10-slides pp presentation on scientific paper: Clinical trial on schizophrenia drug.

1. Efficacy and Tolerability of Asenapine in
Acute Schizophrenia: A placebo and
Risperidone-Controlled Trial
Potkin, S., Cohen, M. Panagides, J.
Dep. Psychiatry and Human Behavior, University of California, Irvine. Brain Imaging Center, Irvine

2. Summary
OBJECTIVE: To asses the efficacy, tolerability and safety of the investigational
psychopharmacologic agent asenapine versus placebo in patients with acute
schizophrenia
RATIONALE: There is not current adequate pharmacologic control for the full
range of symptoms in schizophrenia.
RESULTS: Asenapine treatment produced statistically significant greater
improvement scores in positive and negative schizophrenic symptoms compared
with placebo. Furthermore, it was well tolerated and was not associated with
weight gain or prolactin elevation.

3. Introduction
Asenapine is a novel atypical psychopharmacologic agent in clinical development for
treatment for schizophrenia and bipolar disorder.
Effectiveness of antipsychotic agents is measured against controlling positive
symptoms and prevention or delay in relapse. All psychopharmacologic agent
ameliorate positive symptoms to varying degree but not completely.
 There is not adequate or consistent control of negative symptoms
Asenapine modulates activity at dopamine D2 receptors to control positive
symptoms of schizophrenia. Asenapine shows almost not affinity for muscarinic
receptors and have minimal risks of anticholinergic side effects.
Atypical antipsychotics adverse effects include weight gain, diabetes, dyslipidemia,
sexual dysfunction, sedation, and others.
The unusual pharmacologic characteristics of asenapine may contribute to a
favorable clinical profile in controlling schizophrenia with a high degree of safety and
tolerability

4. Methods
TRIAL DESIGN: Treatment randomly assigned. Double blind, double-dummy, 3-arm, fixed
dose, 6-week, placebo and risperidone-controlled. Institution’s ethics committee or
review board-approved
PATIENT ELIGIBILITY: ≥ 18 years old. Schizophrenia diagnosis within the disorganized,
paranoid, catatonic or undifferentiated subtypes
PRIMARY OUTCOME: Improvement from Baseline in Positive and Negative Syndrome
Scale (PANSS)
 SECONDARY OUTCOME: Changes in Clinical Global Impressions-Severity of Illness (CGI-S)
TREATMENTS: Sublingual asenapine titrated from 1 mg b.i.d. day 1, increasing 1 mg b.i.d
to reach 5 mg b.i.d at day 5 (plus oral placebo). Continued at 5 mg b.i.d.
Oral risperidone titrated from 1mg b.i.d day 1, increasing 1 mg b.i.d to reach 3 mg b.i.d
at day 3 (plus sublingual placebo). Continued at 3 mg b.i.d.
Placebo group received oral and sublingual placebo b.i.d.

5. Results
Table 1. Demographics and Baseline Clinical Characteristics
Characteristics Asenapine Placebo Risperidone
Intent-to-treat N 58 60 56
Men, treated N (%) 46 (7) 49 (79) 36 (61)
Mean age years (range) 38 (21-70) 42 (22-68) 43 (22-61)
Ethnicity white N (%) 25 (42) 20 (32) 25 (42)
black N (%) 28 (47) 32 (52) 26 (44)
Paranoid diagnosis N (%) 50 (85) 60 (97) 50 (85)
Present episode < 1month N (%) 34 (58) 39 (63) 44 (75)
Present episode 1-6 months N (%) 21 (36) 16 (26) 11 (19)
Episodic with prominent
negative symptoms N (%) 23 (39) 20 (32) 22 (37)
Continuous episodic with
Prominent negative symptoms N (%) 11 (19) 9 (15) 10 (17)
Absent, other pattern, other 25 (42) 33 (53) 27 (46)
Treated population N=180

6. Results
Figure 1. Patient dispositiona
Randomly assigned (N=182)
Asenapine 5 mg bid N=60 Risperidone 3 mg bid N=60 Placebo bid N=62
DC before treatment N=1 DC before treatment N=1
N=60 Treated N=59 Treated N=62 Treated
DC N=32 DC N=34 DC N=41
Lack of efficiency N=9 Lack of efficiency N=16 Lack of efficiency N=18
Adverse effects N=6 Adverse effects N=4 Adverse effects N=7
N=27 (46%) Other N=17 N=25 (42%) Other N=14 N=21 (34%) Other N=16
Completed Trial Completed Trial Completed Trial
aNumber of patients randomly assigned, treated and with completed treatment, with reasons for discontinuation (DC)
Figure 2. Primary measure of efficacy in the intent-to-treat population: change from baseline in PANSS
total score a Week
✻p <.05 asenapine vs placebo
LSM Change From Baseline
⁑p ≤ .005 asenapine vs placebo
ℇ p = 0.001 asenapine vs placebo
✻
ℇ a The
ℇ ⁑
⁑ change from baseline in the total score
on PANSS was determined at study end (6
weeks) or end of treatment with last observed
Asenapine Risperidone Placebo
data carried forward, using last square mean
Baseline value 96.48 Baseline value 92.18 Baseline value 92.43 (LSM) and 2-factor analysis of variance

7. Results
Figure 3. Secondary measure of efficacy in the intent-to-treat population a
A. Changes from baseline CGI-S scores B. Changes from baseline PANSS positive symptom scores
Week Week
✻p < .05 asenapine vs placebo
LSM Change From Baseline
LSM Change From Baseline
✝p ≤ .01 asenapine vs placebo
⁑p ≤ 0.005 asenapine vs placebo
‖p < 0.05 asenapine vs placebo
¶ p < 0.01 asenapine vs placebo
‖ # p < 0.005 asenapine vs placebo
‖
‖
‖
¶ ‖
#
‖
⁑ ⁑
✝ ✝ ⁑ ✝
✻
Asenapine Risperidone Placebo Asenapine Risperidone Placebo
Baseline value 4.67 Baseline value 4.59 Baseline value 4.59 Baseline value 25.21 Baseline value 24.70 Baseline value 24.12
C. Changes from baseline PANSS negative symptom scores D. Changes from baseline PANSS general psychopathology scores
Week Week
a The changes from baseline
LSM Change From Baseline
LSM Change From Baseline
in scores on A, B, C, and D
were determined at study
end or end of treatment,
using last square mean
✻ (LSM) and 2-factor analysis
of variance
✝ ✝
✻
✻ ⁑ ⁑
⁑ ✝
Asenapine Risperidone Placebo Asenapine Risperidone Placebo
Baseline value 24.07 Baseline value 21.86 Baseline value 23.10 Baseline value 47.21 Baseline value 45.63 Baseline value 45.22

8. Results
Table 2. Incidence of adverse events in ≥ 10% Table 3. Changec from baseline to end point
of patients in any treatment group in mean scores on extrapyramidal symptom
WHOa preferred Patients N (%)b rating instruments
term Asenapine Placebo Risperidone Asenapine Placebo Risperidone
Insomnia 11(19) 8 (13) 13(22)
(N=56-57) (N=59-60) (N=56)
Somnolence 11(19) 8 (13) 9 (15)
Nausea 11 (19) 8 (13) 7 (12) RATING SCALE BL Change BL Change BL Change
Anxiety 10 (17) 9 (15) 9 (15) BAS 1.00 -0.21 0.53 0.25 0.68 0.14
Agitation 9 (15) 15 (24) 11 (19) SAS 1.11 -0.32 0.64 -0.24 0.75 0.05
Headache 8 (14) 17 (27) 13 (22) AIMS 1.05 0.04 0.93 0.46 1.36 -0.02
Vomiting 8 (14) 7 (11) 3 (5)
Constipation 6 (10) 6 (10) 4 (7)
C Negativechange indicates improvement
Psychosis 6 (10) 4 (6) 4 (7)
Abbreviations: BL= Baseline. BAS=Barnes Akathisia Scale.
Dizziness 5 (8) 9 (15) 4 (7)
SAS=Simpson-Angus Scale. AIMS=Abnormal involuntary
Dyspepsia 4 (7) 5 (8) 7 (12)
Movement Scale
Upper respiratory
Tract infection 4 (7) 3 (5) 6 (10)
Pain 3 (5) 4 (6) 6 (10)
Fatigue 2 (3) 4 (6) 6 (10)
Hypertonia 0 (0) 2 (3) 7 (12)
a World Health organization
b Adverse effects not mutually exclusive between groups

9. Results
Figure 4. Treatment effects on body weighta Figure 5. Treatment effects on serum prolactina
(≥ 7% ) weight gain (% of patients)
Incidence of clinically significant
Mean change from baseline (μg/L)
A
Asenapine Risperidone Placebo
(5 mg bid) (N=46) (3 mg bid) (N=47) (bid) (N=54) Week
Asenapine Risperidone Placebo
aProlactine levels assessed at weekly intervals
B
Mean weight gain (Kg)
to study end (6 weeks) or end of treatment
(last observation carried forward)
Asenapine Risperidone Placebo
a Effectson body weight were assessed at study end or
at end of treatment in terms of (A) incidence of clinical
significant weight gain (≥ 7% increase from baseline) and
(B) actual mean weight gain

10. Conclusions
1. Asenapine 5 mg b.i.d. was superior to placebo in treating the positive
and negative symptoms of schizophrenia.
2. Ripseridone 3 mg b.i.d. was only superior to placebo in positive
symptoms score, not in negative symptoms.
3. Incidence of clinically significant weight gain was similar for asenapine
and placebo. Asenapine and placebo had similar effects on
prolactinelevation. Risperidone had a higher incidence of weight gain and
on levels of prolactincompared to placebo.
4. Asenapine 5 mg b.i.d. was effective and well tolerated in the treatment
of acute schizophrenia and may be a useful option in patients with
negative symptoms.