Lurasidone in the Treatment of Schizophrenia:
`A Randomized, Double-Blind, Placebo- and Olanzapine-
`Controlled Study
`
`Herbert Y. Meltzer, M.D.
`
`Josephine (ucchiaro, Ph.D.
`
`Robert Silva, Ph.D.
`
`Masaaki Ogasa, M.S.
`
`Debra Phillips
`
`Jane Xu, PhD.
`
`Amir H. Kalali, M.D.
`
`Edward Schweizer, M.D.
`
`Andrei Pikalov, M.D., Ph.D.
`
`Antony Loebel, M.D.
`
`Objectlve: The study was designed to
`evaluate the short-term efficacy and safe
`ty of lurasidonc in the treatment of acute
`schizophrenia.
`
`Method: Participants. who were recently
`admitted inpatients with schizophrenia
`with an acute exacerbation of psychotic
`symptoms. were randomly assigned to 6
`weeks of double~blind treatment with 40
`mg of lurasidone. 120 mg of lurasidone.
`15 mg of olanzapine (included to test
`for assay sensitivity), or placebo. dosed
`once daily. Efficacy was evaluated using a
`mixed-model repeated-measures analysis
`of the change from baseline to week 6
`in Positive and Negative Syndrome Scale
`(PANSS) total score (as the primary efficacy
`measure) and Clinical Global lmpressrons
`severity (CGl-S) score (as the key secondary
`efficacy measure).
`Results: Treatment with both doses of
`lurasidone or with olanzapine was asso-
`ciated with significantly greater improve-
`ment at week (3 on PANSS total score.
`
`PANSS positive and negative subscale
`scores. and CGl-S score compared with
`placebo. There was no statistically sig-
`nificant difference in mean PANSS total
`or CGI-S change scores for the Iurasidone
`groups compared with the olanzapine
`group. With responders defined as those
`with an improvement of at
`least 20%
`on the PANSS. endpoint responder rates
`were significant compared with
`pla-
`cebo for olanzapine only. The incidence
`of akathisia was higher with 120 mg of
`lurasidone (22.9%) than with 40 mg of
`lurasidone (11.8%), oianzapine (7.4%),
`or placebo (0.9%). The proportion of pa-
`tients experiencing 27% weight gain was
`5.9% for the lurasidone groups combined.
`34.4% for the olanzapine group, and 7.0%
`for the placebo group.
`Condusions: Lurasidone was an effec-
`tive treatment for patients with acute
`schizophrenia. Safety assessments
`in-
`dicated a higher frequency of adverse
`events associated with 120 mg/day of lur-
`asidone compared with 40 mg/day.
`
`(Am 1 Psychiatry 201 1; 16835 7—967)
`
`AJypical antipsychotic drugsgenerallysharemorepo-
`
`tcnt antagonism for 5+le than dOpaminc D2 receptors
`(1. 2). However. there are significant differences among
`these agents in their relative affinities for 5-HT“, S-ll'l‘x,
`S-l-lTT, alpha-adrenergic, histamine H], muscarinic, and
`other receptors that may affect their efficacy and tolera-
`bility (2). Genetic polymorphisms in receptor proteins, as
`well as in cytochrome P450 isocnzymcs. contribute addi-
`tional between-drug variability in clinical effect (3). Thus.
`atypical antipsychotics do not produce unifonn clinical
`responses in all patients, and it remains important to have
`multiple antipsychotic drug treatment choices to address
`unmet therapeutic needs in patients with schizophrenia
`and other psychotic disorders (4. 5).
`Lurasidone is a novel psychotropic agent that has been
`shown in studies of cloned human receptors to be an an-
`tagonist at the 5-HT2A receptor, with a binding affinity (Ki;
`the dissociation constant of the inhibitor) of 0.47, and a Ki
`of 0.99 at the D2 receptor. It also has a very high affinity for
`the 5-HT7 receptor (Ki, 0.49). which is nearly identical to
`its affinity for the 5-HT“ receptor. In addition, lurasidonc
`This article provides Clinical Guidance (p. 967)
`
`has moderate partial agonist effects at the 5-HT“ receptor
`(Ki, 6.4) and moderately potent antagonist effects at a“ rc~
`ceptor subtypes (Ki, 10.8) (6).
`In a double-blind, placebo-controlled phase 2 clinical
`trial (7), lurasidone demonstrated efficacy in schizophre-
`nia at a fixed daily dose of 80 mg.
`The primary objective of this phase 3 study was to
`evaluate the efficacy of two dosages of lurasidonc (40 and
`120 rug/day) compared with placebo in the treatment of
`patients suffering from an acute exacerbation of chronic
`schizophrenia. The key secondary objective was to evalu-
`ate the cfficacy of lurasidone compared with placebo in
`improving the Clinical Global Impressions severity (CGl-
`S) score. Another major secondary objective was to eval-
`uate the safety and tolerability of the 40 mg and 120 mg
`doses of lurasidone during 6 weeks of treatment.
`
`Method
`
`This was a prospective. multiccnter. parallel-group study in
`which recently admitted acutely ill inpatients with schizophrev
`nla with an acute exacerbation of psyehullc symptoms were
`
`Am 1 Psychiatry 1689, September 207 I
`
`ajp.ps‘ychialryonlineorg
`
`957
`
`1
`
`Exhibit 2061
`Slayback v. Sumitomo
`|PR2020—01053
`
`Exhibit 2061
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`LURASIDONE IN THE TREATMENT OF SCHIZOPHRENIA
`
`randomly assigned to receive 6 weeks of double-blind treatment
`with once—daily doses of 40 mg or 120 mg of lurasidone. 15 mg
`of olanzapine [included to establish assay sensitivity), or pla-
`cebo. The study was conducted between lanuary 31. 2008. and
`June is. 2(X)9. enrolling a total of 478 patients at 25 sites in the
`United States (N=286). five in Colombia (N :48). four in Lithuania
`(N=29). and 18 in Asia (lndia. 14 sites IN=89lz Philippines. four
`sites |.\'=25|).
`All patients who entered the trial reviewed and signed an in-
`formed consent document explaining study procedures and po—
`tential risks before study entry. the study protocol and all related
`forms and amendments were approved by an independent eth-
`ics committee associated with each study center. The study was
`conducted in accordance with the international Conference on
`liarmonivatlon Good Clinical Practices guidelines and with the
`ethical principles of the Declaration of i lelsinki. An independent
`data and safety monitoring board reviewed unblinded safety and
`clinical outcome data.
`
`Entry Criteria
`Hospitalized male and female patients 18—75 years of age who
`met DSM-iV criteria for a primary diagnosis of schizophrenia as
`determined by the Mini international Neuropsychiatric interview
`(8) were enrolled. Patients were also required to have an illness
`duration of at least 1 year and to have been hospitalized for S2
`weeks for an acute exacerbation of psychotic symptoms and. at
`the screening and baseline visits. to have a CGl-S score 24 (mod-
`erate or greater) and a Positive and Negative Syndrome Scale
`(PANSS) total score 280. including a score 24 (moderate) on two
`or more of the following PANSS items: delusions. conceptual dis-
`organization. hallucinations. unusual thought content. and ms
`plclousness.
`
`Study Medication
`All study medication was identically overencapsulated to
`preserve the double-blind. A unique participant number was
`assigned by interactive voice response system when a patient
`entered the screening phase. At baseline (day 0). patients who
`continued to meet all study inclusion criteria were randomly as-
`signed via interactive voice response system (in a 1:1 :1:1 ratio) to
`one of four treatment arms: Iurasidone. 40 mg: lurasidone. 120
`mg: olanzapine. 15 mg; or placebo. Study medication was admin-
`istered in the morning with a meal or within 30 minutes after eat-
`ing. Participants assigned to receive lurasidone started treatment
`at their target dose: patients assigned to olanzapinc treatment
`received 10 mg on days 1-7 and 15 mg thereafter. The olanzapine
`dosage of 15 mg/day was selected because it is widely used and
`because there is substantial evidence that it is an effective dosage
`in patients with schizophrenia. with little evidence that higher
`dosages offer additional efficacy advantages (9. 10). This dosage is
`also consistent with the olanzapinc package insert (http://piJilly.
`com/uslzyprexa-pl.pdf) . which states that efficacy in schizophre-
`nia has been demonstrated in a dosage range of 10-15 mg/ day.
`with higher doses not demonstrated to be more efficacious.
`Limited use of benzodiazepines was permitted for severe anxi-
`ety. agitation. or insomnia. Participants were eligible for hospital
`discharge to a stable residence after 21 days of treatment if they
`had a C(il-S score 3").
`
`Assessments
`
`The screening evaluation consisted of the Mini international
`Neuropsychiatric interview. medical and psychiatric histories. a
`physical examination. measurement of vital signs. ECG. and labo~
`ratory tests
`Efficacy was assessed using the PANSS total and subscale scores
`(including a post hoc analysis of a modified version of the cogni-
`tive subscale. consisting of items P2. N". N7. GIO. Gil) (ll. 12).
`
`the CGl-S. and the Montgomery-Asberg Depression Rating Scale
`(MADRS: 13). PANSS and CGi-S evaluations were performed at
`the screening and baseline visits and. during treaunent. on day 4
`and at each of weeks 1 through 6. The MADRS was administered
`at the screening and baseline visits and at weeks 3 and 6.
`Extrapyramidal symptoms were assessed with the Simpson-
`Angus Rating Scale (14). the Barnes Rating Scale for Drug-in-
`duced Akathisia (15). and the Abnormal involuntary Movement
`Scale (16). Safety evaluations included vital signs. weight. labo-
`ratory tests (including fasting lipids. glucose. glycosylated hemo-
`globin leAtJ' and insulin). I2»lead ECG. and reported adverse
`events. insulin resistance and beta-cell function were measured
`using the homeostasis model assessment for insulin resistance
`(HOMA-lii) method (17).
`
`Statistical Methods
`
`A power calculation was performed that incorporated Bonfer-
`roni‘s procedure for controlling pairwise differences with pla-
`cebo and was obtained via computer simulations. Assuming that
`lurasidone differed from placebo in the change from baseline
`in PANSS total score by 6.8 and 10.0 for the 40 and 120 mg/day
`dosages. respectively. and further assuming a standard deviation
`of 19.1. we calculated that 120 patients per group would provide
`97% power (at an alpha level of0.05. two-sided test) to reject the
`null hypothesis oi'no difference between placebo and at least one
`of the lurasidone dosage groups.
`The primary efficacy analysis was performed on the intent-
`to-trcat sample. which consisted of all participants assigned to a
`treatment group who received at least one dose of study medica-
`tion. had a baseline PANSS assessment. and had at least one post-
`baseline PANSS assessment during the 6—week study. The primary
`efficacy measure was the change from baseline in PANSS total
`score at week 6. and the key secondary efficacy measure was the
`change from baseline in (161 -8 score at week 6. Both measures were
`evaluated by a mixed-model repeated-measures analysis with an
`unstructured covariance matrix. The model included factors for
`pooled center. time (including all scheduled postbaseiine assess-
`ment visits as a categorical variable). baseline PANSS total score or
`CGi-S score. treatment. and treatn‘tent-by-tin'te interaction. The p
`values for the comparison of each lurasidone group with the pla-
`ceho group at week 6 on change from baseline in PANSS total score
`and CGi»S score were adjusted for multiple comparisons using the
`Hommel-based tree-gatekeeplng procedure to control the family-
`wise type i error rate (18). The olanzapine treatment group. which
`was included to confirm the assay sensitivity of the study. was
`compared with placebo using the same mixed-model repeated-
`measures model. without the multiple comparison adjustment. A
`post hoc mixed-model repeated-measures analysis of the PANSS
`total score and CGi-S score was also performed comparing the
`40 mg and 120 mg lurasidone treatment groups to the olanzapine
`treatment group.
`A prespeclfied secondary analysis was conducted for change
`in PANSS total score and CGi-S score. using an analysis of covari-
`ance (AN COVA) model.
`Secondary efficacy measures. including PANSS subscale scores
`(positive. negative. and general psychopathology) and MADRS
`total score. were evaluated using similar mixed-model repeated-
`measures models A post hoc analysis of the modified PANSS
`cognitive subscale was also performed. Participants who had an
`improvement of at least 20% from baseline in PANSS total score
`at week 6 endpoint (last observation carried forward) were de-
`fined as “responders.” A logistic regression was performed using
`the responder outcome as the dependent variable. treatment as a
`categorical factor. and baseline PANSS total score as a covariate.
`The Cohen’s d effect size was calculated for week 6 efficacy
`measures as the between-treatment difference score divided by
`the pooled standard deviation. For adverse events. number need-
`
`958
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`Am 1 Psychiatry 1689, September 2011
`
`

`

`MELTZER, CUCCHIARO. SILVA. ET AL.
`
`TABLE 1. Baseline Characteristics of Patients With Schizophrenia in a 6-Week Randomized, Double-Blind. Placebo- and
`Olanzapine-Controlled Study of Lurasldone
`
`Characteristic“
`
`Male
`Race
`White
`Black
`Asran
`Other
`Hispanic/Latino ethnicity
`24 previous hospitalizations
`
`Age (years)
`Age at onset oi illness (years)
`Duration 0! illness (years)
`Duration of current episode (days)
`PANSS total score
`CGI severity score
`MADRS total score
`
`Treatment Group
`
`Lurasidone, 40 mg
`(N419)
`
`Lurasidone. 120 mg
`(N’118)
`
`Olanzapine,15 mg
`(N’122)
`
`N
`93
`
`44
`39
`31
`5
`23
`51
`Mean
`37.7
`23.9
`13.3
`33.9
`96.6
`5 0
`10.8
`
`34:
`78
`
`37
`33
`26
`4
`19
`43
`SD
`11.0
`8.3
`9.9
`15.3
`10.7
`0.7
`7.0
`
`N
`93
`
`48
`36
`27
`7
`19
`64
`Mean
`37.9
`22.7
`14.7
`33.0
`97.9
`5.0
`11.4
`
`96
`79
`
`41
`31
`23
`6
`16
`54
`SD
`11.2
`8.8
`11.0
`12.9
`11.3
`0.6
`7.2
`
`N
`95
`
`41
`44
`30
`7
`17
`58
`Mean
`38.3
`24.7
`13.2
`33.5
`96.3
`4 9
`10.8
`
`96
`78
`
`34
`36
`25
`6
`14
`48
`SD
`10.2
`7.8
`10.9
`14.5
`12.2
`0.7
`6.2
`
`Placebo (N’114)
`N
`96
`88
`77
`
`36
`41
`27
`10
`16
`53
`Mean
`37.0
`23.9
`12.6
`35.6
`95.8
`4.9
`10.6
`
`32
`36
`24
`9
`14
`46
`SD
`11.3
`8.0
`9.6
`16.8
`10.8
`0.7
`6.1
`
`' PANSSAPositive and Negative Syndrome Scale; CGLCIinical Global Impressions scale; MADRsiMontgomery-Asberg Depression Rating Scale.
`
`ed to harm was calculated as 1 divided by the difference in the risk
`of an adverse event for active drug compared with placebo.
`Significance testing of selected safety parameters was per-
`formed based on a nonparametric rank ANCOVA with baseline
`value as a covariatc. not adjusted for multiple comparisons.
`
`Results
`
`Of a total of 78] patients who were screened and en-
`tered the washout period, 478 were randomly assigned to
`6 weeks of double-blind treaunent (Figure 1). Baseline de-
`mographic and clinical characteristics were comparable
`among the four treatment groups (Table l). The propor-
`tion of patients in thc lurasidone 40 mg group who com-
`pleted the study treatment (64.2%) was similar to the pro~
`portions who completed treatment in the placebo group
`(61.2%) and the olanzapine group (68.3%): a somewhat
`lower proportion of patients in the lurasidone 120 mg
`gmup completed the study treatment (55.5%) (Figure 1).
`
`Efficacy
`
`Based on the m bred-model repeated-measures analysis,
`the change from baseline to week 6 in PANSS total score
`was significantly greater for the lurasidone 40 mg (—25.7;
`adjusted p=0.002] and 120 mg (—23.6; adjusted p=0.022)
`groups compared with the placebo group (—16.0) (Table
`2). The change in PANSS total score was also significantly
`greater for the olanzapine group (-28.7, p<0.001), thus
`confirming the assay sensitivity of the study. Statistically
`significant separation from placebo on the PANSS total
`score was observed from week 1 onward for the lurasidone
`
`40 mg and olanzapinc groups. and from week 3 onward
`for the lurasidone 120 mg gmup (Figure 2; see also Table
`S1 in the online data supplement). Treatment with both
`
`dosages of lurasidone and with olanzapine was also as-
`sociated with significantly greater improvement at week
`6 compared with placebo on the PAN SS positive. negative,
`and general psychopathology subscale scores (Table 2; see
`also Table 51 in the online data supplement). Based on a
`post hoc analysis, treatment with both dosages of lurasi-
`done, as well as with olanzapine, was also associated with
`significantly greater improvement at week 6 on the modi-
`fied PANSS cognitive subscale score (see Table 2).
`For the CGl-S score. the change from baseline to week
`6 was also significantly greater for the lurasidone 40
`mg (—1.5; adjusted p:0.01]) and 120 mg (—1.4; adjusted
`p=0.040) groups compared with the placebo group (—1.1:
`see Table 2). The change in CGI-S score was also signifi—
`cantly greater for the olanzapine group (—1.5; p<0.001).
`Statistically significant separation from placebo on the
`CGl-S was observed from week ] onward for the lurasi-
`
`done 120 mg group, and from week 2 onward for the lur-
`asiclone 40 mg group and the olanzapine group compared
`with the placebo group (see Table 81 and Figure 51 in the
`online data supplement).
`in a post hoe mixed-model repeated-measures analysis
`of PANSS total score and CGi-S score, there was no statisti-
`cally significant difference in least-squares mean change
`scores at week 6 for the olanzapinc group compared with
`either lurasidone group.
`In a secondary analysis. an ANCOVA was performed
`on change from baseline to week 6 (last observation car-
`ried forward) for PANSS total score and CGI-S score. In
`this analysis, the least-squares mean change in PANSS
`total score was significantly greater for the lurasidonc 40
`mg (-23.1. p:0.001; efiect size. 0.43) and 120 mg (—20.0.
`p:0.049; effect size, 0.20) groups compared with the place-
`
`Am] Psychiatry 168:9. September 2011
`
`njp. psychiatryonlineorg
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`959
`
`

`

`LURASIDONE IN THE TREATMENT OF SCHIZOPHRENIA
`
`FIGURE 1. Flow of Patients With Schizophrenia in a Randomized, Double-Blind. Placebo- and Olanzapine-Controllcd Study
`of Lu rasldone
`
`Screened
`(N=781]
`
`Did not meet eligibility criteria
`(N=303)
`
`Up to 14-day drug-free
`screening period; 3- to
`7-day single- blind
`placebo washout
`
`
`
`Underwenl
`random assignment at
`baseline (N=478)
`
`lurasidoner 40 mg
`(N=120)
`
`Lurasidone. 120 mg
`(N=119‘;
`
`Discontinued during
`double-blind treatment (N=43)
`Lack of efficacy (N=16)
`Adverse events (N=8)
`Lost to follow-up (N=1)
`withdrew (onsent (N=16)
`Other (N=2)
`
`
`
`Discontinued during
`double-blind treatment (N=53)
`Lack of efficacy (N=9)
`Adverse events (N=14)
`Lost to follow- up (N=Z]
`withdrew consent (N=28}
`
`Other (N=O)
`
`6-week double blind
`treatment (eligible for
`discharge from
`hospital after 3 weeks)
`
`Corn pleted study
`(N=66)
`
`6-week dou ble~ blind
`treatment (eligible for
`discharge from
`hospital after 3 weeks)
`
`
`
`Completed study
`(N=771
`
`Olanzapine
`(N=123)
`
`6-week double blind
`treatment (eligible for
`discharge from
`hospital after 3 weeks)
`
`
`
`Completed study
`(N=84)
`
`Discontinued during
`doublevblind treatment (N=39)
`Lack of efficacy (N =8)
`
`‘ mar” 9’9"“ ("3)
`Lost to follow-up (N=1)
`withdrew consent (N=19)
`Other (N=3)
`
`hospital after 3 weeks)
`
`Placebo
`(N=116l
`
`6-week double blind
`treatment (eligible for
`discharge from
`
`Corn pleted study
`(N=71)
`
`Discontinued during
`double-blind treatment (N=45)
`Lack of efficacy (N=18)
`Adverse events (N=10)
`lost to follow- up (N=2]
`withdrew consent (N=lZ]
`Other (N=3)
`
`bo group (45.2). Similarly, the least-squares mean change
`in PANSS total score was also significantly greater for the
`olanzapinc group [—26.7, p<0.001). In an ANCOVA analysis
`of CGl-S score. least-squares mean change at week 6 (last
`observation carried forward) was significantly greater for
`the lurasidone 40 mg group compared with the placebo
`group {—12, p:0.012), but the comparison with the pla-
`cebo group was not significant for the lurasidonc 120 mg
`group. The least-squares mean change in CGl-S score was
`significant for the olanzapine group (—1.4. p<0.001). The
`results of these sensitivity analyses for PANSS total score
`and CGl-S score were similar to, and support, the results
`of the primary mixed-model repeated-measures analysis.
`Furthermore, on a pairwise comparison, there were no sig-
`nificant differences in endpoint change between the two
`lurasidone groups on PANSS total score or CGl-S score.
`
`in a logistic regression analysis, responder rates (com-
`pared with placebo) and associated odds ratios at 6 weeks
`(last observation carried forward) were not significant for
`either of the lurasidone groups. but the comparison was
`significant for the olanmpine group (a responder rate of
`74%, compared with a rate of 49% for placebo: odds ra-
`tio=2.9, p<o.001).
`improvement on the MADRS at week 6 was not signifi-
`cantly different between either of the lurasidonc groups
`and the placebo group. whereas the olanzapine group
`showed significantly greater improvement compared with
`the placebo group (Table 2: see also Figure 82 in the online
`data supplement).
`The AN COVA subgroup analyses showed no significant
`treatment interactions by gender. race. ethnicity, region.
`or age for either the PANSS total score or the CGl-S score.
`
`960
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`Am 1 Psychiatry 168.9. September 2011
`
`

`

`MELTZER. CUCCHIARO. SILVA. ET AL.
`
`TABLE 2. Change From Baseline to Week 6 on Efficacy Measures for Patients With Schizophrenia in a Randomized. Double-
`Blind, Placebo- and Olanzapine-Controlled Study of Lurasidone“
`Treatment Gro up
`
`Measure'
`PANSS
`
`Lurasidone, 40 mg
`(N418)
`
`turasidone, 120 mg
`(N418)
`
`Olanzapine, 15 mg
`(N~121)
`
`Placebo (N'11/l]
`
`Estimate
`
`SE
`
`9‘
`
`Estimate
`
`SE
`
`p‘
`
`Estimate
`
`SE
`
`p‘
`
`Estimate
`
`SE
`
`—28.7
`»-9.3
`—6.2
`
`—13.3
`
`1.9
`0.7
`0.5
`
`0.9
`
`<0.001
`<0.001
`<0.001
`
`<0.001
`
`—16.0
`5.4
`—3.6
`
`—7.8
`
`2.1
`0.7
`0.5
`
`1.0
`
`—25.7
`47.7
`—6.0
`
`412.4
`
`2.0
`0.7
`0.5
`
`1.0
`
`<0.001
`0.018
`0.002
`
`0.001
`
`—23.6
`—7.5
`—S.2
`
`—11.1
`
`2.1
`0.7
`0.6
`
`1.0
`
`0.011
`0.035
`0.045
`
`0.022
`
`Total score changc‘
`Positive subscale score change
`Negative subscalc score change
`General psychopathology score
`change
`Cognitive subscale (modified)
`0.4
`—2.7
`<0.001
`0.3
`41.6
`0012
`0.4
`—4.0
`0.005
`0 3
`—4.2
`score change
`0.1
`—1.1
`<0.001
`0.1
`~15
`0.040
`0.1
`-~1.4
`0.006
`0.1
`-~1.S
`CGI severity score cha nge‘
`0.6
`—28
`0.003
`0.5
`45.0
`0.571
`0.6
`—3.2
`0.324
`0.5
`—3.5
`MADRS total score chan e
`
`
`‘ Change was assessed using a mixed-model repeated-measures analysis.
`l' PANSS- Positive and Negative Syndrome Scale; (GI-Clinical Global Impressions scale; MADRS-Montgomeryv/tsberg Depression Rating Scale.
`' Compared with placebo group; p valucsarc unadjusted and are based on a repeated-measures linear regression model of the change from
`baseline score, with iixed eflects for pooled center, assessment visit as a categorical variable, baseline score, treatment, and treatment-by-
`assessment visit interaction, assuming an unstructured covariance matrix.
`" For total score change on the PANSS. the adjusted p values (using the Ilommel-based tree-gatekeeping procedure) (or the lurasidone 40 mg
`and 120 mg groups compared with the placebo group were 0.002 and 0.022, respectively. For each of the lurasidone groups compared with
`the ola nzapine group, unadjusted p values were nonsignilicant.
`‘ For CGI severity score change, the adjusted p values (using the llornmel-based lree-gatekeeping procedure) for the lurasidone 40 mg and
`120 mg groups compared with the placebo group, were 0.011 and 0.040, respectively. For each 01 the lurasidone groups compared With the
`olanzapinc group. unadjusted p values were nonsigniiicant.
`
`FIGURE 2. Change From Baseline in PANSS Total Score in a Randomized, Double-Blind, Placebo- and Olannpine-Controlled
`Study of Lurasidone“
`
`0
`
`2
`
`
`
`
`
`'0' Placebo (N=114)
`
`..- lurasidone. 40 mg (N=118)
`
`+ Lurasidone, 120 mg(N=118)
`
`-O- Olanzapine, 15 mg (N=121)
`
`
`
`8
`
`g -10
`
`8 5i
`
`tin
`
`El -20
`.c
`U
`
`-30
`
`Baseline
`
`Day Week 1
`4
`
`Week 2
`
`Week 3
`
`Week 4
`
`Week 5
`
`Week 6
`
`' Statistical significance was computed on the basis at a repeated-measures linear regression model of the change lrom baseline score. with
`fixed eliects ior pooled site, assessment visit as a categorical variable, baseline score, treatment, and treatrnent-by-assessnient visit interac-
`tion, assuming an unstructured covariance matrix; p values are unadjusted, and only significant p valuesare noted.
`" Week 1 comparison with placebo: p~0.022 for lurasidone 40 mg; p~0.008 lor olanzapine.
`‘ Week 2 comparison with placebo: p:0.008 for lurasidone 40 mg;p:0.00210r olanzapine
`‘ Week 3 comparison with placebo: p:0.002 for lurasidone 40 mg; p:0.004 lor lu rasidone 120 mg; p<0.001 lorolanzapine.
`' Week 4 comparison with placebo: p<0.001 for lurasidone 40 mg; p<0.001 lor lurasidone 120 mg; p<0.001 lorolanzapine.
`' Week Scomparison with placebo: p“0.001 for lurasidone 40 mg; p<0.001 lor lurasidone 120 mg; p<0.001 lorolanzapine.
`' Week 6comparison with placebo: p<0.001 for lurasidone 40 mg; p70.011 lor lurasidone 120 mg; p<0.001 lorolanzapine.
`
`Safety
`Adverse events. A comparable proportion of patients in
`the lurasidone 40 mg group and in the placebo group re-
`ported experiencing at least one adverse event (Table 3);
`
`the incidence was somewhat higher in the lurasidone 120
`mg group and the olanzapinc group. The majority of ad-
`verse events in all treatment groups were rated as mild
`to moderate. Rates of discontinuations due to adverse
`
`Am J Psychiatry 168:9. September 2011
`
`ajp.psychiatryonlineorg
`
`961
`
`

`

`LURASIDONE IN THE TREATMENT OF SCHIZOPHRENIA
`
`TABLE 3. Effect of 6 Weeks of Treatment With Lurasidone, Olanzapine, or Placebo on the Incidence of Adverse Events
`Reported in 5% or More of Participants
`
`Lurasidone, 40 mg
`(N’119)
`
`Treatment Gro up
`
`Lurasidone, 120 mg
`(Nr118)
`
`Olanzapine, 15 mg
`(Nr122)
`
`Placebo
`(Nr116)
`
`N
`90
`26
`14
`12
`15
`11
`12
`13
`14
`9
`6
`5
`6
`5
`7
`2
`3
`6
`1
`2
`4
`2
`2
`
`%
`75.6
`21.8
`1 1.8
`10.1
`12.6
`92
`10.1
`10.9
`11.8
`7.6
`5.0
`4.2
`5.0
`4.2
`5.9
`1.7
`2.5
`5.0
`0.8
`1.7
`3.4
`1.7
`1.7
`
`N
`97
`21
`27
`18
`14
`16
`12
`9
`7
`9
`9
`10
`6
`6
`4
`8
`6
`1
`3
`2
`3
`3
`4
`
`96
`82.2
`17.8
`22.9
`15.3
`11.9
`13.6
`10.2
`7.6
`5.9
`7.6
`7.6
`8.5
`5.1
`5.1
`3.4
`6.8
`5.1
`0.8
`2.5
`1.7
`2.5
`2.5
`3.4
`
`N
`100
`17
`9
`11
`13
`18
`7
`6
`8
`6
`8
`3
`7
`3
`4
`1
`3
`2
`7
`25
`11
`12
`4
`
`%
`82.0
`13.9
`7.4
`9.0
`10.7
`14.8
`5.7
`4.9
`6.6
`4.9
`6.6
`2.5
`5.7
`2.5
`3.3
`0.8
`2.5
`1.6
`5.7
`20.5
`9.8
`9.8
`3.3
`
`Event
`Al least one adverse event
`Headache
`Akathisia
`Somnolcncc
`Insomnia
`Sedation
`Anxiety
`Nausea
`Agitation
`Dyspepsia
`Constipation
`Vomiting
`Back pain
`Dizziness
`Restlessness
`Salivary hypersecretion
`Musculoskelelal stillness
`Appetite decreased
`Appetite increased
`Weight increased
`Toothache
`Dry mouth
`Psychotic disorder
`Extra pyrant idal adverse events
`1.7
`2
`4.9
`6
`11.0
`13
`9.2
`11
`Parkinsonism
`4.3
`5
`5.7
`7
`7.6
`9
`1.7
`2
`Tremor
`
`Dystonia
`4
`3.4
`9
`7.6
`1
`0.8
`1
`0.9
`
`N
`84
`25
`1
`5
`13
`4
`8
`5
`6
`7
`6
`8
`5
`2
`3
`0
`2
`2
`4
`6
`6
`1
`8
`
`%
`72.4
`21.6
`0.9
`4.3
`11.2
`3.4
`6.9
`4.3
`5.2
`6.0
`5.2
`6.9
`4.3
`1.7
`2.6
`0.0
`1.7
`1.7
`3.4
`5.2
`5.2
`0.9
`69
`
`events were relatively low in the lurasidone 40 mg group
`(6.7%), the lurasidone 120 mg group (11.8%), and the
`olanzapine group (6.5%) and were comparable to those
`in the placebo group (8.6%). The four adverse events with
`the highest incidence relative to placebo (that is, the larg-
`est drug-versus-placebo difference; see Table 3) were, for
`thc lurasidone 40 mg group, akathisia (11.8%), agitation
`(11.8%). nausea (10.9%). and parkinsonism (9.2%): for the
`lurasidone 120 mg group. akathisia (22.9%), somnolence
`(15.3%), sedation (13.6%), and parkinsonism (11.0%); and
`for the olanzapine group, increased weight (20.5%), seda-
`tion (14.8%), dry mouth (9.8%), and akathisia (7.4%).
`
`Physical examination and vital signs. There were no clini-
`cally significant treatment-emergent changes in either of
`the lurasidone groups or the olanzapinc group compared
`with the placebo group in pulse rate. systolic or diastolic
`blood pressure, or body temperature.
`
`Extrapyramidal symptoms. The proportion of patients
`treated with an anticholinergic medication was similar
`in the lurasidone 40 mg group (20%) and the olanzapine
`group (18%) but higher in the lurasidone 120 mg group
`(41%). A smaller proportion of patients in the placebo
`group (9%) used anticholincrgic agents. Benztropine was
`
`the most frequently pmcribed medication for parkinson-
`ism-rclated adverse effects (see Table 82 in the onlinc data
`
`supplement). followed by trihexyphenidyl. propranolol,
`and biperiden. The proportions of patients reporting the
`extrapyramidal symptom-related adverse events of par-
`kinsonism, tremor, dystonia, and akathisia during study
`treatment are listed in Table 3. No episodes of opisthoto-
`nos were reported in any treatment group. "No patients
`(1.7%) in the lurasidone 120 mg group discontinued the
`drug because of extrapyraniidal adverse events, whereas
`none in the other three treatment groups did. The mean
`endpoint changes in Simpson-Angus Rating Scale score
`and in the Barnes Rating Scale for Drug-Induced Akathisia
`global clinical assessment scores were small and not clini-
`cally significant in the majority of patients. In the lurasi-
`done 40 mg group and the olanzapine group, change from
`baseline in the least-squares mean Simpson-Angus and
`Barnes scale scores was not significantly different from
`that of the placebo group (see Figures S3 and S4 in the
`online data supplement). In contrast. the lurasidone 120
`mg group had significantly greater Simpson-Angus and
`Barnes change scores compared with the placebo group.
`Consistent with these data, the proportions of patients
`reporting categorical worsening on the Barnes scale, the
`
`962
`
`ajp.psychirilryonlineorg
`
`Am 1 Psychiatry 1689. September 2011
`
`

`

`MELTZER. CUCCHIARO. SILVA. ET AL.
`
`TABLE 4. Effect of 6 Weeks of Treatment with Lurasidone. Olanzapine. or Placebo on Weight. Body Mass Index. Waist
`Circumference, and Laboratory Test Results-
`
`Lurasidone, 40 mg
`(N’119)
`Mean or
`Median
`
`SD
`
`Treatment Group
`
`Lurasidone. 120 mg
`(N~118)
`Mean or
`Median
`
`SD
`
`Olanzapine, 15 mg
`(N" 122)
`Mean or
`Median
`
`SD
`
`Placebo (N416)
`Mean or
`Median
`
`50
`
`Measure
`
`76.4
`+1.0
`+0.9
`
`263
`I 0.3
`1703
`
`91.2
`+1.4
`0.0
`
`197.8
`8.6
`8.0
`
`116.1
`—4.9
`—4.0
`
`19.3
`2.9
`
`5.9
`1.0
`
`15.9
`8.2
`
`43.4
`29.8
`
`34.9
`23.3
`
`75.4
`+1.0
`+0.5
`
`25.5
`10.4
`0.2
`
`90.4
`+1.0
`+0.5
`
`191.9
`, 7.3
`5.0
`
`112.6
`—4.6
`—5.0
`
`18.6
`2.2
`
`5.0
`0.7
`
`13.7
`4.2
`
`42.6
`25.3
`
`33.3
`20.9
`
`76.0
`+4.1
`+3.1“'"’
`
`26.0
`I 1.4
`11.1"“
`
`91.1
`+3.4
`+2.0‘"
`
`193.8
`19.6
`+9.0“"
`
`113.8
`+4.3
`+7.0'
`
`20.1
`4.3
`
`6.1
`1.4
`
`15.2
`4.9
`
`44.9
`31.2
`
`34.7
`25.9
`
`13.2
`9.3
`
`75.2
`4-0.6
`0.0
`
`25.8
`10.2
`0.0
`
`89.1
`+0.6
`0.0
`
`195.7
`76.8
`5.0
`
`113.8
`—1.8
`—4.0
`
`18.6
`2.7
`
`5.4
`0.9
`
`14.0
`5.4
`
`46.2
`28.7
`
`35.7
`24.8
`
`14.0
`8.1
`
`Weight (kg)
`Baseline
`Mean change
`Median change
`Body mass index
`Baseline
`Mean change
`Median change
`Waist circumlerence (cm)
`Baseline
`Mean change
`Median (ha age
`Total cholesterol (mg/dl)
`Baseline
`Mean change
`Median change
`LDL cholesterol (mg/dl)
`Baseline
`Mean change
`Median change
`HDL cholesterol (mg/dl)
`Baseline
`Mean change
`Median change
`Triglycerides [mg/dl)
`Baseline
`Mean (hange
`Median change
`Glucose (mg/dl)
`Baseline
`Mean change
`Median change
`HbA“ Wu)
`Baseline
`Mean change
`Median change
`Insulin (mU/liter)
`Baseline
`Mean change
`Median change
`HOMA-IR (u)
`Baseline
`Mean change
`Med la n cha ngc
`Prolactin (nyml)
`13.0
`11.1
`10.6
`10.2
`Baseline
`—2.5
`+5.0
`+10.9
`+2.1
`Mean change
`—0.7
`+3.8’“
`+4.5"*
`+0.7
`Median change
`laboratory Iesls. HbAIFglycosylaled hemoglobin; HOMA-
`‘ Sample sizes may vary somewhat because of missing values for individual
`lR- homeostatic model assessment oI Insulin resistance (analyzed post hoc); LDL-Iow-density lipoprotein; HDL-high-densnly lipoprotein.
`Indicated p values are lor comparison with placebo.
`"p<0.05. "p<U.01. "*p<0.001.
`
`48.0
`0.9
`—1.0
`
`143.7
`~83
`~10
`
`96.1
`0.0
`—1.0
`
`5.65
`—0.04
`‘010
`
`19.1
`3.1
`—0.6
`
`5.52
`~1.30
`—0.1 2
`
`13.5
`9.3
`
`88.3
`76.2
`
`20.0
`19.2
`
`0.43
`0.24
`
`28.1
`31.5
`
`10.94
`11.57
`
`9.8
`13.9
`
`46.2
`0.4
`0.0
`
`144.9
`—5.0
`+4.5
`
`95.7
`+0.5
`—0.5
`
`5.57
`+0.06
`0.00Mr
`
`15.9
`1.3
`—0.4
`
`4.10
`e028
`—0.09
`
`12.4
`8.5
`
`96.6
`855
`
`19.9
`20.9
`
`0.46
`0.29
`
`24.5
`24.3
`
`7.27
`7.72
`
`12.2
`28.1
`
`48.4
`2.1
`—2.0
`
`133.6
`+500
`+24.0’**
`
`94.2
`+10.3
`+4.0’
`
`5.58
`+0.18
`1005""
`
`13.2
`+ 5.9
`+1.5
`
`3.27
`+2.61
`1055"
`
`74.9
`115.0
`
`17.1
`34.8
`
`0.48
`0.57
`
`13.9
`30.8
`
`4.00
`11.97
`
`13.7
`12.2
`
`40.9
`1.2
`—1.0
`
`131.5
`i0.1
`—1.0
`
`93.9
`+0.4
`+1.0
`
`5.47
`—0.05
`0.00
`
`20.3
`2.4
`—0.1
`
`6.03
`~1.32
`~0.01
`
`85.8
`64.8
`
`20.1
`24.6
`
`0.43
`0.25
`
`41.6
`46.3
`
`16.43
`18.25
`
`16.2
`+16.9
`
`Am 1 Psychiatry 168:9. September 2011
`
`ajp.psychiatryonlineorg
`
`963
`
`

`

`LURASIDONE IN THE TREATMENT OF SCHIZOPHRENIA
`
`TABLE 5. Proportion of Patients Treated for 6 Weeks With Lurasidone, Olanzapine, or Placebo Whose Laboratory Values
`Shifted From Normal to Outside the Normal Range at Endpoint
`Trcalmcnl Group
`
`Lurasidonc. 40 mg
`Lurasidone. 120 mg
`Olanzapinc.15 mg
`Placebo
`
`Measure“
`N
`%
`N
`%
`N
`“A
`N
`%
`
`Glucose (shill to high: 2100 mg/dl)
`HbAh(sl1illl0 high? >6 mg/dl)
`Total cholesterol (shift to high: >200 mg/dl)
`[DL (shill [0 high. >129 mydl)
`IIDL (shift to law: 535 mg/dl)
`Triglycerides (shill to high: >203 mg/dl]
`Prolaclin (shill to high: male, >17.7 ng/ml;
`18.3
`21/115
`10.1
`12/119
`lemalc.>29.2 ng/inl
`‘ lleh—glvcosylated hemoglobin; LDlv Iow‘density lipoprotein; IIDL , highdensity lipoprotein.
`
`18/118
`8/113
`4/115
`4/115
`12/115
`10/115
`
`15.3
`7.1
`35
`3.5
`10.4
`87
`
`11/114
`5/101
`9/102
`9/102
`5/102
`7/102
`
`9.6
`5.0
`8.8
`8.8
`4.9
`6.9
`
`27/121
`7/112
`17/115
`15/115
`10/115
`19/115
`
`16/121
`
`22.3
`6 3
`14 8
`13.0
`8.7
`16.5
`
`13.2
`
`20/113
`5/107
`5/107
`9/107
`11/107
`7/107
`
`8/114
`
`17.7
`4 7
`4 7
`8.4
`10.3
`65
`
`70
`
`Abnormal Involuntary Movement