68 63/72 132/140
Age, years mean (SE) 37.3 (0.9) 40.4 (0.9) 38.8 (0.7)
Body weight, kg mean (SE) 87.5 (2.0) 85.0 (1.8) 86.3 (1.3)
Current episode, n () Manic Mixed 78 (57) 59 (43) 81 (60)54 (40) 159 (58)113 (42)
Age current episode began, years mean (SE) 37.2 (0.9) 40.3 (0.9) 38.8 (0.7)
Rapid cycling, n () Yes No 26 (19)111 (81) 22 (16)113 (84) 48 (18)224 (82)
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
19
Study CN138-074 Mean change in YMRS Total Score
over 3 weeks
Day
0
7
14
21
0
2
4
6
Placebo
Mean change in YMRS Total Score
Aripiprazole
8

10


12


14
plt0.01 p?0.001 LOCF analysis placebo,
n132 aripiprazole, n136 Mean baseline YMRS
Score placebo, 28.80 aripiprazole, 28.45
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
20
Study CN138-074 Efficacy in Subgroups Manic,
Mixed and Rapid Cycling
Manic
Mixed
Rapid cycling
n81/77 n51/59 n20/26
2
6
Placebo
Aripiprazole
10
Mean change in YMRS Total Score
14
p0.002
p0.010
p0.002
18
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
21
Study CN138-074 Response Rates with Aripiprazole
in Bipolar Mania
60



50

40
Placebo
30
Response rate ()
Aripiprazole
20
10
0
Day 2
Day 4
Week 1
Day 10
Week 2
Week 3
plt0.05 plt0.01 plt0.001 LOCF analysis
placebo, n132 aripiprazole, n136 Response
defined as 50 decrease in YMRS Total Score
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
22
Study CN138-074 Mean Change from Baseline in
CGI-BP (overall) Severity Scale
Day
0
7
14
21
0
0.5
Placebo
1
Severity Score
Mean change in CGI-BP
Aripiprazole



1.5
2
Baseline scores placebo, 4.69 aripiprazole,
4.70 plt0.05 plt0.01 LOCF analysis placebo,
n129 aripiprazole, n135
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
23
Study CN138-074 Mean Change from Baseline in
CGI-BP (mania) Severity Scale
Day



Baseline scores placebo, 4.71 aripiprazole,
4.69 plt0.05 plt0.01 LOCF analysis placebo,
n129 aripiprazole, n135
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
24
Study CN138-074 Mean Change from Baseline in
CGI-BP (depression) Severity Scale
Day
0
4
7
10
14
21
0
0.2
Placebo
0.4
Aripiprazole
Severity Score
Mean change in CGI-BP
0.6


0.8
1
Baseline scores placebo, 2.59 aripiprazole,
2.66 plt0.05 LOCF analysis placebo, n129
aripiprazole, n135
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
25
Study CN138-074 CGI-I Improvement Score (overall)
4

3



Placebo
CGI-BP Improvement Score
Aripiprazole
2
1
Day 4
Week 1
Day 10
Week 2
Week 3
LOCF analysis plt0.05 placebo, n129
aripiprazole, n135
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
26
Study CN138-074 CGI-I Improvement Score (mania)




LOCF analysis plt0.05
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
27
Study CN138-074 Mean Change in MADRS
Placebo
Aripiprazole
0
2
4
Mean change in MADRS subscale
pNS
p0.183
6
8
p0.041
10
All patients
Manic
Mixed
n49/59
n127/132
n78/73
Baseline values All patients placebo15.4
aripiprazole 14.9NS, not significant
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
28
Study CN138-074 Improvement in PANSS Total Score
Placebo
Aripiprazole
0
5
Placebo
Aripiprazole
Mean change in PANSS Total Score
10

15
plt0.05 LOCF analysis placebo, n122
aripiprazole, n124 Baseline values
PANSS-Total placebo, 62.5 aripiprazole, 61.8
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
29
Study CN138-074 Mean Change in PANSS Subscales
0
1
Placebo
Mean change in PANSS subscale
Aripiprazole
3
p0.01
p0.01
5
PANSS Positive
PANSS Hostility
n122/124 n122/124
Baseline PANSS Positive placebo, 18.0
aripiprazole, 17.5. PANSS Hostility placebo,
10.8 aripiprazole, 10.6
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
30
Study CN138-074 Treatment-Emergent Adverse
Events ?10 Incidence in Any Treatment Group
Placebo
Anxiety
Aripiprazole
Agitation
Akathisia
Somnolence
Vomiting
Constipation
Dyspepsia
Nausea
Pain extremity
Headache
0
10
20
30
40
50
60
70
80
90
100
of patients
Placebo, n133 aripiprazole, n136
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
31
Study CN138-074 Transient Nature of Adverse
Events
Among patients who experienced the adverse
effect during the first week
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
32
Study CN138-074 Mean Change in EPS Scales
1.0
Placebo
Aripiprazole
0.40
0.5
0.25
0.21
Mean change from baseline
0.06
0.05
0
0.02-
p0.42
p0.03
p0.30
AIMS
BarnesAkathisia
SAS
0.5
LOCF analysis
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
33
Study CN138-074 Change in Mean Weight
4
3
Placebo
2
Aripiprazole
Change in mean weight (kg)
1
0
LOCF
OC
n120/120 n69/77
Baseline weights placebo, 83.8 kg aripiprazole,
87.9 kg
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
34
Study CN138-074 Change in Prolactin Levels
0
5
Mean change in prolactin levels (ng/mL)
Placebo
Aripiprazole
10
15
Baseline levels placebo, 22.3 ng/mL
aripiprazole, 20.3 ng/mL
Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
35
Study CN138-074 Conclusions

• Aripiprazole demonstrated superior efficacy to
  placebo in the treatment of bipolar patients
  having acute manic or mixed episodes
• Efficacy is rapid and sustained, with relief of
  manic symptoms as early as day 4 and continuing
  throughout the study
• Aripiprazole has a favorable safety and
  tolerability profile in this population of
  bipolar patients that has acute manic or mixed
  episodes

Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
36
Study CN138-074 Strengths

• Double-blind study
• Large, randomized study design
• Aripiprazole produced robust improvements in the
  primary efficacy measure as early as day 4
• Patients with rapid-cycling and mixed mania
  responded well to treatment
• Confirms the findings of Keck et al. (2003)

Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
37
Study CN138-074 Weaknesses

• Exclusion of patients with manic episodes gt4
  weeks in duration may limit generalizability to
  patients with severe mania
• High discontinuation rates could limit
  generalizability of results
• High rates of akathisia were seen with
  aripiprazole

Sachs G et al. Aripiprazole in the treatment of
acute manic or mixed episodes in patients with
bipolar I disorder A 3-week placebo-controlled
study. Journal of Psychopharmacology 2006 In
press
38
Study CN138-009
39
Results from Studies 009 and 007
40
Study design

• Study 009
• 3 weeks, inpatient, double-blind
• Flexible dosing aripiprazole vs. placebo
• Starting dose 30 mg, with option to decrease to
  15 mg
• 250 evaluable patients in 38 centers USA
• Study 007
• 3 weeks, inpatient, double-blind
• Fixed doses of 15 mg, 30 mg, vs. placebo
• 375 evaluable patients (125 per arm)
• 56 centers USA, Mexico, Argentina

41
Y-MRS total score LOCF
Placebo
0
Aripiprazole
1
2
3
4

Mean Change From Baseline (SE)
5

6



7
8
9
10
Day 4
Wk 1
Day 10
Wk 2
Wk 3
Note no in figure. delete in legend?
Significance vs. placebo plt0.01 0.01ltp0.05
42
Results of Studies 009 and 007
Study 009 Study 007
43
Results of Studies 009 and 007
Study 009 Study
007
44
Y-MRS total score LOCF
Placebo
4
Aripiprazole 15 mg
5
Aripiprazole 30 mg
6
7
Mean Change From Baseline (SE)
8
9
10
11
12
13
Day 4
1
Day 10
2
3
Significance vs. placebo 0.01ltp0.05 plt0.01
Note No in figure. Add or delete in legend?
45
Acute Mania Tolerability/Safety
46
Bipolar Maintenance
47
Study 008
48
Study CN138-008 Effectiveness of aripiprazole
versus haloperidol in acute bipolar mania
Double-blind, randomised, comparative 12-week
trial
SLIDES FOR INTERNAL USE ONLY DO NOT CIRCULATE
EXTERNALLY Please consult country-specific
regulations regarding external discussions of the
data
Vieta E, Bourin M, Sanchez R, et al.
Effectiveness of aripiprazole v. haloperidol in
acute bipolar mania Double-blind, randomised,
comparative 12-week trial. Br J Psychiatry
2005187 235242
49
Study Overview

• A 12-week, multicenter, double-blind comparison
  of aripiprazole and haloperidol in both in- or
  out-patients experiencing acute manic or mixed
  episodes
• Patients were randomized to receive either
  aripiprazole or haloperidol, using a fixed
  randomization schedule allocating patients
  between the two treatment arms in a 11 ratio

50
Study Design
CGI-BP, Clinical Global Impression - Bipolar
Disorder MADRS, MontgomeryAsberg Depression
rating scale
51
Study Endpoints

• Primary endpoint
• Response Proportion of aripiprazole- and
  haloperidol-treated patients who showed a 50
  decrease from baseline in the YMRS Total score
  and continued on treatment for 12 weeks

52
Study Endpoints

• Secondary endpoints
• Comparison of response rates at end of Week 3
  (patients with 50 decrease from baseline in the
  YMRS Total score and did not discontinue)
• Comparison of patients (at week 12) who continued
  treatment after week 3 with a CGI-BP (mania)
  severity score lt4 and a MADRS Total score lt18 at
  week 3
• Comparison of time to discontinuation for any
  reason
• Both LOCF and OC data set analyses were performed
  at weeks 3 and 12. The OC data set excludes
  patients without YMRS assessments within the week
  3 and week 12 windows
• Safety assessment of aripiprazole and haloperidol
  in all patients

53
Patient Progress Through The Trial
Assessed for eligibility (n372)
Randomized (n347)
Discontinued from haloperidol (n122)
Discontinued from aripiprazole (n86)
One patient was randomized to haloperidol but
treated with aripiprazole
54
Baseline Demographics of Randomized Patients
Aripiprazole group Haloperidol group Total
Patients, n 175 172 347
Male/female, n 76/99 57/115 133/214
Mean age, years (SE) 42.6 (0.9) 41.0 (0.9) 41.8 (0.6)
Mean body weight (SE) 74.6 (1.1) 72.3 (1.1) 73.5 (0.8)
Current episode, n () Manic Mixed 161 (92)14 (8) 148 (86)24 (14) 309 (89)38 (11)
Mean YMRS Total score (SE) 31.1 (0.5) 31.5 (0.6) 31.3 (0.4)
Mean CGI-BP (Mania) Severity score (SE) 5.0 (0.1) 4.9 (0.1) 5.0 (0.0)
Mean MADRS Total score (SE) 9.2 (0.4) 9.9 (0.4) 9.6 (0.3)
CGI-BP, Clinical Global Impression Bipolar
Disorder MADRS, MontgomeryÅsberg Depression
Rating ScaleYRMS, Young Mania Rating Scale.
Aripiprazole, n171 haloperidol, n169 total,
n344 Aripiprazole, n174 haloperidol, n171
total, n345
55
Disposition of patients Weeks 1-12
Disposition of Patients Weeks 112
Number of patients ()
Patient Status
Haloperidol
Aripiprazole
Total
Enrolled
n/a
n/a
372
Baseline failures
n/a
n/a
25
Randomized
172
175
347
122 (70.9)
86 (49.1)
208 (59.9)
Discontinued from 12 Weeks Treatment
Adverse event
84 (48.8)
32 ( 18.3)
116 (33.4)
Lack of efficacy
10 ( 5.8)
30 (17.1)
40 (11.5)
Subject withdrew consent
19 (11.0)
16 ( 9.1)
35 (10.1)
Subject unreliability
1 ( 0.6)
3 ( 1.7)
4 ( 1.2)
Lost to follow-up
4 ( 2.3)
3 ( 1.7)
7 ( 2.0)
Pregnancy
1 ( 0.6)
0
1 ( 0.3)
Other known cause
3 ( 1.7)
2 ( 1.1)
5 ( 1.4)
Completed 12 Weeks Phase
50 (29.1)
89 (50.9)
139 (40.1)
56
Number of Patients Receiving Mean Dose by Week
Haloperidol Haloperidol Haloperidol Aripiprazole Aripiprazole Aripiprazole
Days n () Mean Range n () Mean Range
1-7 169 (100) 10 (8.6-10.7) 175 (100) 15.0 (10.7-17.1)
8-14 130 (76.9) 11.3 (5.0-15.0) 167 (95.4) 21.9 (12.9-30.0)
15-21 108 (63.9) 11.6 (8.6-15.0) 145 (82.9) 22.6 (12.9-34.3)
22-28 90 (53.3) 11.0 (8.6-15.0) 134 (76.6) 22.5 (8.6-30.0)
29-35 80 (47.3) 10.9 (8.6-15.0) 125 (71.4) 22.2 (12.9-32.1)
36-42 75 (44.4) 10.7 (10.0-15.0) 121 (69.1) 22.2 (12.9-32.1)
43-49 70 (41.1) 10.8 (7.5-15.0) 116 (66.3) 21.8 (12.9-30.0)
50-56 68 (40.2) 10.9 (8.6-15.0) 112 (64.0) 21.6 (12.9-30)
57-63 60 (35.5) 11.0 (8.6-15.7) 105 (60.0) 21.6 (12.5-30.0)
64-70 58 (34.3) 10.9 (10.0-15.0) 100 (57.1) 21.3 (6.4-30.0)
71-77 53 (31.4) 11.0 (8.6-15.0) 92 (52.6) 21.6 (6.4-30.0)
78-84 51 (30.2) 11.2 (10.0-15.0) 92 (52.6) 21.6 (15.0-30.0)
gt84 28 (16.6) 11.1 (10.0-15.0) 40 (22.9) 20.8 (7.5-30.0)
84 169 (100) 10.7 (5.0-15.0) 174b (99.4) 21.5 (15.0-30.0)
Data represents information beyond week 12 The
endpoint dose for patient 138008-61-61 is unknown
57
Primary Efficacy Endpoint Response Rate
plt0.001 vs. haloperidol RR, 1.75 (95 CI
1.332.30)
A responder was a patient who had at least a 50
decrease from baseline on the YMRS Total score,
who continued with treatment and who had a YMRS
Total score within the time window for that study
week
58
Secondary Efficacy Endpoints Results
Variable Aripiprazole Haloperidol RR (95 CI) p-value
Proportion of responders at Week 3 89/175 (50.9) 72/169 (42.6) 1.19 (0.951.50) 0.126
Proportion () of responders at Week 3 continuing to respond at Week 12 77/112 (68.8) 42/77 (54.6) 1.26 (1.001.58) 0.048
Proportion of patients in remission at Week 12 87/175 (50) 45/169 (27) 1.87 (1.412.47) lt0.001
Those who completed Week 3, with a CGI-BP
(Mania) Severity score lt4 and a MADRS score lt18
at Week 3 A responder was a patient who had at
least a 50 decrease from baseline on the YMRS
Total score who did not discontinue at or before
Week 12 A patient with remission in a specific
study week was a patient with an YMRS Total score
lt12 who did not discontinue in, or prior to, that
study week
59
Mean Change in Young Mania Rating Scale (YMRS)
Scores from Baseline to Week 12
Treatment duration (weeks)
1
2
3
4
5
6
7
8
9
10
11
12
0
2
4
6
Aripiprazole (n174)
8
10
Haloperidol (n162)
Mean (SE) change from baseline
12
14
16
18
20
22
Mean (SE) baseline LOCF YMRS aripiprazole, 31.1
(0.6) haloperidol, 31.4 (0.6)
60
Mean Change in CGI-BP (Mania) Severity score from
baseline
Treatment duration (weeks)
1
2
3
4
5
6
7
8
9
10
11
12
0
0.5
Aripiprazole (n173)
1
Haloperidol (n164)
1.5
Mean (SE) change from baseline
2
2.5
3
Mean (SE) baseline score aripiprazole, 4.96
(0.07) haloperidol, 4.94 (0.07) LOCF
61
Mean Change in YMRS and CGI-BP Severity of
Illness Scores from Baseline at Week 12
Assessment Data set AripiprazoleMean (SE) HaloperidolMean (SE)
YMRS Total LOCFOC 19.93 (0.98)28.98 (0.45) 18.22 (1.02) 27.44 (0.60)
CGI-BP Severity (Mania) LOCFOC 2.58 (0.13) 3.71 (0.08) 2.27 (0.13) 3.55 (0.10)
CGI-BP Severity (Depression) LOCFOC 0.20 (0.07) 0.02 (0.06) 0.27 (0.08) 0.16 (0.08)
CGI-BP Severity (Overall) LOCFOC 2.01 (0.12) 3.09 (0.09) 1.60 (0.12) 2.91 (0.11)
LOCF aripiprazole, n173 (YMRS, n174)
haloperidol, n164 (YMRS, n162). OC
aripiprazole, n89(YMRS, n90) haloperidol,
n50 plt0.05 vs. haloperidol
62
Mean Change in MADRS Total Scores from Baseline
at Weeks 3 and 12
Week 3
Week 12
0
0.5
1
1.5
Aripiprazole (n173)
2
Mean (SE) change from baseline
Haloperidol (n162)
2.5
3
3.5

4
p0.027 vs. haloperidol LOCF analysis MADRS,
MontgomeryÅsberg Depression Rating Scale
63
Incidence of Adverse Events (10 in Either
Treatment Arm)
Adverse event Aripiprazole ()n175 Haloperidol ()n169
Insomnia 13.7 7.1
Akathisia 11.4 23.1
Depression 11.4 14.2
Headache 10.9 11.8
Extrapyramidal syndrome 9.1 35.5
Tremor 6.9 10.1
64
Adverse Effects (AEs) Leading to Discontinuation
Adverse event leading to discontinuation Aripiprazole ()n175 Haloperidol ()n169
Akathisia 5.1 14.2
Depression 6.3 4.1
Extrapyramidal syndrome 2.9 18.9
Tremor 1.7 3.0
Anxiety 1.1 1.8
Dystonia 0.6 3.0
Hypertonia 0.6 3.0
Adverse events listed in the above table were the
most common effects leading to discontinuation as
demonstrated by the percentage of patients
65
Time to Discontinuation for All Reasons
66
Prior and Concomitant Therapy

• Medications prohibited between screening and end
  of study
• Neuroleptic agents
• Anticholinergic agents
• Carbamazepine
• Valproic acid, sodium valproate, divalproate
  sodium
• Lithium carbonate, lithium citrate
• Lamotrigine and gabapentin
• All other psychotic drugs (other than those
  prescribed by the study protocol)
• Antidepressants

67
Prior and Concomitant Therapy

• Benzodiazepines
• Lorazepam 4 mg/day days 1-4
• 2 mg/day days 5-10
• Oxazepam 60 mg/day day 1-4
• 30 mg/day day 5-10
• If neither lorazepam or oxazepam were available,
  IM diazepam was given for agitation,10 mg for 2
  mg lorazepam
• No medication was allowed after first 10 days of
  the study

68
Mean Change in EPS Rating Scale Scores from
Baseline at Week 12
7
6
5
Aripiprazole
Haloperidol
4
Mean (SE) change from baseline
3
2

1


0
SAS
Barnes-Akathisia
AIMS
n173 n160
n173 n160
n167 n154
p0.002, plt0.001 vs. haloperidol LOCF
analysis SAS, SimpsonAngus Scale AIMS,
Abnormal Involuntary Movement Scale
69
Conclusions

• Aripiprazole shows superior efficacy to
  haloperidol in the treatment of patients with
  acute mania for up to 12 weeks, as measured by
  the YMRS Total scale and continuation of therapy
• A greater proportion of aripiprazole-treated
  patients than haloperidol-treated patients were
  in remission at Week 12
• Aripiprazole was safe and better tolerated than
  haloperidol
• The incidence of AEs was lower in the
  aripiprazole group, and the proportion of
  patients with SAEs and who discontinued due to
  AEs was lower in the aripiprazole group than in
  the haloperidol group
• The rate of EPS-related AEs was higher in the
  haloperidol group than in the aripiprazole group,
  and this was directly related to the increased
  rates of EPS and akathisia that were evident in
  the haloperidol group

70
Study 008 Strengths

• Effectiveness as a primary endpoint
• Double-blind study
• Large, 12-week randomized study design
• Multicenter
• Active comparator

71
Study 008 Weaknesses

• Overall study completion rates could limit
  generalizability of results
• Protocol-specified lack of anticholinergic use
  and high dose range permitted for haloperidol can
  be criticized
• Low tolerability and large attrition rate of
  haloperidol

72
Back-ups
73
Concomitant Medication for Potential Treatment of
EPS



Class of drug

Haloperidol Aripiprazole

n169
n175 Any EPS medication
28 (17)
5 (3) Biperiden

20 (12) 3
(2) Trihexyphenidyl
4 (2)
2 (1) Pridonal

2 (1)
0 Tropatepine
2 (1)
0 Procyclidine

1 (1) 0
Number () of patients with any potential
treatment of EPS
74
Bipolar mania Aripiprazole vs. haloperidol
YMRS (OC)
0
5
10
Aripiprazole
15
(n174)
20
Change in YMRS (OC)
Haloperidol
25
(n162)
30
35
Treatment duration (weeks)
Baseline YMRS scores Aripiprazole 31.07,
Haloperidol 31.39
75
Study 008 Mean Change in CGI-BP Improvement
Scale (mania)
4
p0.85
p0.51
3
Aripiprazole n173
2
Haloperidol n164
Mean change in CGI-I (mania)
1
0
Week 3
Week 12
76
Study 008 MADRS Response Rate
p0.007
p0.001
n 168/159 169/160
Response defined as 50 decrease in MADRS total
score
77
Study 008 Mean Change in PANSS
p0.18
p0.24
Baseline scores - Aripiprazole 61.86 (n167)
haloperidol 61.77 (n150)
78
Study 008 Mean Change in PANSS subscales at Week
12 (LOCF)
0
2
Aripiprazole
Haloperidol
Mean change in PANSS subscale
4
p0.38
p0.31
6
PANSS cognition
PANSS hostility
n 167/150 167/150
Baseline values PANSS - cognition
aripiprazole17.4 haloperidol17.6 PANSS -
hostility aripiprazole12.3 haloperidol12.5
79
Incidence of EPS Spontaneously Reported Adverse
events
40
30
Aripiprazole
Haloperidol
20
Incidence ()
10
0
Extrapyramidal Syndrome
Akathisia
Patient sample Aripiprazole n175 Haloperidol
n169
80
Study 008 Change in Mean Weight
2
1
Aripiprazole
Haloperidol
Change in mean weight (kg)
0
Week 3
Week 8
Week 12
LOCF
n 131/93 106/69 89/50 169/149
1
Baseline weights aripiprazole74.6 kg,
haloperidol 72.3 kg
81
Study 008 Incidence of Clinically Significant
Weight Gain
40
30
Incidence of clinically significant weight gain
()
Aripiprazole
20
Haloperidol
10
0
Week 3
Week 6
Week 12
n 131/93 106/69
89/50
Observed case analysis
82
Title

• Bullet 1
• Sub-bullet
• Next level

83
BMS Colours Reference StyleDelete this slide
from final presentation
Clozapine RGB178/178/178
Aripiprazole RGB255/204/0
Haloperidol RGB0/255/255
Thioridazine RGB51/204/204
Placebo RGB255/255/255
Fluphenazine RGB234/234/234
Quetiapine RGB255/165/165
Molindone RGB204/153/0
Risperidone RGB0/255/0
Valproate RGB255/51/153
Olanzapine RGB255/0/0
Ziprasidone RGB205/153/255
Lithium RGB255/153/0
Chlorpromazine RGB102/255/102
Name. Journal datevolpppp
84
(No Transcript)
85
Maintenance of Efficacy in Bipolar I
DisorderClinical Trial Design
Open-label stabilization Aripiprazole 30
mg/day (option to reduce to 15 mg/day for
tolerability) Mean dose 25.3 mg
Double-blind randomization phase
Screening
BP I recent manic or mixed episode

• Stabilization criteria
• YMRS ?10
• MADRS ?13
• For at least 6 consecutive weeks

Stable patients randomized
Aripiprazole (n78) 15 or 30 mg/day or placebo
(n83) Mean dose 24.3 mg
Primary outcome Time to the number of combined
affective relapses (manic plus depressive)
BP IBipolar I Disorder MADRSMontgomery-Asberg
Depression Rating Scale YMRSYoung Mania Rating
Scale. Physicians who elect to use aripiprazole
for extended periods (that is, longer than 6
weeks) should periodically reevaluate the
long-term usefulness of the drug for the
individual patient. Adapted from a poster
presented by McQuade et al at the XXIVth CINP
Congress June 2004 Paris, France. Data on file
CN138-010.
Continued on next slide.
86
Maintenance of Efficacy in Bipolar I
DisorderClinical Trial Design (contd)

• Primary end point
• Time to relapse of symptoms (manic, mixed, or
  depressive)
• Secondary end points
• Mean change in YMRS and MADRS total scores
• Percent of relapses
• Predefined criteria for relapse (ie,
  discontinuation due to lack of efficacy)
• Hospitalization for manic, mixed, or depressive
  symptoms
• Addition to or increase in their allowed
  psychotropic medications

BP IBipolar I Disorder MADRSMontgomery-Asberg
Depression Rating Scale YMRSYoung Mania Rating
Scale. Adapted from a poster presented by
McQuade et al at the XXIVth CINP Congress June
2004 Paris, France. Data on file CN138-010.
87
Study 010
88
Study 010 A Multicenter, Randomized,
Double-Blind Study of Aripiprazole versus Placebo
in the Bipolar Disorder Relapse Prevention Trial
SLIDES FOR INTERNAL USE ONLY DO NOT CIRCULATE
EXTERNALLY Please consult country-specific
regulations regarding external discussions of the
data
Keck PE, Calabrese J, et al. A placebo-controlled
26-week trial of aripiprazole in recently manic
patients with bipolar I disorder. J Clin
Psychiatry 2006 Submitted
89
Study Overview

• A 26-week multicenter, double-blind,
  placebo-controlled study to assess the efficacy
  and safety of aripiprazole for preventing relapse
  of a mood episode in recently manic or mixed
  patients stabilized on aripiprazole
• Patients were stabilized for 618 weeks on 30
  mg/day but the dose could be decreased to 15
  mg/day
• Patients entering the randomized phase could
  increase or decrease the dose to either 15 mg/day
  or 30 mg/day depending on the investigators
  assessment of efficacy and tolerability

90
Study Design

• Comparison of aripiprazole (15 or 30 mg/day) with
  placebo
• Stabilization open-label phase for 618 weeks
  followed by a randomized double-blind
  continuation phase (up to 26 weeks)
• Criteria for study
• DSM-IV diagnosis of bipolar I disorder
• Aged 18 years or older
• Completion of 3-week placebo-controlled acute
  mania study of aripiprazole
• Manic or mixed episodes requiring hospitalization
  and treatment within the previous 3 months

91
Study Design

• Patients were excluded if they
• Had a history/symptoms of a cognitive disorder
• Had schizophrenia or psychotic symptoms best
  explained by another medical condition or
  attributed to substance abuse
• Patients considered unresponsive to clozapine
• Noncompliant with study medication or were in
  significant violation of the protocol during
  the stabilization phase
• DSM-IV criteria for any psychoactive or
  substance use disorder
• If they tested positive (urine) for cocaine

92
Aripiprazole Bipolar Relapse Prevention Trial
Study Design
Open-label stabilization Aripiprazole 30
mg/day (option to reduce to 15 mg/dayfor
tolerability) Mean dose 25.3 mg/day
Double-blind continuation phase
Screening
Bipolar I disorder (recent manic or
mixedepisode)
Stable patients randomized

• Stabilization criteria
• YMRS ?10
• MADRS ?13
• Visits every 2 weeksfor four consecutive visits
• Mean stabilization time12.7 weeks

Aripiprazole (n78) 15 or 30 mg/day Mean dose
24.3 mg/day OR Placebo (n83)
6 to 18 weeks
26 weeks

• This randomized, double-blind, parallel-group,
  placebo-controlled, multicenter study enrolled
  patients from 76 centers in 3 countries
  (Argentina, Mexico, United States)

Marcus et al. Presented at ACNP, 2003.
93
Aripiprazole Bipolar Relapse Prevention Trial
End Points

• Primary endpoint
• Time to relapse of symptoms (manic, mixed or
  depressive)
• Secondary endpoints
• Time to manic/depressive relapse
• Mean change in YMRS and MADRS
• Percent relapses
• Pre-defined criteria for relapse
• Hospitalization for manic, mixed or depressive
  symptoms
• Addition to or increase in psychotropic
  medications
• Discontinued due to lack of efficacy

Marcus et al. Presented at ACNP, 2003.
94
Patient Disposition
Number of Patients () Patient
Status Placebo Aripiprazole Entered
stabilization phase n/a 567 Completed
stabilization phase n/a 206 (37) Randomized to
double-blind treatment 83 78 Discontinued from
double-blind treatment 55 (66) 39 (50) Adverse
events 1 (1) 5 (6) Lack of efficacy 36 (43) 19
(24) Patient withdrew consent 6 (7) 6
(8) Other causes 12 (14) 9 (12) Completed
double-blind treatment phase 28 (34) 39 (50)
n/a, not available.Marcus et al. Presented at
ACNP, 2003.
95
Stabilization Phase
96
Improvement in Manic Symptoms During
Stabilization Phase
All patients received aripiprazole during this
phase of the study
15
10
Baseline
YMRS Score
Endpoint
5
0
Aripiprazole
n161 patients who would be randomized in
continuation phase
97
Double-Blind Continuation Phase
98
Baseline Demographics
Parameter

Placebo

Aripiprazole

Total

(n83)

(n78)

(n161)


Age
(year)

40.3

39.0

39.6

Gender
() (male/female)

28/72

38/62

33/67


Race
()



(white/hispanic/black)

67/20/6
62/26/6
65/23/6


Age when current


40.4
39.1
39.8
episode began (years)

Current episode




Rapid cycling
17/83

18/82
17/83



(yes/no)

Manic/mixed

78/22

62/38

70/30



99
Time from Randomization to Relapse
1.0
0.9
0.8
0.7
0.6
0.5
Proportion of patients without relapse
0.4
0.3
Aripiprazole
0.2
Log-rank p value 0.020
Placebo
0.1
Relative risk 0.523 (0.30, 0.91)
0.0
0
14
25
42
55
70
84
95
112
125
140
154
168
182
195
210
Days
Patients are 43 less likely to relapse on
aripiprazole than placebo
Marcus et al. Presented at ACNP, 2003.
100
Incidence of Relapses
Placebo (n83)
Aripiprazole (n77)
50
43
40

30
25
Relapse incidence
20
10
Relative risk 0.569 (0.359, 0.902). p0.013
Adapted from Marcus et al. ACNP, 2003.
101
Incidence and Relapse Type

p0.009 Adapted from Marcus et al. ACNP, 2003.
102
Mean Change in YMRS During Continuation
Treatment
10
8
6
Mean change in YMRS Total Score




4

2

0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Weeks
plt0.05 Baseline YMRS Scores aripiprazole 2.55
(n76) placebo 2.06 (n82).
Marcus et al. Presented at ACNP, 2003.
103
Mean Change in MADRS During Continuation
Treatment
10
8
6
Mean change in MADRS Score
4
2
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Weeks
pnot significant Baseline MADRS Scores
aripiprazole3.87 (n76) placebo 4.52(n82)
Marcus et al. Presented at ACNP, 2003.
104
Incidence of Spontaneously Reported AEs ?10
Anxiety
Placebo (n83)
Aripiprazole (n77)
Insomnia
Depression
Nervousness
Headache
Agitation
Reaction manic
0
10
20
30
40
50
Incidence ()
Marcus et al. Presented at ACNP, 2003.
105
Discontinuations from the Maintenance Phase Due
to AEs
25
20
15
of patients
10
6
5
1
0
Data on file, Otsuka America Pharmaceutical, Inc.
Marcus et al. Presented at ACNP, 2003.
106
Mean Change From Baseline in SimpsonAngus and
Barnes Akathisia Scores
1
Placebo (n81)
Aripiprazole (n77)
0.19
0
Mean change from baseline
0.05
0.14
0.14
Barnes Akathisia Scale
SimpsonAngus Scale
1
pnot significant
Marcus et al. Presented at ACNP, 2003.
107
Incidence of EPS and Akathisia as Spontaneously
Reported AEs
50
Placebo (n83)
Aripiprazole (n77)
40
30
Incidence ()
20
6.5
10
1.2
1.2
0
0
Extrapyramidal syndrome
Akathisia
Marcus et al. Presented at ACNP, 2003.
Data on file, Otsuka America Pharmaceutical, Inc.
108
Mean Change in Prolactin
15
Placebo (n59)
10
Aripiprazole (n60)
4.2
5
Mean change from
baseline (ng/mL)
0
0.4

-5
Placebo
Aripiprazole
plt0.05 Mean baseline prolactin placebo 10.4
ng/mL aripiprazole 11.4 ng/mL No significant
difference in clinically significant prolactin
elevations (greater than upper limits of normal)
between groups Marcus et al. Presented at ACNP,
2003. Data on file, Otsuka America
Pharmaceutical, Inc.
109
Incidence of Somnolence as a Spontaneously
Reported AE
50
40
30
Incidence ()
20
10
7.2
5.2
0
Placebo
Aripiprazole
Marcus et al. Presented at ACNP, 2003.
110
Effect on QTc Interval

• No aripiprazole-treated patient experienced
  potentially clinically significant QTc
  prolongation

Clinically significant QTc prolongation defined
as QTc ?450 msec and ?10 increase from baseline
Marcus et al. Presented at ACNP, 2003.
111
Mean Change in Weight
1
LOCF
OC
0
Mean change from baseline (kg)
1
2
pnot significant LOCF analysis. Mean baseline
weight placebo, 85.3 kg aripiprazole, 86.1 kg
Marcus et al. Presented at ACNP, 2003 Data on
file, Otsuka America Pharmaceutical, Inc.
112
Incidence of Significant Weight Change
20

15
Placebo (n60)
10
Aripiprazole (n56)
Incidence ()
5

0
Weight gain
Weight loss
LOCF p0.005 p0.006 Clinically significant
weight change 7 change from baseline
113
Conclusions

• Aripiprazole was statistically superior to
  placebo in maintaining stability in patients with
  bipolar I disorder
• Prolonged time to relapse into manic, mixed or
  depressive symptoms
• Significantly fewer manic relapses
• More likely to complete the trial than
  placebo-treated patients

114
Study Strengths

• Stabilization (open-label) phase (6-18 weeks)
• 26-week, randomized placebo-controlled phase
• Large, long-term study
• Relapse defined clinically (based on either drug
  discontinuation or addition of, or change in,
  dose of other medications) rather than by DSM-IV
  criteria

115
Study Weaknesses

• High discontinuation rates prior to the
  randomized phase could limit generalizability of
  results
• Only patients who responded to aripiprazole in
  the acute phase were enrolled in the longer-term
  follow-up period
• Patients entering the randomized phase may not
  have had the same exposure time to aripiprazole
• Significant weight gain (7 increase from
  randomization) was seen in 13 of aripiprazole
  patients

116
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117
Efficacy in sub-populations of bipolar disorder

• Pooled analysis

118
Stratification by Baseline Y-MRS

• Aripiprazole demonstrated significantly greater
  improvement in acute manic symptoms, as measured
  by Y-MRS total score, in patients presenting with
  more severe manic symptoms (median Y-MRS gt28)

APA NY, may 2004. Poster, Jody et al.
119
Patients presenting with Manic Episodes
APA NY, may 2004. Poster, Jody et al.
120
Patients Presenting with Mixed Episodes
APA NY, may 2004. Poster, Jody et al.
121
Stratified by Presence of Rapid Cycling
APA NY, may 2004. Poster, Jody et al.
122
Stratified by Presence of Psychotic Symptoms

• Significantly improvement with Aripiprazole was
  seen in patients presenting with or without
  psychotic symptoms, with a greater magnitude of
  improvement with aripiprazole in the presence of
  psychotic symptoms

APA NY, may 2004. Poster, Jody et al.
123
Pooled Analysis of the TwoPositive
Placebo-Controlled Trials of Aripiprazole in
Acute Mania in Bipolar I Disorder
124
Acute Mania Efficacy in Bipolar I Disorder
Change in YMRS Total Score in Manic and Mixed
Episodes
Manic
Mixed
Mean Change From Baseline
plt0.001, p0.002


158
167
96
92
n
Pooled post hoc analysis of two positive
placebo-controlled acute mania in Bipolar I
Disorder trials.YMRSYoung Mania Rating Scale
(range 0-60). Adapted from a poster presented by
Jody et al at the American Psychiatric
Association May 2004 New York, NY.Data on file.
125
Acute Mania Efficacy in Bipolar I Disorder
Change in YMRS Total Score in Rapid
and Non-Rapid Cyclers
Non-rapid Cycling
Rapid Cycling
Mean Change From Baseline
plt0.001, p0.003


203
207
51
52
n
Pooled post hoc analysis of two positive
placebo-controlled acute mania in Bipolar I
Disorder trials.YMRSYoung Mania Rating Scale
(range 0-60). Modified from a poster presented
by Jody et al at the American Psychiatric
Association May 2004 New York, NY.Data on file.
126
Acute Mania Efficacy in Bipolar I Disorder
Change in YMRS Total Score Stratified
by Presence of Psychotic Symptoms
Without Psychotic Symptom
With Psychotic Symptom
Mean Change From Baseline
plt0.001, p0.007


200
215
54
44
n
Pooled post hoc analysis of two positive
placebo-controlled acute mania in Bipolar I
Disorder trials.YMRSYoung Mania Rating Scale
(range 0-60). Modified from a poster presented
by Jody et al at the American Psychiatric
Association May 2004 New York, NY.Data on file.
127
Acute Mania Efficacy in Bipolar I Disorder
Summary

• Aripiprazole vs placebo
• Significant improvement for the following end
  points
• YMRS Total Score (primary efficacy end point)
• CGI-BP Severity of Illness Score (Mania)
• Response rates
• PANSS Hostility Subscale Score
• Efficacy trials included patients
• With manic and mixed episodes
• With or without a rapid cycling course
• With or without psychotic features

CGI-BPClinical Global Impressionbipolar
version PANSSPositive and Negative Symptoms
Scale YMRSYoung Mania Rating Scale.
128
Kinetics and Drug Interactions
129
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130
Aripiprazole Pharmacokinetics Dosing Adjustment
Recommendation

• No routine blood monitoring for drug level
  required
• No dosage adjustment required for smokers
• No important interactions with lithium,
  valproate, warfarin, famotidine, omeprazole or
  dextromethorphan
• Low potential to affect plasma levels of other
  drugs metabolized by the CYP450 enzyme system
• Dosage adjustment of aripiprazole is recommended
  with potential inducers of CYP3A4, such as
  carbamazepine and potential inhibitors of CYP3A4,
  such as ketoconazole, or CYP2D6, such as
  quinidine, fluoxetine and paroxetine
• Upon initiation with aripiprazole
• More gradual discontinuation of the previous
  antipsychotic treatment may be the most
  appropriate per clinical judgment.

ABILIFY (aripiprazole) Package Insert, April 2005.
131
Aripiprazole Pharmacokinetics Dosing With
Valproate and Lithium

• When valproate and ABILIFY were coadministered at
  steady state, the Cmax and AUC of ABILIFY were
  decreased by 25
• No dosage adjustment of ABILIFY is required when
  administered concomitantly with valproate
• A pharmacokinetic interaction of ABILIFY with
  lithium is unlikely because lithium is not bound
  to plasma proteins, is not metabolized, and is
  almost entirely excreted unchanged in urine
• Coadministration of therapeutic doses of lithium
  for 21 days with ABILIFY did not result in
  clinically significant changes in the
  pharmacokinetics of ABILIFY or its active
  metabolite, dehydro-aripiprazole (Cmax and AUC
  increased by less than 20)
• No dosage adjustment of ABILIFY is required when
  administered concomitantly with lithium

ABILIFY (aripiprazole) Package Insert, April 2005.