Lurasidone in the Treatment of Schizophrenia:
`A Randomized, Double-Blind, Placebo- and Olanzapine-
`Controlled Study
`
`Herbert Y. Meltzer, M.D.
`
`Josephine Cucchiaro, Ph.D.
`
`Robert Silva, Ph.D.
`
`Masaaki Ogasa, MLS.
`
`Debra Phillips
`
`Jane Xu, Ph.D.
`
`Amir H. Kalali, M.D.
`
`Edward Schweizer, M.D.
`
`Andrei Pikalov, M.D., Ph.D.
`
`AntonyLoebel, M.D.
`
`Objective: The study was designed to
`evaluate the short-term efficacy and safe-
`ty of lurasidonein 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 Impressions
`severity (CGI-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 6 on PANSStotal score,
`
`PANSS positive and negative subscale
`scores, and CGI-S score compared with
`placebo. There was no statistically sig-
`nificant difference in mean PANSS total
`or CGI-S changescores for the lurasidone
`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%), olanzapine (7.4%),
`or placebo (0.9%). The proportion of pa-
`tients experiencing =7% weight gain was
`5.9% for the lurasidone groups combined,
`34.4% for the olanzapine group, and 7.0%
`for the placebo group.
`Conclusions: 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/dayof lur-
`asidone compared with 40 mg/day.
`
`(Am J Psychiatry 2011; 168:957-967)
`
`Avocaantipsychoticdrugsgenerallysharemorepo-
`
`has moderate partial agonist effects at the 5-HT,, receptor
`(Ki, 6.4) and moderately potent antagonisteffects at «,_ re-
`tent antagonism for 5-HT,, than dopamine D, receptors
`(1, 2). However, there are significant differences among
`ceptor subtypes(Ki, 10.8) (6).
`these agentsintheir relative affinities for 5-HT,,, 5-HT.,,
`In a double-blind, placebo-controlled phase 2 clinical
`5-HT,, alpha-adrenergic, histamine H,, muscarinic, and
`trial (7), lurasidone demonstrated efficacy in schizophre-
`
`other receptors that mayaffect their efficacy and tolera- nia atafixed daily dose of 80 mg.
`bility (2). Genetic polymorphismsin receptor proteins, as
`The primary objective of this phase 3 study was to
`well as in cytochrome P450 isoenzymes, contribute addi-
`evaluatetheefficacy of two dosages of lurasidone (40 and
`tional between-drugvariabilityin clinical effect (3). Thus,
`120 mg/day) comparedwith placebo in the treatment of
`atypical antipsychotics do not produce uniform clinical
`patients suffering from an acute exacerbation of chronic
`responsesin all patients, and it remains importantto have
`schizophrenia. The key secondary objective was to evalu-
`multiple antipsychotic drug treatment choices to address
`ate the efficacy of lurasidone compared with placebo in
`unmettherapeutic needs in patients with schizophrenia
`improving the Clinical Global Impressions severity (CGI-
`and other psychotic disorders (4, 5).
`S) score. Another major secondaryobjective wasto eval-
`Lurasidoneis a novel psychotropic agent that has been
`uate the safety and tolerability of the 40 mg and 120 mg
`shownin studies of cloned humanreceptors to be an an-
`dosesof lurasidone during 6 weeks of treatment.
`tagonistat the 5-HT., receptor, with a binding affinity (Ki;
`the dissociation constantofthe inhibitor) of 0.47, and a Ki
`of 0.99 at the D2 receptor.It also has a very high affinityfor
`the 5-HT_ receptor (Ki, 0.49), which is nearly identical to
`its affinity for the 5-HT,, receptor. In addition, lurasidone
`This article provides Clinical Guidance (p. 967)
`
`Method
`
`This was a prospective, multicenter, parallel-group study in
`which recently admitted acutelyill inpatients with schizophre-
`nia with an acute exacerbation of psychotic symptoms were
`
`Am| Psychiatry 168:9, September 2011
`
`ajp.psychiatryonline.org
`
`957
`
`1
`
`Exhibit 2061
`Slayback v. Sumitomo
`IPR2020-01053
`
`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 mgoflurasidone, 15 mg
`of olanzapine (included to establish assay sensitivity), or pla-
`cebo. The study was conducted between January31, 2008, and
`June 16, 2009, 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 (India, 14 sites [N=89]; Philippines, four
`sites [N=26}).
`All patients who entered the trial reviewed and signed an in-
`formed consent documentexplaining study procedures and po-
`tential risks before study entry. The study protocolandall related
`forms and amendments were approved by an independent eth-
`ics committee associated with each studycenter. The study was
`conducted in accordancewith the International Conference on
`Harmonization Good Clinical Practices guidelines and with the
`ethical principles of the Declaration of Helsinki. An independent
`data and safety monitoring board reviewed unblinded safety and
`clinical outcomedata.
`
`Entry Criteria
`Hospitalized male and female patients 18-75 years of age who
`met DSM-IV criteria for a primarydiagnosis of schizophrenia as
`determined bythe Mini International Neuropsychiatric Interview
`(8) were enrolled. Patients were also required to have an illness
`duration of at least | year and to have been hospitalized for <2
`weeks for an acute exacerbation of psychotic symptomsand, at
`the screening and baselinevisits, to have a CGI-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 moreofthe following PANSSitems: delusions, conceptualdis-
`organization, hallucinations, unusual thought content, and sus-
`piciousness.
`
`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 meetall study inclusion criteria were randomly as-
`signedvia interactive voice response system (ina 1:1:1:1 ratio) to
`one of four treatment arms: lurasidone, 40 mg; lurasidone, 120
`mg; olanzapine, 15 mg; or placebo. Study medication was admin-
`istered in the morning with a mealor within 30 minutesafter eat-
`ing. Participants assigned toreceive lurasidone started treatment
`at their target dose; patients assigned to olanzapine treatment
`received 10 mg on days 1-7 and 15 mgthereafter. The olanzapine
`dosage of 15 mg/day wasselected becauseit is widely used and
`becausethere is substantial evidencethatit is an effective dosage
`in patients with schizophrenia, with little evidence that higher
`dosages offer additionalefficacy advantages (9, 10). This dosage is
`also consistent with the olanzapine packageinsert (http://pi.lilly.
`com/us/zyprexa-pi. pdf), which statesthatefficacy in schizophre-
`nia has been demonstrated in a dosage range of 10-15 mg/day,
`with higher doses not demonstrated to be moreefficacious.
`Limited use of benzodiazepines was permitted for severe anxi-
`ety, agitation, or insomnia. Participants wereeligible for hospital
`discharge to a stable residence after 21 days of treatmentif they
`had a CGI-S score $3.
`
`Assessments
`
`The screening evaluation consisted of the Mini International
`Neuropsychiatric Interview, medical and psychiatric histories, a
`physical examination, measurementofvital signs, ECG, and labo-
`ratory tests.
`Efficacy was assessed using the PANSStotal and subscale scores
`(including a post hoc analysis of a modified version of the cogni-
`tive subscale, consisting of items P2, N5, N7, GLO, G11) (11, 12),
`
`the CGI-S, and the Montgomery-Asberg Depression Rating Scale
`(MADRS; 13). PANSS and CGI-S evaluations were performed at
`the screening and baselinevisits and, during treatment, on day4
`and at each of weeks | through 6. The MADRS wasadministered
`at the screening andbaseline 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 (HbA, |, and insulin), 12-lead ECG, and reported adverse
`events. Insulin resistance and beta-cell function were measured
`using the homeostasis model assessmentfor insulin resistance
`(HOMA-IR) method(17).
`
`Statistical Methods
`
`A powercalculation 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 PANSStotal score by 6.8 and 10.0 for the 40 and 120 mg/day
`dosages, respectively, and further assuminga standard deviation
`of 19.1, we calculated that 120 patients per group would provide
`97% power(at an alphalevel of 0.05, two-sided test) to reject the
`null hypothesis ofno difference between placebo and atleast one
`of the lurasidone dosage groups.
`The primary efficacy analysis was performed on the intent-
`to-treat sample, which consisted of all participants assigned to a
`treatment group whoreceivedat least one dose of study medica-
`tion, had a baseline PANSS assessment, and had at least one post-
`baseline PANSS assessmentduring the 6-week study. The primary
`efficacy measure was the change from baseline in PANSStotal
`score at week 6, and the key secondaryefficacy measure was the
`change from baseline in CGI-S 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 postbaseline assess-
`ment visits as a categorical variable), baseline PANSS total score or
`CGI-S score, treatment, and treatment-by-time interaction. The p
`values for the comparison of each lurasidone group with the pla-
`cebo group at week 6 on change from baseline in PANSStotal score
`and CGI-S score were adjusted for multiple comparisonsusing the
`Hommel-basedtree-gatekeeping procedure to control the family-
`wise type I error rate (18). The olanzapine treatment group, which
`wasincluded 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 mglurasidone treatment groupsto the olanzapine
`treatment group.
`A prespecified secondary analysis was conducted for change
`in PANSStotal score and CGI-S score, using an analysis of covari-
`ance (ANCOVA) model.
`Secondaryefficacy measures,including PANSSsubscale 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
`improvementofat 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 outcomeas the dependent variable, treatment as a
`categorical factor, and baseline PANSStotal score as a covariate.
`The Cohen's d effect size was calculated for week 6 efficacy
`measures as the between-treatmentdifference score divided by
`the pooled standard deviation. For adverse events, number need-
`
`958
`
`ajp.psychiatryonline.org
`
`AmJ Psychiairy 168:9, Septernber 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 Lurasidone
`
`Characteristic®
`
`Male
`Race
`White
`Black
`Asian
`Other
`Hispanic/Latino ethnicity
`24 previous hospitalizations
`
`Age years)
`Age at onset of illness (years)
`Duration ofillness (years)
`Duration of current episode (days)
`PANSStotal score
`CGI severity score
`MADRStotal score
`
`Treatment Group
`
`Lurasidone, 40 mg
`(N=119)
`
`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
`
`%
`78
`
`37
`33
`26
`4
`19
`43
`SD
`11.0
`83
`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
`
`%
`79
`
`41
`31
`23
`6
`16
`54
`SD
`11.2
`8.8
`11.0
`12.9
`11.3
`0.6
`Te.
`
`N
`95
`
`41
`44
`30
`7
`17
`58
`Mean
`38.3
`24.7
`13.2
`33.5
`96.3
`49
`10.8
`
`%
`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
`%
`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
`
`» PANSS=Positive and Negative Syndrome Scale; CGI=Clinical Global Impressions scale; MADRS=Montgomery-Asberg Depression Rating Scale.
`
`ed to harm wascalculated as 1 dividedby the differencein the risk
`of an adverse eventfor active drug compared with placebo.
`Significance testing of selected safety parameters was per-
`formed based on a nonparametric rank ANCOVAwith baseline
`value as a covariate, not adjusted for multiple comparisons.
`
`Results
`
`Of a total of 781 patients who were screened and en-
`tered the washoutperiod, 478 were randomly assigned to
`6 weeks of double-blind treatment(Figure 1). Baseline de-
`mographic and clinical characteristics were comparable
`amongthe four treatment groups (Table 1). The propor-
`tion of patients in the lurasidone 40 mg group who com-
`pleted the study treatment (64.2%) wassimilar 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
`group completed the study treatment (55.5%) (Figure 1).
`
`Efficacy
`
`Based on the mixed-model repeated-measuresanalysis,
`the change from baseline to week 6 in PANSStotal 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 PANSStotal 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 PANSStotal
`score was observed from week 1 onward for the lurasidone
`
`40 mg and olanzapine groups, and from week 3 onward
`for the lurasidone 120 mg group(Figure 2; see also Table
`S1 in the online data supplement). Treatment with both
`
`dosages of lurasidone and with olanzapine wasalso as-
`sociated with significantly greater improvement at week
`6 comparedwith placebo on the PANSSpositive, negative,
`and general psychopathology subscale scores (Table 2; see
`also Table $1 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 improvementat week6 on the modi-
`fied PANSScognitive subscale score (see Table 2).
`For the CGI-S score, the change from baseline to week
`6 wasalso significantly greater for the lurasidone 40
`mg (-1.5; adjusted p=0.011) 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
`CGI-S was observed from week 1 onward for the lurasi-
`
`done120 mg group, and from week 2 onwardforthe lur-
`asidone 40 mg group and the olanzapine group compared
`with the placebo group (see Table $1 and Figure $1 in the
`online data supplement).
`In a post hoc mixed-mode] repeated-measures analysis
`of PANSStotal score and CGI-S score, there wasnostatisti-
`cally significant difference in least-squares mean change
`scores at week6 for the olanzapine 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 PANSStotal score and CGI-S score. In
`this analysis, the least-squares mean change in PANSS
`total score wassignificantly greater for the lurasidone 40
`mg (-23.1, p=0.001; effect size, 0.43) and 120 mg (-20.0,
`p=0.049; effect size, 0.26) groups compared withthe place-
`
`Am | Psychiatry 168:9, September 2011
`
`ajp. psychiatryontine.org
`
`959
`
`

`

`LURASIDONE IN THE TREATMENT OF SCHIZOPHRENIA
`
`FIGURE 1. Flow of Patients With Schizophrenia in a Randomized, Double-Blind, Placebo- and Olanzapine-Controlled Study
`of Lurasidone
`
`Screened
`(N=781)
`
`Did not meeteligibility criteria
`(N=303)
`
`Up to 14-day drug-free
`screening period; 3- to
`7-day single-blind
`placebo washout
`
`
`
`Underwent
`random assignmentat
`baseline (N=478)
`
`hospital after 3 weeks)
`
`Discontinued during
`double-blind treatment (N=43)
`Lack ofefficacy (N=16)
`Adverse events (N=8)
`Lost to follow-up (N=1)
`Withdrew consent (N=16)
`Other (N=2)
`
`Discontinued during
`double-blind treatment (N=39)
`Lack of efficacy (N=8)
`Adverse events (N=8)
`Lost to follow-up (N=1)
`Withdrew consent (N=19)
`Other (N=3)
`
`Lurasidone, 40 mg
`(N=120)
`
`6-week double-blind
`treatment(eligible for
`discharge from
`hospital after 3 weeks)
`
`
`
`Completed study
`(N=77)
`
`Olanzapine
`(N=123)
`
`6-week double:blind
`treatment(eligible for
`discharge from
`
`Completed study
`(N=84)
`
`
`
`Discontinued during
`double-blind treatment (N=53)
`Lack ofefficacy (N=9)
`Adverse events (N=14)
`Lost to follow-up (N=2)
`Withdrew consent (N=28)
`Other (N=0)
`
`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=12}
`Other (N=3)
`
`Lurasidone, 120 mg
`(N=119)
`
`6-week double-blind
`treatment (eligible for
`discharge from
`hospital after 3 weeks)
`
`
`
`Completed study
`(N=66)
`
`Placebo
`(N=116)
`
`6-week double-blind
`treatment (eligible for
`discharge from
`hospital after 3 weeks)
`
`Completed study
`(N=71)
`
`bo group(-15.2). Similarly, the least-squares mean change
`in PANSS total score was also significantly greater for the
`olanzapine group(—26.7, p<0.001). Inan ANCOVAanalysis
`of CGI-S score, least-squares mean change at week6 (last
`observation carried forward) wassignificantly greater for
`the lurasidone 40 mg group compared with the placebo
`group (1.2, p=0.012), but the comparison with the pla-
`cebo group was notsignificant for the lurasidone 120 mg
`group. The least-squares mean change in CGI-S score was
`significant for the olanzapine group (-1.4, p<0.001). The
`results of these sensitivity analyses for PANSS total score
`and CGI-S score were similar to, and support,the results
`of the primary mixed-model repeated-measuresanalysis.
`Furthermore, on a pairwise comparison, there were nosig-
`nificant differences in endpoint change between the two
`lurasidone groups on PANSStotal score or CGI-S score.
`
`In a logistic regression analysis, responder rates (com-
`pared with placebo) and associated oddsratios at 6 weeks
`(last observation carried forward) were notsignificant for
`either of the lurasidone groups, but the comparison was
`significant for the olanzapine group (a responder rate of
`74%, compared with a rate of 49% for placebo; odds ra-
`tio=2.9, p<0.001).
`Improvement on the MADRSatweek6 was notsignifi-
`cantly different between either of the lurasidone groups
`and the placebo group, whereas the olanzapine group
`showedsignificantly greater improvement compared with
`the placebo group (Table 2; see also Figure S2 in the online
`data supplement).
`The ANCOVA subgroup analyses showed nosignificant
`treatment interactions by gender, race, ethnicity, region,
`or age for either the PANSStotal score or the CGI-S score.
`
`960
`
`ajp.psychiatryonline.org
`
`Am J Psychiairy 168:9, Septernber 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 Group
`
`Measure®
`PANSS
`
`Lurasidone, 40 mg
`(N=118)
`
`Lurasidone, 120 mg
`(N=118)
`
`Olanzapine, 15 mg
`(N=121)
`
`Placebo (N=114)
`
`Estimate
`
`SE
`
`p*
`
`Estimate
`
`SE
`
`p‘
`
`Estimate
`
`SE
`
`ps
`
`Estimate
`
`SE
`
`25.7
`-7.7
`-6.0
`
`-12.4
`
`2.0
`0.7
`0.5
`
`1.0
`
`<0.001
`0.018
`0.002
`
`0.001
`
`-23.6
`-7.5
`5.2
`
`-11.1
`
`2.1
`0.7
`0.6
`
`1.0
`
`0.011
`0.035
`0.045
`
`0.022
`
`—28.7
`~9.3
`-6.2
`
`—13.3
`
`1.9
`0.7
`0.5
`
`09
`
`<0.001
`<0.001
`<0.001
`
`<0.001
`
`Total score change*
`Positive subscale score change
`Negative subscale score change
`General psychopathology score
`change
`Cognitive subscale (modified)
`04
`2.7
`<0.001
`03
`4.6
`0012
`04
`4.0
`0.005
`03
`42
`score change
`a 0.1
`<0.001
`0.1
`-1.5
`0.040
`041
`—1.4
`0.006
`0.1
`-1.5
`CGI severity score change*
`2.8
`0.6
`0.003
`0.5
`—5.0
`0.571
`06
`-3.2
`0.324
`0.5
`3.5
`MADRStotal score change
`
`* Change wasassessed using a mixed-model repeated-measures analysis.
`® PANSS=Positive and Negative SyndromeScale; CGI=Clinical Global Impressions scale; MADRS=Montgomery-Asberg Depression RatingScale.
`* Compared with placebo group; p values are unadjusted and are based on a repeated-measureslincar regression modelof the change from
`baseline score, with fixed effects 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 Hommel-based tree-gatekeeping procedure)for 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 olanzapine group, unadjusted p values were nonsignificant.
`© For CGI severily score change, the adjusted p values (using the Hommel-based tree-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 of the lurasidone groups compared with the
`olanzapine group, unadjusted p values were nonsignificant.
`
`16.0
`5.4
`3.6
`
`7.8
`
`2.1
`0.7
`0.5
`
`1.0
`
`FIGURE2. Change From Baseline in PANSS Total Score in a Randomized, Double-Blind, Placebo- and Olanzapine-Controlled
`Study of Lurasidone*
`
`0
`
`
`
`
`a
`g ~10
`
`a Aiw c
`
`c
`U
`
`-20
`
`-30
`
`
`
`“lil Placebo (N=114)
`
`~® Lurasidone, 40 mg (N=118)
`== Lurasidone, 120 mg (N=118)
`=@® Olanzapine, 15 mg (N=121)
`
`g
`
`Week 6
`Week 5
`Week4
`Week 3
`Week 2
`Baseline ne Week 1
`* Statistical significance was computed on the basis of a repeated-measureslinear regression model of the change from baseline score, with
`fixed effects for pooled site, assessment visil as a categorical variable, baseline score, treatment, and trealment-by-assessment visit interac-
`tion, assuming an unstructured covariance matrix; p values are unadjusted, and only significant p values are noted.
`’ Week 1 comparison with placebo: p=0.022 for lurasidone 40 mg; p=0.008 for olanzapine.
`‘ Week 2 comparison with placebo: p=0.008 for lurasidone 40 mg; p=0.002 for olanzapine
`* Week 3 comparison with placebo: p=0.002 for lurasidone 40 mg; p=0.004 for lurasidone 120 mg; p<0.001 for olanzapine.
`* Week 4 comparison with placebo: p<0.001 for lurasidone 40 mg; p<0.001 for lurasidone 120 mg; p<0.001 for olanzapine.
`' Week 5 comparison with placebo: p=0.001 for lurasidone 40 mg; p<0.001 for lurasidone 120 mg; p<0.001 for olanzapine.
`* Week 6 comparison with placebo: p<0.001 for lurasidone 40 mg; p=0.011 for lurasidone 120 mg; p<0.001 for olanzapine.
`
`Safety
`Adverse events. A comparable proportion of patients in
`the lurasidone 40 mg group andin the placebo group re-
`ported experiencing at least one adverse event (Table 3);
`
`the incidence was somewhathigherin the lurasidone 120
`mg group and the olanzapine group. The majorityof ad-
`verse events in all treatment groups were rated as mild
`to moderate. Rates of discontinuations due to adverse
`
`AmJ Psychiatry 168:9, September 2011
`
`ajp.psychiatryontine.org
`
`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 Moreof Participants
`
`Lurasidone, 40 mg
`(N=119)
`
`Treatment Group
`
`Lurasidone, 120 mg
`(N=118)
`
`Olanzapine, 15mg
`(N=122)
`
`Placebo
`(N=116)
`
`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
`218
`118
`10.1
`12.6
`9.2
`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
`17
`1.7
`
`N
`97
`21
`27
`18
`14
`16
`12
`9
`x
`9
`9
`10
`6
`6
`4
`8
`6
`1
`3
`2
`3
`3
`4
`
`%
`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
`12
`12
`4
`
`%
`82.0
`13.9
`7.4
`9.0
`10.7
`14.8
`5.7
`49
`6.6
`4.9
`6.6
`2:5
`5.7
`25
`3.3
`08
`25
`1.6
`5.7
`20.5
`9.8
`9.8
`33
`
`Event
`Al least one adverse event
`Headache
`Akathisia
`Somnolence
`Insomnia
`Sedation
`Anxiety
`Nausea
`Agitation
`Dyspepsia
`Constipation
`Vomiting
`Back pain
`Dizziness
`Restlessness
`Salivary hypersecretion
`Musculoskeletal stiffness
`Appetite decreased
`Appetite increased
`Weight increased
`Toothache
`Dry mouth
`Psychotic disorder
`Extrapyramidal adverse events
`1.7
`Z
`4.9
`6
`11.0
`13
`92
`11
`Parkinsonism
`4.3
`5
`5.7
`7
`7.6
`9
`1.7
`-
`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
`43
`11.2
`3.4
`6.9
`43
`5.2
`6.0
`5.2
`69
`43
`17
`2.6
`0.0
`1.7
`1.7
`3.4
`5.2
`5.2
`0.9
`69
`
`events were relatively lowin 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 incidencerelative to placebo(thatis, the larg-
`est drug-versus-placebo difference; see Table 3) were, for
`the 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 noclini-
`cally significant treatment-emergent changesin either of
`the lurasidonegroupsor the olanzapine group compared
`with the placebo groupin 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 anticholinergic agents, Benztropine was
`
`the most frequently prescribed medication for parkinson-
`ism-related adverse effects (see Table S2 in the online 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
`treatmentarelisted in Table 3. No episodes of opisthoto-
`nos were reported in any treatment group. Two patients
`(1.7%) in the lurasidone 120 mg group discontinued the
`drug because of extrapyramidal adverse events, whereas
`nonein 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 assessmentscores were small and notclini-
`cally significant in the majority of patients. In the lurasi-
`done 40 mg group andthe 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 $3 and S4 in the
`online data supplement). In contrast, the lurasidone 120
`mg group hadsignificantly 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 Barnesscale, the
`
`962
`
`ajp.psychiatryonline.org
`
`Am J Psychiairy 168:9, Septernber 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 (N=116)
`Mean or
`Median
`
`sD
`
`Measure
`
`76.4
`+1.0
`+0.9
`
`26.3
`+0.3
`+0.3
`
`91.2
`+14
`0.0
`
`197.8
`8.6
`8.0
`
`116.1
`+49
`4.0
`
`19.3
`29
`
`5.9
`1.0
`
`15.9
`8.2
`
`43.4
`29.8
`
`34.9
`23.3
`
`75.4
`+1.0
`+0.5
`
`25.5
`+0.4
`0.2
`
`90.4
`+10
`+0.5
`
`191.9
`7.3
`5.0
`
`112.6
`4.6
`-5.0
`
`18.6
`22
`
`5.0
`0.7
`
`137
`42
`
`42.6
`25.3
`
`33.3
`20.9
`
`76.0
`+4,1
`+3,19""
`
`26.0
`11.4
`“ae (i boda
`
`91.1
`+3.4
`+2.0%"*
`
`193.8
`+9.6
`+9,0"**
`
`113.8
`+4.3
`+7.0"
`
`20.1
`4.3
`
`6.1
`1.4
`
`1S
`49
`
`44.9
`31.2
`
`34.7
`25.9
`
`13.2
`9.3
`
`75.2
`+0.6
`0.0
`
`25.8
`+0.2
`0.0
`
`89.1
`+0.6
`0.0
`
`195.7
`6.8
`5.0
`
`113.8
`-1.8
`-4.0
`
`18.6
`ae
`
`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 circumference (cm)
`Baseline
`Mean change
`Median change
`Tota! cholesterol (mg/dl)
`Baseline
`Mean change
`Median change
`LDL cholesterol (mg/dl)
`Baseline
`Mean change
`Median change
`HDLcholesterol (mg/dl)
`Baseline
`Mean change
`Median change
`Triglycerides (mg/dl)
`Baseline
`Mean change
`Median change
`Glucose (mg/dl)
`Baseline
`Mean change
`Median change
`HbA,, (%)
`Baseline
`Mean change
`Median change
`Insulin (mU/liter)
`Baseline
`Mean change
`Median change
`HOMA-IR (U)
`Baseline
`Mean change
`Median change
`Prolactin (ng/ml)
`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 tests. HbA, =glycosylated hemoglobin; HOMA-
`* Sample sizes may vary somewhat because of missing values for individual
`IR=homeostatic model assessment of insulin resistance (analyzed post hoc); LDL-low-density lipoprotein; HDL—high-density lipoprotein.
`Indicated p values are for comparison with placebo.
`*p<0.05. **p<0.01. ***p<0.001,
`
`48.0
`0.9
`-1.0
`
`143.7
`~83
`3.0
`
`96.1
`0.0
`1.0
`
`5.65
`—0.04
`0.10
`
`19.1
`3.1
`0.6
`
`5.52
`~1.30
`0.12
`
`13.5
`93
`
`883
`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
`0.00**
`
`15.9
`13
`0.4
`
`4.10
`-0.28
`0.09
`
`124
`8.5
`
`96.6
`85.5
`
`19.9
`20.9
`
`0.46
`0.29
`
`24.5
`243
`
`7.27
`7.72
`
`12.2
`28.1
`
`48.4
`2.1
`~2.0
`
`133.6
`+50.0
`+24.07**
`
`94.2
`+10.3
`+4,0*
`
`5.58
`+0.18
`+0.05***
`
`13.2
`+59
`+15
`
`3.27
`+2.61
`+0.55*
`
`74.9
`115.0
`
`17.1
`34.8
`
`0.48
`0.57
`
`13.9
`30.8
`
`4.00
`11.97
`
`13.7
`12.2
`
`48.9
`1.2
`—1.0
`
`1315
`+0.1
`1.0
`
`93.9
`+0.4
`+1.0
`
`5.47
`—0.05
`0.00
`
`20.3
`24
`0.1
`
`6.03
`~1.32
`0.01
`
`85.8
`64.8
`
`20.1
`24.6
`
`0.43
`0.25
`
`41.6
`16.3
`
`16.48
`18.25
`
`16.2
`+16.9
`
`AmJ Psychiatry 168:9, September 2011
`
`ajp.psychiatryontine.org
`
`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
`Treatment Group
`
`Lurasidone, 40 mg
`Lurasidone, 120 mg
`Olanzapine, 15 mg
`Placebo
`
`Mcasure*
`N
`%
`N
`%
`N
`%
`N
`%
`
`Glucose (shift to high: 2100 mg/dl)
`HbA,, (shift to high: >6 mg/dl)
`Total cholesterol! (shift to high: >200 mg/dl)
`LDL (shift to high: >129 mg/dl)
`HDL(shift to low: <35 mg/dl)
`Triglycerides(shift to high: >203 mg/dl)
`Prolactin (shift to high: male, >17.7 ng/ml;
`18.3
`21/115
`10.1
`12/119
`female, >29.2 ng/ml
`* HbA,=glycosylated hemoglobin; LDL=low-density lipoprotein; HDL=high-density lipoprotein.
`
`11/114
`5/101
`9/102
`9/102
`5/102
`7/102
`
`9.6
`5.0
`8.8
`8.8
`4.9
`6.9
`
`18/118
`8/113
`4/115
`4/115
`12/115
`10/115
`
`15.3
`71
`3.5
`3.5
`10.4
`8.7
`
`27/121
`WVW12
`17/115
`15/115
`10/115
`19/115
`
`16/121
`
`223
`63
`148
`13.0
`8.7
`16.5
`
`13.2
`
`20/113
`5/107
`5/107
`9/107
`11/107
`7/107
`
`8/114
`
`FAT:
`47
`47
`8.4
`10.3
`6.5
`
`7.0
`
`IR (+2.61 U compared with —-1.32 U; see Figure $8 in the
`online data supplement).
`Prolactin and other laboratory values. The median
`changein prolactin level at endpoint (last observation
`carried forward) was comparable in the lurasidone 40 mg
`and placebo groups (+0.7 ng/m! and -0.7 ng/ml, respec-
`tively) but wassignificantly higher